Antibiotics for acute maxillary sinusitis in adults.

Antibiotics for acute maxillary sinusitis in adults (Review) Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 2 http://www.thecochranelibrary.com

Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Antibiotics versus placebo, Outcome 3 Clinical failure defined as a lack of full recovery at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Antibiotics versus placebo, Outcome 4 Clinical failure defined as a lack of full recovery at 16 to 60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days. . . . . . . . . Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 Drop-outs due to adverse effects. . . . . . . Analysis 2.1. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . Analysis 2.2. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . Analysis 2.3. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 3 Drop-outs due to adverse effects (cephalosporins). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.4. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 4 Macrolides versus amoxclav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . Analysis 2.5. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 5 Macrolides versus amoxclav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . Analysis 2.6. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 6 Drop-outs due to adverse effects (macrolides). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . Analysis 3.2. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . . . Analysis 3.3. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 3 Drop-outs due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.1. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . Analysis 4.2. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 2 Drop-outs due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1 1 2 3 6 6 7 10 11 13 20 21 26 26 27 38 145 147 147 148 149 149 150 151 152 153 154 155 156 157 158 159 160 161 161 165 i

FEEDBACK . . . . . . . . . WHAT’S NEW . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . . NOTES . . . . . . . . . . . INDEX TERMS . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .


. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

169 175 175 176 176 177 177 177

ii

[Intervention Review]

Antibiotics for acute maxillary sinusitis in adults Anneli Ahovuo-Saloranta1 , Ulla-Maija Rautakorpi1 , Oleg V Borisenko2 , Helena Liira3 , John W Williams Jr4 , Marjukka Mäkelä5 1 Finnish

Office for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Tampere office, Tampere, Finland. 2 Synergus AB, Danderyd, Sweden. 3 Department of General Practice, University of Helsinki, Kirkkonummi, Finland. 4 Departments of Medicine and Psychiatry, Durham VAMC and Duke University Medical Center, Durham, NC, USA. 5 Finnish Office for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Helsinki, Finland Contact address: Anneli Ahovuo-Saloranta, Finnish Office for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Tampere office, Finn-Medi 3, Biokatu 10, Tampere, FI-33520, Finland. [email protected]. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 2, 2014. Review content assessed as up-to-date: 20 March 2013. Citation: Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M. Antibiotics for acute maxillary sinusitis in adults. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD000243. DOI: 10.1002/14651858.CD000243.pub3. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Sinusitis is one of the most common diagnoses among adults in ambulatory care, accounting for 15% to 21% of all adult outpatient antibiotic prescriptions. However, the role of antibiotics for sinusitis is controversial. Objectives To assess the effects of antibiotics in adults with acute maxillary sinusitis by comparing antibiotics with placebo, antibiotics from different classes and the side effects of different treatments. Search methods We searched CENTRAL 2013, Issue 2, MEDLINE (1946 to March week 3, 2013), EMBASE (1974 to March 2013), SIGLE (OpenSIGLE, later OpenGrey (accessed 15 January 2013)), reference lists of the identified trials and systematic reviews of placebocontrolled studies. We also searched for ongoing trials via ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). We imposed no language or publication restrictions. Selection criteria Randomised controlled trials (RCTs) comparing antibiotics with placebo or antibiotics from different classes for acute maxillary sinusitis in adults. We included trials with clinically diagnosed acute sinusitis, confirmed or not by imaging or bacterial culture. Data collection and analysis Two review authors independently screened search results, extracted data and assessed trial quality. We calculated risk ratios (RRs) for differences between intervention and control groups in whether the treatment failed or not. All measures are presented with 95% confidence intervals (CIs). We conducted the meta-analyses using either the fixed-effect or random-effects model. In meta-analyses of the placebo-controlled studies, we combined data across antibiotic classes. Primary outcomes were clinical failure rates at 7 to 15 days and 16 to 60 days follow-up. We used GRADEpro to assess the quality of the evidence. Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1

Main results We included 63 studies in this updated review; nine placebo-controlled studies involving 1915 participants (seven of the studies clearly conducted in primary care settings) and 54 studies comparing different classes of antibiotics (10 different comparisons). Five studies at low risk of bias comparing penicillin or amoxicillin to placebo provided information on the main outcome: clinical failure rate at 7 to 15 days follow-up, defined as a lack of full recovery or improvement, for participants with symptoms lasting at least seven days. In these studies antibiotics decreased the risk of clinical failure (pooled RR of 0.66, 95% CI 0.47 to 0.94, 1084 participants randomised, 1058 evaluated, moderate quality evidence). However, the clinical benefit was small. Cure or improvement rates were high in both the placebo group (86%) and the antibiotic group (91%) in these five studies. When clinical failure was defined as a lack of full recovery (n = five studies), results were similar: antibiotics decreased the risk of failure (pooled RR of 0.73, 95% CI 0.63 to 0.85, high quality evidence) at 7 to 15 days follow-up. Adverse effects in seven of the nine placebo-controlled studies (comparing penicillin, amoxicillin, azithromycin or moxicillin to placebo) were more common in antibiotic than in placebo groups (median of difference between groups 10.5%, range 2% to 23%). However, drop-outs due to adverse effects were rare in both groups: 1.5% in antibiotic groups and 1% in control groups. In the 10 head-to-head comparisons, none of the antibiotic preparations were superior to another. However, amoxicillin-clavulanate had significantly more drop-outs due to adverse effects than cephalosporins and macrolides. Authors’ conclusions There is moderate evidence that antibiotics provide a small benefit for clinical outcomes in immunocompetent primary care patients with uncomplicated acute sinusitis. However, about 80% of participants treated without antibiotics improved within two weeks. Clinicians need to weigh the small benefits of antibiotic treatment against the potential for adverse effects at both the individual and general population levels.

PLAIN LANGUAGE SUMMARY Antibiotics for acute maxillary sinusitis Sinusitis is one of the most common reasons for visiting a doctor and an estimated 20 million cases of acute sinusitis occur every year in the USA alone. There are four pairs of sinuses linked to the bony structures around the nose: maxillary, frontal, ethmoidal and sphenoidal sinuses. In sinusitis, these membrane-lined air spaces become infected, which causes pain and discharge from the nose. Treatment options include decongestants, steroid drops or sprays, mucus-clearing drugs (mucolytics), antihistamines and antibiotics and sometimes sinus puncture and irrigation for removal of purulent secretions. In most cases sinusitis occurs during viral infections where antibiotics are ineffective, but the few cases that also have a bacterial infection (one or two out of every 100 patients with sinus symptoms) could benefit. Unfortunately it is difficult to distinguish between those who have a bacterial infection and those who do not. It is important to avoid unnecessary use of antibiotics and limit the potential for antibiotic resistance. This updated review compiled data from 63 separate studies that used a variety of antibiotics for simple maxillary sinus infection, i.e. non-complicated acute sinusitis in a person with a healthy immune system. Nine of the studies compared antibiotics to placebo (1915 participants; seven of the studies conducted in primary care), and 54 studies compared different classes of antibiotics. Five of the nine placebo-controlled studies involving 1058 participants found that most participants got better within two weeks, regardless of whether they received the antibiotic or not (roughly 9 out of 10 participants in antibiotic groups and 8 out of 10 in placebo groups). Although all the five studies in this main outcome were assessed as having low risk of bias, the overall evidence was assessed only as being of moderate quality (it is possible that a new large study can change the estimate). In the remaining 54 studies comparing different antibiotics (10 different comparisons), no antibiotic was found to be superior to another. The evidence is current to March 2013. The small benefit gained by antibiotics may be overridden by the negative effects of the drugs. In addition to patient-related adverse effects (like skin rash and gastrointestinal problems such as diarrhea, abdominal pain and vomiting), side effects include the risk of increased resistance to antibiotics amongst community-acquired pathogens (bacteria). This review found that antibiotics will help some people a bit, but do not make a major difference to most people with acute maxillary sinusitis being treated in primary care. Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Antibiotics compared to placebo for uncomplicated acute maxillary sinusitis Patient or population: patients with uncomplicated acute maxillary sinusitis Settings: primary care Intervention: antibiotics: penicillin V, amoxicillin and azithromycin Comparison: placebo Outcomes

Clinical failure rate Follow-up: 7 to 15 days

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Placebo

Antibiotics

Relative effect (95% CI)

Failure defined as a lack Failure defined as a lack RR 0.66 of full recovery or im- of full recovery or im- (0.47 to 0.94) provement provement 136 per 1000

1084 ⊕⊕⊕ patients randomised and moderate2 1058 evaluated (5 studies1 )

716 patients randomised ⊕⊕⊕⊕ and 680 evaluated high4 (5 studies3 )

448 per 1000 (387 to 522)

Clinical failure rate Failure defined as a lack Failure defined as a lack RR 0.85 Follow-up: 16 to 60 days of full recovery or im- of full recovery or im- (0.36 to 1.98) provement provement 122 per 1000

Quality of the evidence (GRADE)

90 per 1000 (64 to 128)

Failure defined as a lack Failure defined as a lack RR 0.73 of full recovery of full recovery (0.63 to 0.85) 614 per 1000

No of participants (studies)

104 per 1000 (44 to 241)

169 patients randomised ⊕⊕

and 169 evaluated low5,6 (1 study)

Comments

Adverse effects8 : antibiotics 8% to 59%; placebo 6% to 38%

3


Failure defined as a lack Failure defined as a lack RR 0.63 of full recovery of full recovery (0.38 to 1.05) 329 per 1000

169 patients randomised ⊕⊕

and 169 evaluated low5 (1 study)

207 per 1000 (125 to 346)

Quality of life and activ- Impact Number of participants ity impairment (studies) Follow-ups: Inconsistent effect. There were differences in: out- 270 patients evaluated 3, 6 to 8, 10 days come measures, follow-up times and results (2 studies7 )

⊕

very low

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Five

4

studies at ’low’ risk of bias for the five key domains of allocation concealment, blinding, selective outcome reporting, incomplete outcome data and baseline comparability. 2 Because the effect size seems to be small and the number of evaluated participants so far is 1058, it is not unreasonable to anticipate that a new large study could change this estimate. 3 Five studies at ’low’ risk of bias for the five key domains of allocation concealment, blinding, selective outcome reporting, incomplete outcome data and baseline comparability. 4 When including one study at ’unclear’ risk of bias in the analysis, the results did not change (RR of 0.73, 95% CI 0.63 to 0.85). 5 Only one small study at ’low’ risk of bias (Haye 1998). 6 Also the study of Hadley 2010 at ’unclear’ risk of bias (comparing moxifloxacin to placebo) did not find a significant difference between antibiotic and placebo either (RR value of 0.62, 95% CI 0.37 to 1.03). These two studies represent almost the utmost ends of the clinical variation; Haye 1998 excluded participants with radiographic findings more than mild and Hadley 2010 included only participants with bacteriologically confirmed sinusitis.


7 Two

studies at ’unclear’ risk of bias, published in 2010 and 2012 in the USA. of reported adverse effects in eight studies.

8 Variation

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

5

BACKGROUND

alone. Acute bacterial sinusitis is more likely if the symptoms have lasted for more than one week (Gwaltney 2005).

Description of the condition Sinusitis is a prevalent and important cause of ill health in adults. In the US alone, an estimated 20 million cases of acute sinusitis occur each year (Gwaltney 2005). Sinusitis is the third to fifth most common diagnosis for which an antibiotic is prescribed within primary care settings in Nordic countries (Andre 2002; Rautakorpi 1999) and the US (SAHP 2004). Sinusitis accounts for 15% to 21% of all antibiotic prescriptions for adults in outpatient care. Acute bacterial maxillary sinusitis is often preceded by an acute viral upper respiratory tract infection (URTI). Up to 90% of patients with acute URTIs have symptoms of rhinosinusitis (Gwaltney 1994). Following a common cold lasting for one week, up to 39% of adults (Puhakka 1998) have reversible abnormalities in the sinus cavity which show up in magnetic resonance imaging or X-ray. It has been estimated that 0.5% to 2% of patients with a common cold have complications in the form of acute bacterial infection of the sinuses (Berg 1986; Gwaltney 1996). However, distinguishing patients with bacterial infection from those with symptoms of rhinosinusitis with a viral origin is challenging. A bacterial sinus infection can be caused by one or more bacterial species. Commonly isolated bacteria include Streptococcus pneumoniae (S. pneumoniae),Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. catarrhalis) (Gwaltney 1992; Low 1997). In approximately a third of suspected bacterial sinusitis cases, bacterial cultures from the sinus cavity come back negative (Axelsson 1972; Gwaltney 1992; Jousimies-Somer 1988). Formally sinusitis is classified as acute or chronic, depending on the pathological findings and duration of symptoms (Fokkens 2007; ICD-10). In this classification, acute sinusitis is defined as lasting less than 12 weeks. However, clinically sinusitis can be classified to more than two classes: acute, subacute or chronic, depending on the duration of the symptoms (Lanza 1997; Meltzer 2004; Slavin 2005). In this case acute maxillary sinusitis is usually defined as lasting less than four weeks and subacute as four to 12 weeks (Ah-See 2007; Lanza 1997). Subacute maxillary sinusitis, although not a distinct disease entity from acute sinusitis, may differ histopathologically and require different therapy from acute or chronic maxillary sinusitis (Hickner 2001; Lanza 1997). Many cases of chronic sinusitis again represent a separate entity with underlying problems, for example, mechanical obstruction of sinus drainage, abnormalities in mucociliary clearance or immunology (Gwaltney 2005). For research purposes it is recommended that acute sinusitis be defined as lasting less than four weeks (Meltzer 2006). Typical signs and symptoms of acute sinusitis include purulent nasal discharge, postnasal drip, sinus pain at palpation, nasal obstruction with poor response to decongestants, unilateral facial pain and maxillary toothache (Axelsson 1972; Williams 1993), but none of the signs or symptoms is diagnostic when presenting

Description of the intervention Clinical guidelines for acute sinusitis currently recommend antibiotic treatment for patients with severe or persistent moderate symptoms and specific findings of bacterial sinusitis (Fokkens 2007; Slavin 2005; Snow 2001). Unnecessary antibiotic prescriptions should be avoided for several reasons: in addition to patientrelated adverse effects, side effects are associated with resistance to antibiotics among community-acquired pathogens. The correlation between resistance and community antibiotic use has been seen in many countries (Albrich 2004; Arason 1996; Bronzwaer 2002; Goossens 2005; Seppälä 1995; Steinke 2001). Not only the volume of antibiotic use but also the selection of broad-spectrum drugs, low doses and long duration of antibiotic treatment increase antibiotic resistance (Guillemot 1998; Hay 2005; Odenholt 2003). The European Antimicrobial Resistance Surveillance System (EARSS) has revealed significant geographical differences in resistance rates within Europe (Goossens 2005); high rates of antibiotic resistance were seen more often in southern and eastern European countries with high antibiotic use. For example, there are remarkable differences between European countries in the prevalence of resistance to penicillin and macrolide antibiotics in treating S. pneumoniae (EARSS 2008). In recent years, an increasing number of published studies have also suggested that antibiotics might have other harmful effects on health through the disturbance of human microbiota (Kilkkinen 2002; Maxwell 2002; Velicer 2004) and perhaps predispose to new infections (Arason 2005; Howard 1976; Joki-Erkkilä 2000; Margolis 2005; Smith 1997).

How the intervention might work The purpose of antibiotics is, by eradicating bacteria from the sinuses, to decrease the signs and symptoms of infections, restore the normal function of the sinuses and to prevent complications and the development of chronic sinusitis.

Why it is important to do this review The purpose of this systematic review was to quantify the effectiveness of antibiotic therapy for patients diagnosed with acute sinusitis and treated in ambulatory settings. The word ’antibiotic’ is used as a general term referring to all antibacterials.

OBJECTIVES


6

To compare the effects of antibiotics versus placebo on clinical failure rates for acute maxillary sinusitis. To compare different classes of antibiotics for treatment of acute maxillary sinusitis. To compare the effect of short-course versus long-course antibiotics for acute maxillary sinusitis. To compare the side effects of different treatments.

We included trials with a mixed population of acute (symptoms less than 30 days) and non-acute sinusitis or acute exacerbations of chronic sinusitis if they separately reported data on the subgroup with acute sinusitis, or if at least 80% of participants had acute sinusitis. We excluded trials that focused on patients with complicated sinusitis such as pansinusitis or frontal sinusitis (or solely ethmoidal or sphenoidal sinusitis), or infections of dental origin. Types of interventions

METHODS

Criteria for considering studies for this review

Types of studies Randomised controlled trials (RCTs) evaluating and comparing antibiotics to a placebo, or different classes of antibiotics for acute sinusitis, and reported in full-text. We included trials having a sample size of at least 30 participants with acute maxillary sinusitis. This is to guarantee that data in individual studies are as unbiased as possible. Also in very small samples many estimators are known to be sensitive to variation. We excluded studies reported only as abstracts because there is evidence that there are discrepancies between data reported in the abstract and the final published full report and that information on trial quality indicators is often lacking (Chokkalingam 1998; Hopewell 2006). Thus we required full-text reports to ensure reliable data extraction and assessment of risk of bias. To diminish the risk of publication bias, we attempted to contact authors of potential abstracts to obtain information as to whether a full-text report of the study (unpublished or published) was available. Types of participants We included trials with adults or trials that separately reported data on subgroups of adults. We accepted adolescents (at least 12 years old) if less than 20% of participants were under 18 years of age. Acute maxillary sinusitis was defined by: 1. a history of URTI lasting seven to 30 days, with at least two clinical signs or symptoms (sinus pain at palpation, postnasal drip, purulent nasal discharge, nasal obstruction, unilateral facial pain, maxillary toothache, impaired sense of smell); or 2. radiography, ultrasound or other imaging; or 3. bacterial culture from a sinus secretion obtained by puncture or endoscopy and irrigation or aspiration. In studies where the clinical diagnosis was not clearly described, diagnosis of acute maxillary sinusitis should be confirmed in at least of 80% of participants by imaging or culture.

We reviewed the following drug therapies: 1. antibiotics versus control; and 2. comparisons between different antibiotic classes. We systematically recorded co-interventions such as decongestants, antihistamines, mucolytics, non-steroidal anti-inflammatory drugs and corticosteroids. Types of outcome measures Primary outcomes

1. Clinical failure rate at 7 to 15 days after the start of treatment. Failure is defined as lack of full recovery or improvement of participants with acute maxillary sinusitis at follow-up. 2. Clinical failure rate at 16 to 60 days after the start of treatment. Failure is defined as lack of full recovery or improvement of participants with acute maxillary sinusitis at follow-up. As spontaneous cure rate or cure plus improvement rate in maxillary sinusitis is expected to also be fairly high in the placebo group, we decided after careful consideration to select the negative outcome ’failure’ instead of ’success’. This will enable clinicians to consider the risks of not prescribing antibiotics as opposed to the benefits of prescribing them, compared to possible adverse effects of antibiotics. Secondary outcomes

1. Clinical failure rate at 7 to 15 days after the start of treatment. Failure is defined as lack of full recovery of participants with acute maxillary sinusitis at follow-up. 2. Clinical failure rate at 16 to 60 days after the start of treatment. Failure is defined as lack of full recovery of participants with acute maxillary sinusitis at follow-up. 3. Bacteriological failure. 4. Radiographic failure. 5. Relapse rates: new acute episodes of sinusitis after 60 days from the start of the treatment. 6. Drop-outs due to adverse effects. 7. Quality of life. 8. Activity impairment and ability to work.


7

Search methods for identification of studies

Electronic searches For this 2013 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 2, part of The Cochrane Library, www.thecochranelibrary.com (accessed 20 March 2013), which contains the Cochrane Acute Respiratory Infections Group’s Specialised Register, MEDLINE (1946 to March week 3, 2013) and EMBASE (1974 to March 2013). We searched CENTRAL and MEDLINE using the search strategy described in Appendix 1. The MEDLINE search was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precisionmaximising version; Ovid format (Lefebvre 2011). We adapted the search strategy for EMBASE (Appendix 2). We also searched: 1. the System for Information on Grey Literature in Europe (SIGLE) to locate grey literature. SIGLE is currently known as OpenGrey. The search strategy was adapted to the new system’s search language. The search was run on the Exalead search engine at http://www.opengrey.eu/ (accessed 15 January 2013) (Appendix 3); 2. ClinicalTrials.gov (to 4 February 2013) to locate ongoing trials (Appendix 4); 3. WHO International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp (to 4 February 2013) to locate ongoing trials (Appendix 4). Searching other resources We used the function for finding related articles in PubMed for the already identified placebo-controlled trials to track down additional, relevant articles. We reviewed reference lists of the identified trials and 14 systematic reviews (13 previously identified systematic reviews Appendix 5, and the new Cochrane review Lemiengre 2012) considering placebo-controlled study designs for additional, appropriate studies. For a previous review version (Williams 2003), pharmaceutical companies that manufacture antibiotics used in the treatment of acute sinusitis were contacted and data and references from all published and unpublished trials on acute sinusitis were requested. Further, three experts in the field had been contacted and asked to review the bibliography of the initial review (Williams 1999) for completeness. Details of previous searches are in Appendix 5.

Two review authors (AAS and UMR) independently selected papers on the basis of the title, keywords and abstract, and decided on eligibility. We obtained the full text of every article considered for inclusion. If the information relevant to the inclusion criteria was unavailable in the abstract or if the title was relevant but the abstract was unavailable, we obtained the full text of the report. We resolved any disagreements by consensus between these two review authors. We contacted trial authors of the placebo-controlled studies to obtain additional information if the study seemed to fulfil the inclusion criteria for this review but the information in the report was insufficient to make the final assessment of inclusion or exclusion. Data extraction and management Two review authors (AAS, UMR) extracted data from all included studies. We also extracted data presented only in graphs and figures whenever possible. Extracted information relating to study methodology or quality included: randomisation concealment, blinding, time of followup, percentage of missing data during follow-up and baseline comparability of the groups. Characteristics relating to methods that we extracted included: criteria for accepting participants into the study (diagnosis on clinical/radiography/culture basis), definition of cure/failure and treatment compliance. Characteristics relating to participants that we extracted included the number of participants in treatment and control groups at start, the mean age of participants (plus age range), the number of men and women, the year the study was published, the location where the study was conducted (country and setting where participants were recruited). Characteristics of the intervention that we extracted included: intervention comparisons, courses of antibiotics and information about co-interventions. We extracted information on clinical, bacteriological and radiographic outcomes and adverse event rates. We mainly extracted outcome information as numbers of participants with clinical failure/non-failure by study group. We classified relapse within 60 days from the onset of the treatment as a clinical failure. In some studies the results were given at more than one follow-up point. We extracted all data for preselected times, which were 7 to 15 days, 16 to 60 days and over 60 days of follow-up. We carried out meta-analyses at these preselected times based on the available data. Two review authors (AAS, UMR) agreed on final results and reached decisions by consensus. Assessment of risk of bias in included studies

Data collection and analysis

Selection of studies

Two authors (AAS, UMR) independently assessed the risk of bias of the included studies. We resolved disagreements by consensus. Attempts were made to contact trial authors of the included placebo-controlled studies if the information in the report was insufficient for assessment. We presented the questions as open-


8

ended, for example, “how was randomisation performed in practice?” As recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), we assessed the following six domains. Within each domain, we judged each study as having a ’low’, ’high’ or ’unclear’ risk of bias, the latter indicating either lack of information or uncertainty over the potential for bias.

Random sequence generation

Was the method used to generate the allocation sequence appropriate to produce comparable groups?

We graded this domain ’low’ risk of bias if authors described a random component in the sequence generation process (for example, random number table, coin tossing, drawing of lots). If there was no or insufficient information about the random sequence generation process, we graded this domain ’unclear’ risk. In this review we excluded studies which were identified as quasi-randomised (for example, if allocation method was alternation, use of case record numbers, dates of birth or day of the week).

Allocation concealment

Was the method used to conceal the allocation sequence appropriate to prevent the allocation being known in advance of, or during, enrolment?

We graded this domain ’low’ risk of bias if the authors described adequate concealment (for example, by means of central randomisation or sequentially numbered, opaque and sealed envelopes) and ’high’ risk of bias if inadequate concealment was documented or allocation concealment was not used. If no information about allocation concealment was provided or the information was unclearly reported, we graded this domain ’unclear’ risk of bias.

Blinding

Were participants, personnel and investigators (outcome assessors) blinded about the intervention a participant had received?

We graded this domain ’low’ risk of bias if at least the participant and the investigator were blinded. If the study only reported a double-blind design without detailed description of the methods of blinding, we graded this domain ’unclear’ risk of bias.

Incomplete outcome data How complete were the outcome data for the clinical outcomes? Were drop-out rates and reasons for withdrawals reported? Were missing data imputed appropriately?

The judgements were restricted to clinical efficacy outcomes at 7 to 15 or at 16 to 60 days after the start of treatment. If the clinical efficacy outcomes in a trial were reported at both follow-up periods, the judgement of this domain was based on the 7 to 15 days after the start of treatment but the risk of bias was separately assessed and reported in the ’Risk of bias’ table also for the second follow-up period in case it was used in the review analyses. We decided to grade this domain to ’low’ risk of bias if the total proportion of the missing outcome data was marginal (less than 5%); or when the proportion of the missing outcome data was less than 20% and the groups were balanced in numbers and reasons for missing data (regardless of reason or population used in the analyses); or if missing data were imputed using appropriate methods. Also, if reasons for exclusion of the participants after randomisation were justifiable and not seen to affect the randomisation, a higher proportion of missing data could be accepted. For example, if a positive culture of sinus excretion was defined as inclusion criterion, a higher number of exclusions due to absence of pathogen in pretreatment cultures is justifiable because it is anticipated and the results of the cultures are available only several days after the start of the treatment. If there was no information on reasons for missing data across intervention groups or proportions of missing data were documented as total proportion (5% to 20%), not by groups, the judgement was ’unclear’ risk of bias. Classifying the total proportion of the missing data over 20% as ’high’ risk of bias (besides the exception described above) was a pragmatic approach to this domain to make the judgement uniform and transparent. Selective reporting Were appropriate outcomes reported and were key outcomes missing?

To be included in this review, clinical outcomes had to be reported. However, studies could also report other (secondary) outcomes, for example radiological and bacteriological responses, relapse rates, chronic evolution and adverse effects. In this review, we graded freedom from selective reporting ’low’ risk of bias if the study’s prespecified outcomes (those of interest in this review) had been reported in the prespecified way. Other sources of bias This domain included information on the baseline comparability of the intervention and control groups, on possible use of the cointerventions by group and on funding. We assessed each of these features in their own entries.


9

1. Balance in baseline characteristics between the study groups is an essential feature representing the methodological quality of the trial. We graded this entry ’high’ risk of bias if there were important differences in demographic characteristics or sinusitis severity at baseline between the study groups. If baseline characteristics were not described clearly enough we graded this entry as ’unclear’ risk of bias. 2. We graded the co-intervention entry ’low’ risk of bias if the groups were balanced in amount and quality of co-interventions or no co-interventions were included in the protocol, and ’high’ risk of bias if the groups received a different amount or quality of co-interventions during the trial. If no information was provided on co-interventions we graded this entry ’unclear’ risk of bias. 3. We graded the funding entry ’low’ risk of bias if the

funding was only from academic or public sources, and ’high’ risk of bias if the study was funded by a pharmaceutical company, since there is evidence that industry-sponsored trials may overestimate the treatment effect (Bekelman 2003; Bhandari 2004; Lexchin 2003). The judgement was ’unclear’ risk if there was pharmaceutical industry funding but the researchers had full rights to the data and manuscript or one or more of the authors had affiliations to pharmaceutical company; or when the funding source was unclear. We completed a ’Risk of bias’ table for each included study (Characteristics of included studies). Results are presented graphically by domain over all studies (Figure 1) and by study (Figure 2).

Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


10

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.


11

Summary assessments of risk of bias

To draw conclusions about the overall risk of bias for the main clinical outcomes within a study, we decided to classify the studies into three categories: studies with ’low’, ’unclear’ or ’high’ risk of bias. The five main clinical outcomes were: clinical failure rate at 7 to 15 days after the start of treatment and failure defined as 1) a lack of full recovery or improvement of participants, or 2) a lack of full recovery of participants; clinical failure rate at 16 to 60 days after the start of treatment and failure defined as 3) a lack of full recovery or improvement of participants, or 4) a lack of full recovery of participants; 5) quality of life and activity impairment. Our classification was based on five domains which we considered as most fundamental in assessing the quality of studies: allocation concealment, blinding, selective outcome reporting, incomplete outcome data and baseline comparability. The ’Risk of bias’ categories were defined as follows. 1. Low risk of bias (plausible bias unlikely to seriously alter the results) if all five fundamental domains defined above were graded as ’low’ risk of bias. 2. Unclear risk of bias (plausible bias that raises some doubt about results) if one or more of the domains were graded as ’unclear’. 3. High risk of bias (plausible bias that seriously weakens confidence in the results) if one or more domains were graded as ’high’ risk of bias. We used the GRADEprofiler software version 3.2 (GRADEpro 2008) to provide the overall grading of the quality of evidence for the clinical outcomes in the following comparisons: antibiotics compared to placebo (Summary of findings for the main comparison) and antibiotic versus antibiotic (Summary of findings 2).

were randomly allocated to two or several groups and a single result for each outcome from each individual was collected and analyzed. Dealing with missing data We performed the analyses using an available case data analysis as presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). This approach for calculating the response rate uses the total number of participants who had data recorded for the particular outcome in question as a denominator. If the missing outcome data were reported to be over 35% or if there was a significant imbalance in missing data rates between the intervention and control groups, we excluded the study from the meta-analyses. Excluding these studies in the analyses was seen as a quality issue, especially when there are a lack of universal strategies for handling missing data (Unnebrink 2001). In this review, limiting meta-analyses to studies with a missing data rate of less than 35% was a pragmatic approach to make comparisons without compromising the reliability of the overall results. In assessing the influence of missing data (less than 35%) on the overall results of the meta-analyses of primary outcomes in studies comparing antibiotic with placebo, we used two ways of imputing data for sensitivity analyses: assuming the outcomes of participants for whom no outcome was recorded as a) failures, or b) non-failures. The analyses comparing antibiotic versus antibiotic were undertaken by using available case data without imputations. When a study provided available case data for the first follow-up but not for the second one, we included the study in the second follow-up meta-analyses if the missing data rate (compared to the first follow-up) was marginal (about 5% at most).

Measures of treatment effect

Assessment of heterogeneity

All studies presented the outcome results in dichotomous form. We calculated risk ratios (RR) for differences between intervention and control groups for whether the treatment failed or not, along with appropriate standard errors and 95% confidence intervals (CI), using RevMan 2012. In calculating drop-out rates due to adverse effects, we used the Peto odds ratio (OR) as the outcome measure. In placebo-controlled studies with multiple antibiotic arms, the data from the antibiotic arms were combined and compared to placebo or control group as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

We assessed the significance of any discrepancies in the estimates of the treatment effects from the different trials by means of Cochran’s test for heterogeneity and by a measure of the I2 statistic. The I 2 statistic describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error. A value greater than 50% may be considered to represent substantial heterogeneity (Higgins 2003).

Unit of analysis issues The unit of analysis was an individual because all RCTs included in this review were simple parallel-group trials in which participants

Assessment of reporting biases If there had been sufficient numbers of trials (more than 10) in any meta-analysis, publication bias would have been assessed according to the recommendations on testing for funnel plot asymmetry as described in the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011). If asymmetry was identified we would have examined possible causes.


12

Data synthesis The data consisted of comparisons for antibiotic versus placebo and antibiotic versus antibiotic. The antibiotic versus antibiotic comparisons were macrolide/cephalosporins versus amoxicillinclavulanate, non-penicillin antibiotics versus beta-lactamase sensitive penicillins and tetracyclines versus mixed classes of antibiotics. We conducted the meta-analyses in RevMan 2012, using either the fixed-effect or the random-effects model. In meta-analyses including two or three studies, we used the fixed-effect model, and in those including four or more studies, the random-effects model. We pooled the data for the studies in each comparison regardless of whether the studies could represent somewhat different kinds of populations (depending on the definition of the diagnosis of acute maxillary sinusitis; clinical diagnosis only versus radiological/bacteriological confirmation). In meta-analyses of the placebo-controlled studies, we combined data across antibiotic classes. These decisions were made because the main interest was to estimate the average intervention effects. We pooled the Peto ORs of individual studies, estimating the drop-out rate due to adverse effects, using the fixed-effect model. To incorporate the ’Risk of bias’ assessments in analyses, we decided to pool data from the studies in each comparison by restricting the analyses to studies at ’low’ risk of bias. We performed sensitivity analyses to see how conclusions were affected by including studies at ’unclear’ risk or ’high’ risk of bias in the analyses, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). However, if all studies in a comparison were graded as ’unclear’ or ’high’ risk of bias, we pooled the results of these studies in a meta-analysis. The methodological classifications were taken into consideration when interpreting the results. Subgroup analysis and investigation of heterogeneity We had planned to conduct further analyses to identify subgroups of participants that might get more benefit from antibiotic treatment (for example, regarding type of signs or symptoms, their severity or duration). Due to insufficient information from studies, it was not possible to undertake such subgroup analyses.

Description of studies

Results of the search In this 2013 update, we retrieved a total of 138 new records, after duplicates were removed from searches in MEDLINE (60 records), EMBASE (137 records), CENTRAL (20 records) and OpenGrey (three records). One of the 138 records was identified by checking the reference list of a new systematic review by Lemiengre 2012. The electronic searches did not identify any potential ongoing trials for this review. The total number of records considered from all updates was 2347, including 2209 records from the earlier searches and 138 new records from this 2013 update search. Detailed descriptions of the earlier search results are in Appendix 6. Of these 2347 records, we rejected 2052 records as definitely not meeting the inclusion criteria simply on the basis of title or abstract or because they were duplicates (in the earlier searches). From all updates we obtained altogether 295 full-text reports. From these 295 reports, 131 were clearly irrelevant for this review leaving 164 reports for final assessment. The main reasons for irrelevance were: trials without control group, studies with treatments other than antibiotic, studies comparing the same classes of antibiotics and studies regarding children. We identified 164 reports to be evaluated in detail. We considered 68 reports representing 63 individual studies to be eligible for inclusion in the review. Compared to the previous version of this review, we included three new antibiotic versus placebo studies (Garbutt 2012; Hadley 2010; Meltzer 2005) and one new antibiotic versus antibiotic study (Lari 2010). The reasons for exclusion of the 89 studies with 96 reports are explained in the Characteristics of excluded studies table.

Included studies Nine of the 63 included studies compared antibiotic treatment to placebo. The remaining 54 studies compared different classes of antibiotics. The studies of Lindbaek 1996 and Lindbaek 1998 were conducted as the same trial but used different randomised study populations with different inclusion criteria, and they are handled as separate studies in the study descriptions and analyses.

Sensitivity analysis To test the robustness of the results, we undertook sensitivity analyses to explore the effect of missing data and overall risk of bias in the studies on the clinical outcomes. We also planned to carry out sensitivity analyses to examine the effect of different diagnostic criteria for acute sinusitis (clinical or radiograph/bacteriological) but the number of trials was not sufficient for such analysis.

RESULTS

Description of the studies comparing antibiotics versus placebo

Nine trials with 1915 randomised participants evaluated antibiotic treatments compared with non-antibiotic controls for acute maxillary sinusitis (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997). Four studies compared amoxicillin versus placebo (Garbutt 2012; Meltzer 2005; Merenstein 2005; van Buchem 1997), two studies compared penicillin V and amoxicillin


13

to placebo (Lindbaek 1996; Lindbaek 1998), one study compared azithromycin to placebo (Haye 1998), and one study compared moxifloxacin to placebo (Hadley 2010). The study by Axelsson 1970 did not have a placebo group but the comparison of penicillin V plus oxymetazoline versus oxymetazoline alone was included in this review. In four studies diagnosis was based on clinical signs and symptoms lasting at least seven days (Garbutt 2012; Haye 1998; Meltzer 2005; Merenstein 2005). In four studies, diagnosis was confirmed by a radiograph (criteria: secretion in the study of Axelsson 1970; and mucosal thickening more than 5 mm, presence of air-fluid level or total opacification in the van Buchem 1997 study); or by a computer tomography (criteria: presence of air-fluid level or total opacification in the study by Lindbaek 1996; and mucosal thickening of 5 mm or more without fluid level or total opacification in the study by Lindbaek 1998). In one study (Hadley 2010) the diagnosis was confirmed by a radiograph (criteria: presence of airfluid levels and/or opacification on a radiographic paranasal sinus film) and a sinus puncture for bacterial culture of the sinuses; only culture-positive patients with target pathogen (Streptococcus pneumonia (S. pneumoniae), Haemophilus influenzae (H. influenzae), Moraxella catarrhalis (M. catarrhalis), Streptococcus pyogenes (S. pyogenes) or Staphylococcus aureus (S. aureus)) were included in the analyses. In the study by Haye 1998 radiography was used to exclude patients with empyema. Nasal decongestants and/or analgesics were allowed but not prescribed in three studies (Hadley 2010; Lindbaek 1996; Lindbaek 1998). Three studies used decongestants, cough medication and/ or analgesics as a prescribed supplementary therapy in all groups (Axelsson 1970; Garbutt 2012; van Buchem 1997). Over-thecounter medications without further specification were allowed in one study (Merenstein 2005) and one study did not provide any information on co-interventions (Haye 1998). One study allowed nasal or broncho-inhaled corticosteroids if they had been in stable use for over four weeks prior to enrolment (Hadley 2010). In one study all concomitant medications were prohibited (Meltzer 2005) (Table 1). Of the nine studies, three were conducted in Norway (Haye 1998; Lindbaek 1996; Lindbaek 1998), three in the USA (Garbutt 2012; Hadley 2010; Merenstein 2005), one in Sweden (Axelsson 1970) and one in the Netherlands (van Buchem 1997). One study was multinational (Meltzer 2005). Participants were clearly recruited from community-based general practices in seven of the nine studies. The study by Axelsson 1970 did not describe the treatment setting, and in the multinational study by Meltzer 2005 the nature of participating medical centres was not described. The average age of the participants was approximately 36 years and some 65% were women. Ear, nose and throat (ENT) co-morbidity was assessed in three studies (Garbutt 2012; Meltzer 2005; van Buchem 1997). The study of van Buchem 1997 reported that 12% of participants had an allergic disease. The study of Garbutt 2012 reported allergic rhinitis in 32%, asthma in 11%

and a history of sinus disease in 74% of participants in each group; in this study 13% were smokers in the amoxicillin group and 26% in placebo group. The study by Meltzer 2005 reported that 42% of participants had either seasonal or perennial allergic rhinitis in the amoxicillin and placebo groups. In the study of Axelsson 1970 patients with a history of nasal allergy were excluded. In addition to clinical outcomes, radiological outcomes were reported in three studies (Axelsson 1970; Lindbaek 1996; van Buchem 1997). No studies reported bacteriological outcomes. Description of the studies comparing antibiotic versus antibiotic

Fifty-four studies comparing different classes of antibiotics were included in the review. Treatment comparisons were: non-penicillin antibiotic versus beta-lactamase sensitive penicillins (n = 8); non-tetracycline versus tetracycline (n = 5) (one study of these was also included in the comparison of non-penicillin antibiotic versus beta-lactamase sensitive penicillin); macrolides versus amoxicillinclavulanate (n = 11); cephalosporins versus amoxicillin-clavulanate (n = 10); and miscellaneous comparisons (n = 21). Participants were recruited from otolaryngology speciality settings in 17 studies, primary care settings in 12 studies and mixed settings in three studies. The recruitment or treatment setting was not described or unclear in 22 studies. The average age of the participants was approximately 38 years; three studies did not report the mean age of the participants. In 37 studies, the male to female ratio was mostly about 1:1 or 1:1.5. Fourteen studies assessed ENT co-morbidity. The diagnosis was based only on clinical signs and symptoms in three studies. In 38 studies diagnosis was confirmed by a radiograph and in 13 studies by radiograph and/or culture. In addition to clinical outcomes, bacteriological outcomes were reported in 28 studies and radiological outcomes in 11 studies. Three studies reported the effects on function or quality of life. Topical decongestants and/or antihistamines were prescribed in seven studies. They were allowed but not prescribed in 21 studies, prohibited in one study and not described in 25 studies. One trial prescribed nasal corticosteroids as part of the intervention (Pessey 1996). For more detailed information on the included studies see the Characteristics of included studies table. Excluded studies The Characteristics of excluded studies table presents the reasons for exclusion of controlled clinical studies. Only those controlled clinical studies which compared antibiotic treatment with placebo or antibiotics of different classes for acute maxillary sinusitis are included in the table. Studies without a control group were excluded. Of the 89 excluded studies, 13 studies included comparison of antibiotic versus placebo and 76 studies compared antibiotic ver-


14

sus antibiotic. The reasons for exclusion were varied and in many studies there were several reasons for exclusion. In 19 out of the 89 studies there was no mention of random allocation or the study design was clearly not randomised; two of these studies were placebocontrolled. In the other 11 randomised, placebo-controlled studies, the diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review.

Risk of bias in included studies We contacted the authors of the included placebo-controlled studies to obtain additional information to assess the methodological quality issues if the information in the report was insufficient to make final decisions. We requested additional information from seven studies (Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005). Authors of four of those seven studies could deliver additional information on quality issues (Garbutt 2012; Lindbaek 1996; Lindbaek 1998; Merenstein 2005) and information was not available for this update from three studies (Hadley 2010; Haye 1998; Meltzer 2005). We did not contact the authors of the Axelsson 1970 study because the report was published 40 years ago. Quality assessments for each individual study are presented in ’Risk of bias’ tables included in the Characteristics of included studies, and the results are presented graphically by study (Figure 2) and by domain over all studies (Figure 1).

concealment had been fulfilled (additional information not received from the trial authors). Two studies did not report the allocation concealment method (Axelsson 1970; Hadley 2010) and the judgement was ’unclear’ risk of bias. Antibiotics versus antibiotics

Random sequence generation was adequate, indicating ’low’ risk of bias in 19 of the 54 studies (35%) comparing different classes of antibiotics. In most of these studies the sequence generation was computer-based. Thirty-five studies did not report the random sequence generation method and the judgement was ’unclear’ risk. However, although random sequence generation was reported in 19 studies, the allocation concealment was adequately described in only 13 out of 54 studies (24%) to allow this domain be graded ’low’ risk of bias. In these studies, the allocation concealment was mostly executed by a third party (for example, in pharmaceutical company or by a statistician not involved with the personnel in the studies). Forty-one studies did not report the random allocation concealment method at all or the description was not clear enough to make the assessment and the judgement was ’unclear’ risk of bias. Blinding

Antibiotics versus placebo

Allocation


Random sequence generation was adequate, indicating ’low’ risk of bias in seven of the nine placebo-controlled studies (Garbutt 2012; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997). In five studies the random sequence generation was made by computer (Garbutt 2012; Haye 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997) and in the other two studies by dice (Lindbaek 1996; Lindbaek 1998). Two studies did not report the randomisation method (Axelsson 1970; Hadley 2010) and the judgement was ’unclear’ risk of bias. Allocation concealment was graded ’low’ risk of bias in the same seven studies as those assessed to have adequate random sequence generation. Allocation concealment was performed centrally in the study of van Buchem 1997 (hospital pharmacy-controlled randomisation), by an investigational pharmacist in the study of Garbutt 2012 and by a statistician in the studies of Lindbaek 1996, Lindbaek 1998 and Merenstein 2005. Although the studies of Haye 1998 and Meltzer 2005 did not give exact information on how the randomisation result was concealed, the method of random sequence generation (computer-randomised code) and information on double-dummy design gave the impression that

Seven of the nine placebo-controlled studies documented adequate blinding of participants and investigators (Garbutt 2012; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997). The study medications were delivered by a third party and the authors did not know which medicine each participant had received. The participants were not aware which treatment they received, and most of the studies stated that treatment and placebo products were indistinguishable from each other. Two studies were justified as ’unclear’ risk of bias: the study of Axelsson 1970 did not report anything about the blinding, and Hadley 2010 only stated the study to be double-blinded with matching placebos but did not give any other information on the procedures. Antibiotics versus antibiotics

We documented and assessed blinding of participants and investigators as adequate in 19 out of the 54 studies (35%) comparing different classes of antibiotics. In most cases study medications were delivered by a third party and matched placebo tablets were used to ensure blinding of participants. Twenty of the 54 studies were open-labelled (37%) and 10 studies (19%) single-blinded and we graded these as having ’high’ risk of bias. In five studies the description was not clear enough to assess this domain and the judgement was ’unclear’ risk of bias.


15

Incomplete outcome data

Selective reporting



We assessed eight placebo-controlled studies to have ’low’ risk of bias in this domain (Axelsson 1970; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997). The reported total missing data rates were between 0.6% and 14% at 7 to 15 days follow-up. All of those eight studies except one (Lindbaek 1998) adequately reported missing data rates by study group. In the study by Lindbaek 1998 the total missing data rate was 5/68 (7.4%). However, we obtained additional information from the trial author that there were dropouts in each of the three groups. Thus we assessed the study of Lindbaek 1998 as having a ’low’ risk of bias in this domain. The ninth placebo-controlled study by Garbutt 2012 was graded as ’unclear’ risk of bias at day 10. The study reported different drop-out rates: in the amoxicillin group 4/85 (4.7%) and in the placebo group 10/81 (12.3%) on day 10. Although there probably was not any systematic difference in reasons for drop-outs between the groups (the authors gave additional information that participants simply missed the interviews), the difference in proportions of missing outcomes (7.6%) compared to the difference in anticipated failure risks (10% to 20%) may be big enough to cause bias. Two studies reported results at 16 to 60 days follow-up and had total missing data rates of 0% (Haye 1998) and 6% (Hadley 2010), indicating ’low’ risk of bias.

All nine placebo-controlled studies reported all prespecified outcomes adequately and were graded as ’low’ risk of bias in this domain (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997).

Antibiotics versus antibiotics

In this domain we assessed 31 out of 54 studies (57%) comparing antibiotics with antibiotics to have ’low’ risk of bias, 12 studies (22%) to have ’high’ risk of bias, and in 11 studies (20%) the judgement was ’unclear’ risk of bias. The way of reporting the results made it difficult to assess this domain in many of the studies. Several of the 12 studies graded as having ’high’ risk of bias reported responses only for per-protocol populations and the proportion of missing data was high. Even when studies reported clinical responses for both intention-to-treat (ITT) and per-protocol populations, often only the clinical cure rates were reported while failure rates were not. The indeterminate/missing data were then usually categorised as failures in ITT analyses and it remained unclear how many of the responses were true failures in each group. Three studies had to be downgraded from ’unclear’ to ’high’ risk of bias because of this particular problem. In the 11 studies with the judgement ’unclear’ risk, the description was not clear enough to assess this domain (especially regarding reasons for missing data across groups). We excluded three studies from the meta-analyses because the proportion of missing data was too high (38% in Marple 2010, 44% in Luterman 2003 and 52% in Steurer 2000).


Prespecified outcomes were adequately reported in 47 out of 54 studies (87%) comparing different classes of antibiotics. In two studies the reporting was deficient and they were graded as having ’high’ risk of bias. In five studies the description was too vague to make an assessment and the judgement was ’unclear’ risk of bias. Other potential sources of bias


Baseline comparability Demographic characteristics and disease severity ratings were described and assessed to be balanced across the groups in eight placebo-controlled studies. In the study of Hadley 2010 this domain was graded as ’unclear’ risk of bias because in the placebo group there were 9% more bilateral sinus infections than in the moxifloxacin group (38% versus 29%) and no by-group description was provided on allowed concomitant medications (especially stable-use nasal corticosteroids). Co-interventions Seven of the nine placebo-controlled studies reported co-interventions during the trial (Axelsson 1970; Garbutt 2012; Hadley 2010; Lindbaek 1996; Lindbaek 1998; Merenstein 2005; van Buchem 1997). In these studies co-interventions were mainly symptomrelieving over-the-counter medications which we judged not to cause bias. The study of Meltzer 2005 prohibited all concomitant medications, and the study of Haye 1998 did not provide any information on co-interventions. We graded seven out of the nine studies as having a ’low’ risk of bias in this domain (Axelsson 1970; Garbutt 2012; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem 1997. The study of Hadley 2010 did not give a detailed description of the use of allowed co-interventions (especially nasal corticosteroids which also may have a curative effect) and was judged as having ’unclear’ risk of bias, as well as Haye 1998 which had no information on co-interventions.


16

Funding Four of the nine placebo-controlled studies were funded by governmental or academic sources, or independent research foundations (Garbutt 2012; Lindbaek 1996; Lindbaek 1998; Merenstein 2005) and were judged as having a ’low’ risk of bias. Two studies did not state the funding source (Axelsson 1970; van Buchem 1997) and in one study (Haye 1998) one of the trial authors was affiliated with a pharmaceutical company. In these three studies the funding domain was graded as ’unclear’ risk. Two studies were supported by a pharmaceutical company and were classified as having a ’high’ risk of bias in this domain (Hadley 2010; Meltzer 2005).


Baseline comparability Demographic characteristics and disease severity ratings were described and assessed to be balanced across the groups in 34 out of 54 studies (63%) comparing different classes of antibiotics. In two studies we assessed the groups to be imbalanced and they were graded as having ’high’ risk of bias. In 18 studies the information was insufficient to assess this domain and the judgement was ’unclear’ risk.

Co-interventions In 30 out of the 54 studies (56%) we graded this domain as having ’low’ risk of bias. In most cases the co-interventions were symptomrelieving over-the-counter medications and they were seen not to cause bias. In 24 studies the judgement was ’unclear’ risk because no information was provided.

Funding Thirty out of the 54 studies (56%) were supported by a pharmaceutical company and they were graded as having ’high’ risk of bias. In 24 studies one or more of the authors were affiliated to a pharmaceutical company or the funding source was not stated, and this domain was graded as ’unclear’ risk.

Effects of interventions See: Summary of findings for the main comparison Antibiotics compared to placebo for uncomplicated acute maxillary sinusitis; Summary of findings 2 Antibiotics compared to other antibiotics for uncomplicated acute maxillary sinusitis Clinical outcomes were reported in all trials and evaluated quantitatively. We evaluated radiological and bacteriological outcomes only for placebo-controlled studies. However, none of the

placebo-controlled studies reported bacteriological outcomes. Radiographic outcomes are described qualitatively due to the small number of trials reporting these data. Primary outcomes


1. Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days follow-up Eight studies provided data for comparison of antibiotic treatment to placebo when clinical failure was defined as a lack of full recovery or improvement at 7 to 15 days follow-up (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; van Buchem 1997). In two studies unclearness of data (Garbutt 2012; Hadley 2010) and in one study the difference in the design (Hadley 2010) were seen to cause too much uncertainty, which prevented including them in the meta-analysis. Five of the remaining six studies were assessed as ’low’ risk of bias and were included in the main analysis (Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; van Buchem 1997) and one study at ’unclear’ risk of bias was used in the sensitivity analysis (Axelsson 1970). In each of the five individual studies of the main analysis the effect estimate of risk ratio (RR) indicated a small benefit for antibiotics but the confidence interval in all studies crossed the no difference line 1.0. When pooling the estimates of effects of these studies in the meta-analysis, antibiotics were found to be statistically significantly beneficial with a RR of 0.66 (95% confidence interval (CI) 0.47 to 0.94), based on a random-effects model using available case data (1058 evaluated participants; Analysis 1.1). The failure rates were 8.7% and 13.6% in antibiotic and placebo groups, respectively. This is the main result presented in the Summary of findings for the main comparison. There was no statistically significant heterogeneity between the studies in the analysis (I2 statistic = 0%). When double-checking the result using a fixed-effect model the result was similar (RR 0.65, 95% CI 0.46 to 0.92). Also, when using odds ratio (OR) as the effect measure the inference of the result was similar (OR 0.62, 95% CI 0.41 to 0.92) and there was no heterogeneity (data not shown). When including Axelsson 1970 (at ’unclear’ risk of bias) in the main analysis (with the five other studies) the results did not change (RR 0.66, 95% CI 0.47 to 0.91) (data not shown). The Axelsson 1970 study was graded as ’unclear’ risk of bias because no information on randomisation, allocation concealment and blinding was given. Lack of information may be related to the way studies were reported 40 years ago but it was not possible to get additional information. The amount of missing data in each of the five studies was balanced between the antibiotic and placebo groups, ranging from 0% to


17

5% by group (actual numbers zero to five per treatment group). In sensitivity analyses assuming missing outcomes as failures or full recoveries/improvements did not significantly affect the result of the meta-analysis: RR 0.68, 95% CI 0.50 to 0.93 and RR 0.67, 95% CI 0.48 to 0.95, respectively (data not shown). The meta-analyses, including sensitivity analyses, slightly favoured antibiotics. However, in the individual six studies the difference between groups in the full recovery or improvement rates was small, being on average 90% (range 83% to 98%) in antibiotic groups and 84% (range 72% to 89%) in placebo groups.

The results of the studies by Hadley 2010 and Garbutt 2012 The results by Hadley 2010 (at ’unclear’ risk of bias) comparing moxifloxacin 400 mg once daily to placebo for five days and (unlike the other placebo-controlled trials) recruiting only patients with isolation of pathogenic bacteria from the sinus secretion, were in line with the results of the individual studies included in the main analysis. Hadley 2010 reported that on day six to eight, clinical cure rates were numerically greater in the moxifloxacin arm (57/73, 78.1%) than the placebo arm (30/45; 66.7%) but this difference was not statistically significant (P = 0.189). Hadley 2010 measured clinical response at days six to eight after the start of therapy while other studies included in the meta-analysis did so at days 10 to 14. The study by Garbutt 2012 (graded as having an ’unclear’ risk of bias) comparing amoxicillin 500 mg three times daily to placebo reported there was no statistically significant difference in symptom improvement at day 10 (78% in amoxicillin group versus 80% in placebo group; P = 0.71). The study was not considered in the main analysis because it remained unclear whether the patients who received rescue therapy were classified as non-improved or not. 2. Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days follow-up Two studies provided data for an antibiotic versus placebo comparison at 16 to 60 days follow-up (Hadley 2010; Haye 1998). Neither of these studies found a significant difference between antibiotic treatment and placebo at this follow-up, Hadley 2010 with a RR value of 0.62 (95% CI 0.37 to 1.03) and Haye 1998 with a RR value of 0.85 (95% CI 0.36 to 1.98) (Analysis 1.2). The study of Haye 1998 was assessed to be at ’low’ risk of bias at this follow-up, and the study of Hadley 2010 at ’unclear’ risk of bias, and thus data from these two studies were not pooled in the meta-analysis. Further, the populations of these studies were very different; Haye 1998 excluded participants with radiographic findings of more than a mild sinusitis and Hadley 2010 included only participants with bacteriologically confirmed sinusitis. At this follow-up, the drop-out rate was 6% in the study of Hadley 2010 and 0% in the study of Haye 1998.

Secondary outcomes

1. Clinical failure defined as a lack of full recovery at 7 to 15 days follow-up Five studies were included in the meta-analysis (Haye 1998; Lindbaek 1996; Lindbaek 1998; Merenstein 2005; van Buchem 1997) and one was used in the sensitivity analysis (Axelsson 1970). These studies found a significant benefit for antibiotics with a RR of 0.73 (95% CI 0.63 to 0.85) (Analysis 1.3). The failure rates were 47% and 61% in the antibiotic and placebo groups, respectively. There was no statistically significant heterogeneity between studies. When including the study by Axelsson 1970 at ’unclear’ risk of bias in the analysis, the results did not change: RR of 0.73 (95% CI 0.63 to 0.85) (data now shown).

2. Clinical failure defined as a lack of full recovery at 16 to 60 days follow-up One study at ’low’ risk of bias provided data for an antibiotic versus placebo comparison at 16 to 60 days follow-up (Haye 1998). The difference failed to reach statistical significance with a RR of 0.63 (95% CI 0.38 to 1.05) (Analysis 1.4). The failure rates were 20.7% and 33% in the antibiotic and placebo groups, respectively.

3. Bacteriological failure None of the studies reported this outcome.

4. Radiographic failure Radiographic outcomes were reported in three studies (Axelsson 1970; Lindbaek 1996; van Buchem 1997) and the results were consistent with the clinical outcomes in the individual studies. In the study by Axelsson 1970, the nasal decongestant group was less improved than the other groups, measured by the mean number of radiological severity points per sinus. In the study by Lindbaek 1996, computer tomography scores improved significantly more for individuals treated with antibiotics. In the study by van Buchem 1997, more participants treated with antibiotics showed radiographic resolution (74% versus 60%).

5. Relapse rate after 60 days Only one study reported long-term relapse rates (van Buchem 1997). During a one-year follow-up, relapse and recurrence rates were not significantly different between antibiotic (21%) and placebo (17%) groups, with a RR of 1.25 (95% CI 0.72 to 2.19) (Analysis 1.5).


18

6. Drop-outs due to adverse effects


Drop-outs due to adverse effects were rare in both groups: 15 out of 1013 (1.5%) in antibiotic groups and 8 out of 805 (1%) in control groups (Analysis 1.6). Three out of the nine placebocontrolled studies reported no drop-outs due to side effects in the antibiotic or control groups.

In comparisons of antibiotic versus antibiotic, we only analyzed data for the primary outcomes measures: clinical failure rate at seven to 15 days follow-up and at 16 to 60 days follow-up (clinical failure defined as a lack of full recovery or improvement) and for two secondary outcome measures: relapse rates and drop-outs due to adverse effects.

7. Quality of life

Cephalosporins and macrolides versus amoxicillin with clavulanate

Two studies (Garbutt 2012; Hadley 2010) documented patient-reported symptom improvements evaluated by the SNOT-16 questionnaire (Sinonasal Outcome Test-16, a validated disease-specific quality of life instrument, where lower scores indicate less severe symptoms (scale from 0 to 3)). The study of Garbutt 2012 reported the results as mean scores (baseline value 1.71 in amoxicillin and 1.70 in placebo group). Similar quality of life in both groups was documented at day three and 10 but a difference at day seven favoured amoxicillin (P = 0.02). The mean change in SNOT-16 scores was at three days: amoxicillin group 0.59 (95% CI 0.47 to 0.71) versus placebo group 0.54 (95% CI 0.41 to 0.67); at seven days 1.06 (95% CI 0.93 to 1.20) versus 0.86 (95% CI 0.71 to 1.02); and at 10 days 1.23 (95% CI 1.08 to 1.37) versus 1.20 (95% CI 1.07 to 1.32), respectively. The study of Hadley 2010 reported the results as SNOT-16 total scores (scale from 0 to 48). Moxifloxacin-treated patients were stated to have experienced a significantly greater mean reduction in total score compared to placebo-treated patients at day six to eight (-17.54 versus -12.83 (P = 0.032) from baseline values of about 28 in both groups).

8. Activity impairment and ability to work Only one study gave information on patients’ ability to work ( Garbutt 2012). The mean period missed from work was stated to be the same, 0.55 days in both groups (amoxicillin and placebo). In addition, two studies provided information on patients’ activity impairment (Garbutt 2012; Hadley 2010). Hadley 2010 stated that from day three moxifloxacin-treated patients experienced a greater improvement in activity impairment than placebo-treated patients evaluated by a five-item questionnaire (scale from 0 (no impairment) to 20 (maximum impairment)). At day six to eight, the mean changes in the scores for activity impairment were: -6.1 (standard deviation (SD) ± 5.9) in the moxifloxacin group and 3.7 (± 5.8) in the placebo group. The study by Garbutt 2012 reported a non-significant difference between the groups in the period of being unable to do usual nonwork activities (mean 1.15 days (95% CI 0.76 to 1.54) in the amoxicillin group and 1.67 days (95% CI 1.08 to 2.26) in the placebo group).

Twenty-one studies compared a cephalosporin or a macrolide (cephalosporin, n = 10; macrolide, n = 11) to amoxicillin-clavulanate. Seventeen studies provided data for meta-analyses; nine studies compared cephalosporin (other than first generation) to amoxicillin-clavulanate and eight studies compared macrolides (azithromycin, clarithromycin, roxithromycin or telithromycin) to amoxicillin-clavulanate. We assessed all the studies to be at ’unclear’ or ’high’ risk of bias regardless of the follow-up time. Six studies, involving 1887 participants, provided data for comparison of cephalosporins to amoxicillin-clavulanate at seven to 15 days follow-up when clinical failure was defined as a lack of full recovery or improvement. These studies found a statistically significant difference for amoxicillin-clavulanate with a RR of 1.37 (95% CI 1.04 to 1.80) (Analysis 2.1). The average failure rate was 12% in the cephalosporin group and 8% in the amoxicillin-clavulanate group. The missing data rates ranged from 2% to 21%, and the missing data rates were approximately equal across the treatment groups in the studies. None of the studies were graded as having ’low’ risk of bias and the two studies having highest weight (70% altogether) in the meta-analysis were graded as having ’high’ risk of bias. Confidence in this finding is limited by the low methodological quality. Seven studies provided data for comparison of cephalosporins to amoxicillin-clavulanate at 16 to 60 days follow-up. These studies did not find any significant difference between the antibiotics, with a RR of 1.08 (95% CI 0.85 to 1.37) (Analysis 2.2). Seven studies, involving 1807 participants, provided data for comparison of macrolides to amoxicillin-clavulanate at seven to 15 days follow-up. These studies failed to reach significant difference between the antibiotics with a risk ratio value of 0.83 (95% CI 0.62 to 1.13) (Analysis 2.4). The missing data rates ranged from 3.4% to 15%. Four studies provided data for comparison of macrolides to amoxicillin-clavulanate at 16 to 60 days follow-up. These studies did not find any significant difference between the antibiotics, with a RR of 0.85 (95% CI 0.57 to 1.27) (Analysis 2.5). None of the studies comparing cephalosporins or macrolides to amoxicillin-clavulanate reported long-term relapse rates after 60 days. Drop-outs due to adverse effects occurred significantly less often in the macrolide group (2.1%) compared to the amoxicillin-clavu-


19

lanate group (4.8%), with a Peto OR of 0.47 (95% CI 0.30 to 0.72) (the macrolide group ranged from 0% to 3.4%; the amoxicillin-clavulanate group ranged from 0% to 10.3%) (Analysis 2.6). Participants dropped out significantly more often also in the amoxicillin-clavulanate group (4.4%) compared to the cephalosporin group (1.3%) with a Peto OR of 0.32 (95% CI 0.21 to 0.49) (in the cephalosporin group range 0% to 2.1%; in the amoxicillinclavulanate group 0% to 11%) (Analysis 2.3).

Non-penicillins versus beta-lactamase sensitive penicillins Eight studies compared a non-penicillin antibiotic (cephalosporins, n = 3; macrolides, n = 3; minocycline, n = 1; folate inhibitor, n = 1) to a penicillin-class antibiotic (amoxicillin, n = 7; penicillin V, n = 1), where n is the number of studies. Seven of the eight studies were classified as having ’unclear’ or ’high’ risk of bias, and one as ’low’ risk of bias (Haye 1996). Because there was only one study at ’low’ risk of bias, we combined the results of all studies in the meta-analyses. Seven of these eight studies (involving 1083 participants) provided data for clinical outcome at 7 to 15 days follow-up and we combined the data from these studies regardless of the antibiotic used. The studies failed to find a significant difference between antibiotics, with a RR of 0.70 (95% CI 0.47 to 1.06) (Analysis 3.1). When excluding the study of Haye 1996(at ’low’ risk of bias) from the analyses, the result of the meta-analysis did not change the conclusions (RR of 0.75, 95% CI 0.48 to 1.17). The missing data rates of these seven studies ranged from 0% to 33%, and the missing data rates were approximately equal across the treatment groups in the studies. One study (Haye 1996) provided data at 16 to 60 days followup and did not find a significant difference between the treatment groups with a risk ratio value of 0.67 (95% CI 0.37 to 1.20) (Analysis 3.2). This study was assessed to be at ’low’ risk of bias also at this second follow-up. None of the studies reported long-term relapse rates after 60 days.

Drop-outs due to adverse effects were infrequent, occurring in 1.3% and 2.3% of the non-penicillin and penicillin-treated groups, respectively (Analysis 3.3). Tetracycline antibiotics versus mixed classes of antibiotics Five studies, involving 807 participants, compared a tetracycline (doxycycline, n = 3; tetracycline, n = 1; minocycline, n = 1) to a heterogenous mix of antibiotics (folate inhibitor, n = 2; cephalosporin, n = 1; macrolide, n = 1; amoxicillin, n = 1). All these studies provided data for clinical failure defined as a lack of full recovery or improvement at 7 to 15 days follow-up, and we combined the data from these studies, despite the antibiotic used. The studies failed to find a significant difference between antibiotics, with a RR of 1.09 (95% CI 0.70 to 1.71) (Analysis 4.1). The missing data rates of these five studies ranged from 0% to 20%, and the missing data rates were approximately equal across the treatment groups in the studies. All the studies in this comparison were graded as ’unclear’ or ’high’ risk of bias. None of the studies reported long-term relapse rates after 60 days. Drop-outs due to adverse effects were infrequent, occurring in 2.6% and 3.5% of the tetracycline and mixed classes of antibiotics groups, respectively (Analysis 4.2). Miscellaneous comparisons Twenty-one studies made the following comparisons: macrolide to fluoroquinolone (n = 5), fluoroquinolone to cephalosporin (n = 4), macrolide to cephalosporin (n = 3), fluoroquinolone to amoxicillin-clavulanate (n = 5), streptogramin to cephalosporin (n = 2) and faropenem to cephalosporin (n = 2). None of these studies reported a statistically significant difference in the clinical outcomes. Comparison of the effect of short versus long courses of antibiotics

We did not perform this comparison because there were no placebo-controlled studies available to undertake it.


20

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Antibiotics compared to other antibiotics for uncomplicated acute maxillary sinusitis Patient or population: patients with uncomplicated acute maxillary sinusitis Settings: primary care Comparisons: non-penicillin antibiotic versus beta-lactamase sensitive penicillins (n = 8), non-tetracycline versus tetracycline (n = 5, of which one study was also included in the comparison of non-penicillin antibiotic versus beta-lactamase sensitive penicillins) , macrolides versus amoxicillin-clavulanate (n = 11), cephalosporins versus amoxicillin-clavulanate (n = 10) and miscellaneous comparisons (n = 21) Outcomes

Impact

No of participants (studies)

Quality of the evidence (GRADE)

Clinical failure rate (fail- No difference in failure 54 studies representing ⊕⊕⊕ ure defined as a lack of rates 10 different comparisons moderate2 1 full recovery or improvement or a lack of full recovery) Follow-ups: 7 to 15 days and 16 to 60 days

Comments

Adverse effects3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Many

of the 54 studies were non-inferiority studies. studies were at ’low’ risk of bias and the other 50 at ’unclear’ or ’high’ risk of bias. 3 Amoxicillin-clavulanate had significantly more drop-outs due to adverse effects than cephalosporins and macrolides. 2 Four

DISCUSSION Summary of main results Antibiotics versus placebo

In this review, the risk of treatment failure (defined as lack of full recovery or improvement) was statistically slightly smaller in antibiotic groups than in placebo groups, at 7 to 15 days in participants with acute sinusitis diagnosed either clinically or by radiography (main analysis, five studies; Summary of findings for the main comparison). However, the clinical benefit was small. The difference between groups in the full recovery or improvement


21

rates was 10% at most in all of the eight studies available for this comparison. The average cure or improvement rate in the antibiotic groups was 87% (range 78% to 98%) and in the placebo groups 81% (range 67% to 89%) (Table 1). On the other hand, stronger statistical significance favouring antibiotics in terms of clinical failure rates, defined as lack of full recovery (at 7 to 15 days; five studies; Summary of findings for the main comparison), might indicate a faster cure rate with antibiotics than without. The average full recovery rate in the antibiotic groups was about 50% (range 30% to 65%) and in the control groups 35% (range 11% to 52%) (all six available studies for this comparison, Table 1). At day 16 to 60 follow-up there was no significant difference between the antibiotic and placebo groups in relieving signs and symptoms regardless of the definition of failure (full recovery or improvement (Hadley 2010; Haye 1998); full recovery (Haye 1998)) (Summary of findings for the main comparison). Although not statistically significant, Haye 1998 reported higher full recovery rates in the antibiotic group (69 out of 87 patients (79%)) than in the placebo group (55 out of 82 of patients (67%)). None of the nine placebo-controlled studies reported severe complications. Even longer follow-up times would be needed to assess the efficacy of antibiotic treatment in the longer term and to assess potential adverse effects. There is some evidence from other respiratory tract infections that the use of antibiotics increases relapse rates and may end up increasing antibiotic consumption (Arason 2005; JokiErkkilä 2000). Therefore, in optimal circumstances, the sinusitis trials should monitor signs, infection rates and drug use over one year. Only one study in this review reported long-term relapse rates (van Buchem 1997) during a one-year follow-up. The relapse and recurrence rates were not significantly different between groups.

Patient perspective on recovery

Quality of life and activity impairment were assessed in two studies (Garbutt 2012; Hadley 2010) (Summary of findings for the main comparison). Both of these studies reported somewhat better quality of life in the antibiotic than in the placebo group at days six to eight. However, the Garbutt 2012 trial documented that quality of life was similar in the antibiotic and placebo groups at day three and day 10 follow-ups. Garbutt 2012 also reported equal mean periods missed from work in the antibiotic and placebo groups (0.55 days) and a non-significant difference in the period where participants were unable to do usual non-work activities (mean 1.15 days in amoxicillin and 1.67 days in the placebo group; P = 0.14). Hadley 2010, on the other hand, reported that from day three to days six to eight, patients in the antibiotic group experienced a greater improvement in activity impairment than patients in the placebo group. The differences in change in mean activity impairment scores were 1 at day three and 2.4 at days six to eight

in favour of the antibiotic group. The significance of the results remains unclear because baseline scores (in the scale 0 to 20) were not reported, and even the five items of the questionnaire were not specified. In both studies it remained unclear whether data for participants who received rescue therapy were included in these results. In this review the primary outcome was failure at 7 to 15 days after the start of the treatment because recovery from acute maxillary sinusitis takes generally more than one week (Gwaltney 2005). However, from the patient’s perspective, fast symptom relief is important and data are also needed on short-term improvement. Six studies (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek 1996; Merenstein 2005) also reported cure or improvement rates prior to one-week follow-up. Three of the six studies reported higher improvement rates for antibiotic than placebo (Hadley 2010: improvement rate 85% versus 73% at day three; Lindbaek 1996: improvement rate 60% versus 36% at day three; Merenstein 2005: the average number of days to entire improvement was consistently two to two and a half days shorter in the antibiotic group among those participants who had entirely improved by day 14). Two of these studies represented patients with a more severe form of disease (Hadley 2010; Lindbaek 1996). The other three studies reported only minor differences between the groups at day three to five (Axelsson 1970: full recovery or improvement rate was 69% in the antibiotic group versus 65% in the placebo group; Garbutt 2012: 37% versus 34%; Haye 1998: 80% versus 79%, respectively). The data do not make it possible to draw strong conclusions on the short-term improvement of patients’ symptoms. Although we found slight statistical significance and potentially faster resolution of symptoms favouring antibiotics, the clinical significance of the result is questionable because of the considerable improvement rate in the placebo group. Also, the possible benefit needs to be weighed against the potential for adverse effects at both the individual and population levels. The results were based on studies of penicillin, amoxicillin, azithromycin and moxifloxacin performed in middle and northern Europe in five studies (Axelsson 1970; Haye 1998; Lindbaek 1996; Lindbaek 1998; van Buchem 1997), in the USA in three studies (Garbutt 2012; Hadley 2010; Merenstein 2005) and one study was multinational (Meltzer 2005). Key information about placebo-controlled studies is collated in Table 1.

Different classes of antibiotics In the study designs comparing different classes of antibiotics, the antibiotics had a similar efficacy to each other (Summary of findings 2). However, at 7 to 15 days follow-up, the risk of clinical failure was statistically significantly lower for amoxicillinclavulanate than for cephalosporins, but the significance of the difference disappeared at longer follow-up.


22

Amoxicillin and penicillin have the advantage of low cost but are often recommended at a three times a day dose, a dosing schedule associated with decreased compliance compared to once or twice daily regimens. A more serious concern is the rising prevalence of beta-lactamase-producing organisms and penicillin and macrolide-resistant pneumococci. In eight studies comparing nonpenicillin antibiotics to a beta-lactamase sensitive penicillin, clinical outcomes were virtually identical. These studies were conducted mostly in the 1990s, four of them in the USA, three in Nordic countries and one in Switzerland. Among the newer, extended-spectrum antibiotics, the long-term efficacy (at 16 to 60 days follow-up) was similar but amoxicillin-clavulanate had significantly more adverse effects than cephalosporins and macrolides. At 7 to 15 days follow-up, however, the risk of clinical failure was statistically significantly lower for amoxicillin-clavulanate than for cephalosporins, but the significance of the difference disappeared at longer follow-up. The studies were conducted in the 1990s and 2000s. None of the antibiotic preparations were superior to each other. Given the similar efficacy, the differences in the adverse effects, costs and risk of promoting bacterial resistance should be considered when choosing antibiotic treatment for acute sinusitis.

Adverse effects In general, adverse effects were more common in the antibiotic than in the placebo groups (median of difference between groups 10.5% in seven of the nine studies, range 2% to 23%) (Table 1). The adverse effects rates of penicillin and amoxicillin differed among the placebo-controlled studies. In the study by Axelsson 1970, the rate for penicillin was 8% (in the control group 6%) and in the study by Lindbaek 1996 59% (in the placebo group 36%). The mean adverse effect rate based on five studies for amoxicillin was 31% (range 16% to 56%), while the corresponding rate for placebo was 22% (9% to 38%) (Garbutt 2012; Lindbaek 1996; Meltzer 2005; Merenstein 2005; van Buchem 1997). The study by Haye 1998 reported 28% adverse effects for azithromycin and 18% for placebo; and the study by Hadley 2010 reported 14% for moxifloxacin and 7% for placebo. The most commonly reported adverse effects in antibiotic groups were: gastrointestinal problems (for example, diarrhea, abdominal pain, vomiting) and skin rash. However, drop-outs due to adverse effects were rare (1.5%) for penicillin, amoxicillin, azithromycin and moxifloxacin in the placebo-controlled studies. In the antibiotic versus antibiotic comparisons, the drop-out rates due to adverse effects were significantly different only in the comparisons of amoxicillin-clavulanate versus macrolides (Analysis 2.6) and cephalosporins (Analysis 2.3). There were 17 studies comparing amoxicillin-clavulanate to macrolides or cephalosporins. The drop-out rate due to adverse effects varied from 0% to 11% in the amoxicillin-clavulanate groups (median 3.4% in 17 studies), and from 0% to 3.4% in macrolide and cephalosporin groups

(medians 2% in eight studies and 1.4% in nine studies, respectively). One problem in the sinusitis trials is that standardised information on side effects is available in fewer than half of the cases (Ioannidis 2002). It may be that the true rate of side effects equals or even exceeds the marginal benefits of the treatments. On the other hand, both severe adverse effects and severe complications (for example, anaphylaxis and meningitis) are such rare events that they are seldom manifested in randomised controlled trials with limited numbers of patients.

Overall completeness and applicability of evidence

Setting and diagnostic methods This review is restricted to adults. This is because sinusitis in children differs from that in adults, for example regarding anatomy, diagnosis, epidemiology and microbiology (Hsin 2010). Newborns have maxillary sinuses the size of a bean. The sinuses start to widen at the age of three or four, the development takes a long time and only by the age of 15 to 18 is the anatomy of the sinuses fully developed (Lawson 2008). It is difficult to find figures, but a common expert opinion is that although purulent nasal discharge is a common symptom in children, sinusitis appears to be more rare than among adults and often chronic, concentrating in special groups like asthmatic and immunocompromised children and those with cystic fibrosis (Wu 2009). On the other hand, complications of acute sinusitis appear to be about three times more common among children than adults (Hansen 2012) and these develop during the first days of acute respiratory infection (Kristo 2009). Because sinusitis in children seems to be quite different in many aspects compared to that in adults, we chose to limit our review to studies of adults. As the role of radiographs in diagnosing acute sinusitis is controversial, we decided also to include trials that included participants based on clinical criteria only. The diagnosis of acute maxillary sinusitis was based solely on clinical diagnosis in four studies (Garbutt 2012; Haye 1998; Meltzer 2005; Merenstein 2005), confirmed by radiograph in three studies (Axelsson 1970; Hadley 2010; van Buchem 1997) and confirmed by computer tomography (CT) scan in two studies (Lindbaek 1996; Lindbaek 1998). Haye 1998 used X-rays to exclude patients who had evidence of empyema. The studies with radiographic confirmation of diagnosis accepted participants with air-fluid level or opacification (Axelsson 1970; Hadley 2010) and van Buchem 1997 also those with more than 5 mm mucosal thickening. In the study by Lindbaek 1996 the acute maxillary sinusitis was confirmed by a CT scan showing opacity or air-fluid level. Lindbaek 1998 included only patients with mucosal thickening in a CT scan.


23

Three studies reported that bacteriological samples were taken. Hadley 2010 included only culture-positive patients with specified target pathogens in the analyses. Lindbaek 1996 reported that in 58% of participants bacteriological specimens obtained from the nasopharynx grew bacteria connected with sinusitis. Haye 1996 reported that only in some samples taken from the posterior part of the nasal cavity was growth of pathogenic bacteria obtained. On the whole, the proportion of participants with true bacterial sinusitis remained unclear in seven out of the nine placebo-controlled studies, as is the case in real clinical practice. Participants in seven of the nine studies were clearly recruited from community-based general practices, where these kinds of patients are frequently treated. Thus the results in this review are valid in adult patients in general practice settings.

to background factors that have an effect on recovery. Therefore, studies with acute exacerbations of chronic sinusitis were included only if they reported separately data on the subgroup with acute sinusitis, or if not reported separately at least 80% of participants had acute sinusitis. Different classes of antibiotics We combined data from all placebo-controlled studies, regardless of the type of antibiotic used. We anticipated that there would be only some placebo-controlled studies available for the analyses, and the main interest would be whether antibiotic treatment in general is beneficial. We presumed that researchers in different countries had local reasons for selecting particular antibiotics for their trials, for example taking into account local resistance rates to antibiotics among community-acquired pathogens.

Strengths and weaknesses of diagnostic options The diagnosis of acute sinusitis is challenging in primary care, especially when trying to differentiate between a viral or bacterial origin of disease. The high proportion of participants that improved in the non-antibiotic group indicates that only some of the participants defined (by these criteria) as having acute sinusitis benefit from antibiotic treatment. Clinical examination is sensitive in ruling out sinusitis (Williams 1993) but not in identifying bacterial disease. Specific methods would be needed to find the subgroups of patients that might benefit from antibiotics. Some official opinions support the practice of diagnosing acute maxillary sinusitis by clinical examination. For example, the expert panel of five national societies in the USA has stated that sinusitis can be diagnosed, in the majority of patients, by using only the history and physical examination (Meltzer 2004). In the referral guideline for imaging of the European Commission, radiograph is not indicated as a routine diagnostic method (ECRP 2000). Further, it states that thickened mucosa is a non-specific finding and may occur in asymptomatic patients. CT scan has a role in cases of treatment failure with suspicion of complications or malignancy or when surgery is considered (ECRP 2000; Meltzer 2004). In Nordic countries, the diagnosis of sinusitis is often confirmed by means of an ultrasound device that is suitable for primary care but its use requires training and experience. Sinusitis can be ruled out in patients with no fluid retention in sinuses with this method, so it may reduce the use of antibiotics (Puhakka 2000; Varonen 2003b).

Duration of signs and symptoms Bacterial sinusitis is more likely if the signs and symptoms have lasted at least seven days (Meltzer 2004) and therefore studies with shorter illness duration, without confirmed diagnosis by radiograph or culture, were excluded. Acute exacerbations of chronic sinusitis were considered as part of the chronic form of the disease, which is a separate and more complicated entity, often related

Duration of treatment One of our aims was to evaluate the effect of short and long courses of antibiotics. Our view is that, for this purpose, antibiotic versus antibiotic study designs without a non-antibiotic group are not valid enough. Unfortunately, there were no placebo-controlled studies available to undertake this comparison. Antibiotics also have side effects; therefore more placebo-controlled trials are needed to find the optimal duration of treatment and those subgroups that might benefit from the treatment. The same applies to other respiratory tract infections in primary health care.

Quality of the evidence

Antibiotics versus placebo The body of evidence comparing antibiotics with placebo at one to two weeks comprised five randomised studies. When a failure was defined as a lack of full recovery or improvement (the main analysis), we assessed the body of evidence as being of moderate quality according to the GRADE assessment criteria (Summary of findings for the main comparison). This implies that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. The pooled estimate of the five studies slightly favoured antibiotics with a RR of 0.66 (95% CI 0.47 to 0.94). Because the effect size seems to be small and the number of evaluated participants so far is 1058, it is not unreasonable, however, to anticipate that a new large study could change this estimate. When a failure was defined as a lack of full recovery, we assessed the body of evidence as being of high quality according to the GRADE assessment criteria (the RR for failure was 0.73 (95% CI 0.63 to 0.85). This implies that further research is very unlikely to change our confidence in the estimate of effect.


24

The body of evidence comparing antibiotics with a placebo at two to nine weeks comprised only one randomised study which was assessed as being of low quality according to the GRADE assessment criteria (Summary of findings for the main comparison). This implies that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. The RR for failure was 0.85 (95% CI 0.36 to 1.98) when a failure was defined as a lack full recovery or improvement, and 0.63 (95% CI 0.38 to 1.05) when a failure was defined as a lack of full recovery.

2010 compared to the other studies. The study of Lindbaek 1996 differed in only accepting participants with opacity or fluid-level in the sinuses, not with mucosal thickening alone, by using CT scan. The study also reported pathogenic bacteria connected with acute sinusitis in 58% of participants. The study of Hadley 2010, which was not included in the meta-analyses, differed by including only patients with isolation of pathogenic bacteria from the sinus secretion. It is obvious that the participants selected for these two studies represented people with a more severe form of the disease. Definition of cure

Antibiotics versus antibiotics We assessed the quality of the body of evidence for comparing one class of antibiotic against another as being of moderate quality according to the GRADE assessment criteria (Summary of findings 2). Although the number of the studies was large (54 studies) most of them were non-inferiority studies and often supported by pharmaceutical companies. Because most patients with sinusitis will improve without antibiotics and the margin of getting added clinical benefit from antibiotics on the whole, compared to placebo, is small (about 10%), it is easy to show non-inferiority between antibiotics. There were 54 studies comparing an antibiotic to another antibiotic. In general, we assessed the methodological quality of the studies to be modest, mostly due to incomplete blinding and/or incomplete reporting of other methodological issues, especially of randomisation (Figure 1; Figure 2). We graded only four of the 54 studies as having ’low’ risk of bias based on the methodological criteria used in this review, and graded the other 50 as ’unclear’ or ’high’ risk of bias. In the only comparison in this review where a slight statistical difference was found between antibiotics, we graded none of the studies as having ’low’ risk of bias and the two studies having highest weight (70% altogether) in the metaanalysis also had a ’high’ risk of bias. This comparison was for cephalosporins versus amoxicillin-clavulanate at seven to 15 days follow-up with clinical failure defined as a lack of full recovery or improvement (Analysis 2.1). Confidence in this finding is limited by the low methodological quality and the disappearance of significance at longer follow-up.

Potential biases in the review process

Diagnosis We expected that the diagnostic method in an individual placebocontrolled study (clinical diagnosis alone versus radiological/bacteriological confirmation) might have had an influence on the results. In the meta-analyses, however, no statistically significant heterogeneity between individual study results was observed. Clinical diversity was plausible in the studies of Lindbaek 1996 and Hadley

The definitions of full recovery, improvement and failure in individual studies can influence the data extraction and the results, both at study and meta-analysis level, especially in cases where only a few studies are available for analysis. In studies with a dichotomous classification of the outcomes, the criteria can vary between studies, as well as compared to studies with multi-level classifications. In this review, four of the nine placebo-controlled studies reported success dichotomously. The highest number of categories was used in the studies by Lindbaek 1996 and Lindbaek 1998. The outcomes were classified into five categories: restored, much better, somewhat better, unimproved and worse. Two other studies reported outcomes in three categories and one in four categories. Dichotomising different outcome classifications for the analyses causes uncertainty in the results.

Agreements and disagreements with other studies or reviews Three other recent systematic reviews have considered comparison of antibiotics with placebo for acute maxillary sinusitis. These reviews have used more permissive eligibility criteria than our review and would therefore include a more heterogeneous sample of individuals with and without acute bacterial rhinosinusitis. Overall, these reviews found similar antibiotic treatment effects, despite differing eligibility criteria. The study by Rosenfeld 2007 found that antimicrobials, compared to placebo control, increased clinical improvement rates at two weeks for 800 patients by an absolute difference of 7% (95% CI 2 to 13%). Diarrhoea (1583 patients, risk difference (RD) of 0.05 (95% CI 0.01 to 0.09)) and any adverse events (1853 patients, RD of 0.11 (95% CI 0.05 to 0.16)) were more common in the group treated with antimicrobials. A patient-level meta-analysis (Young 2008) of 10 placebo-controlled trials involving 2640 patients specifically excluded trials that enrolled patients on the basis of laboratory, imaging or bacterial culture results. This study found a small increase in clinical cures with antibiotics within two weeks (OR of 1.35, 95% CI 1.15 to 1.59) and a number needed to treat to benefit (NNTB) of 15 (95% CI 7 to infinity). The authors conclude that “common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom antibiotic treatment is


25

clearly justified, not even if a patient reports symptoms for longer than 7 to 10 days”. In the third meta-analysis by Falagas 2008a, including 16 randomised, double-blind trials with 2648 patients, antibiotics were associated with a higher rate of cure or improvement within two weeks (OR 1.64, 95% CI 1.35 to 2.00) but with more adverse effects (12 trials with 1963 patients, OR 1.87 (95% CI 1.21 to 2.90)). The authors conclude that “use of antibiotics for acute sinusitis confers a small therapeutic benefit over placebo with a raise in risk of adverse effects, and that antibiotics should be reserved for carefully selected patients with a higher probability for bacterial disease”. Another review by Falagas 2008b evaluated the effects of short (up to seven days) versus longer-course (at least two days longer than short-course) antibiotic treatment for acute rhinosinusitis. Twelve trials compared the same antibiotic for varying durations. Rates of clinical success did not vary significantly for short- versus longer-term treatment (OR 0.95, 95% CI 0.81 to 1.12). Our review did not include studies comparing different durations of the same antibiotic because there were no placebo-controlled studies measuring this.

AUTHORS’ CONCLUSIONS

both individual and general population level (for example, local bacterial resistance).

Implications for research Given the small number of trials, additional high-quality, placebocontrolled trials are needed to identify the potential subgroups of sinusitis patients that may benefit from antibiotics. Diagnosis should be made on prespecified recommended clinical criteria which also allow subgroup analyses according to severity of the disease. The benefit of adding a nasopharyngeal swab in the diagnosis of patients with sufficient clinical criteria is also unclear. The data in this review did not allow such subgroup analyses. Special attention should be paid to identifying the prognostic factors of sinusitis and finding factors that potentially modify the treatment effect, such as co-morbid conditions (for example, asthma, allergies), lifestyle and other individual factors (for example, smoking). Effects on functional status, work performance and quality of life may provide important additional information. The trials should be double-blinded, with adequate allocation and concealment procedures, and should report clinical outcomes and time to clinical response. Large trials may be needed to identify clinical predictors of the need for antibiotics. Different treatment durations should also be studied in placebo-controlled settings.

Implications for practice Antibiotics have a small benefit for clinical outcomes in patients with symptoms of uncomplicated acute sinusitis lasting for more than seven days in a primary care setting. However, about 80% of patients treated with a placebo also improve within two weeks. The patients in the placebo-controlled studies were enrolled from unselected primary care populations (except perhaps Axelsson 1970; Meltzer 2005). The individual studies represented clinical conditions ranging from mild to more severe, depending on the inclusion criteria, as in a real general practice setting. All but one of the placebo-controlled studies favoured antibiotics to some extent. We see that the overall result of the meta-analysis for the main outcome corresponds fairly well to the mixture of patients in primary care. However, compared to situations where no imaging is used, the benefit of antibiotics may be somewhat overestimated. It seems that even when special effort is put into selecting patients from primary care settings who most probably have bacterial sinusitis, the actual benefit of antibiotics is modest. It is obvious that there are individual patients who benefit from antibiotics but we do not have proper means to identify them in primary care settings. Clinicians and people responsible for producing guidelines need to weigh the moderate benefits of antibiotic treatment against the patient’s general condition and the potential for adverse effects at

ACKNOWLEDGEMENTS We would like to thank the Cochrane Acute Respiratory Infections Group’s Trials Search Co-ordinator Sarah Thorning for help in searching the literature and the Managing Editor, Elizabeth Dooley, for all her help. We warmly thank Information Specialist Jaana Isojärvi at National Institute for Health and Welfare/THL, Finland for her help in the supplementary search of the literature. We would also like to thank Johannes Hang Guo, Ryuki Kassai, Sachiyo Yoshida, Jaana Elberkennou, Tiina Lehmussaari and Helena Laasonen for translating trial reports published in Chinese, Japanese, French, Spanish and Portuguese. We are also grateful to Systems Manager Marko Ekqvist, English Language Editor Mark Phillips, and MSC Niina Kovanen for their inputs in the previous version of this review. We would also like to thank Dr An de Sutter, Dr Jane M. Garbutt, Dr Morten Lindbaek, Dr Eli O. Meltzer, Dr Dan Merenstein and Dr Ian G Williamson for providing additional information about their trials, and Schering-Plough Research Institute for providing information on their unpublished study. We are grateful to Bruce Arroll, Sree Nair, Dilip Raghavan and Meenu Singh for valuable referee comments in previous versions, and to Bruce Arroll, Abimbola Farinde, José Luis Ferrero Albert, Terry Neeman and Devada Singh-Franco in the current version.


26

REFERENCES

References to studies included in this review Adelglass 1998a {published data only} Adelglass J, Jones TM, Ruoff G, Kahn JB, Wiesinger BA, Rielly-Gauvin K, et al.A multicenter, investigator-blinded, randomized comparison of oral levofloxacin and oral clarithromycin in the treatment of acute bacterial sinusitis. Pharmacotherapy 1998;18(6):1255–63. Adelglass 1998b {published data only} Adelglass J, Bundy JM, Woods R. Efficacy and tolerability of cefprozil versus amoxicillin/clavulanate for the treatment of adults with severe sinusitis. Clinical Therapeutics 1998; 20(6):1115–29. [MEDLINE: 99113644] Adelglass 1999 {published data only} Adelglass J, DeAbate A, McElvaine P, Fowler CL, LoCocco J, Campbell T. Comparison of the effectiveness of levofloxacin and amoxicillin-clavulanate for the treatment of acute sinusitis in adults. Otolaryngology - Head and Neck Surgery 1999;120:320–7. Arndt 1994 {published data only} Arndt J, Riebenfeld D, Maier H, Weidauer H. Therapeutic efficacy and tolerability of brodimoprim in comparison with doxycycline in acute sinusitis in adults. Journal of Chemotherapy 1994;6(5):322–7. [MEDLINE: 95165185] Arrieta 2007 {published data only} Arrieta JR, Galgano AS, Sakano E, Fonseca X, AmabileCuevas CF, Hernandez-Oliva G, et al.Moxifloxacin vs amoxicillin/clavulanate in the treatment of acute sinusitis. American Journal of Otolaryngology 2007;28(2):78–82. Axelsson 1970 {published data only} Axelsson A, Chidekel N, Grebelius N, Jensen C. Treatment of acute maxillary sinusitis. A comparison of four different methods. Acta Otolaryngologica (Stockholm) 1970;70(1): 71–6. [MEDLINE: 70286389] Boezeman 1988 {published data only} Boezeman AJ, Kayser AM, Siemelink RJ. Comparison of spiramycin and doxycycline in the empirical treatment of acute sinusitis: preliminary results. Journal of Antimicrobial Chemotherapy 1988;22(Suppl B):165–70. [MEDLINE: 89033421] Buchanan 2003 {published data only} Buchanan PP, Stephens TA, Leroy B. A comparison of the efficacy of telithromycin versus cefuroxime axetil in the treatment of acute bacterial maxillary sinusitis. American Journal of Rhinology 2003;17(6):369–77.

maxillary sinusitis. Archives of Family Medicine 1993;2(8): 837–40. [MEDLINE: 94154893] Camacho 1992 {published data only} Camacho AE, Cobo R, Otte J, Spector SL, Lerner CJ, Garrison NA, et al.Clinical comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of patients with acute bacterial maxillary sinusitis. American Journal of Medicine 1992;93(3):271–6. [MEDLINE: 92397909] Chatzimanolis 1998 {published data only} Chatzimanolis E, Marsan N, Lefatzis D, Pavlopoulos A. Comparison of roxithromycin with co-amoxiclav in patients with sinusitis. Journal of Antimicrobial Chemotherapy 1998; 41(Suppl B):81–4. [MEDLINE: 98239321] Clement 1998 {published data only} Clement PA, de Gandt JB. A comparison of the efficacy, tolerability and safety of azithromycin and co-amoxiclav in the treatment of sinusitis in adults. Journal of International Medical Research 1998;26(2):66–75. [MEDLINE: 98265694] Clifford 1999 {published data only} Clifford K, Huck W, Shan M, Tosiello R, Echols RM, Heyd A. Double-blind comparative trial of ciprofloxacin versus clarithromycin in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group. Annals of Otology, Rhinology and Laryngology 1999;108(4):360–7. [MEDLINE: 99229596] Desrosiers 2008 {published data only} Desrosiers M, Ferguson B, Klossek JM, Drugeon H, Mösges R. Clinical efficacy and time to symptom resolution of 5day telithromycin versus 10-day amoxicillin-clavulanate in the treatment of acute bacterial sinusitis. Current Medical Research and Opinion 2008;24(6):1691–702. Dubois 1993 {published data only} Dubois J, Saint-Pierre C, Tremblay C. Efficacy of clarithromycin vs. amoxicillin/clavulanate in the treatment of acute maxillary sinusitis. Ear, Nose and Throat Journal 1993;72(12):804–10. [MEDLINE: 94147948] Ferguson 2004 {published data only} Ferguson BJ, Guzzetta RV, Spector SL, Hadley JA. Efficacy and safety of oral telithromycin once daily for 5 days versus moxifloxacin once daily for 10 days in the treatment of acute bacterial rhinosinusitis. Otolaryngology - Head and Neck Surgery 2004;131:207–14.

Burke 1999 {published data only} Burke T, Villanueva C, Mariano H, Huck W, Orchard D, Haverstock D, et al.Comparison of moxifloxacin and cefuroxime axetil in the treatment of acute maxillary sinusitis. Clinical Therapeutics 1999;21(10):1664–77. [MEDLINE: 20030839]

Garbutt 2012 {published and unpublished data} Garbutt J, Spitznagel E, Piccirillo J. Use of the modified SNOT-16 in primary care patients with clinically diagnosed acute rhinosinusitis. Archives of Otolaryngology - Head and Neck Surgery 2011;137(8):792–7. ∗ Garbutt JM, Banister C, Spitznagel E, Piccirillo JF. Amoxicillin for acute rhinosinusitis: A randomized controlled trial. JAMA 2012;307(7):685–92.

Calhoun 1993 {published data only} Calhoun KH, Hokanson JA. Multicenter comparison of clarithromycin and amoxicillin in the treatment of acute

Gehanno 1996a {published data only} Gehanno P, Barry B, Chauvin JP, Hazebroucq J. Clarithromycin versus amoxicillin/clavulanic acid in acute


27

maxillary sinusitis in adults [Clarithromycine versus amoxicilline acide–clavulanique dans le traitement de la sinusite maxillaire aigue de l’adulte]. Pathologie Biologie (Paris) 1996;44(4):293–7. [MEDLINE: 96306077] Gehanno 1996b {published data only} Gehanno P, Berche P, Sinusitis Study Group. Sparfloxacin versus cefuroxime axetil in the treatment of acute purulent sinusitis. Journal of Antimicrobial Chemotherapy 1996;37 (Suppl A):105–14. Gehanno 1998 {published data only} Gehanno P, Pessey JJ, Beauvillain De Montreuil C, Dubreuil C, Levy D, Berche P, et al.Cefatrizine versus amoxicillinclavulanate in acute maxillary sinusitis in adults [Etude comparative de la cefatrizine et de l’amoxicilline–acide clavulanique dans le traitement des sinusites maxillaires aigues de l’acute]. Médecine et Maladies Infectieuses 1998; 28:208–15. Gehanno 2004 {published data only} Gehanno P, Berche P, Hercot O, d’ Arras L, CabrillacRives S, Derobert E, et al.Efficiency of a four-day course of pristinamycin compared to a five-day course of cefuroxime axetil for acute bacterial maxillary sinusitis in adult outpatients [Efficacite comparee de la pristinamycine en quatre jours et du cefuroxime axetil en cinq jours dans le traitement des sinusites maxillaires aigues bacteriennes de l’adulte]. Medecine et Maladies Infectieuses 2004;34: 293–302. Gwaltney 1997 {published data only} Gwaltney JM Jr, Savolainen S, Rivas P, Schenk P, Scheld WM, Sydnor A, et al.Comparative effectiveness and safety of cefdinir and amoxicillin-clavulanate in treatment of acute community-acquired bacterial sinusitis. Cefdinir Sinusitis Study Group. Antimicrobial Agents and Chemotherapy 1997; 41(7):1517–20. [MEDLINE: 97354383] Hadley 2010 {published data only} Hadley JA, Mösges R, Desrosiers M, Haverstock D, van Veenhuyzen D, Herman-Gnjidic Z. Moxifloxacin five-day therapy versus placebo in acute bacterial rhinosinusitis. Laryngoscope 2010;120(5):1057–62. Haye 1996 {published data only} Haye R, Lingaas E, Hoivik HO, Odegård T. Efficacy and safety of azithromycin versus phenoxymethylpenicillin in the treatment of acute maxillary sinusitis. European Journal of Clinical Microbiology and Infectious Diseases 1996;15(11): 849–53. [MEDLINE: 97151573] Haye 1998 {published data only} Haye R, Lingaas E, Hoivik HO, Odegård T. Azithromycin versus placebo in acute infectious rhinitis with clinical symptoms but without radiological signs of maxillary sinusitis. European Journal of Clinical Microbiology and Infectious Diseases 1998;17:309–12. Henry 2003 {published data only} Henry DC, Riffer E, Sokol WN, Chaudry NI, Swanson RN. Randomized double-blind study comparing 3- and 6day regimens of azithromycin with a 10-day amoxicillin-

clavulanate regimen for treatment of acute bacterial sinusitis. Antimicrobial Agents and Chemotherapy 2003;47(9):2770–4. Henry 2004 {published data only} Henry DC, Kapral D, Busman TA, Paris MM. Cefdinir versus levofloxacin in patients with acute rhinosinusitis of presumed bacterial etiology: a multicenter, randomized, double-blind study. Clinical Therapeutics 2004;26(12): 2026–33. Huck 1993 {published data only} Huck W, Reed BD, Nielsen RW, Ferguson RT, Gray DW, Lund GK, et al.Cefaclor vs amoxicillin in the treatment of acute, recurrent, and chronic sinusitis. Archives of Family Medicine 1993;2(5):497–503. [MEDLINE: 94163345] Jareoncharsri 2004 {published data only} Jareoncharsri P, Bunnag C, Fooanant S, Tunsuriyawong P, Voraprayoon S, Srifuengfung S, et al.An open label, randomized comparative study of levofloxacin and amoxicillin/clavulanic acid in the treatment of purulent sinusitis in adult Thai patients. Rhinology 2004;42(1):23–9. Karma 1991 {published data only} Karma P, Pukander J, Penttilä M, Ylikoski J, Savolainen S, Olen L, et al.The comparative efficacy and safety of clarithromycin and amoxycillin in the treatment of outpatients with acute maxillary sinusitis. Journal of Antimicrobial Chemotherapy 1991;27(Suppl A):83–90. [MEDLINE: 91216883] Klapan 1999 {published data only} Klapan I, Culig J, Oreskovic K, Matrapazovski M, Radosevic S. Azithromycin versus amoxicillin/clavulanate in the treatment of acute sinusitis. American Journal of Otolaryngology 1999;20(1):7–11. [MEDLINE: 99133606] Lari 2010 {published data only} Lari AR, Ghaffariyeh A, Etesam N, Mostafavi H, Alaghehbandan R. A randomized controlled trial of 5day regimen of azithromycin and a 10-day regimen of coamoxiclav for treatment of acute sinusitis. Iranian Journal of Clinical Infectious Diseases 2010;5(3):137–41. Lasko 1998 {published data only} Lasko B, Lau CY, Saint-Pierre C, Reddington JL, Martel A, Anstey RJ. Efficacy and safety of oral levofloxacin compared with clarithromycin in the treatment of acute sinusitis in adults: a multicentre, double-blind, randomized study. The Canadian Sinusitis Study Group. Journal of International Medical Research 1998;26(6):281–91. [MEDLINE: 99327309] Lindbaek 1996 {published and unpublished data} Lindbaek M, Hjortdahl P, Johnsen UL. Randomised, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313(7053):325–9. [MEDLINE: 96343743] Lindbaek 1998 {published and unpublished data} Lindbaek M, Kaastad E, Dolvik S, Johnsen U, Laerum E, Hjortdahl P. Antibiotic treatment of patients with mucosal thickening in the paranasal sinuses, and validation of cutoff points in sinus CT. Rhinology 1998;36:7–11.


28

Luterman 2003 {published data only} Luterman M, Tellier G, Lasko B, Leroy B. Efficacy and tolerability of telithromycin for 5 or 10 days vs amoxicillin/ clavulanic acid for 10 days in acute maxillary sinusitis. Ear, Nose & Throat Journal 2003;82(8):576-80, 582-4, 586 passim. Marple 2010 {published data only} Marple BF, Roberts CS, Frytak JR, Schabert VF, Wegner JC, Bhattacharyya H, et al.Azithromycin extended release vs amoxicillin/clavulanate: symptom resolution in acute sinusitis. American Journal of Otolaryngology - Head and Neck Medicine and Surgery 2010;31(1):1–8. Matthews 1997 {published data only} Matthews BL, Suprax/Amoxicillin Clinical Sinusitis Study Team. Effectiveness and safety of cefixime and amoxicillin in adults with acute bacterial sinusitis. Managing Sinusitis: A Postgraduate Medicine Special Report 1997:41–9. Mattucci 1986 {published data only} Mattucci KF, Levin WJ, Habib MA. Acute bacterial sinusitis. Minocycline vs amoxicillin. Archives of Otolaryngology Head and Neck Surgery 1986;112(1):73–6. [MEDLINE: 86076561] Meltzer 2005 {published and unpublished data} ∗ Meltzer EO, Bachert C, Staudinger H. Treating acute rhinosinusitis: comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, and placebo. Journal of Allergy and Clinical Immunology 2005;116:1289–95. Meltzer EO, Gates D, Bachert C. Mometasone furoate nasal spray increases the number of minimal-symptom days in patients with acute rhinosinusitis. Annals of Allergy, Asthma & Immunology 2012;108:275–9. Merenstein 2005 {published and unpublished data} Merenstein D, Whittaker C, Chadwell T, Wegner B, D’Amico F. Are antibiotics beneficial for patients with sinusitis complaints? A randomized double-blind clinical trial. Journal of Family Practice 2005;54(2):144–51. Murray 2005 {published data only} Murray JJ, Emparanza P, Lesinskas E, Tawadrous M, Breen JD. Efficacy and safety of a novel, single-dose azithromycin microsphere formulation versus 10 days of levofloxacin for the treatment of acute bacterial sinusitis in adults. Otolaryngology - Head and Neck Surgery 2005;133:194–201. Nyffenegger 1991 {published data only} Nyffenegger R, Riebenfeld D, Macciocchi A. Brodimoprim versus amoxicillin in the treatment of acute sinusitis. Clinical Therapeutics 1991;13(5):589–95. [MEDLINE: 92191253] O’Doherty 1996 {published data only} O’Doherty B. An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections. Journal of Antimicrobial Chemotherapy 1996;37(Suppl C):71–81. [MEDLINE: 96415941] Olmo 1994 {published data only} Olmo A, Sabater F, Broto J, Traserra J. Amoxicillin/ clavulanic acid versus cefuroxime axetil in acute sinusitis

[Amoxicilina–acido clavulanico y axetilo de cefuroxima en el tratamiento de la sinusitis aguda. Evaluacion clinica, radiologica y bacteriologica]. Acta Otorrinolaringologica Espanola 1994;45(1):25–9. [MEDLINE: 94263593] Otte 1983 {published data only} Otte J, Viada JA, Buchi MD, Salgado O. Tratamiento de los procesos sinusales agudos del adulto con tetraciclina y una combinacion de sulfametopirazona-trimetoprim. Revista Medica de Chile 1983;111(11):1157–61. [MEDLINE: 84273842] Pessey 1996 {published data only} Pessey JJ, Dubreuil C, Gehanno P, Artaz MA, Scheimberg A. Four days cefixime, 10 days cefixime, or 10 days amoxicillin-clavulanate, for the treatment of acute sinusitis in adults [Efficacite et tolerance du cefuxime en traitement de 4 jour ou de 10 jours versus 10 jours d’amoxicilline–acide clavulanique dans les sinusites aigues de l’adulte]. Medecine et Maladies Infectieuses 1996;26(10):839–45. Pessey 2001 {published data only} Pessey JJ. Pristinamycin in the outpatient treatment of acute sinusitis in adults [Place de la pristinamycine dans le traitement des sinusites aigues de l’adulte en ville]. Presse Medicale 1999;28(Suppl 1):10–2. [MEDLINE: 99436765] ∗ Pessey JJ, Gehanno P, Dabernat H. Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis in adults. Medicine et Maladies Infectieuses 2001;31(6):425–32. Rakkar 2001 {published data only} Rakkar S, Roberts K, Towe BF, Flores SM, Heyd A, Warner J. Moxifloxacin versus amoxycillin clavulanate in the treatment of acute maxillary sinusitis: a primary care experience. International Journal of Clinical Practice 2001; 55(5):309–15. Riffer 2005 {published data only} Riffer E, Spiller J, Palmer R, Shortridge V, Busman TA, Valdes J. Once daily clarithromycin extended-release vs twice-daily amoxicillin/clavulanate in patients with acute bacterial sinusitis: a randomized, investigator-blinded study. Current Medical Research and Opinion 2005;21(1):61–70. Russell 1997 {published data only} Russell MD, Nolen T, Allen JM, Skuba K, De Regis RG, Nicaise C. Cefprozil versus amoxicillin/clavulanate in the treatment of acute, uncomplicated maxillary sinusitis in adults. A randomized, prospective clinical trial. Infections in Medicine 1997;14(Suppl):43–50. [MEDLINE: 1998004027] Sher 2002 {published data only} Sher LD, McAdoo MA, Bettis RB, Turner MA, Li NF, Pierce PF. A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day amoxicillin/ clavulanate in patients with acute bacterial sinusitis. Clinical Therapeutics 2002;24(2):269–81. Siegert 2000 {published data only} Siegert R, Gehanno P, Nikolaidis P, Bagger-Sjöbäck D, Ibanez JM, Hampel B, et al.A comparison of the safety and efficacy of moxifloxacin (BAY 12-8039) and cefuroxime


29

axetil in the treatment of acute bacterial sinusitis in adults. Respiratory Medicine 2000;94:337–44. [MEDLINE: 20302041] Siegert 2003 {published data only} Siegert R, Berg O, Gehanno P, Leiberman A, Martinkenas JL, Nikolaidis P, et al.Comparison of the efficacy and safety of faropenem daloxate and cefuroxime axetil for the treatment of acute bacterial maxillary sinusitis in adults. European Archives of Oto-Rhino-Laryngology 2003;260(4): 186–94. SSG 1993 {published data only} Scandinavian Study Group. Loracarbef versus doxycycline in the treatment of acute bacterial maxillary sinusitis. Journal of Antimicrobial Chemotherapy 1993;31(6):949–61. [MEDLINE: 93366716] Stefansson 1998 {published data only} Stefansson P, Jacovides A, Jablonicky P, Sedani S, Staley H. Cefuroxime axetil versus clarithromycin in the treatment of acute maxillary sinusitis. Rhinology 1998;36(4):173–8. [MEDLINE: 99121815] Sterkers 1997 {published data only} Sterkers O. Efficacy and tolerability of ceftibuten versus amoxicillin/clavulanate in the treatment of acute sinusitis. Chemotherapy 1997;43(5):352–7. [MEDLINE: 97454963] Steurer 2000 {published data only} Steurer M, Schenk P. Efficacy and safety of cefdinir in the treatment of maxillary sinusitis. European Archives of Otorhinolaryngology 2000;257:140–8. [MEDLINE: 20296297] Sydnor 1992 {published data only} Nielsen RW. Acute bacterial maxillary sinusitis: results of U.S. and European comparative therapy trials [review]. American Journal of Medicine 1992;92(Suppl 6A):70–3. [MEDLINE: 92321191] ∗ Sydnor TA Jr, Scheld WM, Gwaltney J Jr, Nielsen RW, Huck W, Therasse DG. Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis. Ear, Nose and Throat Journal 1992;71(5):225–32. [MEDLINE: 92371213] Upchurch 2006 {published data only} Upchurch J, Rosemore M, Tosiello R, Kowalsky S, Echols R. Randomized double-blind study comparing 7- and 10-day regimens of faropenem medoxomil with a 10-day cefuroxime axetil regimen for treatment of acute bacterial sinusitis. Otolaryngology - Head and Neck Surgery 2006;135 (4):511–7. van Buchem 1997 {published data only} Van Buchem F, Knottnerus J, Schrijnemaekers V, Peeters M. No benefit of antibiotic treatment in acute maxillary sinusitis: a randomized double-blind placebo-controlled study. Nederlands Tijdschrift Voor Geneeskunde 1997;141 (49):2405–11. ∗ van Buchem FL, Knottnerus JA, Schrijnemaekers VJ, Peeters MF. Primary-care-based randomised placebocontrolled trial of antibiotic treatment in acute maxillary

sinusitis. Lancet 1997;349(9053):683–7. [MEDLINE: 97232963] von Sydow 1995 {published data only} von Sydow C, Savolainen S, Söderqvist A. Treatment of acute maxillary sinusitis-comparing cefpodoxime proxetil with amoxicillin. Scandinavian Journal of Infectious Diseases 1995;27(3):229–34. [MEDLINE: 96143362]

References to studies excluded from this review Agbim 1974 {published data only} Agbim OG. A comparative study of doxycycline and ampicillin in the treatment of acute sinusitis. Chemotherapy 1975;21(Suppl 1):68–75. ∗ Agbim OG. A comparative trial of doxycycline (’Vibramycin’) and ampicillin in the treatment of acute sinusitis. Current Medical Research and Opinion 1974;2(5): 291–4. Alvart 1992 {published data only} Alvart R. An open multicentre study to compare the efficacy and safety of sultamicillin with that of cefuroxime axetil in acute ear nose and throat infections in adults. Journal of International Medical Research 1992;20(Suppl 1):53A–61A. Axelsson 1971 {published data only} Axelsson A, Chidekel N, Grebelius N, Jensen C, Särne S. Treatment of acute maxillary sinusitis. II. A comparison of five further methods. Acta Otolaryngologica (Stockholm) 1971;72(1):148–54. Axelsson 1973 {published data only} Axelsson A, Chidekel N, Jensen C, Grebelius N, Singer F. Treatment of acute maxillary sinusitis. Doxycycline and spiramycin with and without irrigation. Annals of Otology, Rhinology and Laryngology 1973;82(2):186–91. Axelsson 1975 {published data only} Axelsson A, Grebelius N, Jensen C, Melin O, Singer F. Treatment of acute maxillary sinusitis. IV. Ampicillin, cephradine and erythromycinestolate with and without irrigation. Acta Otolaryngologica (Stockholm) 1975;79(5-6): 466–72. Axelsson 1981 {published data only} Axelsson A, Jensen C, Melin O, Singer F, von Sydow C. Treatment of acute maxillary sinusitis. V. Amoxicillin, azidocillin, phenylpropanolamine and pivampicillin. Acta Otolaryngologica (Stockholm) 1981;91(3-4):313–8. Bandak 1999 {published data only} Bandak S, Bolzon L, Johns D, Henle S, Allen B. Cefaclor advanced formulation 750mg twice daily versus clarithromycin 500mg twice daily in the treatment of acute maxillary sinusitis. Current Therapeutic Research 1999;60 (4):185–94. Beatson 1985 {published data only} Beatson JM, Marsh BT, Talbot DJ. A clinical comparison of pivmecillinam plus pivampicillin (Miraxid) and a triple tetracycline combination (Deteclo) in respiratory infections treated in general practice. Journal of International Medical Research 1985;13(4):197–202.


30

Bockmeyer 1994 {published data only} Bockmeyer M, Riebenfeld D, Clasen B. Controlled study of brodimoprim and cephalexin in the treatment of patients with acute sinusitis in general practice. Clinical Therapeutics 1994;16(4):653–61. Brodie 1989 {published data only} Brodie DP, Knight S, Cunningham K. Comparative study of cefuroxime axetil and amoxicillin in the treatment of acute sinusitis in general practice. Journal of International Medical Research 1989;17(6):547–51. Brook 2006 {published data only} Brook I, Hausfeld JN. Effect of telithromycin and azithromycin on nasopharyngeal bacterial flora in patients with acute maxillary sinusitis. Archives of Otolaryngology Head & Neck Surgery 2006;132(4):442–5. Bucher 2003 {published data only} Bucher HC, Tschudi P, Young J, Periat P, Welge-Luussen A, Zust H, et al.Effect of amoxicillin-clavulanate in clinically diagnosed acute rhinosinusitis: a placebo-controlled, double-blind, randomized trial in general practice. Archives of Internal Medicine 2003;163(15):1793–8.

Ekedahl 1987 {published data only} Ekedahl C. [Akute Sinusitis bei Erwachsenen]. Infection 1987;15(Suppl 3):120–2. Elies 2001 {published data only} Elies W. Short course therapy with cefuroxime axetil for five days in comparison to ten days of therapy with clarithromycin in acute sinusitis [Kurzzeittherapie mit cefuroximaxetil uber funf tage im vergleich zur zehn–tage–therapie mit clarithromycin bei akuter sinusitis]. Chemotherapie Journal 2001;10(3):105–9. Falser 1988 {published data only} Falser N, Mittermayer H, Weuta H. Antibacterial treatment of otitis and sinusitis with ciprofloxacin and penicillin V. A comparison. Infection 1988;16(Suppl 1):51–4. Federspil 1983 {published data only} Federspil P, Koch J. Double-blind comparative trial of trimethoprim/sulfamethopyrazine once daily vs erythromycin 4 x daily in patients with ENT infections. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1983;21(10):535–9.

Carenfelt 1975 {published data only} Carenfelt C, Eneroth CM, Lundberg C, Wretlind B. Evaluation of the antibiotic effect of treatment of maxillary sinusitis. Scandinavian Journal of Infectious Diseases 1975;7 (4):259–64.

Felstead 1991 {published data only} Felstead SJ, Daniel R. Short-course treatment of sinusitis and other upper respiratory tract infections with azithromycin: a comparison with erythromycin and amoxycillin. European Azithromycin Study Group. Journal of International Medical Research 1991;19(5):363–72.

Casiano 1991 {published data only} Casiano RR. Azithromycin and amoxicillin in the treatment of acute maxillary sinusitis. American Journal of Medicine 1991;91(Suppl 3A):27–30.

Fiscella 1991 {published data only} Fiscella RG, Chow JM. Cefixime for treatment of maxillary sinusitis. American Journal of Rhinology 1991;5(5):193–7.

Correa 1986 {published data only} Correa A, Hernandez C. Estudio comparativo de la asociacion trimetoprim - sulfametopirazina y amoxocilina en sinusitis maxilar aguda. Revista Medica de Chile 1986; 114(3):215–20. De Abate 1992 {published data only} De Abate CA, Perrotta RJ, Dennington ML, Ziering RM. The efficacy and safety of once-daily ceftibuten compared with co-amoxiclav in the treatment of acute bacterial sinusitis. Journal of Chemotherapy 1992;4(6):358–63. De Sutter 2002 {published and unpublished data} De Sutter A, Lemiengre M, Van Maele G, van Driel M, De Meyere M, Christiaens T, et al.Predicting prognosis and effect of antibiotic treatment in rhinosinusitis. Annals of Family Medicine 2006;4(6):486–93. ∗ De Sutter AI, De Meyere MJ, Christiaens TC, Van Driel ML, Peersman W, De Maeseneer JM. Does amoxicillin improve outcomes in patients with purulent rhinorrhea? A pragmatic randomized double-blind controlled trial in family practice. Journal of Family Practice 2002;51(4): 317–23. Edelstein 1993 {published data only} Edelstein DR, Avner SE, Chow JM, Duerksen RL, Johnson J, Ronis M, et al.Once-a-day therapy for sinusitis: a comparison study of cefixime and amoxicillin. Laryngoscope 1993;103(1 Pt 1):33–41.

Freche 1988 {published data only} Freche C, Fombeur JP, Pappo M. Evaluation du cefuroximeaxetil dans le traitement des sinusites aigues de l’adulte. Etude comparative avec le cefaclor. Therapie 1988;43(Suppl 4):365–8. Gananca 1973 {published data only} Gananca M, Trabulsi LR. The therapeutic effects of cyclacillin in acute sinusitis: in vitro and in vivo correlations in a placebo-controlled study. Current Medical Research and Opinion 1973;1(6):362–8. Gananca 1977 {published data only} Gananca M, Gasel J. A double-blind study with the association tetracycline, acetylsalicylic acid, phenacetin, caffeine and phenyltoloxamine in the treatment of acute sinusitis. Folha Medica 1977;75(5):583–5. Garcia 1998 {published data only} Garcia C, Velert V, Orts A, Pardo M, Esparcia N. Comparison of azithromycin, amoxicillin/clavulanic acid and cefaclor in the treatment of acute ENT infections [Comparacion de azithromicina, amoxicilina/acido clavulanico y cefaclor en el tratamiento de la infeccion aguda otorrinolaringologica]. Acta Otorrinolaringologica Espanola 1998;49(4):306–12. Gladkov 1979 {published data only} Gladkov AA, Andrijchuk AI, Neporada VP. Sravnitel’naia effektivnost’ lecheniia bol’nykh ostrym i khronicheskim


31

gnoinym vospaleniem verkhnecheliustnoi pazukhi rastvorami dekametoksina, formal’degida i penitsillina. Zhurnal Ushnykh, Nosovykh i Gorlovykh Boleznei 1979;3: 21–5. Goumas 1997 {published data only} Goumas P, Naxakis S, Bassaris C, Skoutelis A. Comparative efficacy and tolerability of clarithromycin and cefaclor in the treatment of outpatients with acute maxillary sinusitis. Clinical Drug Investigation 1997;13(3):128–33. Gurdogan 2001 {published data only} Gurdogan K, Senol E. Comparison of 3-day course of azithromycin with penicillin V and amoxicillin+clavulanate in the treatment of upper respiratory tract infections [Ust solunum yolu enfeksiyonlarinin tedavisinde uc gun sureli azitromisin ile penisilin V ve amoksisilin+klavulonatin karsilastirilmasi]. Mikrobiyoloji Bulteni 2001;35(2):239–43. Gwaltney 1981 {published data only} ∗ Gwaltney JM Jr, Sydnor A Jr, Sande MA. Etiology and antimicrobial treatment of acute sinusitis. Annals of Otology, Rhinology and Laryngology 1981;90(Suppl 84):68–71. Hamory BH, Sande MA, Sydnor A Jr, Seale DL, Gwaltney JM Jr. Etiology and antimicrobial therapy of acute maxillary sinusitis. Journal of Infectious Diseases 1979;139 (2):197–202. Hansen 2000 {published data only} Hansen J, Schmidt H, Grinsted P. [Penicillinbehandling af akut kaebehulebetaendelse hos voksne]. Ugeskrift for Laeger 2000;162(40):5351–3. ∗ Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo controlled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in general practice. Scandinavian Journal of Primary Health Care 2000; 18:44–7. [MEDLINE: 20269180] Hebblethwaite 1987 {published data only} Hebblethwaite EM, Brown GW, Cox DM. A comparison of the efficacy and safety of cefuroxime axetil and augmentin in the treatment of upper respiratory tract infections. Drugs Under Experimental and Clinical Research 1987;13(2):91–4. Henry 1999a {published data only} Henry DC, Moller DJ, Adelglass J, Scheld WM, Jablonski CK, Zhang H, et al.Comparison of sparfloxacin and clarithromycin in the treatment of acute bacterial maxillary sinusitis. Sparfloxacin Multicenter AMS Study Group. Clinical Therapeutics 1999;21(2):340–52. Henry 1999b {published data only} Henry DC, Sydnor A Jr, Settipane GA, Allen J, Burroughs S, Cobb MM, et al.Comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of acute bacterial sinusitis. Clinical Therapeutics 1999;21(7):1158–70. Husfeldt 1993 {published data only} Husfeldt P, Egede F, Nielsen PB. Antibiotic treatment of sinusitis in general practice. A double-blind study comparing ofloxacin and erythromycin. European Archives of Otorhinolaryngology 1993;250(Suppl 1):S23–5.

Jeppesen 1970 {published data only} Jeppesen F, Schaldemose HJ. Doxycycline (Vibramycin) in the treatment of sinusitis [Doxycyclinum (Vibramycin) i behandlingen af sinuitis]. Ugeskrift for Laeger 1970;132: 437–43. Johnson 1999 {published data only} Johnson PA, Rodriquez HP, Wazen JJ, Huck W, Shan M, Tosiello R, et al.Ciprofloxacin versus cefuroxime axetil in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group. Journal of Otolaryngology 1999;28(1):3–12. Karpov 1998 {published data only} Karpov OI. The clinical and economic efficacies of short courses of azithromycin in acute sinusitis. Antibiotiki i Khimioterapiia 1999;44(10):28–32. ∗ Karpov OI, Riabova MA, Karpishchenko SA, Zaitseva AA. Comparative trial of 3-day azithromycin versus 10-day coamoxilav course efficacy in acute sinusitis. Terapevticheskii Arkhiv 1998;70(5):72–6. Klein 1998 {published data only} Klein GL, Whalen E, Echols RM, Heyd A. Ciprofloxacin versus cefuroxime axetil in the treatment of adult patients with acute bacterial sinusitis. Journal of Otolaryngology 1998;27(1):10–6. Lacroix 2002 {published data only} Kaiser L, Morabia A, Stalder H, Ricchetti A, Auckenthaler R, Terrier F, et al.Role of nasopharyngeal culture in antibiotic prescription for patients with common cold or acute sinusitis. European Journal of Clinical Microbiology & infectious Diseases 2001;20(7):445–51. ∗ Lacroix JS, Ricchetti A, Lew D, Delhumeau C, Morabia A, Stalder H, et al.Symptoms and clinical and radiological signs predicting the presence of pathogenic bacteria in acute rhinosinusitis. Acta Oto-Laryngologica 2002;122(2):192–6. Li 2000 {published data only} Li XP, Qin ZM, Zheng RH, Tan QL, Zhou YY, Zhu L, et al.Comparison of the effectiveness of levofloxacin and cefuroxime for the treatment of sinusitis. Lin Chuang Erh Pi Yen Hou Ko Tsa Chih (Journal of Clinical Otorhinolaryngology) 2000;14(12):573–5. Lopez 1975 {published data only} Lopez Rubio A, Estrada Velasco A, Ibarra J, Lazos O. [Antibioticoterapia de espectro intermedio en infecciones O.R.L]. Prensa Medica Mexicana 1975;40(7-8):256–8. Luchikhin 2005 {published data only} Luchikhin LA, Troitskii SA. Etiotropic therapy with sparfioxamine in ENT practice. Vestnik Otorinolaringologii 2005;6:43–5. Mannhardt 1980 {published data only} Mannhardt J, Held J. Eine randomisierte Vergleichsstudie der therapeutischen Wirkung von amoxicillin und doxycyclin bei Sinusitis. Therapiewoche 1980;30:2087–9. Manzini 1993 {published data only} Manzini M, Caroggio A. Efficacy and tolerability of brodimoprim and roxithromycin in acute sinusitis of bacterial origin in adults. Journal of Chemotherapy 1993;5 (6):521–5.


32

Marchi 1990 {published data only} Marchi E. Comparative efficacy and tolerability of clarithromycin and amoxycillin in the treatment of outpatients with acute maxillary sinusitis. Current Medical Research and Opinion 1990;12(1):19–24.

Panosetti 1992 {published data only} Panosetti E. Phlegmonous and abscess-forming ENT infections: comparative efficacy of ceftriaxone versus amoxicillin-clavulanic acid. ORL - Journal for Oto-RhinoLaryngology and its Related Specialties 1992;54(2):95–9.

Marcolino 1999 {published data only} Marcolino FMD, Ferracini NW, Gobbato LH, Hernandes MAR. Open comparative study of the efficacy and tolerability of azithromycin versus amoxycillin in the treatment of acute rhinosinusitis [Estudo comparativo e aberto sobre a eficacia e a tolerabilidade da azithromicina vs amoxicilina em rinossinusites agudas em adultos]. Revista Brasileira de Medicina 1999;56(4):294–8.

Peyramond 1991 {published data only} Peyramond D, Abenhaim N, Chiche D. Community acquired respiratory infections: cefuroxime axetil versus amoxicillin/clavulanic acid [Etude du traitement antibiotique des infections respiratoires acquises en ville: cefuroxime axetil vs amoxicilline/acide clavulanique]. Medecine et Maladies Infectieuses 1991;21(Special Issue): 98–102.

Mesure 1973 {published data only} Mesure R. [Essai en double aveugle de l’association de sulfamethoxazole et de trimethoprime dans les infections oto–rhino–laryngologiques]. Acta Otorhinolaryngologica Belgica 1973;27(1):27–33.

Piragine 1988 {published data only} Piragine F, Sellari-Franceschini S, Berrettini S, Bruschini P, Grossi P. Amoxicillin-clavulanic acid combination in ORL infection with a proven bacterial etiology. Rivista Italiana di Otorinolaringologia, Audiologia e Foniatria 1988;8(4): 321–5.

Mira 2001 {published data only} Mira E, Benazzo M. A multicenter study on the clinical efficacy and safety of roxithromycin in the treatment of ear-nose-throat infections: comparison with amoxycillin/ clavulanic acid. Journal of Chemotherapy 2001;13(6):621–7. Miyamoto 2005 {published data only} Miyamoto N, Murakami S, Watanabe N, Ozeki M. Bacteriological and clinical evaluation of azithromycin and cefcapene-pivoxil in otorhinolaryngological infections. Japanese Journal of Chemotherapy 2005;53(7):417–20. Moorhouse 1985 {published data only} Moorhouse EC, Hickey MP, O’Hanrahan MT, Clarke PC. General practice studies with combined pivampicillin/ pivmecillinam (Miraxid). Irish Medical Journal 1985;78 (11):314–7. Norrelund 1978 {published data only} Norrelund N. [Behandling af sinusitis i almenpraksis. En kontrolleret undersogelse over pivampicillin (Pondocillin)]. Ugeskrift for Laeger 1978;140(45):2792–5. Olsson 1976 {published data only} Olsson O, Henning C. Clinical study on bacampicillin in otitis media acuta and sinusitis acuta. Penicillins and cephalosporins. In: Williams JD, Geddes AM editor(s). Chemotherapy. Vol. 5, New York: Plenum Press, 1976: 145–50. Osman 1983 {published data only} Osman MF, Menday AP. Single-blind comparison of miraxid and co-trimoxazole in patients with sinusitis and otitis. Proceedings of the 13th International Congress of Chemotherapy. Vienna, 1983; Vol. 1, issue 1–5:26–9. Pallestrini 1995 {published data only} Pallestrini E, Cimino A, Colletti V, Conticello S, De Campora E, De Martini E, et al.[Rufloxacina in confronto a claritromicina nel trattamento short–term delle patologie infettive di interesse otorinolaringoiatrico]. Rivista Italiana di Otorinolaringologia, Audiologia e Foniatria 1995;15(3): 236–45.

Podvinec 1982 {published data only} Podvinec M. [Co–tetroxazin (Tibirox) und Doxycyclin (Vibramycin) in der Behandlung von Infekten der Oberen Luftwege: eine Doppelblindstudie]. Therapeutische Umschau 1982;39(10):815–20. Polonovski 2006 {published data only} Polonovski JM, El Mellah M. Treatment of acute maxillary sinusitis in adults. Comparison of cefpodoxime-proxetil and amoxicillin-clavulanic acid. Presse Medicale 2006;35(1 Pt 1):33–8. Quick 1973 {published data only} Quick CA, Wagner D. Trimethoprim-sulfamethoxazole in the treatment of infections of the ears, nose and throat. Journal of Infectious Diseases 1973;128(Suppl):696–700. Quick 1975 {published data only} Quick CA. Comparison of penicillin and trimethoprimsulfamethoxazole in the treatment of ear, nose and throat infections. Canadian Medical Association Journal 1975;112 (13 Spec No):83–6. Rantanen 1973 {published data only} Rantanen T, Arvilommi H. Double-blind trial of doxicycline in acute maxillary sinusitis. A clinical and bacteriological study. Acta Otolaryngologica (Stockholm) 1973;76(1):58–62. Rechtweg 2004 {published data only} Rechtweg J, Moinuddin R, Houser S, Mamikoglu B, Corey J. Quality of life in treatment of acute rhinosinusitis with clarithromycin and amoxicillin/clavulanate. Laryngoscope 2004;114(5):806–10. Riedel 1987 {published data only} Riedel H, Schmidt A, Upmeyer HJ. Is supplementary antibiotic treatment of sinusitis advantageous?. Therapiewoche 1987;37:4189–97. Rimmer 1997 {published data only} Rimmer D, Suprax/Amoxicillin Clinical Study Team. Efficacy of cefixime and amoxicillin in adults with


33

acute sinusitis. A Special Report. Sinusitis: optimizing management strategies. Postgraduate Medicine 1998:50–7. Roenning 1987 {published data only} Roenning Arnesen A, Spada L. Double-blind comparison of spiramycin and phenoxymethylpenicillin in treatment of upper respiratory tract infections (tonsillitis and rhinosinusitis). Chemioterapia 1987;6(Suppl 2):451–2. Sabater 1995 {published and unpublished data} Sabater F, Larrosa F, Guiroa M, Ciges M, Figuerola A, Fernandez F. Cefpodoxime proxetil (5 days) vs amoxicillin/ clavulanic acid (8 days) in the treatment of acute maxillarethmoidal sinusitis in adult outpatients. Canadian Journal of Infectious Diseases 1995;6(Suppl C):Abstract 3100. Salmi 1986 {published data only} Salmi HA, Lehtomäki K, Kylmämaa T. Comparison of brodimoprim and doxycycline in acute respiratory tract infections. A double-blind clinical trial. Drugs Under Experimental and Clinical Research 1986;12(4):349–53. Salmi 1993 {published data only} Salmi HA. Brodimoprim in acute respiratory tract infections. Journal of Chemotherapy 1993;5(6):532–6. Schering-Plough 2003 {unpublished data only} Schering-Plough Research Institute. Efficacy and safety of 200 mcg QD or 200 mcg BID mometasone fuorate (MFNS) vs. amoxicillin vs. placebo as primary treatment of subjects with acute rhinosinusitis (Protocol P02692). Kenilworth: Schering-Plough Research Institute 2003. Serra 2007 {published data only} Serra A, Schito GC, Nicoletti G, Fadda G. A therapeutic approach in the treatment of infections of the upper airways: thiamphenicol glycinate acetylcysteinate in sequential treatment (systemic-inhalatory route). International Journal of Immunopathology and Pharmacology 2007;20(3):607–17. Söderström 1991 {published data only} Söderström M, Blomberg J, Christensen P, Hovelius B. Erythromycin and phenoxymethylpenicillin (penicillin V) in the treatment of respiratory tract infections as related to microbiological findings and serum C-reactive protein. Scandinavian Journal of Infectious Diseases 1991;23(3): 347–54. Spindler 1985 {published data only} Spindler JJ, Marsh BT, Talbot DJ. Respiratory infections in general practice. A clinical comparison of pivmecillinamplus-pivampicillin (Miraxid) and cephalexin (Ceporex). Clinical Trials Journal 1985;22(4):293–9. Stahl 1989 {published data only} Stahl JP, Pappo M. A multicenter randomized trial of cefuroxime-axetil versus amoxicillin with clavulanic acid in community-acquired ENT and lower respiratory tract infections [Etude comparative du cefuroxime–axetil versus l’association d’amoxicilline et d’acide clavulanique dans les infections ORL et bronchiques]. Semaine des Hopitaux 1989;65(5):247–51.

Stalman 1997a {published data only} ∗ Stalman W, van Essen GA, van der Graaf Y, de Melker RA. The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice? A placebocontrolled double-blind randomized doxycycline trial. British Journal of General Practice 1997;47(425):794–9. Strachunskii 1993 {published data only} Strachunskii LS, Tikhonov VG, Kuleshov SE, Asmolovski VM. [Sravnitel’naia klinicheskaia effektivenost’ i perenosimost’ azitromitsina (sumamded) i eritromitsina u bol’nykh s sinusitami]. Antibiotiki i Khimioterapiia 1993;38 (1):13–6. Sydnor 1989 {published data only} Sydnor A Jr, Gwaltney JM Jr, Cocchetto DM, Scheld WM. Comparative evaluation of cefuroxime axetil and cefaclor for treatment of acute bacterial maxillary sinusitis. Archives of Otolaryngology - Head and Neck Surgery 1989;115(12): 1430–3. Taub 1967 {published data only} Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye, Ear, Nose and Throat Monthly 1967; 46(3):361–5. Varonen 2003a {published data only} Varonen H, Kunnamo I, Savolainen S, Mäkelä M, Revonta M, Ruotsalainen J, et al.Treatment of acute rhinosinusitis diagnosed by clinical criteria or ultrasound in primary care. A placebo-controlled randomised trial. Scandinavian Journal of Primary Health Care 2003;21:121–6. von Sydow 1984 {published data only} von Sydow C, Axelsson A, Jensen C. Treatment of acute maxillary sinusitis. Erythromycin base and phenoxymethylpenicillin (penicillin V). Rhinology 1984;22(4):247–54. Wallace 1985 {published data only} Wallace RB, Marsh BT, Talbot DJ. A multi-centre general practice clinical evaluation of pivmecillinam plus pivampicillin (’Miraxid’) and co-trimoxazole (’Septrin’) in respiratory tract infections. Current Medical Research and Opinion 1985;9(10):659–65. Weis 1998 {published data only} Weis M, Hendrick K, Tillotson G, Gravelle K, Rhinosinusitis Investigation Group. Multicenter comparative trial of ciprofloxacin versus cefuroxime axetil in the treatment of acute rhinosinusitis in a primary care setting. Clinical Therapeutics 1998;20(5):921–32. Westerman 1975 {published data only} Westerman T, Panzer JD, Atkinson WH. Comparative efficacy of clindamycin HC1 and tetracycline HCl in acute sinusitis. Eye, Ear and Nose Monthly 1975;54(6):236–8. Williamson 2007 {published and unpublished data} Williamson IG, Rumsby K, Benge S, Moore M, Smith PW, Cross M, et al.Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis. JAMA 2007;298(21): 2487–96. Young 2003 {published data only} ∗ Young J, Bucher H, Tschudi P, Periat P, Hugenschmidt C, Welge-Lussen A. The clinical diagnosis of acute bacterial


34

rhinosinusitis in general practice and its therapeutic consequences. Journal of Clinical Epidemiology 2003;56: 377–84. Young J, Tschudi P, Periat P, Hugenschmidt C, WelgeLussen A, Bucher HC. Patients’ expectations about the benefit of antibiotic treatment: lessons from a randomised controlled trial. Forschende Komplementärmedizin und Klassische Naturheilkunde 2005;12:347–9. Zbären 1983 {published data only} Zbären P, Pradervand M. [Etude clinique comparative en double aveugle entre co–tetroxacine et amoxicilline dans les infections ORL courantes]. Schweizerische Rundschau fur Medizin Praxis 1983;72(47):1491–3.

Additional references

Berg 1986 Berg O, Carenfelt C, Rystedt G, Änggård A. Occurrence of asymptomatic sinusitis in common cold and other acute ENT-infections. Rhinology 1986;24:223–5. Bhandari 2004 Bhandari M, Busse JW, Jackowski D, Montori VM, Schunemann H, Spraque S, et al.Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Canadian Medical Association Journal 2004;170(4):477–80. Bronzwaer 2002 Bronzwaer SL, Cars O, Buchholz U, Mölstad S, Goettsch W, Veldhuijzen IK, et al.A European study on the relationship between antimicrobial use and antimicrobial resistance. Emerging Infectious Diseases 2002;8(3):278–82.

Ah-See 2007 Ah-See KW, Evans AS. Sinusitis and its management. BMJ 2007;334:358–61.

Chokkalingam 1998 Chokkalingam A, Scherer R, Dickersin K. Agreement of data in abstracts compared to full publications. Controlled Clinical Trials 1998;19(Suppl):61–2.

Albrich 2004 Albrich WC, Monnet DL, Harbarth S. Antibiotic selection pressure and resistance in Streptococcus pneumoniae and Streptococcus pyogenes. Emerging Infectious Diseases 2004; 10(3):514–7.

de Bock 1997 de Bock GH, Dekker FW, Stolk J, Springer MP, Kievit J, van Houwelingen JC. Antimicrobial treatment in acute maxillary sinusitis: a meta-analysis. Journal of Clinical Epidemiology 1997;50(8):881–90.

Andre 2002 Andre M, Odenholt I, Schwan Å, The Swedish Study Group on Antibiotic Use. Upper respiratory tract infections in general practice: diagnosis, antibiotic prescribing, duration of symptoms and use of diagnostic tests. Scandinavian Journal of Infectious Diseases 2002;34(12):880–6.

de Ferranti 1998 de Ferranti SD, Ioannidis JPA, Lau J, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. BMJ 1998; 317:632–7.

Arason 1996 Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Mölstad S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study. BMJ 1996;313:387–91. Arason 2005 Arason VA, Sigurdsson JA, Kristinsson KG, Getz L, Gudmundsson S. Otitis media, tympanostomy tube placement, and use of antibiotics. Scandinavian Journal of Primary Health Care 2005;23(3):184–91. Axelsson 1972 Axelsson A, Chidekel N. Symptomatology and bacteriology correlated to radiological findings in acute maxillary sinusitis. Acta Otolaryngologica 1972;74:118–22. Bekelman 2003 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003;289(4):454–65. Benninger 2000 Benninger MS, Sedory Holzer SE, Lau J. Diagnosis and treatment of uncomplicated acute bacterial rhinosinusitis: Summary of the Agency for Health Care Policy and Research evidence-based report. Otolaryngology - Head and Neck Surgery 2000;122(1):1–7.

EARSS 2008 The European Antimicrobial Resistance Surveillance System. EARSS interactive database. http://www.rivm.nl/ earss/database (accessed August 2010). ECRP 2000 European Commission on Radiation Protection 118. Referral guidelines for imaging. http://ec.europa.eu/energy/ nuclear/radioprotection/publication/doc/118˙en.pdf (accessed June 2010). Falagas 2008a Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos G, Karageorgopoulos DE. Comparison of antibiotics with placebo for treatment of acute sinusitis: a meta-analysis of randomised controlled trials. Lancet Infectious Diseases 2008;8:543–52. Falagas 2008b Falagas ME, Karageorgopoulos DE, Grammatikos AP, Matthaiou DK. Effectiveness and safety of short vs. long duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials. British Journal of Clinical Pharmacology 2008;67(2):161–71. Fokkens 2007 Fokkens WJ, Lund VJ, Mullol J, on behalf of the European Position Paper on Rhinosinusitis and Nasal Polyps group. European Position Paper on Rhinosinusitis and Nasal Polyps. Rhinology 2007;45(Suppl 20):1–139.


35

Goossens 2005 Goossens H, Ferech M, Vander Stichele R, Elseviers M, for the ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005;365:579–87. GRADEpro 2008 Brozek J, Oxman A, Schünemann H. GRADEpro Version 3.2 for Windows. 2008. Guillemot 1998 Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, Vauzelle-Kervroedan F, et al.Low dosage and long treatment duration of ß-lactam. Risk factors for carriage of penicillinresistant Streptococcus pneumoniae. JAMA 1998;279(5): 365–70. Gwaltney 1992 Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. Journal of Allergy and Clinical Immunology 1992;90:457–62. Gwaltney 1994 Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. New England Journal of Medicine 1994;330(1):25–30. Gwaltney 1996 Gwaltney JM Jr. Acute community-acquired sinusitis. Clinical Infectious Diseases 1996;23:1209–25. Gwaltney 2004 Gwaltney JM Jr, Wiesinger BA, Patrie JT. Acute communityacquired bacterial sinusitis: the value of antimicrobial treatment and the natural history. Clinical Infectious Diseases 2004;38:227–33. Gwaltney 2005 Gwaltney JM Jr. Sinusitis. In: Mandell GL, Bennett JE, Dolin R editor(s). Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Elsevier, 2005:772–83. Hansen 2012 Hansen FS, Hoffmans R, Georgalas C, Fokkens WJ. Complications of acute rhinosinusitis in The Netherlands. Family Practice 2012;29(2):147–53. Hay 2005 Hay AD, Thomas M, Montgomery A, Wetherell M, Lovering A, McNulty C, et al.The relationship between primary care antibiotic prescribing and bacterial resistance in adults in the community: a controlled observational study using individual patient data. Journal of Antimicrobial Chemotherapy 2005;56(1):146–53. Hickner 2001 Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Annals of Internal Medicine 2001;134:498–505.

Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557–60. Higgins 2011a Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochranehandbook.org. 5.1. Chichester, UK: Wiley-Blackwell, 2011. Higgins 2011b Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochranehandbook.org. 5.1. Chichester, UK: Wiley-Blackwell, 2011. Hopewell 2006 Hopewell S, Clarke M, Askie L. Reporting of trials presented in conference abstracts needs to be improved. Journal of Clinical Epidemiology 2006;59:681–4. Howard 1976 Howard JE, Nelson JD, Clahsen J, Jackson LH. Otitis media of infancy and early childhood. A double-blind study of four treatment regimens. American Journal of Diseases of Children 1976;130(9):965–70. Hsin 2010 Hsin CH, Su MC, Tsao CH, Chuang CY, Liu CM. Bacteriology and antimicrobial susceptibility of pediatric chronic rhinosinusitis: a 6-year result of maxillary sinus punctures. American Journal of Otolaryngology 2010;31(3): 145–9. ICD-10 International Classification of Diseases (ICD-10). http:// apps.who.int/classifications/apps/icd/icd10online/ 2010 (accessed September 2010). Ioannidis 2001 Ioannidis JPA, Contopoulos-Ioannidis DG, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections. Journal of Antimicrobial Chemotherapy 2001;48:677–89. Ioannidis 2002 Ioannidis JPA, Chew P, Lau J. Standardized retrieval of side effects data for meta-analysis of safety outcomes. A feasibility study in acute sinusitis. Journal of Clinical Epidemiology 2002;55(6):619–26. Ip 2005 Ip S, Fu L, Balk E, Chew P, DeVine D, Lau J. Update on acute bacterial rhinosinusitis. Evidence Report/Technology Assessment No. 124. AHRQ Publication No. 05-E0202. Rockville, MD: Agency for Healthcare Research and Quality 2005. [: Prepared by Tufts–New England Medical Center Evidence–based Practice Center under Contract No. 290–02–0022]


36

Joki-Erkkilä 2000 Joki-Erkkilä VP, Pukander J, Laippala P. Alteration of clinical picture and treatment of pediatric acute otitis media over the past two decades. International Journal of Pediatric Otorhinolaryngology 2000;55(3):197–201.

Margolis 2005 Margolis DJ, Bowe WP, Hoffstad O, Berlin JA. Antibiotic treatment of acne may be associated with upper respiratory tract infections. Archives of Dermatology 2005;141(9): 1132–6.

Jousimies-Somer 1988 Jousimies-Somer HR, Savolainen S, Ylikoski JS. Bacteriological findings of acute maxillary sinusitis in young adults. Journal of Clinical Microbiology 1988;26(10): 1919–25.

Maxwell 2002 Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. American Journal of Gastroenterology 2002;97(1):104–8.

Kilkkinen 2002 Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen P, Adlercreutz H. Use of oral antimicrobials decreases serum enterolactone concentration. American Journal of Epidemiology 2002;155(5):472–7. Kristo 2009 Kristo A, Uhari M. Timing of rhinosinusitis complications in children. Pediatric Infectious Disease Journal 2009;28(9): 769–71. Lanza 1997 Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngology - Head and Neck Surgery 1997;117(Suppl): 1–7. Lawson 2008 Lawson W, Patel ZM, Lin FY. The development and pathologic processes that influence maxillary sinus pneumatization. Anatomical Record (Hoboken) 2008;291 (11):1554–63. Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochrane-handbook.org. 5.1. Chichester, UK: Wiley-Blackwell, 2011.

Meltzer 2004 Meltzer E, Hamilos D, Hadley J, Lanza D, Marple B, Nicklas R, et al.Rhinosinusitis: establishing definitions for clinical research and patient care. Journal of Allergy and Clinical Immunology 2004;114(Suppl):155–212. Meltzer 2006 Meltzer E, Hamilos D, Hadley J, Lanza D, Marple B, Nicklas R, et al.Rhinosinusitis: developing guidance for clinical trials. Otolaryngology - Head and Neck Surgery 2006; 135(Suppl):31–80. Odenholt 2003 Odenholt I, Gustafsson I, Löwdin E, Cars O. Suboptimal antibiotic dosage as a risk factor for selection of penicillinresistant Streptococcus pneumoniae: in vitro kinetic model. Antimicrobial Agents and Chemotherapy 2003;47(2):518–23. Puhakka 1998 Puhakka T, Mäkelä MJ, Alanen A, Kallio T, Korsoff L, Arstila P, et al.Sinusitis in the common cold. Journal of Allergy and Clinical Immunology 1998;102(3):403–8. Puhakka 2000 Puhakka T, Heikkinen T, Mäkelä MJ, Alanen A, Kallio T, Korsoff L, et al.Validity of ultrasonography in diagnosis of acute maxillary sinusitis. Archives of Otolaryngology - Head and Neck Surgery 2000;126(12):1482–6.

Lemiengre 2012 Lemiengre MB, van Driel ML, Merenstein D, Young J, de Sutter AIM. Antibiotics for clinically diagnosed acute rhinosinusitis in adults. Cochrane Database of Systematic Reviews 2012, Issue 10. [DOI: 10.1002/ 14651858.CD006089.pub4]

Rautakorpi 1999 Rautakorpi U-M, Lumio J, Huovinen P, Klaukka T. Indication-based use of antimicrobials in Finnish primary health care. Description of a method for data collection and results of its application. Scandinavian Journal of Primary Health Care 1999;17(2):93–9.

Lexchin 2003 Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167–70.

RevMan 2012 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Linder 2003 Linder JA, Singer DE, van den Ancker M, Atlas SJ. Measures of health-related quality of life for adults with acute sinusitis. Journal of General Internal Medicine 2003; 18:390–401.

Rosenfeld 2007 Rosenfeld RM, Singer M, Jones S. Systematic review of antimicrobial therapy in patients with acute rhinosinusitis. Otolaryngology - Head and Neck Surgery 2007;137(Suppl): 32–45.

Low 1997 Low DE, Desrosiers M, McSherry J, Garber G, Williams JW Jr, Remy H, et al.A practical guide for the diagnosis and treatment of acute sinusitis. Canadian Medical Association Journal 1997;156(Suppl 6):1–14.

SAHP 2004 Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis 2004. Otolaryngology - Head and Neck Surgery 2004;130(Suppl 1): 1–50.


37

Seppälä 1995 Seppälä H, Klaukka T, Lehtonen R, Nenonen E, Huovinen P. Outpatient use of erythromycin: link to increased erythromycin resistance in group A streptococci. Clinical Infectious Diseases 1995;21(6):1378–85. Slavin 2005 Slavin RG, Spector SL, Bernstein IL, Sinusitis Update Workgroup. The diagnosis and management of sinusitis. A practice parameter update. Journal of Allergy and Clinical Immunology 2005;116(Suppl):13–47. Smith 1997 Smith HS, Hughes JP, Hooton TM, Roberts P, Scholes D, Stergachis A, et al.Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clinical Infectious Diseases 1997;25(1):63–8. Snow 2001 Snow V, Mottur-Pilson C, Hickner JM. Principles of appropriate antibiotic use for acute sinusitis in adults. Annals of Internal Medicine 2001;134(6):495–7. Stalman 1997b Stalman W, van Essen GA, van der Graaf Y, de Melker RA. Maxillary sinusitis in adults: an evaluation of placebocontrolled double-blind trials. Family Practice 1997;14(2): 124–9. Steinke 2001 Steinke D, Davey P. Association between antibiotic resistance and community prescribing: a critical review of bias and confounding in published studies. Clinical Infectious Diseases 2001;33(Suppl 3):193–205. Sterne 2011 Sterne JAC, Egger M, Moher D (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Intervention. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochranehandbook.org. Chichester, UK: Wiley-Blackwell, 2011. Unnebrink 2001 Unnebrink K, Windeler J. Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases. Statistics in Medicine 2001;20: 3931–46. Varonen 2003b Varonen H, Savolainen S, Kunnamo I, Heikkinen R, Revonta M. Acute rhinosinusitis in primary care:

a comparison of symptoms, signs, ultrasound, and radiography. Rhinology 2003;41(1):37–43. Velicer 2004 Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Antibiotic use in relation to the risk of breast cancer. JAMA 2004;291(7):827–35. Williams 1993 Williams JW Jr, Simel DL. Does this patient have sinusitis?. JAMA 1993;270(10):1242–6. Wu 2009 Wu AW, Shapiro NL, Bhattacharyya N. Chronic rhinosinusitis in children: what are the treatment options?. Immunology and Allergy Clinics of North America 2009;29 (4):705–17. Young 2008 Young J, De Sutter A, Merenstein D, van Essen GA, Kaiser L, Varonen H, et al.Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis of individual patient data. Lancet 2008;371:908–14.

References to other published versions of this review Ahovuo-Saloranta 2008 Ahovuo-Saloranta A, Borisenko OV, Kovanen N, Varonen H, Rautakorpi U-M, Williams Jr JW, et al.Antibiotics for acute maxillary sinusitis. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/ 14651858.CD000243.pub2] Ahovuo-Saloranta 2011 Ahovuo-Saloranta A, Rautakorpi U-M, Borisenko OV, Liira H, Williams Jr JW, et al.Antibiotics for acute maxillary sinusitis. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD000243.pub2] Williams 1999 Williams Jr. JW, Aguilar C, Makela M, Cornell J, Hollman DR, Chiquette E, et al.Antimicrobial therapy for acute maxillary sinusitis. Cochrane Database of Systematic Reviews 1999, Issue 3. [DOI: 10.1002/ 14651858.CD000243.pub2] Williams 2003 Williams Jr JW, Aguilar C, Cornell J, Chiquette E. Dolor RJ, Makela M, et al.Antibiotics for acute maxillary sinusitis. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD000243.pub2] ∗ Indicates the major publication for the study


38

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Adelglass 1998a Methods

Randomised, single-blind study (investigator). Diagnosis of acute sinusitis confirmed radiographically by at least 5 mm mucosal thickening, opacification or air-fluid level. Outcomes assessed by an investigator; cure defined as disappearance of clinical signs and symptoms without need for further antimicrobial therapy. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 12% on day 16 to 19

Participants

The study setting was not described. Participants were 40 years old on average (range 18 to 83) and included 122 men and 69 women. ENT co-morbidity was assessed; about 50% of patients had hay fever. Country - USA

Interventions

2 treatment arms: Group 1: levofloxacin 500 mg daily for 14 days Group 2: clarithromycin 500 mg BID for 14 days Acetaminophen and diphenhydramine were allowed

Outcomes

Clinical outcomes were assessed in 190 out of 216 randomised patients (in 101 out of 108 patients in levofloxacin group and in 89 out of 108 patients in clarithromycin group) . Outcomes were assessed on day 16 to 19. Second follow-up on 42 to 46 days

Notes

Study supported by a pharmaceutical company. 5 of the authors were affiliated to a pharmaceutical company

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “The subject randomization list was computer-generated and stratified by site. Equal numbers of subjects were assigned to each treatment group”

Allocation concealment (selection bias)

Low risk

Quote: “To reduce potential bias during data collection and evaluation of clinical end points, a qualified third party assumed responsibility for all procedures related to the study drugs including dispensing”

Selective reporting (reporting bias)

Unclear risk

Outcomes reported: clinical response, adverse effects and quality of life Comment: in the methods section it is stated that repeat sinus X-rays were taken at 16 to 19 days giving the impression that


39

Adelglass 1998a

(Continued)

this was an outcome. However, the results were not reported Blinding? (Participant and investigator)

High risk

Quote: “Single-blinded (investigator)”

Incomplete outcome data addressed? High risk (Clinical efficacy outcomes)

Missing data: 7/108 (6%) in levofloxacin group and 19/108 (18%) in clarithromycin group on day 16 to 19 Comment: imbalance in numbers of missing data across groups

Free of other bias? Baseline comparability

Low risk

Comment: detailed description of demographic characteristics and sinusitis severity rating with which to assess the comparability of the groups at baseline

Free of other bias? Co-interventions

Low risk

Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect on recovery (thus did not cause bias)

Free of other bias? Funding

High risk

Study supported by a pharmaceutical company. 5 of the authors were affiliated to a pharmaceutical company

Adelglass 1998b Methods

Randomised, unblinded trial. Diagnosis by clinical signs and symptoms (mean duration of symptoms prior to enrolment 9 days) and radiograph showing at least 4 mm mucosal thickening. Cure defined as absence of symptoms or a score of 1 or less on a 10-point symptom scale. At least 80% of assigned doses were taken by 94% of participants. Proportion of the participants without known or reported clinical outcome 21% on day 11 to 15

Participants

The study setting was not described. Mean age approximately 37; 128 men and 150 women. About 40% of patients had ENT or eye diseases. Country - USA

Interventions

2 treatment arms Group 1: cefprozil 500 mg twice daily for 10 days Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 days Mucolytics and decongestants allowed and taken by < 50%

Outcomes

Clinical outcomes assessed at day 11 to 15 in 219 out of 278 randomised patients (in 108 out of 140 patients in cefprozil group and in 111 out of 138 patients in amoxicillinclavulanate group). Second follow-up 2 weeks post-treatment. Radiographic and bacteriological outcomes not reported


40

Adelglass 1998b

(Continued)

Notes

Study was supported by a grant from a pharmaceutical company

Risk of bias Bias



Random sequence generation (selection Unclear risk bias)

No information provided


Unclear risk



Low risk

Outcomes reported: clinical response, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way

Blinding? (Participant and investigator)

High risk

Quote: “Open-label study”


Missing data: 32/140 (22.9%) in cefprozil group and 27/138 (19.6%) in amoxicillinclavulanate group on day 11 to 15. Total missing data rate 21% on day 11 to 15 and 28% on day 24 Comment: total missing data rate over 20%


Low risk



Low risk



High risk



41

Adelglass 1999 Methods

Randomised, unblinded trial. Diagnosis by clinical symptoms and radiograph showing at least 4 mm mucosal thickening, opacification or air-fluid level. Cure defined as disappearance of symptoms and signs, and stabilisation or improvement of radiographic findings. Treatment compliance not reported. Proportion of the participants included in the clinically evaluable population was 87% on day 12 to 19

Participants

Participants were recruited from community-based primary care and otolaryngology clinics. Mean age 39 (range 18 to 85); 225 men and 390 women. Country - USA

Interventions

2 treatment arms Group 1: levofloxacin 500 mg daily for 10 to 14 days Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 to 14 days The use of antihistamines and decongestants was encouraged

Outcomes

Study reported clinical responses for clinically evaluable patients only. Clinical outcomes for clinically evaluable population were assessed on day 12 to 19 in 535 out of 615 randomised patients (in 267 out of 307 patients in levofloxacin group and in 268 out of 308 patients in amoxicillin-clavulanate group). (To be clinically evaluable, the patient had to be evaluable for safety, have a confirmed clinical diagnosis of acute sinusitis, have received at least 7 days of therapy, have followed the protocol, and have a clinical evaluation within 2 to 10 days after ending therapy.) Radiographic outcomes not separately reported. Long-term follow-up at 28 to 32 days after completion of therapy to assess relapse

Notes

Study was supported by a pharmaceutical company

Risk of bias Bias






Unclear risk



Unclear risk

Outcomes reported: overall clinical response (clinical response + radiographic response) and adverse effects Comment: prespecified outcomes (in methods) were unclearly reported (3 analyses groups for treatment comparison defined in methods section but the role of mITT and ITT populations in results remains unclear)


High risk



42

Adelglass 1999

(Continued)

Incomplete outcome data addressed? Low risk (Clinical efficacy outcomes)

Missing data: 40/307 (13%) in levofloxacin group and 40/308 (13%) in amoxicillinclavulanate group on day 12 to 19 Comment: the groups were balanced in numbers and reasons for missing data


Unclear risk

Comment: information on comparability at baseline was insufficient to assess whether the groups were comparable at baseline or not (no information on severity rating)


Low risk

Quote: “The use of antihistamines and decongestants was encouraged” Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect on recovery (thus did not cause bias)


High risk

Study was supported by a pharmaceutical company

Arndt 1994 Methods

Randomised, unblinded study. Diagnosis = clinical evidence, an abnormal radiograph and nasal swab. Radiographic criteria not described. Cure defined as “complete resolution of clinical signs/symptoms of infection”; improvement as “clear regression of clinical signs within 4 to 5 days without having entirely disappeared on completion of therapy.” Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 20%

Participants

Participants were recruited from academic, outpatient otolaryngology clinics. Participants were 33 years old on average (range 18 to 65) and included 25 men and 31 women. Country - Germany

Interventions

2 treatment arms Group 1: brodimoprim 200 mg once daily for 8 to 12 days Group 2: doxycycline 100 mg once daily for 8 to 12 days Only non-specific medications were allowed (most patients received concomitant medications, mainly nasal decongestants)

Outcomes

Clinical and radiographic outcomes were assessed in 56 out of 70 randomised patients. Outcomes were assessed on day 8 to 12 after randomisation. Bacteriological outcomes were reported in 50 patients

Notes

1 of the authors was affiliated to a pharmaceutical company


43

Arndt 1994

(Continued)

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical, radiological and bacteriological responses; and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Open study”

Incomplete outcome data addressed? Unclear risk (Clinical efficacy outcomes)

Quote: “In total 14 of 70 randomized participants had to be excluded shortly after the trial began due to negative culture at baseline or because some of them did not come back after the first visit” Comment: the missing data rates not reported by study group. It remains unclear how many participants were excluded because of negative culture in each group


Low risk



Low risk



Unclear risk



44

Arrieta 2007 Methods

Randomised, unblinded design. Diagnosis by clinical signs and symptoms lasting 7 to 28 days, confirmed by computed tomography or X-ray (criteria not specified). Culture by sinus puncture or endoscopy of middle meatus, or both (51% of participants had at least 1 causative organism identified before study entry). Clinical resolution was defined as total resolution of signs and symptoms related to acute sinusitis and, at least, improvement in the radiographic or computer tomographic scan appearance of the sinuses to the extent that no additional or alternative antimicrobial therapy was necessary. Treatment compliance unclearly reported. Proportion of the participants included in the per-protocol population was 80% on day 17 to 24 (there was no description of missing data)

Participants

Multicentre (31 centres), multinational trial (Argentina, Brazil, Chile and Mexico). Demographic data reported for per-protocol population at baseline: 459 outpatients, 172 men and 287 women; mean age was 37 years. ENT co-morbidity was not assessed

Interventions

2 treatment arms: Group 1: moxifloxacin 400 mg once daily for 7 days Group 2: amoxicillin-clavulanate 500/125 mg 3 times daily for 10 days Concomitant therapies were not reported

Outcomes

Study reported clinical resolution rates for intention-to-treat and per-protocol populations. However, only per-protocol population could be used as basis for clinical outcome calculating in this review because failure rates were not reported and there was no description of the reasons and amounts of missing data. Clinical outcomes for per-protocol population (patients who completed the course of treatment) were assessed on day 17 to 24 in 459 out of 575 randomised participants (in 226 out of 289 participants in moxifloxacin group and in 233 out of 286 participants in amoxicillin/clavulanate group) . Bacteriological outcomes for per-protocol population were assessed in 234 participants

Notes

Study supported by a pharmaceutical company but the authors stated that although they received a grant from the company to conduct the study, results were in no way modified in favour of the sponsor’s product. 4 of the authors were affiliated to the same pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response (including radiological findings), bacteriological response in 234 participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


45

Arrieta 2007

(Continued)


High risk



Missing data: 63/289 (22%) in moxifloxacin group and 53/286 (19%) in amoxicillin/clavulanate group on day 17 to 24 Comment: no description of reasons for missing data


Low risk

Comment: very detailed description of demographic characteristics and sinusitis severity rating with which to assess the comparability of the groups at baseline


Unclear risk



Unclear risk

Study supported by a pharmaceutical company but the authors stated that although they received a grant from the company to conduct the study, results were in no way modified in favour of the sponsor’s product. 4 of the authors were affiliated to the same pharmaceutical company

Axelsson 1970 Methods

Randomised trial. Blinding was not reported. Patients with clinically suspected sinusitis were radiologically examined; only patients with secretion were included. Secretion was confirmed by a single diagnostic irrigation for those with completely opaque maxillary sinuses. Clinical outcomes assessed by an investigator but “cure” and “improvement” were not defined. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 7% on day 10

Participants

The study setting was not described. It is unclear if participants were a convenience sample or a consecutive series of eligible patients. Participants were 33 years old on average (range 13 to 80) and included 62 men and 94 women. Patients with a history of nasal allergy were excluded. Country - Sweden

Interventions

4 treatment arms: (only groups 1 and 3 used in the analysis) Group 1: oxymetazoline only (no placebo control) Group 2: oxymetazoline plus sinus irrigation Group 3: oxymetazoline plus penicillin V 400 mg 3 times daily for 10 days Group 4: oxymetazoline plus lincomycin 500 mg 3 times daily for 8 days

Outcomes

Clinical outcomes were assessed in 142 out of 156 randomised participants (in 35 out of 38 patients in penicillin group and in 32 out of 34 patients in oxymetazoline group) . Outcomes were assessed on day 10 after randomisation. Radiographic outcomes were reported as mean number of severity points per sinus (not by patient)


46

Axelsson 1970

(Continued)

Notes

There was no identified funding source

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response, radiological response and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Unclear risk



Missing data: 8% (3/38) in penicillin group and 6% (2/34) in oxymetazoline group Comment: although the reasons for missing data were not stated, we decided to judge this domain ’low’ risk of bias because the missing data rates were equal and marginal in both groups


Low risk

Comment: detailed description of radiological sinusitis severity rating at baseline. It appears that the groups were balanced although the information on demographic characteristics was scarce


Low risk

Comment: both groups received the same co-intervention during the trial


Unclear risk


Boezeman 1988 Methods

Randomised, but unblinded trial. Diagnosis by clinical symptoms, confirmed by radiograph showing sinus opacity and positive culture taken near the ostium of, or by aspiration from, maxillary sinus. Clinical outcomes assessed by an investigator but a definition of clinical cure was not given. Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 18%

Participants

The study setting was not described. Outpatients were 30 years old on average (range 13 to 76) and included 23 men and 10 women. Country - The Netherlands


47

Boezeman 1988

(Continued)

Interventions

2 treatment arms Group 1: spiramycin 1000 mg twice daily for 10 days Group 2: doxycycline 200 mg on day 1 then 100 mg each day for 10 days Nasal decongestants were allowed but were not given as part of the study treatment

Outcomes

Clinical outcomes were assessed in 27 out of 33 randomised participants (in 15 out of 18 patients in doxycycline group and in 12 out of 15 patients in spiramycin group). Outcomes were assessed on day 11 after randomisation. Radiographic and bacteriological outcomes were reported for 27 out of 33 patients

Notes


Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical, radiological and bacteriological outcomes, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Exclusions from analyses: absence of pathogen in pretreatment cultures 3/15 in spiramycin group and 3/18 in doxycycline group; other missing data 0% Comment: the absence of pathogen was seen not to cause bias


High risk

Comment: the severity rating at baseline was different across the groups


Low risk



Unclear risk



48

Buchanan 2003 Methods

Randomised, double-blind design. Diagnosis by clinical signs and symptoms lasting at least 7 days, confirmed by radiograph showing at least 10 mm mucosal thickening, opacification or air fluid level in a sinus radiograph or CT. Bacteriological specimens were obtained by sinus puncture (in US sites) or endoscopy collection (non-US sites). Clinical cure assessed by investigators and defined as dichotomous - either cure or failure. Cure defined according to the following criteria: return to preinfection state, with no ABMS-related signs and symptoms present, as determined on a scale of 0 to 3 points in which 0 = absent, 1 = mild, and 3 = severe, supplemented by a sinus X-ray/CT scan confirming no worsening of infection or the presence of only those residual symptoms indicative of a normal course of clearance in the infection process, with no requirement for additional antibiotic treatment. Compliance among available patients was in average 95% (assessed by unused capsule count). Proportion of the participants included in the per-protocol clinically evaluable population was 72% on day 16 to 24

Participants

Multicentre, multinational trial (USA, Argentina, France, South Africa). 148 men and 208 women, mean age about 40 years (range from 14 to 84) ENT co-morbidity was not assessed

Interventions

2 treatment arms Group 1: telithromycin 800 mg once daily for 5 days Group 2: cefuroxime axetil 250 mg twice daily for 10 days Concomitant treatments were not described

Outcomes

Study reported clinical cure rates for modified intention-to-treat and per-protocol evaluable populations. However, only per-protocol evaluable population could be used as basis for clinical failure rate calculating in this review because true failures were not reported and indeterminate responses were included in failures in mITT analyses. Clinical outcomes for per-protocol evaluable population assessed on day 16 to 24 in 278 out of 385 randomised patients (in 189 out of 260 participants in telithromycin group and in 89 out of 125 participants in cefuroxime axetil group). Per-protocol clinically evaluable population defined as patients who met the diagnostic criteria, and had no major protocol violation. Bacteriologic outcomes assessed on day 16 to 24 in 149 patients. Radiologic outcomes were not reported

Notes

Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated to pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response (including radiological findings) and bacteriological response, and adverse effects


49

Buchanan 2003

(Continued)

Comment: prespecified outcomes (in methods) were reported in prespecified way Blinding? (Participant and investigator)

Low risk

Quote: “Double-blind”. “To ensure blinding matched placebo capsules were used in telithromycin group” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 71/260 (27%) in telithromycin group and 36/125 (29%) in cefuroxime axetil group on day 16 to 24 Comment: total missing data rate 28%


Unclear risk

Comment: information on comparability of intervention and control groups at baseline reported only for modified intentionto-treat population, not for per-protocol evaluable population which was used in the analyses


Unclear risk



High risk

Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated to pharmaceutical company

Burke 1999 Methods

Randomised, double-blind trial. Diagnosis by symptoms lasting 1 to 4 weeks and radiograph showing air-fluid level, opacity or at least 6 mm mucosal thickening. Clinical resolution was defined resolution or improvement of clinical symptoms and radiographic findings and no need for additional antimicrobial treatment. To be included in the efficacy-valid population the compliance had to be at least 80%. Proportion of the participants without known or reported clinical outcome 16%

Participants

Mixed otolaryngology and primary care. Mean age 40; 178 men, 279 women. Country - USA

Interventions

2 treatment arms Group 1: cefuroxime axetil 250 mg twice daily for 10 days Group 2: moxifloxacin 400 mg daily for 10 days Decongestants, antihistamines and phenylephrine drops were allowed; systemic or topical corticosteroids not allowed


50

Burke 1999

(Continued)

Outcomes

Study reported clinical cure rates for intention-to-treat and efficacy-valid populations but clinical failure rates only for efficacy-valid population. Clinical outcomes were assessed on day 17 to 24 in 457 out of 542 randomised patients (in 234 out of 275 participants in cefuroxime axetil group and in 223 out of 267 participants in moxifloxacin group). The efficacy-valid population defined as patients who met diagnostic criteria and were without major protocol violations. Radiographic outcomes not reported. Long-term follow-up on 37 to 41 days

Notes

Study supported by a research grant from a pharmaceutical company. 3 of the authors were affiliated to a pharmaceutical company

Risk of bias Bias




Quote: “Block-design random code” Comment: although the description of the sequence generation was incomplete, this domain was graded ’low’ risk of bias because description gives an impression of computer-based method


Unclear risk



Low risk

Outcomes reported: clinical response (including radiological findings) and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Medications were encapsulated in gelatin for masking purposes. Placebo capsules used in moxifloxacin group” Comment: although the description of the blinding was incomplete (regarding blinding of investigator), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 41/275 (15%) in cefuroxime axetil group and 44/267 (16%) in moxifloxacin group on day 17 to 24 Comment: the groups were balanced in numbers and reasons for missing data


51

Burke 1999

(Continued)


Low risk

Comment: although the proportion of patients with severe sinusitis was 47/223 (21%) in moxifloxacin group and 36/234 (15%) in cefuroxime axetil group, this domain was graded ’low’ risk of bias


Low risk



High risk

Study supported by a research grant from a pharmaceutical company. 3 of the authors were affiliated to a pharmaceutical company

Calhoun 1993 Methods

Randomised, single-blind trial (investigator). Diagnosis established by clinical symptoms and abnormal radiograph (criteria not reported). Clinical outcomes were assessed by an investigator. Clinical cure defined as signs and symptoms of infection resolved. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 18%

Participants

Consecutive patients were recruited from academic, primary care clinics. Mean age was 37 (range 14 to 77); 84 women and 58 men. ENT co-morbidity was not assessed. Country - USA

Interventions

2 treatment arms Group 1: clarithromycin 500 mg twice daily for 7 to 14 days Group 2: amoxicillin 500 mg 3 times daily for 7 to 14 days Both groups received oxymetazoline 2 sprays twice daily for 3 days

Outcomes

Clinical outcomes were assessed in 116 out of 142 randomised participants (in 55 out of 70 patients in clarithromycin group and in 61 out of 72 patients in amoxicillin group) . Outcomes were assessed on day 7 to 16 after randomisation. Radiographic outcomes were assessed in 116 out of 142 patients randomised. Bacteriological outcomes were not reported

Notes

Study was supported in part by a grant from a pharmaceutical company

Risk of bias Bias




52

Calhoun 1993

(Continued)




Unclear risk



Low risk

Outcomes reported: clinical and radiological responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “A third party dispensed the antibiotics and assessed compliance, ensuring the single-blind (investigator-blind) nature of the study. The single-blind design was necessary because of the difficulty in packaging the two drugs in identical capsules. Patients were instructed not to discuss the dosing schedule with their physicians” Comment: no blinding of the participants


Missing data: 15/70 (21.4%) in clarithromycin group and 11/72 (15.3%) in amoxicillin group Comment: all reasons for missing data were not reported by group


Low risk



Low risk



High risk



53

Camacho 1992 Methods

Randomised, single-blind design (investigator). Clinical diagnosis of acute sinusitis and an abnormal radiograph (mucosal thickening, opacity or air-fluid level). Sinus puncture performed. Clinical outcomes assessed by an investigator; cure defined as “resolution of clinical symptoms with radiographic evidence of sinus decongestion with no further therapy required”. Improvement defined as “clinical symptoms substantially reduced but radiographic evidence of residual sinus congestion”. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 25% on day 11 to 38

Participants

Patients were recruited from academic and community settings; probably otolaryngology practices. Mean age = 35 (range 18 to 79); 171 men and 146 women. ENT co-morbidity was not assessed. Countries - Brazil, Chile, Columbia, USA

Interventions

2 treatment arms Group 1: cefuroxime axetil 250 mg twice daily for 10 days Group 2: amoxicillin-clavulanate 500 mg 3 times daily for 10 days Concomitant therapies were not described

Outcomes

Clinical outcomes were assessed on day 11 to 38 in 239 out of 317 randomised participants (in 115 out of 157 participants in cefuroxime axetil group and in 124 out of 160 participants in amoxicillin-clavulanate group). Radiographic outcomes were not reported. Bacteriological outcomes were assessed in 76 participants

Notes

Study was supported in part by a pharmaceutical company

Risk of bias Bias




Quote: “Computer-generated randomized code”


Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response for a proportion of participants, adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Investigator-blinded”



Missing data: 42/157 (27%) in cefuroxime axetil group and 36/160 (23%) in amoxicillin-clavulanate group on day 11 to 38 Comment: total missing data over 20%

54

Camacho 1992

(Continued)


Unclear risk

Comment: information on comparability was insufficient to assess whether the groups were comparable at baseline or not


Unclear risk



High risk

Study was supported in part by a pharmaceutical company

Chatzimanolis 1998 Methods

Randomised, unblinded design. Diagnosis of acute or recurrent sinusitis documented by clinical and endoscopic findings, bacteriology (sinus puncture) and X-ray. Clinical cure not defined. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 7%

Participants

Study setting not described. Mean age 38; 34 men and 26 women. ENT co-morbidity not assessed. Country - Greece

Interventions

2 treatment arms Group 1: roxithromycin 150 mg twice daily for 10 to 14 days Group 2: amoxicillin-clavulanate (500 mg/ 125 mg) 3 times daily for 10 to 15 days Concomitant treatments not reported

Outcomes

Clinical outcomes reported on day 10 to 17 for 56 out of 60 randomised participants (for 29 out of 31 participants in roxithromycin group and for 27 out of 29 participants in amoxicillin-clavulanate group). Radiographic outcomes not reported by group

Notes

Study funded by a pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



55

Chatzimanolis 1998

(Continued)


Missing data: 2/31 (6.5%) in roxithromycin group and 2/29 (7%) in amoxicillin-clavulanate group Comment: the groups were balanced in numbers and reasons for missing data


Low risk



Unclear risk



High risk

Study funded by a pharmaceutical company

Clement 1998 Methods

Randomised, unblinded design. Clinical diagnosis of ethmoid or maxillary sinusitis confirmed by fibre-optic examination (purulent discharge from ostium of affected sinus) and computed tomography (criteria not specified). Pus samples were collected endoscopically for bacteriological culture. Clinical outcomes assessed by an investigator but were not defined. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 8% on day 10 to 14

Participants

Participants were recruited from otolaryngology clinics. Mean age 41; 103 men, 151 women. ENT co-morbidity not assessed. Country - Belgium

Interventions

2 treatment arms Group 1: azithromycin 500 mg daily for 3 days Group 2: amoxicillin 500 mg/clavulanic acid 125 mg 3 times daily for 10 days Concomitant therapies (decongestants, corticosteroids, mucolytics) were allowed but not prescribed. 133 participants used a concomitant treatment

Outcomes

Clinical outcomes were assessed on day 10 to 14 in 233 of 254 participants (in 151 out of 165 participants in azithromycin group and in 82 out of 89 participants in amoxicillinclavulanate group) and on day 21 to 28 in 210 of 254 participants. Bacteriological outcomes were assessed in 100 participants

Notes

Study funding provided by a pharmaceutical company

Risk of bias Bias


Random sequence generation (selection Unclear risk bias) Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement No information provided

56

Clement 1998

(Continued)


Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response for a proportion of participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Missing data: 14/165 (8.5%) in azithromycin group and 7/89 (7.9%) in amoxicillinclavulanate group on day 10 to 14. Total missing data 8% on day 10 to 14 and 17% on day 21 to 28 Comment: the groups appeared to be balanced in numbers and reasons for missing data. Available case data given for both follow-ups


Low risk



Unclear risk

Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed. Corticosteroids may have effect on recovery but their use was not reported


High risk


Clifford 1999 Methods

Randomised, double-blind trial. Participants with acute sinusitis and acute exacerbation of chronic sinusitis included. Proportion of the participants with acute sinusitis 75% and their results reported separately. Clinical diagnosis, confirmed by radiograph showing airfluid level, opacification or at least 6 mm mucosal thickening. Cure defined as symptom resolution and radiographic improvement. Proportion of the participants without known or reported clinical outcome 18% for the whole study population including participants with acute sinusitis and participants with acute exacerbation of chronic sinusitis

Participants

Study setting not described. Mean age approximately 41 (range 18 to 76); 187 men and 270 women. 25% of participants with acute exacerbation of chronic sinusitis in efficacyvalid population. About 26% of participants had allergic rhinitis. Country - USA


57

Clifford 1999

(Continued)

Interventions

2 treatment arms Group 1: ciprofloxacin 500 mg twice daily for 10 days Group 2: clarithromycin 500 mg twice daily for 14 days Decongestants allowed. Nasal corticosteroids prohibited

Outcomes

Clinical outcomes for participants with acute maxillary sinusitis were separately reported only for efficacy-valid population (342 participants at day 14). Efficacy-valid population was defined as participants who completed the course of treatment and did not use other antimicrobial agents concomitantly with the study drug. Radiographic outcomes not reported

Notes

Study supported by a research grant from a pharmaceutical company

Risk of bias Bias




Quote: “The patients were randomly assigned to 1 of 2 treatment groups by means of a block design random code computergenerated”


Low risk

Comment: central allocation (randomisation made at a pharmaceutical company)


Low risk

Outcomes reported: clinical response (including radiographic findings) and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind”. “The study drugs were encapsulated in gelatin capsules for blinding purposes. Matched placebos used” Comment: although the description of the blinding was incomplete (in respect of investigator-blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described



Comment: missing data not described separately for the participants with acute sinusitis and participants with acute exacerbation of chronic sinusitis

58

Clifford 1999

(Continued)


Low risk



Low risk



High risk

Study supported by a research grant from a pharmaceutical company

Desrosiers 2008 Methods

Randomised, unblinded trial. Diagnosis by clinical signs and symptoms lasting for 7 to 28 days (purulent nasal discharge; 1 additional major sign and symptom (facial pain/ pressure/tightness over the maxillary sinuses; nasal congestion/obstruction, hyposmia/ anosmia; fever) or 2 minor signs and symptoms (headache, halitosis, dental pain, ear pressure/fullness, cough, fatigue)), confirmed by abnormal maxillary sinus X-rays or limited sinus computed tomography scans or sinus ultrasound (at least 1 of the following: air/fluid level, total opacification, mucosal thickening at least 10 mm). Samples for microbiological analysis were taken by using rhinoscopic aspiration or micro-swabbing of the maxillary sinus (middle meatus). Clinical outcome was defined as “success”, “failure” or “indeterminate” (success was defined as cured or improved). Clinical failure was recorded if at least on the following criteria was met: all signs/symptoms remained unchanged or had worsened, at least 1 additional antibiotic had to be prescribed and/ or added to the study treatment for sinusitis, sinusitis-related complications occurred, sinus puncture or drainage had been performed. Treatment compliance at least 80% for those patients who were included in the per-protocol population. Proportion of the participants included in the per-protocol population was 83% on day 17 to 21

Participants

Multicentre (41 centres), multinational trial (Canada, Germany, Greece, Portugal and Turkey). Demographic data reported for modified intention-to-treat population at baseline: participants’ mean age was 39 years; 109 men and 181 women. ENT co-morbidity was assessed; 1 participant had allergic rhinitis, 2 participants had chronic sinusitis and 5 participants had nasal septal deviation

Interventions

2 treatment arms Group 1: telithromycin 800 mg once daily for 5 days Group 2: amoxicillin-clavulanate 875/125 mg twice daily for 10 days Concomitant therapies were not clearly reported

Outcomes

Study reported clinical cure rates for modified intention-to-treat and per-protocol populations. However, only per-protocol population could be used as basis for clinical failure rate calculating in this review because true failures were not reported and it seemed that indeterminate and missing responses were included in failures in mITT analyses.


59

Desrosiers 2008

(Continued)

Clinical outcomes for per-protocol population were assessed in 248 of 298 randomised participants on day 17 to 21 and on day 41 to 49. Per-protocol population was defined as all randomised participants with clinically and radiographically confirmed sinusitis, and were without major protocol violations. Bacteriological outcomes reported for 103 participants on day 17 to 21. Health-related quality of life measured by SF-36 questionnaire completed by 278 participants at baseline, and on day 41 to 49 Notes


Risk of bias Bias




Quote: “Centrally generated randomization list”


Low risk

Quote: “Centrally generated randomization list”


Low risk

Outcomes reported: clinical response, bacteriological response for a proportion of participants, quality of life and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk




8 out of 298 randomised participants were excluded at the beginning of the study because of the unconfirmed sinusitis. No information provided how these participants were divided across the 2 groups. Calculating missing data by group was therefore based on the modified intentionto-treat (mITT) population (290 participants) which was defined as all randomised participants with clinically and radiographically confirmed sinusitis, and who received at least 1 dose of study medication Missing data: 21/144 (14.6%) in telithromycin group and 21/146 (14.4%) in amoxicillin-clavulanate group on day 17 to 21 Comment: groups appeared to be balanced in numbers and reasons for missing data

60

Desrosiers 2008

(Continued)


Low risk



Unclear risk

Concomitant therapies were not clearly reported


High risk


Dubois 1993 Methods

Randomised, single-blind (investigator) trial. Diagnosis established by symptoms, an abnormal maxillary radiograph (minimum criteria were not given) and a positive culture of sinus fluid (collected by puncture or endoscopically). Clinical outcomes assessed by an investigator; ”cure“ defined as pretreatment signs and symptoms resolved; ”improvement“ defined as improved but not resolved.” Treatment compliance not reported but participants had to take at least 70% of prescribed treatment to be included in the efficacy analysis. Total proportion of the participants without known clinical outcome 48%. Patients were excluded mostly due to negative culture; exclusions because of other reasons marginal 3.4%

Participants

Participants were recruited from outpatient ENT and primary care settings. It is unclear if the study sample represents a consecutive series of participants or a convenience sample. Country - Canada

Interventions

2 treatment arms Group 1: clarithromycin 500 mg every 12 hours for a maximum of 14 days Group 2: amoxicillin-clavulanate 500 mg every 8 hours for a maximum of 14 days Both groups received oxymetazoline 0.05% nasal sprays twice daily for the first 3 days

Outcomes

Clinical, radiographic and bacteriological outcomes were assessed in 260 out of 497 randomise participants (in 132 out of 246 participants in clarithromycin group and in 128 out of 251 participants in amoxicillin-clavulanate group). Outcomes were assessed on about day 15 after randomisation

Notes


Risk of bias Bias







Unclear risk


61

Dubois 1993

(Continued)


Low risk

Outcomes reported: clinical, radiological and bacteriological responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Investigators were blind to the drug being administered” Comment: no description of blinding of the participants


Exclusions from analyses: absence of pathogen in pretreatment cultures 103/246 in clarithromycin group and 117/251 in amoxicillin-clavulanate group; other exclusions 10 (4.1%) and 7 (2.8%) of participants in clarithromycin group and amoxicillin-clavulanate group, respectively Comment: the absence of pathogen was seen not to cause bias. Other missing data marginal


Low risk



Low risk

Comment: both groups received the same co-intervention during the first 3 days


High risk


Ferguson 2004 Methods

Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed by radiograph showing at least 10 mm mucosal thickening, total sinus opacity or airfluid level in a sinus radiograph. Pretreatment cultures of rhinoscopic aspirations or deep nasal Calgiswab samples were compared with cultures taken at 17 to 24 days of followup. Clinical success was defined: the patient was either cured or showed improvement relative to baseline (including no worsening of radiological findings) without addition of a new antibiotic. Treatment compliance reported as over 90% assessed by capsule counts. Proportion of the participants included in the per-protocol population was 78% on day 17 to 24

Participants

Multicentre study, 41 sites in USA. Median age approximately 45 (range 18 to 85); 123 men and 199 women. ENT co-morbidity not described


62

Ferguson 2004

(Continued)

Interventions

2 treatment arms Group 1: telithromycin 800 mg once daily for 5 days Group 2: moxifloxacin 400 mg once daily for 10 days

Outcomes

Study reported clinical success rates for modified intention-to-treat and per-protocol populations. However, only per-protocol population could be used as basis for clinical response calculating in this review because true failures were not reported and all instances of not completing the study were included in failures in mITT analyses. Clinical outcomes for per-protocol population were assessed at days 17 to 24 in 272 of 349 randomised participants (in 135 out of 173 participants in telithromycin group and in 137 out of 176 participants in moxifloxacin group). The per-protocol population was defined as all randomised participants who received at least 1 dose of study medication and had signs and symptoms of acute maxillary sinusitis and radiologic findings supporting the diagnosis and were without major protocol violations. Long-term follow-up at 31 to 36 days. Bacteriological outcomes were assessed in 67 participants

Notes

Study supported by a grant from a pharmaceutical company. 4 of the authors had received research support/grants from and/or acted as consultants for the same pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response (including radiologic findings), bacteriological response in 67 participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Placebocapsules used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described



Missing data: 38/173 (22%) in telithromycin group and 39/176 (22%) in moxifloxacin group on day 17 to 24 Comment: missing data over 20%, insuffi63

Ferguson 2004

(Continued)

cient description of reasons for missing data Free of other bias? Baseline comparability

Unclear risk

Comment: information on comparability was insufficient to assess whether the groups were comparable at baseline or not (information given for mITT population, not for per-protocol population)


Unclear risk



High risk

Study supported by a grant from a pharmaceutical company. 4 of the authors had received research support/grants from and/ or acted as consultants for the same pharmaceutical company


64

Garbutt 2012 Methods

Randomised, placebo-controlled trial. Clinical diagnosis of acute sinusitis was based on clinical findings, with history of maxillary pain or tenderness in the face or teeth, purulent nasal secretions, and rhinosinusitis symptoms for 7 days or more and 28 days or less that were not improving or worsening, or rhinosinusitis symptoms lasting for less than 7 days that had significantly worsened after initial improvement. The symptoms had to be moderate, severe or very severe. Mean duration of symptoms was 11 days in both groups (median 10.0, interquartile range (25th to 75th percentile) 7.0 to 14.0). Because the proportion of the participants with symptoms less than 7 days was small (14%), and because the reason to include those patients was that patients’ symptoms had significantly worsened, this study was included in this review Clinical outcomes were assessed by telephone interview using a structured questionnaire. Participants used a 6-point scale (a lot or a little worse or better, the same or no symptoms) to retrospectively assess symptom change since enrolment. Those reporting their symptoms as a lot better or absent were categorised as significantly improved. In total, 23 participants (14%) (11 in the amoxicillin group and 12 in placebo group) did not complete the 10-day course of treatment. Sixteen were treated with another antimicrobial (5 in the amoxicillin group and 11 in the placebo group). Proportion of the participants without known or reported clinical outcome 7% on day 7; and 8% on day 10; and 4% on day 28. Follow-up time chosen for analyses of this review was 10 days. The 7-day follow-up was not used because the treatments lasted for 10 days. The 28 day follow-up was not considered because the outcome measure at this time point was recurrence or relapse and did not include all failures, and thus the outcome is not in accordance with the outcome definition of this review. The study was not considered in the primary analysis of this review because it remained unclear whether the patients who received rescue therapy were classified as non-improved or not The results, as reported in the original article, are presented in the Results section

Participants

Participants recruited from 10 offices of primary care physicians. 60 men and 106 women; mean age 32 (range 18 to 69) years. Allergic rhinitis in 32%, asthma in 11% and history of sinus disease in 74% of participants in each group. Smokers 13% in amoxicillin and 26% in placebo group. Country - USA

Interventions

2 treatment arms Group 1: amoxicillin 500 mg 3 times daily for 10 days Group 2: placebo 3 times daily for 10 days Concomitant therapies All patients received a 5 to 7-day supply of the following symptomatic treatments to be used as needed: acetaminophen for pain or fever at a dose of 500 mg every 6 hours, guaifenesin to thin secretions at a dose of 600 mg every 12 hours, 10 mg/5ml of dextromethorphan hydrobromide and 100 mg/5 ml of guaifenesin for cough at a dose of 10 ml every 4 to 6 hours, pseudoephedrine-sustained action for nasal congestion at a dose of 120 mg every 12 hours, and 0.65% saline spray using 2 puffs per nostril as needed Concurrent use of symptomatic treatments was 92% and did not vary by study group. No new nasal steroid use was reported


65

Garbutt 2012

(Continued)

Outcomes

Clinical outcomes were assessed on day 7 in 155 of 166 randomised participants (in 80 out of 85 participants in amoxicillin group and in 75 out of 81 participants in placebo group), on day 10 in 152 of 166 randomised participants (in 81 out of 85 participants in amoxicillin group and in 71 out of 81 participants in placebo group), and on day 28 in 159 of 166 randomised participants (in 82 out of 85 participants in amoxicillin group and in 77 out of 81 participants in placebo group) Outcomes were assessed by telephone interview using a structured questionnaire. Participants used a 6-point scale (a lot or a little worse or better, the same or no symptoms) to retrospectively assess symptom change since enrolment Analyses were based on the intention-to-treat principle (all of the eligible participants as randomised)

Notes

Study supported by a grant from the National Institute of Allergy and Infectious Diseases, which did not have a role in the design and conduct of the study, management and analysis of data, or in the preparation, review or approval of the manuscript

Risk of bias Bias




Quote: “Using a blocked randomization scheme, computer-generated random numbers were used to determine how the 2 study drugs were allocated to the consecutively numbered study treatment packages”


Low risk

Quote: “Randomisation was performed in advance by the investigational pharmacist who did not participate in patient enrolment or outcome assessment. Randomisation occurred when the research assistant assigned the treatment package”


Low risk

Outcomes reported: clinical responses, quality of life and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Placebo was similar in appearance and taste and dispensed in the same fashion than the antibiotic. Telephone interviews were conducted by trained research assistants blinded to group assignment”



Missing data: in amoxicillin group 5/85 (5. 9%) and in placebo group 6/81 (7.4%) on day 7; 4/85 (4.7%) and 10/81(12.3%) on day 10; and 3/85 (3.5%) and 4/81 (4.9%) 66

Garbutt 2012

(Continued)

on day 28, respectively Total missing data rates 6.6% on day 7; and 8.4% on day 10; and 4.2% on day 28 Comment: although the authors gave additional information that participants simply missed the interviews and there was probably not any systematic difference in reasons for drop-outs between the groups, we graded this domain ’unclear’ risk of bias at day 10. Although the difference in dropout rates between groups was not statistically significant (P value 0.077), difference in proportions of missing outcomes (7.6%) compared to the difference of anticipated failure risks (10% to 20%) may be big enough to cause bias Free of other bias? Baseline comparability

Low risk



Low risk

Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect on recovery (thus did not cause bias) Concurrent use of symptomatic treatments was 92% and did not vary by study group. No new nasal steroid use was reported


Low risk

Comment: no pharmaceutical company funding

Gehanno 1996a Methods

Randomised, unblinded study. Diagnosis established by clinical symptoms and radiograph showing sinus opacity or air-fluid level. Culture based on the sample from the middle meatus; 79% of participants had positive cultures. Clinical outcomes assessed by investigator; cure defined as resolution of facial pain, purulent discharge, air-fluid level by radiograph and no recurrence of symptoms. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 7%

Participants

Multicentre study, 284 outpatients; 136 men and 148 women. Mean age was 40. Fewer than 25% of participants had concurrent allergic disease. Country - France


67

Gehanno 1996a

(Continued)

Interventions

2 treatment arms Group 1: clarithromycin 500 mg daily for 8 days Group 2: amoxicillin-clavulanic acid 500 mg 3 times daily for 8 days Intranasal decongestants were allowed

Outcomes

Clinical outcomes were assessed on about day 10 in 263 out of 284 randomised participants (in 134 out of 145 participants in clarithromycin group and in 129 out of 139 participants in amoxicillin-clavulanate group). Radiographic and bacteriological outcomes were not reported

Notes

2 of the authors were affiliated to a pharmaceutical company

Risk of bias Bias




Central randomisation (computer-generated?)


Low risk

Central random allocation


Low risk



High risk



Missing data: 11/145 (7.6%) in clarithromycin group and 10/139 (7.2%) in amoxicillin-clavulanate group on day 10 Comment: the groups appeared to be balanced


Low risk



Low risk



Unclear risk



68

Gehanno 1996b Methods

Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed by radiograph (criteria not reported) and/or bacteriological culture of the middle meatus aspirate (76% of participants had a positive culture). Clinical success defined as resolution of all signs and symptoms. Treatment compliance was not reported. Total proportion of the participants without known or reported clinical outcome 21%. Patients were excluded mostly due to normal sinus X-ray and a negative bacteriological culture at inclusion; exclusions because of other reasons 6%

Participants

Multicentre study. 376 outpatients; 160 men and 216 women, mean age about 41 years. ENT co-morbidity was not assessed. Country - France

Interventions

2 treatment arms Group 1: sparfloxacin 200 mg for 5 days Group 2: cefuroxime axetil 250 mg twice daily for 8 days

Outcomes

Clinical outcomes were assessed on days 10 to 12 in 302 of 382 randomised participants (in 153 out of 193 participants in the sparfloxacin group and in 149 out of 189 participants in the cefuroxime axetil group)

Notes

There was no identified funding source. However, 2 pharmaceutical companies were mentioned in the methods section

Risk of bias Bias






Low risk

Central allocation by a pharmaceutical company


Low risk

Outcomes reported: clinical response, overall response (included clinical, radiological and bacteriological efficacy) and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Blinding was prepared by a pharmaceutical company and maintained throughout the study. Placebo-tablets used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


69

Gehanno 1996b

(Continued)


Exclusions from analyses on day 10 to 12: normal sinus X-ray and a negative bacteriological culture at inclusion 28/193 in the sparfloxacin group and 29/189 in the cefuroxime axetil group; other exclusions 12 (6%) and 11 (6%) of participants in the sparfloxacin and cefuroxime axetil group, respectively Comment: exclusions because of lack of inclusion criteria were seen not to cause bias. The groups appeared to be balanced in numbers and reasons for missing data


Unclear risk

Comment: detailed description of demographic characteristics and sinusitis severity rating at baseline to assess the comparability of the groups for whole randomised population, not separately for the efficacy evaluable population


Unclear risk



Unclear risk

There was no identified funding source. However, 2 pharmaceutical companies were mentioned in the methods section

Gehanno 1998 Methods

Randomised, unblinded trial. Diagnosis by symptoms and radiograph showing > 5 mm mucosal thickening, sinus opacity or air-fluid level. A causative pathogen was isolated in the pus sample at study entry, in 51% of the 241 participants enrolled. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 2% on day 10 to 12

Participants

Participants recruited from community-based otolaryngology clinics. Mean age 42; 105 men and 136 women. Country - France

Interventions

2 treatment arms Group 1: cefatrizine 500 mg twice daily for 10 days Group 2: amoxicillin-clavulanate 500 mg 3 times daily for 10 days Vasoconstrictors and paracetamol allowed

Outcomes

Clinical outcomes assessed on days 10 to 12 in 236 out of 241 randomised participants (in 121 out of 123 participants in cefatrizine group and in 115 out of 118 participants in amoxicillin-clavulanate group). Second follow-up on day 30. Radiographic outcomes assessed in 214. Bacteriologic outcomes not reported

Notes



70

Gehanno 1998

(Continued)

Risk of bias Bias




Quote: “Central random allocation” (computer-generated?)


Low risk

Quote: “Central random allocation”


Low risk

Outcomes reported: clinical and radiographic responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Missing data: 2/123 (1.6%) in cefatrizine group and 3/118 (2.5%) in amoxicillinclavulanate group on days 10 to 12. Total missing data rate 2% on day 10 to 12 and 4.5% at day 30 Comment: marginal missing data rate


Low risk



Low risk



Unclear risk


Gehanno 2004 Methods

Randomised, double-blind design. Diagnosis by clinical signs and symptoms, confirmed by radiograph showing at least 5 mm mucosal thickening, opacity or air-fluid level. A rhinoscopic bacteriologic sampling was made on the middle nasal meatus (cultures were positive in 46% of participants). Clinical cure based on resolution of symptoms. Treatment compliance for per-protocol population 98%. Proportion of the participants without known or reported clinical outcome 11%


71

Gehanno 2004

(Continued)

Participants

Participants were recruited by otorhinolaryngologists. The mean age of the participants was 43 years; women 60% and men 40%. Multinational trial (France, Tunisia, Poland, Argentina)

Interventions

2 treatment arms Group 1: pristinamycin 1 g BID for 4 days Group 2: cefuroxime axetil 250 mg BID for 5 days Topical vasoconstrictors prescribed for 3 days. Anti-inflammatory analgesic allowed. Corticosteroids and mucolytics prohibited

Outcomes

Study reported clinical cure rates for modified intention-to-treat and per-protocol populations. However, only per-protocol population could be used as basis for clinical failure rate calculating in this review because true failures were not reported in mITT population. Clinical outcomes were assessed on day 12 to 19 in 434 out of 485 randomised participants (in 220 out of 250 participants in pristinamycin group and in 214 out of participants 235 in cefuroxime axetil group). The per-protocol population was defined as participants who met the diagnostic criteria (radiologically confirmed) and had no major protocol violation. Bacteriological outcomes reported in 199

Notes

Study was supported by a pharmaceutical company. 3 of the authors were affiliated with the same pharmaceutical company

Risk of bias Bias




Comment: although the description of the sequence generation was incomplete, this domain was graded ’low’ risk of bias because description gives an impression of computer-based method


Low risk

Quote: “Central allocation in blocks of 4”


Low risk

Outcomes reported: clinical responses, bacteriological response in 199 and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Placebotablets used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


72

Gehanno 2004

(Continued)


Missing data: 30/250 (12%) in pristinamycin group and 21/235 (9%) in cefuroxime axetil group on day 12 to 19 Comment: the groups appeared to be balanced in numbers and reasons for missing data


Low risk



Low risk



High risk

Study was supported by a pharmaceutical company. 3 of the authors were affiliated with the same pharmaceutical company

Gwaltney 1997 Methods

Randomised, investigator-blind design. Clinical diagnosis confirmed by radiograph (criteria not specified). Bacterial cultures obtained by sinus aspirations. Cure and improvement reported as combined outcome. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 19% on day 7 to 14

Participants

Study setting not described. Median age 35; 789 men and 1009 women. ENT comorbidity not described. Countries - USA and Europe

Interventions

3 treatment arms Group 1: cefdinir 600 mg once daily for 10 days Group 2: cefdinir 300 mg twice daily for 10 days Group 3: amoxicillin-clavulanate (500 mg) 3 times daily for 10 days Concomitant treatments not reported Group 1 and Group 3 used in the analysis

Outcomes

Clinical outcomes reported at day 7 to 14 in 1446 out of 1798 people randomised (in 474 out of 585 participants in cefdinir 600 mg once daily group and in 491 out of 603 participants in amoxicillin-clavulanate group). Long-term follow-up at 3 to 5 weeks for participants cured or improved at the first follow-up. Radiographic outcomes not reported. Bacteriological outcomes not reported by group

Notes

3 of the authors were affiliated with a pharmaceutical company


73

Gwaltney 1997

(Continued)

Risk of bias Bias






Low risk

Quote: “Medications were dispensed by a third party, and all records regarding study medication were kept at a separate site”


Low risk

Outcomes reported: clinical and bacteriological responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Investigator-blind study”. “Patients were instructed to with-hold details of study medication appearance and dosing schedule”


Missing data: 111/585 (19%) in cefdinir 600 mg once daily group and 112/603 (19%) in amoxicillin-clavulanate group on day 7 to 14 Quote: “The 3 groups were comparable in the reasons for their non-evaluability” Comment: the groups appeared to be balanced in numbers and reasons for missing data on day 7 to 14 Additional missing data at 3 to 5 weeks compared to the first follow-up about 12%. Data not used in the long-term follow-up meta-analysis


Unclear risk



Unclear risk



Unclear risk



74

Hadley 2010 Methods

Randomised (2:1), double-blind, multicentre, phase III trial. Diagnosis by clinical signs and symptoms present for at least 7 days (but less than 28 days) as defined by radiographic and clinical criteria. Radiographic criteria included the presence of air-fluid levels and/or opacification on a radiographic paranasal sinus film. Eligible patients had to be at least 18 years of age and had to have 2 major symptoms (purulent anterior or posterior nasal discharge and unilateral facial pain or malar tenderness) or at least 1 major and 1 minor symptom (frontal headache or fever). A sinus puncture for bacterial culture of the sinuses was performed; only culture positive patients with target pathogen (S. pneumoniae, H. influenzae, M. catarrhalis, Streptococcus pyogenes or Staphylococcus aureus) were included in the analyses. Clinical cure was defined as resolution or improvement in the signs and symptoms such that no further therapy (antimicrobial, corticosteroid or irrigation) was required. Patients who received rescue therapy were deemed clinical failures. Compliance not reported for modified intention-to-treat population (which was used in the primary analyses) but in the per-protocol population 80% compliance was required. Total proportion of the participants without known clinical outcome 68%. Patients were excluded mostly due to negative culture or non-target pathogen in it; exclusions because of other reasons 6% on day 6 to 8 The study was not considered in the primary analysis because the way of reporting left the exact numbers of failures somewhat unclear. Further, the data were not seen to be comparable with the data from the other trials (the clinical response was measured already at days 6 to 8 after start of therapy while other studies included in the meta-analyses did it at days 10 to 14; unlike the other placebo-controlled trials, in this study isolation of pathogenic bacteria from the sinus secretion was a prerequisite for inclusion) The results at day 6 to 8, as reported in the original article, are presented in the Results section The study was, however, included in the analysis of “clinical failure defined as a lack of full recovery or improvement at 16 to 60 days follow-up” (but not pooled)

Participants

Participants recruited from 37 centres (ear, nose and throat practices, family practitioners and general medical clinics). Mean age 39 years; 45 men and 73 women (in modified intention-to-treat population; 118 out of 374 randomised). ENT co-morbidity was not assessed. Country - USA

Interventions

2 treatment arms Group 1: moxifloxacin 400 mg once daily for 5 days Group 2: placebo once daily for 5 days The following concomitant medications were allowed: oral or nasal decongestants or antihistamines, nasal sprays and nasal inhalants containing corticosteroids or corticosteroids used as broncho-inhalants if the patient had been on a stable dose for over 4 weeks prior to enrolment and there was no increase of their dose during the study period

Outcomes

The modified intention-to-treat population was the main analysis population and consisted of all patients who received at least 1 dose of study drug and whose initial quantitative culture was positive. Clinical outcomes were assessed on day 6 to 8 and on day 20 to 26 in 118 of 374 randomised participants (in 73 out of 251 participants in moxifloxacin group and in 45 out of 123 participants in placebo group). No radiological or


75

Hadley 2010

(Continued)

bacteriological outcomes Notes

Study supported by a pharmaceutical company. 3 of the 6 authors were employees of the same pharmaceutical company

Risk of bias Bias



Support for judgement Quote: “multicenter, placebo-controlled, 2:1 randomized, double-blind, phase IIIb clinical trial” Comment: no detailed information provided


Unclear risk



Low risk

Outcomes reported: clinical response during therapy and at follow-up, patient-reported symptom improvement, questionnaire scores, assessment of activity impairment via questionnaire and safety Comment: prespecified outcomes (in methods) were reported in prespecified way


Unclear risk

Quote: “Double-blinded trial, matching placebos” Comment: no detailed information provided


Exclusions from analyses: negative culture or non-target pathogen 161/251 (64%) in moxifloxacin group and 72/123 (58.5%) in placebo group; other exclusions 17 (6. 8%) and 6 (4.9%) of participants in moxifloxacin group and placebo group, respectively, on day 6 to 8 and on day 20 to 26 Comment: non-target pathogen or absence of pathogen was seen not to cause bias. Other missing data were balanced in numbers and reasons across the groups


Comment: in the placebo group there were 9% more bilateral sinus infections than in the moxifloxacin group (38% versus 29%) and no by-group description was provided on allowed concomitant medications (es-

Unclear risk


76

Hadley 2010

(Continued)

pecially stable-use nasal corticosteroids) Free of other bias? Co-interventions

Unclear risk

Comment: no detailed description of the use of co-interventions (especially nasal corticosteroids which may have also curative effect)


High risk

Study supported by a pharmaceutical company. 3 of the 6 authors were employees of the same pharmaceutical company

Haye 1996 Methods

Randomised, double-blind design. Diagnosis established clinically (symptoms lasting for 10 to 30 days) and radiograph showing at least 6 mm mucosal thickening. Culture was not done. Clinical outcomes assessed by investigator; cure defined as “disappearance of all pretreatment symptoms relevant to infection.” Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 0.9% on day 10 to 12

Participants

Patients recruited from general practices in Norway; 150 men and 288 women. Mean age 40 (range 19 to 71). ENT co-morbidity was not assessed. Country - Norway

Interventions

2 treatment arms Group 1: azithromycin 500 mg daily for 3 days Group 2: phenoxymethylpenicillin 1.3 g 3 times daily for 10 days

Outcomes

Clinical outcomes were assessed on day 10 to 12 in 434 out of 438 randomised participants and on day 23 to 27 in 436 out of 438 participants. Radiographic and bacteriological outcomes were not reported

Notes

1 of the authors had affiliation to a pharmaceutical company

Risk of bias Bias




Quote: “Patients were computer-randomised in blocks of six to one of two treatment groups”


Comment: although there is no exact information on how the randomisation result was concealed, the method of sequence generation and information that placebo tablets were used give the impression that the concealment was real

Low risk


77

Haye 1996

(Continued)


Low risk

Outcomes reported: clinical responses and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind, double-dummy study. Placebo-tablets were used” Comment: although the description of the blinding was incomplete (in respect of investigator-blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 4/438 on day 10 to 12 and 2/438 participants on day 23 to 27 Comment: marginal missing data rates


Low risk



Low risk

Quote: “In addition to the clinical assessment, the amount of analgesics taken, compliance, concomitant medication, and adverse events were recorded” Comment: although there was no information on use of analgesics or concomitant medication, this domain was graded ’low’ risk of bias, because the way of reporting gives an impression that use of analgesics and concomitant medication was allowed for both groups but of such quality that they would not cause bias


Unclear risk



78

Haye 1998 Methods

Randomised, double-blind, double-dummy design. Clinical diagnosis of acute sinusitis was based on clinical findings, which had to include 1 or both of the following signs: presence of nasal secretion (purulent at the time of examination) for > 10 and < 30 days, and maxillary sinus tenderness and/or pain of < 30 days duration (87% had both signs). Radiograph was taken to exclude participants with more than 6 mm mucosal thickening, complete opacity or an air-fluid level. Samples of nasal secretions (cotton-tipped swabs) were taken from the posterior part of the nasal cavity in 75 participants (only some samples had the growth of pathogenic bacteria). Clinical failure defined as no change or a worsening of the pretreatment symptoms and relapse if there was initial improvement or disappearance of pretreatment symptoms followed by worsening (failure and relapse figures are combined in the analyses in this review). Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 0.6% on day 10 to 12

Participants

Patients recruited from Norwegian General Practices. 44 men and 125 women; mean age 40 (range 21 to 70) years in the azithromycin group and 43 (range 18 to 68) years in placebo group. ENT co-morbidity was not assessed. Country - Norway

Interventions

2 treatment arms Group 1: azithromycin 500 mg once daily for 3 days Group 2: placebo once daily for 3 days

Outcomes

Clinical outcomes were assessed on day 10 to 12 in 168 out of 169 participants randomised (in 86 out of 87 patients in antibiotic group and in 82 out of 82 participants in placebo group) and on day 23 to 27 in 169 participants

Notes


Risk of bias Bias




Quote: “Patients were computer-randomised in blocks of six to either of the two treatment groups”


Low risk

Comment: although there is no exact information on how the randomisation result was concealed, the method of sequence generation and information that the tablets were indistinguishable from each other give the impression that the concealment was real


Low risk



79

Haye 1998

(Continued)


Low risk

Quote: “Double-blind, double-dummy study. The azithromycin and placebo tablets were indistinguishable” Comment: although the description of the blinding was incomplete (in respect of investigator-blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and double-dummy, and blinding method was partly described


Missing data: 0.6% at 10 to 12 days, and 0% at 23 to 27 days Comment: minimal missing data rates


Low risk



Low risk

Quote: “In addition to the clinical assessment, the amount of analgesics taken, compliance, concomitant medication, and adverse events were recorded” Comment: although there was no information on use of analgesics or concomitant medication, this domain was graded ’low’ risk of bias, because the way of reporting gives an impression that use of analgesics and concomitant medication was allowed for both groups but of such quality that they would not cause bias


Unclear risk



80

Henry 2003 Methods

Randomised, double-blind study. Diagnosis by clinical signs and symptoms (presence of either purulent nasal discharge or facial pain and/or pressure and/or tightness for 7 to 28 days), confirmed radiologically by presence of opacity or air-fluid level or mucosal thickening of more than 6 mm. Mean duration of symptoms prior to enrolment about 13 days. Clinical response was assessed by investigator; cure was defined as resolution of signs and symptoms to the level that existed prior to the occurrence of the acute illness; improvement defined as partial but incomplete resolution of the signs and symptoms. Compliance was measured by investigators reporting exact doses taken, reasons for missed doses and the amounts of study medication returned by participants at the end of therapy visit. Compliance was reported as 99% in the 3-day azithromycin group and 82% in the amoxicillin-clavulanate group. Proportion of the participants included in the perprotocol population was 85% on day 8 to 15

Participants

Multicentre study. 936 outpatients, 381 men and 555 women; mean age was 41 years (range 18 to 84). Allergic rhinitis was reported in 39% of participants. Country - USA

Interventions

3 treatment arms: (only groups 1 and 3 used in the analysis) Group 1: azithromycin 500 mg once daily for 3 days Group 2: azithromycin 500 mg once daily for 6 days Group 3: amoxicillin-clavulanate 500/125 mg 3 times daily for 10 days Concomitant treatments not reported

Outcomes

Study reported clinical cure rates for intention-to-treat and per-protocol populations. However, only per-protocol population could be used as basis for clinical failure rate calculating in this review because true failures were not reported and there was unclear description of missing data in the ITT population. Clinical outcomes for per-protocol population were assessed at days 8 to 15 in 799 out of 941 randomised participants (in 269 out of 316 patient in azithromycin for 3 days - group and in 259 out of 314 participants in co-amoxiclav group). Second follow-up at days 22 to 36. Radiographic outcomes were not reported

Notes


Risk of bias Bias






Unclear risk



Low risk



81

Henry 2003

(Continued)


Unclear risk

Quote: “Double-blind, double-dummy study” Comment: no description of the blinding procedure


Comment: there was not a clear statement about missing data


Low risk



Unclear risk



High risk


Henry 2004 Methods

Randomised, double-blind study. Clinical diagnosis (presence of facial pain/pressure/ tightness over 1 or both maxillary sinus areas, facial swelling or toothache, as well as purulent discharge for > 7 and < 21 days) was confirmed by radiograph or CT (opacification or air/fluid level). Clinical response was assessed by investigator and cure was defined as resolution of at least 1 of the acute signs and symptoms of the original infection, with no worsening in the remaining symptoms or the radiographic appearance of the sinus. Compliance was assessed by inspection of returned blister cards and by counting unused study medication; to be clinically evaluable the patient had to have received at least 80% of study medication. Proportion of the participants without known or reported clinical outcome 11% on 19 to 24 days

Participants

Multicentre, multinational study (USA, Poland). 271 ambulatory participants, 146 women and 95 men, mean age was about 41 years. ENT co-morbidity was not assessed

Interventions

2 treatment arms Group 1: cefdinir 600 mg once daily for 10 days Group 2: levofloxacin 500 mg once daily for 10 days There was no restriction on the use of medications for symptom relief (decongestants, antihistamines)

Outcomes

Clinical outcomes were reported for clinically evaluable population only and assessed in 241 out of 271 randomised participants on 19 to 24 days (in 123 out of 138 patients in cefdinir group and in 118 out of 133 participants in levofloxacin group). Clinically evaluable population defined as participants who met the study selection criteria, received at least 80% of the intended amount of study drug, underwent an assessment at 19 to 24 days, and did not receive any other antibiotic before the assessment. Radiographic outcomes were assessed in 239 participants at 19 to 24 days


82

Henry 2004

(Continued)

Notes


Risk of bias Bias




Quote: “Computer-generated randomization schedule that determined each patient’s treatment assignment by patient number”


Low risk

Centralised randomisation Quote: “Randomisation made by the statistics department of a pharmaceutical company. Study personnel called a centralized interactive voice response system to receive a code/randomization number and the corresponding drug”


Low risk



Low risk

Quote: “Double-blind study”. “Drugs were over-encapsulated to achieve an identical appearance. The drugs were prepackaged and dispensed in blister cards in such a way that each patient received the appropriate quantity of active drug for 10 days of therapy” Comment: although the description of the blinding was incomplete (in respect of investigator blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 15/138 (11%) in cefdinir group and 15/133 (11%) in levofloxacin group on 19 to 24 days Comment: the groups were balanced in numbers and reasons for missing data



Low risk


83

Henry 2004

(Continued)


Low risk



Unclear risk


Huck 1993 Methods

Randomised, double-blind trial. Diagnosis established by symptoms of acute, recurrent or chronic sinusitis with a positive radiograph showing, at a minimum, mucosal thickening. Sinus puncture was performed. Clinical outcomes assessed by investigator; improvement defined as “the patient’s signs and symptoms had improved or resolved during therapy.” No separate categories for “cured” and “improved.” Treatment compliance reported as about 97% assessed by pills taken by participants. Proportion of the participants without known or reported clinical outcome 11% for the whole study population

Participants

Patients were recruited from community-based otolaryngology clinics. Participants were 38.4 years old on average (range 16 to 73) and included 50 men and 58 women. ENT comorbidity was assessed: fewer than 25% of participants had chronic sinusitis. Country - USA

Interventions

2 treatment arms Group 1: cefaclor 500 mg twice daily for 10 days Group 2: amoxicillin 500 mg 3 times daily for 10 days Concomitant treatments not reported

Outcomes

Clinical outcomes were assessed in 96 out of 108 randomised participants overall. 56 participants with acute sinusitis and 25 participants with recurrent acute sinusitis with more than 1 episode per year with clinical improvement between episodes were considered in this review (15 participants with chronic sinusitis were not included). Outcomes were assessed on day 10 to 12 after randomisation. Radiographic and bacteriological outcomes were not measured

Notes


Risk of bias Bias







Unclear risk


84

Huck 1993

(Continued)


Low risk



Low risk

Quote: “Double-blind”. “To maintain blinding, drugs and placebo were placed in identical capsules and given to participants in identical bottles” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Total amount of missing data 11% Comment: no description of missing data across intervention groups (when chronic participants are excluded)


Unclear risk

Comment: information on comparability at baseline was insufficient to assess whether the groups were comparable at baseline or not (no information on severity rating)


Unclear risk



High risk


Jareoncharsri 2004 Methods

Randomised, unblinded design. 80% of participants had acute maxillary sinusitis and 20% had acute exacerbation of chronic sinusitis. Diagnosis by clinical symptoms and signs confirmed by the finding of mucopurulent discharge in the middle meatus or maxillary ostium as seen by nasal endoscopy and abnormal radiograph (criteria not specified); about 88% of patients had air-fluid level or opacity on X-ray. Bacteriological specimens were collected by sinus aspiration. Clinical cure was assessed by investigators using a 4-point scale; cure was defined as complete resolution of signs and symptoms with no radiological evidence of remaining disease; improvement defined as incomplete resolution of signs and symptoms and improvement of radiological findings. Treatment compliance was not reported. Proportion of participants without known or reported clinical outcome 2%

Participants

Participants (n = 60) were recruited from 2 otolaryngologic centres. Mean age 36 (range 17 to 68); 23 men and 37 women. 20% of participants had acute exacerbation of chronic sinusitis (n = 12). About 28% of participants had allergic rhinitis. Country - Thailand


85

Jareoncharsri 2004

(Continued)

Interventions

2 treatment arms Group 1: levofloxacin 300 mg once daily for 14 days Group 2: co-amoxiclav 625 mg 3 times a day for 14 days Concomitant treatments were not described

Outcomes

Clinical outcomes were assessed in 47 out of 48 randomised participants with acute maxillary sinusitis. Outcomes were assessed on day 21 after the start of treatment. Bacteriological outcomes were assessed in 37 participants with acute maxillary sinusitis on day 14. Radiological findings were not reported separately for participants with acute maxillary sinusitis

Notes

Study was financially supported by a pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported for participants with acute maxillary sinusitis: clinical response (including radiological findings), bacteriological response and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Missing data: 2% Comment: marginal missing data rate


Low risk

Comment: detailed description of demographic characteristics and sinusitis severity rating with which to assess the comparability of the groups at baseline Concomitant allergy was more frequent in levofloxacin group than in co-amoxiclav group, but this was seen not to cause bias


Unclear risk



High risk



86

Karma 1991 Methods

Randomised, single-blinded trial. Diagnosis was established by at least 1 symptom of sinusitis plus an antral puncture showing fluid (study protocol required that pathogens cultured from sinus fluid be susceptible to both the study antibiotics). Radiographs showed findings “suggestive” of sinusitis. Clinical outcomes were assessed by an investigator. Clinical cure was defined as “pretreatment signs and symptoms of infection resolved.” Improvement was defined as “improvement but not complete resolution of the infection.” Compliance with treatment was not reported. Total proportion of the participants without known or reported clinical outcome 33% on day 11 to 13. Participants were excluded mostly due to absence of appropriate pathogens in pretreatment cultures; exclusions because of other reasons marginal (3%)

Participants

Participants were recruited from academic, outpatient otolaryngology clinics. Mean age was approximately 30 (range 17 to 69); 89 men and 11 women. Country - Finland and Sweden

Interventions

2 treatment arms Group 1: clarithromycin 500 mg twice daily for 9 to 11 days Group 2: amoxacillin 500 mg every 8 hours for 9 to 11 days Both groups received oxymetazoline 0.05% twice daily for the first 3 days

Outcomes

Clinical outcomes were assessed in 67 out of 100 randomised participants (in 32 out of 50 participants in clarithromycin group and in 35 out of 50 participants in amoxicillin group) on day 11 to 13. Radiographic and bacteriological outcomes were assessed in 68 participants

Notes


Risk of bias Bias






Unclear risk



Low risk



High risk

Quote: “Single-blinded study”



Exclusions from analyses: absence of appropriate pathogens in pretreatment cultures 16/50 in clarithromycin group and 14/50 in amoxicillin group; other exclusions 2 (4%) and 1 (2%) of participants in clar87

Karma 1991

(Continued)

ithromycin group and amoxicillin group, respectively Comment: the absence of pathogen was seen not to cause bias. Other missing data marginal Free of other bias? Baseline comparability

Low risk



Low risk



Unclear risk


Klapan 1999 Methods

Randomised, unblinded design. Diagnosis based on symptoms (lasting on average 7 days) and radiograph showing at least 4 mm mucosal thickening, opacity or air-fluid level. Sinus puncture performed in a subset of participants. Cure defined as complete disappearance of signs and symptoms; improvement as partial disappearance of symptoms without need for further antibiotics. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 6% on day 10 to 12

Participants

The study setting not described. Mean age approximately 33 years old (range 15 to 50) ; 77 men and 23 women. Coexisting allergic rhinitis in 30%. Country - Croatia

Interventions

2 treatment arms Group 1: azithromycin 500 mg daily for 3 days Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 days Concomitant treatments not reported

Outcomes

Clinical outcomes assessed on day 10 to 12 in 94 out of 100 randomised participants (in 47 out of 50 participants in azithromycin group and in 47 out of 50 participants in amoxicillin-clavulanate group); and 4 weeks after the initiation of treatment in 89 participants. Bacteriological cure assessed in 47 participants. Radiographic outcomes not reported

Notes

1 of the authors had affiliation to a pharmaceutical company. Copyright by pharmaceutical company

Risk of bias Bias




88

Klapan 1999

(Continued)




Unclear risk



Low risk



High risk



Missing data: 3/50 (6%) in azithromycin group and 3/50 (6%) in amoxicillin-clavulanate group on day 10 to 12. Missing data 6% on day 10 to 12 and 11% at 4 weeks Comment: the groups were balanced in numbers and reasons for missing data. Available case data given for both followups


Low risk



Unclear risk



High risk

1 of the authors had affiliation to a pharmaceutical company. Copyright by pharmaceutical company


89

Lari 2010 Methods

Randomised, single-blinded design. Outpatients, both genders, 18 years or older. Diagnosis of acute sinusitis was based on clinical symptoms of postnasal discharge and facial pain and tenderness in maxillary sinus area for at least 7 and at last 28 days. Cure defined as complete disappearance of signs and symptoms to the level that existed prior to the occurrence of the acute illness and without requirement for other antibiotics; improvement (applicable only at the end of the treatment) as partial disappearance of symptoms without need for further antibiotics. Treatment compliance not reported. Proportion of the participants without known clinical outcome not reported (results give, however, an impression that at least at 10 days there are drop-outs) Data not used in the meta-analysis in this review because exact data and participant numbers remain unclear at follow-ups (results given only as percentages)

Participants

Setting not described. In total 76 patients; detailed demographic characteristics not given. Patients with chronic sinusitis were excluded (chronic sinusitis was defined as sinusitis 3 or more times during the past 6 months). Country - Iran

Interventions

2 treatment arms Group 1: azithromycin 250 mg (500 mg single dose on the first day and 250 mg once daily for 4 days) Group 2: co-amoxiclav 625 mg, 3 times daily for 10 days Concomitant therapies were not reported

Outcomes

Clinical outcomes assessed on day 10 and 30 but the numbers of participants are missing and the results are given only as percentages

Notes

There was no identified funding source. 2 authors were employees of a pharmaceutical company

Risk of bias Bias




Quote: “This was a single blind randomized clinical trial” No further information provided


Unclear risk



High risk

Outcomes reported: clinical responses Comment: in conclusions it was stated that “results revealed that azithromycin has less side effects, and patients were able to tolerate the medications better with a higher compliance and less economic cost than coamoxiclav regimen”. However, any results for adverse effects were not reported


90

Lari 2010

(Continued)


High risk

Quote: “This was a single blind randomized clinical trial” Comment: single-blinded trial


Comment: the numbers of participants at follow-ups are missing and the results give an impression that at least at 10 days there are drop-outs


Unclear risk

Quote: “Signs and symptoms of patients in both groups were more or less similar. Symptoms and signs prevalence and duration of symptoms before treatment were similar in both therapy groups. Participants also had similar age distribution” Comment: no detailed information on the severity of symptoms and demographic characteristics


Unclear risk



Unclear risk

There was no identified funding source. 2 of the authors had affiliation to a pharmaceutical company

Lasko 1998 Methods

Randomised, double-blind design. Clinical diagnosis confirmed by radiograph showing > 5 mm mucosal thickening, opacity or air-fluid level. Cure defined by symptom resolution. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 19%

Participants

Setting not described. Mean age 40; 102 men and 134 women. Country - Canada

Interventions

2 treatment arms Group 1: levofloxacin 500 mg daily for 10 to 14 days Group 2: clarithromycin 500 mg twice daily for 10 to 14 days Antihistamines and decongestants prohibited

Outcomes

Clinical outcomes reported at day 12 to 19 in 191 out of 236 participants randomised (in 98 out of 119 participants in levofloxacin group and in 93 out of 117 participants in clarithromycin group). Radiographic and bacteriological outcomes not reported

Notes

Study funding provided by a pharmaceutical company. 2 of the authors affiliated to the same pharmaceutical company

Risk of bias Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

91

Lasko 1998

(Continued)

Bias




Quote: “Patients were assigned either to levofloxacin 500 mg once daily or to clarithromycin 500 mg twice daily, based on a computer-generated randomization schedule”


Unclear risk



Unclear risk

Outcomes reported: clinical response and adverse effects Comment: in the methods section it is stated that repeat sinus X-rays were taken at 42 to 46 days giving the impression that this was an outcome. However, the results were not reported


Low risk

Quote: “Double-blinding was accomplished by encapsulation of tablets. The size of the capsule necessitated the use of the 250 mg tablet and each dose was therefore 2 capsules morning and evening”. “Identical morning and evening bottles”. “Placebotablets used” Comment: although the description of the blinding was incomplete (in respect of investigator), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 21/119 (18%) in levofloxacin group and in 24/117 (21%) in clarithromycin group Comment: the groups were balanced in numbers and reasons for missing data


Low risk



Low risk

No co-interventions allowed


High risk

Study funding provided by a pharmaceutical company. 2 of the authors affiliated to the same pharmaceutical company


92

Lindbaek 1996 Methods

Randomised, double-blind design. Clinical diagnosis of acute sinusitis (> 7 and < 30 days), confirmed by computed tomography (the criteria for confirming the diagnosis were presence of fluid level or total opacification in any sinus). Bacteriological specimens were obtained from the nasopharynx of 125 participants (42% had “normal nasal flora”) . Participants assessed response as “restored”, “much better”, “somewhat better”, “unimproved” or “worse” Treatment compliance was not reported. In total, 12 participants (9%) (5 in the amoxicillin group and 7 in placebo group) did not complete the 10-day course of treatment. 9 were treated with another antimicrobial (2 in the amoxicillin group and 7 in the placebo group) Proportion of the participants without known or reported clinical outcome 2% on day 10

Participants

Participants recruited from Norwegian General Practices. 45 men and 85 women; mean age 39 (range 16 to 74) years. ENT co-morbidity was not assessed. Country - Norway

Interventions

3 treatment arms Group 1: penicillin V 1320 mg 3 times daily for 10 days Group 2: amoxicillin 500 mg 3 times daily for 10 days Group 3: placebo 3 times daily for 10 days Groups 1 and 2 were combined in the analyses Nasal decongestants and analgesics were allowed but not prescribed

Outcomes

Clinical and radiographic outcomes were assessed on day 10 in 127 out of 130 participants randomised (in 83 out of 86 participants in antibiotic groups and in 44 out of 44 participants in placebo group)

Notes

Study was funded by governmental sources

Risk of bias Bias




Quote: “The randomization was performed in blocks of three within each of the six subgroups (3 subgroups by CT and 2 subgroups by a severity scale) by using a dice to generate the random allocations” Comment: randomisation was done by a statistician (information obtained from the author)


The statistician sent the randomisation list to the company who produced the medication boxes with numbers according to the list. The author received the numbered boxes for each of the subgroups from the company. The randomisation codes were

Low risk


93

Lindbaek 1996

(Continued)

broken after the whole study was finished Comment: information obtained from the author Selective reporting (reporting bias)

Low risk



Low risk

Quote: “The trial was double blind; neither the patients, the general practitioner, nor the radiologists were aware of the allocation of treatment” Comment: the randomisation codes were broken after the whole study was finished (information obtained from the author)


Missing data: 2% on day 10 Comment: marginal missing data rate


Low risk

Comment: detailed description of demographic characteristics and sinusitis severity rating at baseline but actual numbers are not given


Low risk

Quote: “Nasal decongestants and mild analgesics allowed in both groups” Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect on recovery (thus did not cause bias)


Low risk


Lindbaek 1998 Methods

Same study as Lindbaek 1996 but separate randomised population. Randomised, double-blind design. Clinical diagnosis of acute sinusitis (> 7 and < 30 days), confirmed by computed tomography showing mucosal thickening of 5 mm or more in any sinus without fluid level or total opacification. Patients assessed response as “restored”, “much better”, “somewhat better”, “unimproved” or “worse”. Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 7.4% on day 10

Participants

Patients recruited from Norwegian General Practices. 27 men and 43 women; mean age 40 (range 16 to 83) years. ENT co-morbidity was not assessed. Country - Norway


94

Lindbaek 1998

(Continued)

Interventions

3 treatment arms Group 1: penicillin V 1320 mg 3 times daily for 10 days Group 2: amoxicillin 500 mg 3 times daily for 10 days Group 3: placebo 3 times daily for 10 days Groups 1 and 2 combined in the analyses. Nasal decongestants and analgesics were allowed but not prescribed

Outcomes

Clinical outcomes (based on patient diary) were assessed on day 10 in 63 out of 68 participants randomised (no information for drop-outs per group)

Notes


Risk of bias Bias




A dice Comment: information obtained from the author


Low risk

The statistician sent the randomisation results to the company who produced the medication boxes. The author received the numbered boxes from the company. The randomisation codes were broken after the whole study was finished Comment: information obtained from the author


Low risk



Low risk

Quote: “The trial was double-blind: Neither the patients, the general practitioner, nor the radiologists were aware of the treatment allocation” Comment: the randomisation codes were broken after the whole study was finished (information obtained from the author)


Total drop-out rate 5/68 (7.4%) Comment: although there were no exact numbers on the drop-out rates across the 3 groups, this domain was graded ’low’ risk of bias. The total drop-out rate was seen


95

Lindbaek 1998

(Continued)

as marginal. Further, the author gave information that there were drop-outs in all groups Free of other bias? Baseline comparability

Low risk



Low risk

Quote: “Nasal decongestants and mild analgesics allowed in both groups” Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect on recovery (thus did not cause bias)


Low risk


Luterman 2003 Methods

Randomised, double-blind trial. Diagnosis by clinical symptoms and by radiograph showing air-fluid level, opacity or at least 6 mm mucosal thickening. Sinus puncture performed in a small subset of participants. About 60% of participants had had symptoms for longer than 7 days before enrolment to the study. Clinical cure defined as disappearance of infection, clinical improvement or a return to the preinfection state with regard to all signs and symptoms and sinus X-ray findings that were normal, improved or at least not worse. Treatment compliance was reported with over 90% of participants in each group taking at least 70% of their doses. Proportion of the participants without known or reported clinical outcome 44% on day 17 to 24 and therefore data are not used in the meta-analyses in this review

Participants

Multicentre, multinational trial (USA, Canada, South Africa, Argentina and Chile). Demographic data reported for modified intention-to-treat population at baseline: participants’ mean age was 39 years (range 16 to 84); 248 men and 359 women. ENT comorbidity was not assessed

Interventions

3 treatment arms Group 1: telithromycin 800 mg once daily for 5 days Group 2: telithromycin 800 mg once daily for 10 days Group 3: amoxicillin-clavulanate 500/125 mg 3 times daily for 10 days Concomitant therapies were not reported

Outcomes

Results reported for per-protocol population only. Clinical outcomes were assessed on day 17 to 24 in 423 out of 754 randomised participants; and on day 31 to 45 in 399 participants. The per-protocol population was defined as participants who met the diagnostic criteria and had no major protocol violation. Bacteriological outcomes were assessed in 24 participants


96

Luterman 2003

(Continued)

Notes

Study funded by an unrestricted grant from a pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response (including radiological findings) and bacteriological response for a small proportion of the participants, adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “The identity of all drugs was concealed by placing them in identical opaque capsules. Placebocapsules were also used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Total missing data 44% on day 17 to 24


Unclear risk

Comment: the demographic and severity rating reported only on modified intention-to-treat population, not on the perprotocol population used in analysis of the study


Unclear risk



Unclear risk

Study funded by an unrestricted grant from a pharmaceutical company


97

Marple 2010 Methods

Randomised, open-label study. Clinical diagnosis of acute sinusitis was based on signs and symptoms lasting for between 7 and 30 days (pain, pressure and/or tightness associated with 1 or both maxillary sinuses that worsened with movement or percussion, and discoloured (yellow-green) nasal discharge or discoloured drainage in the posterior pharynx or from the maxillary sinus orifice, together with 2 or more of fever, frequent coughing, nasal congestion or postnasal drainage). Treatment success by day 28 (the only time point eligible in this review) was defined as resolution of symptoms within the study period, no unscheduled sinusitis visits and no additional antibiotics prescribed for sinusitis. Treatment compliance not reported. Proportion of the participants included in the per-protocol population was 62% on day 28; data not used in the meta-analyses of this review

Participants

Multicentre study, participants were recruited in primary care settings by 70 study investigators. Demographic data for per-protocol population at baseline: participants’ mean age was 46 years; 151 men and 323 women. ENT co-morbidity was assessed; about 37% of participants had history of allergic rhinitis. Country - USA

Interventions

2 treatment arms Group 1: azithromycin extended release (2 g), single dose Group 2: amoxicillin-clavulanate potassium 875 mg/125 mg 2 times daily for 10 days Concomitant therapies were not reported

Outcomes

Clinical responses on day 28 were reported for per-protocol population only. Clinical responses (based on follow-up telephone interviews) were assessed on day 28 in 462 out of 751 participants randomised (in 231 out of 380 participants in azithromycin group and in 231 out of 371 participants in amoxicillin-clavulanate group). The per-protocol population was defined as all eligible randomised participants who completed the diary and first telephone interview (at day 5) and reported taking at least 1 dose of the study medication

Notes

The study was sponsored by a pharmaceutical company. 3 of the authors had affiliation to, and other 3 of the authors were paid consultants of, the same pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical responses, quality of life, satisfaction with treatment and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



98

Marple 2010

(Continued)


Missing data: 149/380 (39%) in azithromycin group and 140/371 (38%) in amoxicillin-clavulanate group on day 28 Comment: total missing data over 20%


Low risk

Comment: detailed description of demographic characteristics and sinusitis severity rating for per-protocol population to assess the comparability of the groups at baseline


Unclear risk



High risk

The study was sponsored by a pharmaceutical company. 3 of the authors had affiliation to, and other 3 of the authors were paid consultants of, the same pharmaceutical company

Matthews 1997 Methods

Randomised, unblinded design. Diagnosis by clinical symptoms and signs, confirmed by radiograph showing opacity, clouding or air-fluid level. Bacteriological specimens were obtained by antral puncture. Acute and chronic sinusitis included (acute reported separately). Success defined as cure or improvement. Proportion of the participants without known or reported clinical outcome 24% among participants with acute sinusitis. Data not used in the meta-analyses of this review because time points for outcome measure were not clearly reported

Participants

Participants recruited from otolaryngology clinics. Mean age of 42 (range 18 to 78). 93 of 182 participants had acute sinusitis. Country - USA

Interventions

2 treatment groups Group 1: cefixime 400 mg once daily for 10 to 14 days Group 2: amoxicillin 500 mg 3 times daily for 10 to 14 days Aspirin prohibited. Acetaminophen, antacids and nasal decongestants were permitted

Outcomes

Clinical outcomes reported in 71 out of 93 randomised participants with acute sinusitis (in 37 out of 49 participants in cefixime group and in 34 out of 44 participants in amoxicillin group). Bacteriological outcomes assessed in 32 participants with acute sinusitis. Drop-outs due to adverse events reported for acute and chronic sinusitis combined

Notes

Study funding not stated

Risk of bias Bias




99

Matthews 1997

(Continued)


Quote: “Patients were randomized by a computer-generated schedule to receive oral doses of either 400 mg of cefixime once daily or 500 mg of amoxicillin every 8 hours”


Unclear risk



Low risk

Outcomes reported: clinical and bacteriologic responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Open label study”


Missing data: 12/49 (24%) in cefixime group and 10/44 (23%) in amoxicillin group Comment: missing data over 20%


Unclear risk

Comment: information on comparability was insufficient to assess whether the intervention groups with acute sinusitis were comparable at baseline or not


Low risk



Unclear risk

Study funding not stated

Mattucci 1986 Methods

Randomised trial; unblinded. Diagnosis was established by a clinical diagnosis of acute sinusitis plus a radiograph showing “clouding” of the nasal sinus and a positive culture from or near the sinus ostium. Clinical outcomes were assessed by an investigator; clinical cure was not defined. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 19%

Participants

Patients were recruited from outpatient otolaryngology clinics. Participants were 40 years old on average (range 12 to 76) and included 23 men and 35 women. ENT co-morbidity was not assessed. Country - USA

Interventions

2 treatment arms Group 1: minocycline 100 mg twice daily for 10 to 20 days (mean 11.6) Group 2: amoxicillin 250 mg every 8 hours for 10 to 20 days (mean 11.4)


100

Mattucci 1986

(Continued)

Both groups were allowed to take decongestants or analgesics but these were not prescribed by the investigators (all of the participants took decongestants during the trial) Outcomes

Clinical outcomes were assessed in 47 out of 58 randomised participants (in 25 out of 29 participants in minocycline group and in 22 out of 29 participants in amoxicillin group) . Outcomes were assessed on day 10 to 20 after randomisation. Radiographic outcomes were assessed in 42 participants and bacteriological in 46

Notes


Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response, radiological response for 42 participants, bacteriological response for 46 participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Exclusions from analyses: absence of pathogen in pretreatment cultures 3/29 in minocycline group and 3/29 in amoxicillin group; other exclusions 1 (3.4%) and 4 (13. 8%) of participants in minocycline group and amoxicillin group, respectively Comment: the absence of pathogen was seen not to cause bias. Other missing data in numbers not balanced between the groups


High risk

Quote: “The proportion of participants with severe sinusitis 68% in minocycline group and 43% in amoxicillin group”


Low risk



101

Mattucci 1986

(Continued)


Unclear risk


Meltzer 2005 Methods

Randomised, double-blind, double-dummy, placebo-controlled study. Clinical diagnosis of acute sinusitis was based on clinical findings with signs and symptoms of acute rhinosinusitis lasting at least 7 but less than 29 days. In addition, the major symptom score (MSS) had to be at least 5 but less than 13 at screening and baseline visits with no more than 3 of the 5 symptoms rated severe. MSS was defined as sum of the scores for rhinorrhoea, postnasal drip, nasal congestion/stuffiness, sinus headache and facial pain/ pressure/tenderness on palpation over the paranasal sinuses (each scaled from 0 (none) to 3 (severe)). Duration of symptoms at enrolment 6 to 14 days in 61% of participants in amoxicillin group and 58% in placebo group (out of the total 981 randomised patients 9 were enrolled with 6 days’ duration of symptoms instead of the originally specified minimum of 7 days). Participants were excluded if they had signs or symptoms suggestive of fulminant bacterial rhinosinusitis. Clinical failure defined by worsening or no improvement of symptoms by day 3 to 4 or thereafter jointly evaluated by the investigator and the participant. Protocol noncompliance 1% in amoxicillin and placebo groups. Proportion of the participants without known or reported clinical outcome 1.8% by day 15

Participants

Participants recruited from 71 medical centres in 14 countries. Study population consisted of a total of 981 randomised patients in 4 groups: 243 in mometasone furoate nasal spray (MFNS) 200 µg once daily, 235 in MFNS 200 µg twice daily, 251 in amoxicillin and 252 in placebo. 338 men and 643 women; mean age 35 years (4% of participants were 12 to 17 years of age in amoxicillin group and 6% in placebo group). ENT comorbidity: 42% of participants had either seasonal or perennial allergic rhinitis in amoxicillin and placebo groups

Interventions

4 treatment arms Group 1: MFNS 200 µg in the morning with placebo spray in the evening for 15 days plus placebo capsules 3 times daily for 10 days Group 2: MFNS 200 µg in the morning and evening for 15 days plus placebo capsules 3 times daily for 10 days Group 3: Amoxicillin 500 mg 3 times daily for 10 days plus placebo nasal spray twice daily for 15 days Group 4: Placebo capsules 3 times daily for 10 days plus placebo nasal spray twice daily for 15 days Groups 3 and 4 considered in this review. Concomitant medications that would interfere with study evaluations were not permitted, including nasal saline, nasal cromolyn sodium, ipratropium bromide, corticosteroids (excluding oral inhaled corticosteroids for mild to moderate persistent asthma), antihistamines, decongestants and leukotriene pathway modifiers. Analgesics and nonsteroidal anti-inflammatory drugs were prohibited for the treatment of acute rhinosinusitis

Outcomes

The original article reported the total failure rates during the 15-day treatment phase per group but exact numbers of the assessed participants were not given (only numbers and reasons for discontinued participants per group). It remains unclear whether all other


102

Meltzer 2005

(Continued)

discontinued participants than those lost to follow-up were assessed or not. The original article used intention-to-treat principle in the analyses. We decided to exclude in our analyses those randomised participants who were reported to be lost to follow-up (1 in antibiotic group and 4 in placebo group) and those 4 participants in placebo group who did not meet the protocol criteria for entry. Thus clinical failures were assessed during the 15-day treatment phase in 494 out of 503 randomised participants (in 250 out of 251 participants in amoxicillin group and in 244 out of 252 participants in placebo group). Figures for failures at the follow-up phase (days 16 to 29) not given Notes

Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated to a pharmaceutical company

Risk of bias Bias




Quote: “Randomisation was performed according to a computer-generated code, stratified on the basis of duration of rhinosinusitis symptoms before baseline (7-14 days and 15-28 days)”


Low risk

Comment: although there is no exact information on how the randomisation result was concealed, the method of sequence generation of this multicentre study (71 centres in 14 countries) and information that placebo nasal sprays and placebo capsules were used, give the impression that the concealment was real


Low risk



Low risk

Quote: “Double-blind, double-dummy study. Those receiving amoxicillin a matching placebo nasal spray twice daily; patients randomized to placebo received placebo capsules 3 times daily and placebo nasal spray twice daily” Comment: although the description of the blinding was incomplete (in respect of investigator blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and double-dummy, and blinding method was partly described


103

Meltzer 2005

(Continued)


Missing data: 1/251 (0.4%) in amoxicillin group and in 8/252 (3.2%) in placebo group Comment: marginal missing data rate


Low risk



Low risk

Quote: “Concomitant medications that would interfere with study evaluations were not permitted” Comment: medications that might cause bias were prohibited


High risk

Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated to a pharmaceutical company

Merenstein 2005 Methods

Randomised, double-blind design. Clinical diagnosis of acute sinusitis was based on clinical findings, which had to include at least 1 of the following: purulent nasal discharge predominating on 1 side, facial pain on 1 side, purulent nasal discharge on both sides, pus in the nasal cavity, lasting for at least 7 days. About 50% of participants had at least 2 of these signs at baseline (the study did not report any subjective symptoms); mean duration of symptoms prior to enrolment 11 days. Clinical cure defined as dichotomous - either “completely improved” or “not improved”. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 14% on day 14

Participants

Participants recruited from a suburban primary care office. 42 men and 93 women; mean age 34 years. ENT co-morbidity was not assessed. Country - USA

Interventions

2 treatment arms Group 1: amoxicillin 500 mg twice daily for 10 days Group 2: placebo twice daily for 10 days Over-the-counter medications were allowed in both groups (information obtained from the authors)

Outcomes

Clinical outcomes (based on follow-up telephone interviews of participants) were assessed on day 14 in 116 out of 135 participants randomised (in 56 out of 67 participants in antibiotic group and in 60 out of 68 participants in placebo group)

Notes

Study was funded mostly by academic sources


104

Risk of bias Bias




Quote: “Permuted block randomization stratified for the 3 participating clinicians was used to determine treatment assignment” Comment: computer-generated by a statistician who gave the authors a list to follow (information obtained from the authors)


Low risk

Comment: a statistician made the randomisation and gave the authors a list that they followed (information obtained from the authors)


Low risk

Outcomes reported: several clinical responses and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Patients were given an envelope containing either a placebo medicine taken twice daily for 10 days or antibiotic medicine taken twice daily for 10 days. The envelopes were opaque, and each had 40 identical-appearing pills” Comment: the authors followed the randomisation list without knowing which medicine was given to each patient (information obtained from the authors)


Missing data: 16.4% (11/67) in antibiotic group and 11.8% (8/68) in placebo group at 14 days Comment: the groups appeared to be balanced in numbers and reasons for missing data


Low risk

Comment: very detailed description of demographic characteristics and sinusitis severity rating with which to assess the comparability of the groups at baseline. The groups appeared to be balanced at baseline


Low risk

Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and was of such quality that it did not have an effect


105

Merenstein 2005

(Continued)

on recovery (thus did not cause bias) Free of other bias? Funding

Low risk

Funded mostly by academic sources

Murray 2005 Methods

Randomised, double-blind trial. Clinical diagnosis of acute sinusitis (> 6 and < 29 days) , confirmed by radiograph (the criteria for confirming the diagnosis were presence of airfluid level or total or partial opacification). Sinus puncture for all participants. Clinical outcomes were assessed by an investigator. Clinical failure was defined as the persistence or worsening of signs and symptoms requiring additional antibiotics or development of new signs and symptoms requiring antibiotics. Treatment compliance reported over 96%. Proportion of the participants without known or reported clinical outcome 6%

Participants

Multicentre study; 81 outpatient centres in the United States, India, Europe and Latin America. 225 men and 313 women; mean age 38 (range 18 to 88) years. ENT comorbidity was assessed; about one-third of participants suffered from allergic rhinitis

Interventions

2 treatment arms Group 1: azithromycin-microspheres 2 g single dose Group 2: levofloxacin 500 mg once daily for 10 days

Outcomes

Clinical outcomes were assessed at days 17 to 24 in 507 out of 541 participants randomised. Bacteriologic outcomes assessed in 213 participants

Notes

Study funded by a pharmaceutical company. 2 of the authors were affiliated to a pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical and bacteriologic responses, clinical response by baseline pathogen and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind, double-dummy trial”. “Placebo medication used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study


106

Murray 2005

(Continued)

was reported to be double-blind and blinding method was partly described Incomplete outcome data addressed? Low risk (Clinical efficacy outcomes)

Missing data: 14/270 (5%) in azithromycin group and 17/268 (6%) in levofloxacin group The information on number of randomised participants across groups was insufficiently reported. In calculating the missing data, the population who received at least 1 dose of study medication was used as the baseline population (missing only 3 participants from the total randomised population) Comment: although reasons for missing data across groups were not reported, this domain was graded ’low’ risk of bias because missing data were marginal and balanced in numbers


Low risk

Comment: detailed description of demographic characteristics and sinusitis severity rating with which to assess the comparability of the groups at baseline Although the information was provided only for the whole treated population (not for clinically evaluable population which was the primary efficacy endpoint) this domain was graded ’low’ risk of bias because the missing data rate was small


Unclear risk



High risk

Study funded by a pharmaceutical company. 2 of the authors were affiliated to a pharmaceutical company


107

Nyffenegger 1991 Methods

Randomised, unblinded study. Diagnosis was established by a clinical diagnosis of acute sinusitis, confirmed by a radiograph (criteria were not specified), transillumination and a positive bacterial culture obtained from samples of discharge from the sinuses. Clinical outcomes were assessed by an investigator. Clinical cure was defined as complete disappearance of clinical symptoms at completion of treatment; improvement was defined as a clear regression of the clinical symptomatology. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 0%

Participants

Participants were recruited from an outpatient otolaryngology clinic. Participants represented a convenience sample, not a consecutive series. Participants were 37.8 years old on average (range 18 to 75) and included 30 men and 50 women. ENT co-morbidity was not assessed. Country - Switzerland

Interventions

2 treatment arms Group 1: brodimoprim 200 mg once daily for 7 to 10 days Group 2: amoxicillin 750 mg 3 times daily for 7 to 10 days Mucolytic nose drops and steam inhalations were allowed but not prescribed as part of the intervention

Outcomes

Clinical outcomes were assessed in 80 out of 80 randomised participants. Outcomes were assessed on day 7 to 10 after randomisation. Radiographic outcomes were not reported. Bacteriological outcomes were reported for 40 participants

Notes

2 of the authors were affiliated to pharmaceutical company

Risk of bias Bias




Quote: “According to a computer-generated list, the patients were randomly assigned to receive 200 mg of brodimoprim once daily or 750 mg of amoxicillin three times daily for seven to 10 days”


Unclear risk



Unclear risk

Outcomes reported: clinical response, bacteriological response for 40 patients and adverse effects Comment: it remains unclear why only a proportion of the population was included in the bacteriological response and how were they selected


High risk

Quote: “Unblinded study”


108

Nyffenegger 1991

(Continued)


Missing data rate 0%


Unclear risk

Comment: detailed description of demographic characteristics. However, no information on the severity rating across the groups


Low risk



Unclear risk

2 of the authors were affiliated to pharmaceutical company

O’Doherty 1996 Methods

Randomised, unblinded design. Participants with otitis media, pharyngitis/tonsillitis or sinusitis included. Sinusitis diagnosis was established clinically and confirmed by a radiograph (criteria not given). Throat swabs, nasopharyngeal swabs or exudates, as appropriate, were collected for bacterial culture. Clinical outcomes were assessed by an investigator; clinical cure defined as “disappearance of all signs and symptoms of infection”. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 14%

Participants

Recruitment settings were not described. Mean age was 35 for all diagnoses. ENT comorbidity was not assessed. Countries - UK, Ireland

Interventions

2 treatment arms Group 1: azithromycin 500 mg daily for 3 days Group 2: cefaclor 250 mg 3 times daily for 10 days Adjuvant treatments were not described

Outcomes

Clinical outcomes were assessed on day 11 to 15 and reported separately for 78 out of 91 randomised participants with sinusitis (in 41 out of 48 participants in azithromycin group and in 37 out of 43 participants in cefaclor group). Radiographic outcomes were not reported. Bacteriological outcomes were assessed in 18 participants

Notes


Risk of bias Bias




109

O’Doherty 1996

(Continued)




Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response for 18 participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Missing data: 7/48 (15%) in azithromycin group and 6/43 (14%) in cefaclor group on day 11 to 15 Comment: no information on reasons for missing data separately for sinusitis participants across groups


Unclear risk

Comment: information on comparability was insufficient to assess whether the groups were comparable at baseline or not (information not stated separately for participants with sinusitis)


Unclear risk



Unclear risk


Olmo 1994 Methods

Randomised, obviously unblinded design. Diagnosis was established by clinical symptoms and a radiograph showing sinus opacity or air-fluid level. 66% of participants had positive culture. Clinical outcomes were assessed by an investigator; clinical cure was “remission of symptoms within the treatment time”. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 0% on day 24 to 26

Participants

Participants were recruited from emergency rooms. Mean age was not reported (>= 20 for inclusion); 28 men and 19 women. ENT co-morbidity was not assessed. Country Spain

Interventions

2 treatment arms Group 1: cefuroxime axetil 500 mg twice daily for 8 days Group 2: amoxicillin-clavulanate 500 mg 3 times daily for 8 days Adjuvant therapies were not described


110

Olmo 1994

(Continued)

Outcomes

Overall clinical outcomes (including also radiological response and bacteriological response for those participants with positive culture at baseline) were assessed in 48 out of 48 randomised participants on day 24 to 26. Bacteriological outcomes were also reported separately for the 31 participants with positive culture at baseline

Notes


Risk of bias Bias




Quote: “Random numbers table”


Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Unclear risk



No missing data


Unclear risk



Unclear risk



Unclear risk


Otte 1983 Methods

Randomised, double-blind design. Diagnosis based on symptoms and abnormal radiograph (criteria not given). Bacteriological culture was performed. Clinical cure based on resolution of symptoms and normal radiograph. Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 0% on day 10

Participants

Patients recruited from outpatient otolaryngology clinics. Mean age was 32 (range 17 to 56); 12 men and 19 women. ENT co-morbidity was not assessed. Country - Chile


111

Otte 1983

(Continued)

Interventions

2 treatment arms Group 1: sulfamethopyrazin 200 mg/ trimethoprim 250 mg, 2 doses on day 1, then 1 dose per day for 10 days Group 2: tetracycline 500 mg 4 times daily for 10 days Adjuvant therapies were not described

Outcomes

Clinical outcomes were assessed on day 10 in all 31 participants randomised. Radiological outcomes reported on day 20 in 31 participants, bacteriological outcomes for 27 participants

Notes


Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical and radiological responses for all participants, bacteriological response for a proportion of the participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Placebotables were used; antibiotics and placebo tablets were identical. Tablets were delivered in numbered envelopes”


Missing data rate 0%


Unclear risk



Unclear risk



Unclear risk



112

Pessey 1996 Methods

Randomised, open design. Diagnosis established clinically and by a radiograph showing at least 5 mm mucosal thickening, sinus opacity or fluid-level. Clinical outcomes were assessed by an investigator and clinical cure was defined as resolution of clinical symptoms and radiographic cure or improvement. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 4% on day 10 to 15

Participants

Participants were recruited from community, otolaryngology clinics. Mean age = 43; 99 men and 143 women. Country - France

Interventions

3 treatment arms: (only groups 2 and 3 used in the analysis) Group 1: cefixime 200 mg twice daily for 4 days (+ placebo for 6 days) Group 2: cefixime 200 mg twice daily for 10 days Group 3: amoxicillin clavulanic acid 500 mg 3 times daily for 10 days All groups received prednisolone 40 mg daily and oxymetazoline 3 sprays daily for 4 days

Outcomes

Clinical outcomes were assessed on day 10 to 15 in 242 out of 253 randomised participants (in 85 out of 87 participants in cefixime for 10 days group and in 77 out of 82 participants in amoxicillin clavulanic acid group). Second follow-up on day 33. Radiographic outcome was not reported separately

Notes


Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: overall response including clinical and radiological responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Open study” (when comparing group 2 to group 3)



Missing data: 2/87 (2.3%) in cefixime group and 5/82 (6.1%) in amoxicillin clavulanic acid group on day 10 to 15. Total missing data 4% on day 10 to 15 and 9% on day 33 Comment: missing data rate marginal on day 10 to 15. The judgement on day 33 was 113

Pessey 1996

(Continued)

’unclear’ because the study did not report the reasons for missing data by study groups Free of other bias? Baseline comparability

Low risk



Low risk

Comment: groups received the same cointerventions during the trial


Unclear risk

2 of the authors were affiliated to a pharmaceutical company(?)

Pessey 2001 Methods

Randomised, double-blind design. Diagnosis based on clinical signs and symptoms confirmed by radiograph (total opacity of sinus or air-fluid level). Culture based on an aspirate from the middle meatus; 52% of participants had positive cultures. Clinical cure based on resolution of symptoms. Treatment compliance over 90%. Proportion of the participants without known or reported clinical outcome 0.6% on day 10 to 12

Participants

Multicentre study; 47 community-based ENT specialists in 10 regions. Mean age = 43 years; men 141 and 167 women. ENT co-morbidity was not assessed. Country - France

Interventions

2 treatment arms Group 1: pristinamycin 1000 mg 2 times daily for 8 days Group 2: cefuroxime axetil 500 mg twice daily for 8 days Nasal decongestants prescribed for 3 days. Corticosteroids prohibited

Outcomes

Clinical outcomes were assessed on day 10 to 12 in 308 out of 310 randomised participants (in 160 out of 161 participants in pristinamycin group and in 148 out of 149 participants in cefuroxime axetil group). Follow-up (29 to 36 days) for those participants who were cured at the end of treatment. Participant-related radiographic and bacteriological outcomes were not reported

Notes


Risk of bias Bias




Support for judgement Quote: “Treatment was allocated by means of a randomization code. The randomization was balanced in each center by blocks of 4 participants” Comment: although the description of the sequence generation was incomplete, this 114

Pessey 2001

(Continued)

domain was graded ’low’ risk of bias because description gives an impression of computer-based method Allocation concealment (selection bias)

Low risk

Quote: “Sealed individual envelopes containing the identification of the treatment to be administered to each patient were handed to each investigator” Comment: although the description of the allocation concealment was incomplete, this domain was graded ’low’ risk of bias because the way of reporting the blinding also gives an impression of adequate allocation concealment


Low risk



Low risk

Quote: “Double-blind, double-dummy study”. “Sealed individual envelopes containing the identification of the treatment to be administered to each patient were handed to each investigator. The code number of each patient was noted on each of the envelopes. The treatments had to be assigned by the investigator in ascending order of the numbers on the envelopes”


Missing data: 1/161 (0.6%) in pristinamycin group and 1/149 (0.7%) in cefuroxime axetil group on day 10 to 12 Comment: marginal missing data rate


Low risk



Low risk

Comment: in both groups the same concomitant medication was prescribed


Unclear risk



115

Rakkar 2001 Methods

Randomised, unblinded design. Diagnosis of acute sinusitis was based on clinical findings (purulent nasal discharge, nasal congestion, postnasal drainage, frequent coughing or throat clearing, frontal headache, malar tenderness/pain); lasting for at least 7 days. Clinical response was assessed by investigator and it was defined as disappearance of acute signs and symptoms related to the infection or sufficient improvement such that additional or alternative antimicrobial therapy was not required. Treatment compliance not reported but to be included in the per-protocol population the patient had to have received at least 80% of study medication. Proportion of the participants included in the per-protocol population was 72% on day 24 to 31

Participants

Multicentre study; primary care participants. 156 men and 315 women; mean age approximately 42 (range 18 to 87) years. ENT co-morbidity was not assessed. Country USA

Interventions

2 treatment arms Group 1: moxifloxacin 400 mg once daily for 10 days Group 2: amoxicillin clavulanate 875 mg twice daily for 10 days Use of oral or nasal decongestants or antihistamines was permitted; systemic or topical corticosteroids were not allowed

Outcomes

Available case data were basically possible to extract for per-protocol population only. However, the way of reporting does not enable identification of clinical failure rates because of inconsistent description of clinical response in results (it remains unclear in which outcome group improvements are included). Clinical outcomes for per-protocol population on day 24 to 31 were reported in 341 out of 475 randomised participants (in 170 out of 238 participants in moxifloxacin group and in 171 out of 237 participants in amoxicillin clavulanate group). (The per-protocol population included all participants with no major protocol violation who had received a study antibiotic for at least 72 hours if a clinical failure, had completed the evaluation at 14 to 21 days post-treatment, and had adequate compliance documented with at least 80% of study medication administered)

Notes

Study supported by a research grant from a pharmaceutical company. 2 of the authors were affiliated to the same pharmaceutical company

Risk of bias Bias




Quote: “Block design random code” Comment: although the description of the sequence generation was incomplete, this domain was graded ’low’ risk of bias because description gives an impression of computer-based method


Unclear risk



Low risk

Outcomes reported: clinical responses and adverse effects


116

Rakkar 2001

(Continued)

Comment: prespecified outcomes (in methods) were reported in prespecified way Blinding? (Participant and investigator)

High risk

Quote: “Non-blinded”


Missing data: 68/238 (29%) in moxifloxacin group and 66/237 (28%) in amoxicillin clavulanate group Comment: missing data rate over 20%


Low risk



Low risk



High risk

Study supported by a research grant from a pharmaceutical company. 2 of the authors were affiliated to the same pharmaceutical company

Riffer 2005 Methods

Randomised, investigator-blinded design. Diagnosis by clinical symptoms and opacification or an air/fluid level in a sinus radiograph or CT. Sinus fluid samples were obtained by aspiration or fibreoptic endoscopy. Clinical cure defined as resolution or improvement in purulent nasal discharge and at least 1 additional sinusitis sign or symptom observed at baseline. Treatment compliance at least 80% for those participants who were included in the clinically evaluable population. Proportion of the participants without known or reported clinical outcome 16% on day 16 to 18

Participants

Multicentre, multi-country trial. Mean age was 37 (range 13 to 79); 194 men and 243 women. ENT co-morbidity was not assessed

Interventions

2 treatment arms Group 1: clarithromycin ER 1000 mg once daily for 14 days Group 2: amoxicillin/clavulanate 875/125 mg twice daily for 14 days Oral sympathomimetic agents, nasal decongestants and antihistamines were used by 23. 8%, 8.9% and 6.9% of participants, respectively

Outcomes

Study reported clinical cure rates for intention-to-treat and clinically evaluable populations. However, only clinically evaluable population could be used as basis for clinical failure rate calculation in this review because true failures were not reported and


117

Riffer 2005

(Continued)

it seemed that indeterminate and missing responses were included in failures in ITT analyses. Clinical outcomes were assessed on day 16 to 18 in 373 of 437 randomised participants (in 188 out of 221 participants in clarithromycin group and in 185 out of 216 participants in amoxicillin-clavulanate group) and on day 24 to 31 in 361 participants. The clinically evaluable population was defined as all randomised participants with clinically and radiographically confirmed sinusitis, and were without major protocol violations. Bacteriological outcomes assessed on day 16 to 18 in 109 of 218 participants. Radiographic outcomes assessed on day 24 to 31 in 366 of 423 participants. Quality of life measured by symptom assessment and the SNOT-16 test Notes

The study was supported by a grant from a pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical, radiological and bacteriological responses, adverse effects and quality of life Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: investigator-blinded study. To maintain the study blind, participants were instructed not to discuss the appearance of study drug or any aspect of dosing with the investigator Comment: no blinding of the participants


Missing data: 33/188 (17.5%) in clarithromycin group and 31/216 (14.4%) in amoxicillin-clavulanate group on day 16 to 18. Total missing data 16% on day 16 to 18 and 17% day 24 to 31 Comment: the groups appeared to be balanced in numbers and reasons for missing data



Low risk


118

Riffer 2005

(Continued)


Low risk



High risk

The study was supported by a grant from a pharmaceutical company

Russell 1997 Methods

Randomised trial. Blinding not stated. Diagnosis by clinical signs and symptoms, confirmed by X-ray or CT (opacification, air/fluid level or mucosal thickening). Clinical outcomes were assessed by an investigator; clinical cure defined as all clinical signs and symptoms were resolved and no new clinical signs and symptoms were present and/or the follow-up radiograph showed resolution/improvement. Approximately 80% of participants received the prescribed antibiotic course. Proportion of the participants without known or reported clinical outcome 12% on day 20 to 35

Participants

Study setting not described. Mean age was approximately 38 (range 13 to 79); 172 men and 256 women. 84% of participants had a history of ENT or eye-related medical conditions. Country - USA

Interventions

3 treatment arms: (groups 1 and 3 used in the analysis) Group 1: cefprozil 250 mg twice daily for 10 to 15 days Group 2: cefprozil 500 mg twice daily for 10 to 15 days Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 to 15 days Adjuvant therapies permitted but not described

Outcomes

Clinical outcomes were assessed on day 20 to 35 in 428 out of 479 participants (in 146 out of 158 participants in cefprozil 250 mg group, in 147 out of 160 participants in cefprozil 500 mg group and in 135 out of 161 participants in amoxicillin-clavulanate group). Radiographic and bacteriological outcomes not reported

Notes

Study was supported by a pharmaceutical company. 3 of the authors were affiliated to pharmaceutical company

Risk of bias Bias







Unclear risk


119

Russell 1997

(Continued)


Low risk



Unclear risk



Missing data: 12/158 (8%) in cefprozil 250 mg group and 26/161 (16%) in amoxicillin-clavulanate group on day 20 to 35 Comment: the groups were imbalanced in numbers of missing data


Low risk



Unclear risk



High risk

Study was supported by a pharmaceutical company. 3 of the authors were affiliated to pharmaceutical company

Sher 2002 Methods

Randomised, investigator-blinded design. Diagnosis by clinical signs and symptoms lasting at least 7 days, confirmed by radiograph showing at least 5 mm mucosal thickening, opacification or air fluid level in a sinus radiograph. Clinical outcomes were assessed by an investigator and clinical cure was defined as improvement in or resolution of all acute signs and symptoms of the original infection, with no need for further antimicrobial therapy. Treatment compliance for clinically evaluable population over 80% by counting unused study medication. Proportion of the participants without known or reported clinical outcome 9%

Participants

Multicentre study; 30 centres. Participants were 42 years old on average (range 18 to 89); 159 men and 286 women. ENT co-morbidity was assessed; for example, 60% of participants had a history of allergic rhinitis. Country - USA

Interventions

3 treatments arms Group 1: gatifloxacin 400 mg once daily for 5 days Group 2: gatifloxacin 400 mg once daily for 10 days Group 3: amoxicillin/clavulanate 875 mg twice daily for 10 days Medications for symptom relief (for example, decongestants and antihistamines) were allowed


120

Sher 2002

(Continued)

Outcomes

Study reported results for clinically evaluable participants only. Clinical outcomes were assessed on day 10 to 13 and on day 17 to 24 in 405 out of 445 randomised participants (in 137 out of 149 participants in 5-day gatifloxacin group, in 127 out of 141 participants in 10-day gatifloxacin group and in 141 out of 155 participants in amoxicillin-clavulanate group). Clinically evaluable participants were those who met the inclusion criteria and had received at least 80% of the intended amount of study drug, had undergone the testof-cure assessment (7 to 14 days after the completion of treatment), and had not received any other antibiotic during the study or before the test-of-cure visit for an infection other than sinusitis. Long-term follow-up on day 31 to 38 by telephone Radiographic and bacteriological outcomes not reported

Notes


Risk of bias Bias




Quote: “Patients were randomized to treatment by means of a centralized telephone system. A permuted block design was used to minimize imbalance in treatment arms at each site and in the study overall”


Low risk

Quote: “Patients were randomized to treatment by means of a centralized telephone system. A permuted block design was used to minimize imbalance in treatment arms at each site and in the study overall”


Low risk



Unclear risk

Quote: “Investigator-blinded trial”. “Matching placebo-tablets were used, and drugs and placebos were supplied by the respective manufacturers” Comment: although blinding of participants was also described, this domain was graded ’unclear’ because the study was reported to be only investigator-blinded



Missing data: 12/149 (8%) in 5-day gatifloxacin group, 14/141 (10%) in 10-day gatifloxacin group and 14/155 (9%) in amoxicillin/clavulanate group Quote: “The 40 unevaluable participants 121

Sher 2002

(Continued)

were distributed evenly between groups and between reasons for non-evaluability” Comment: although there was no detailed description of the reasons for missing data, this domain was graded ’low’ risk of bias because the study stated that the groups were balanced Free of other bias? Baseline comparability

Unclear risk

Comment: detailed description of demographic characteristics and sinusitis severity rating at baseline to assess the comparability of the groups for whole randomised population, not separately for clinically evaluable population


Low risk

Comment: no co-interventions included in the protocol. In both groups the same concomitant medication was allowed and of such quality that it does not have effect on recovery (thus not cause bias)


Unclear risk


Siegert 2000 Methods

Randomised, double-blind trial. Diagnosis by clinical signs and symptoms, confirmed by radiograph (mucosal thickening, opacification or air-fluid level) or bacteriologically (either by a swab collected under endoscopic view, cannulation of the middle meatus or a sinus puncture; positive cultures were obtained in 52% of participants). Clinical cure was not defined. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 5%

Participants

Multicentre (60 centres), multinational trial (Finland, France, Germany, Greece, Israel, Spain, Sweden). Mean age 40; 220 men, 273 women. ENT co-morbidity not reported

Interventions

2 treatment arms Group 1: cefuroxime axetil 250 mg twice daily, 10 days Group 2: moxifloxacin 400 mg daily, 7 days Nasal decongestants and mucolytic drugs allowed; systemic or topical corticosteroids not allowed

Outcomes

Clinical outcomes assessed on day 14 in 468 out of 493 randomised (in 241 out of 251 participants in cefuroxime axetil group and in 227 out of 242 participants in moxifloxacin group). Bacteriological outcomes in 224; radiographic outcomes not assessed

Notes



122

Siegert 2000

(Continued)

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response for 224 participants and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind study”. “Placebocapsules used” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 10/251 (4%) in cefuroxime axetil group and 15/242 (6%) in moxifloxacin group on day 14 Comment: marginal missing data rate


Unclear risk

Comment: it appears that the groups were imbalanced in respect of severity of the sinusitis (more participants with severe disease in moxifloxacin group)


Low risk



Unclear risk



123

Siegert 2003 Methods

Randomised, double-blind trial. Diagnosis by clinical symptoms and radiograph showing at least 6 mm mucosal thickening, opacification or air-fluid level. Sinus material for bacteriological culture by puncture or by middle meatus swab under endoscopic guidance. Clinical cure defined as disappearance of signs and symptoms or significant improvement and no further therapy required. Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 19% on day 14 to 23

Participants

Multicentre, multinational trial. Participants were enrolled by otolaryngologists at 43 centres in 7 countries: France, Germany, Greece, Israel, Lithuania, Spain and Sweden. Participants were 42 years old on average and included 193 men and 259 women. ENT co-morbidity was not assessed

Interventions

2 treatment arms Group 1: faropenem daloxate 300 mg twice daily for 7 days Group 2: cefuroxime axetil 250 mg twice daily for 7 days Decongestants, antihistamines and mucolytics were allowed. Intranasal or oral corticosteroids were not permitted

Outcomes

Study reported clinical responses for clinically evaluable patients only. Clinical outcomes assessed on day 14 to 23 in 452 out of 558 randomised participants (in 228 out of 279 participants in faropenem daloxate group and in 224 out of 279 participants in cefuroxime axetil group). Clinically evaluable population was defined as patients who had clinically and radiologically confirmed diagnosis, did not receive any concomitant antimicrobials and/or corticosteroids, and were assessed on day 14 to 23. Bacteriological outcomes were assessed in 136 participants

Notes

Study was supported by a grant from a pharmaceutical company. 2 of the authors were affiliated to a pharmaceutical company

Risk of bias Bias




Quote: “Patients were randomly assigned 1:1 to one of two treatment groups using a block design computer-generated random code”


Unclear risk



Low risk



Low risk

Quote: “Double-blind study”. “For blinding purposes, matched placebos were used in one group and encapsulated tablets in


124

Siegert 2003

(Continued)

the other group” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described Incomplete outcome data addressed? Unclear risk (Clinical efficacy outcomes)

Missing data: 51/279 (18%) in faropenem daloxate group and 55/279 (20%) in cefuroxime axetil group on day 14 to 23 Comment: reasons for missing data across groups insufficiently described


Low risk



Low risk



High risk

Study was supported by a grant from a pharmaceutical company. 2 of the authors were affiliated to a pharmaceutical company

SSG 1993 Methods

Randomised, double-blind trial. Diagnosis was established by purulent rhinorrhoea, a radiograph consistent with sinusitis or a sinus puncture and that isolated a bacterial pathogen (about 50% of participants had a pathogen). Clinical outcomes were assessed by an investigator. Clinical cure was defined as resolution of pretreatment signs and symptoms and no recurrence within 72 hours post-treatment; improvement was defined as a reduction in the number or severity of signs and symptoms but without complete resolution. Compliance with treatment was not reported. Proportion of the participants without known or reported clinical outcome 2%

Participants

Participants were recruited from outpatient otolaryngology clinics. Demographic data reported only for evaluable participants (defined as participants with isolated bacterial pathogen plus no protocol violations): mean age approximately 35 (range 16 to 73); 186 men and 152 women. ENT co-morbidity was not assessed. Countries - Sweden, Finland, Iceland

Interventions

2 treatment arms Group 1: loracarbef 400 mg twice daily for 10 days


125

SSG 1993

(Continued)

Group 2: doxycycline 200 mg first dose followed by 100 mg daily for 10 days Adjuvant therapies were not described Outcomes

Clinical outcomes were assessed in 648 out of 662 randomised participants (in 323 out of 330 participants in doxycycline group and in 325 out of 332 participants in loracarbef group). Outcomes were assessed on day 7 to 13 after randomisation. Radiographic outcomes were not reported. Bacteriological outcomes were assessed in 324 participants

Notes


Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical response, bacteriological response for those participants who had positive culture at baseline and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Double-blind”. “Participants in the doxycycline group also received a capsule containing a placebo in order to ensure blinding of both the participants and observers” Comment: although the description of the blinding was incomplete, this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 7/332 (2%) in loracarbef group and 7/330 (2%) in doxycycline group Comment: minimal missing data rate


Comment: information on comparability of intervention and control groups at baseline reported only from evaluable participants which was half of the enrolled population

Unclear risk


126

SSG 1993

(Continued)


Unclear risk



High risk


Stefansson 1998 Methods

Randomised, double-blind trial. Diagnosis by symptoms and sinus opacity or air-fluid level on radiograph. Cure defined as clinical signs and symptoms improved or resolved at post-treatment (11 to 13 days) and radiographically confirmed absence at follow-up (38 to 45 days). Treatment compliance was not reported. Proportion of the participants without known or reported clinical outcome 4% on day 11 to 13

Participants

Study setting not described. Mean age 37; 157 men and 213 women. ENT co-morbidity was not assessed. Countries - 8 European, Middle Eastern and African

Interventions

2 treatment arms Group 1: cefuroxime axetil 250 mg twice daily for 10 days Group 2: clarithromycin 250 mg twice daily for 10 days Nasal corticosteroids prohibited; other adjuvant treatments not described

Outcomes

Clinical outcomes were assessed on day 11 to 13 in 354 out of 370 randomised participants. Second follow-up on day 38 to 45 in 310 participants

Notes


Risk of bias Bias






Unclear risk



Unclear risk

Outcomes reported: clinical response (including also radiological findings at second follow-up) and adverse effects Comment: the radiological responses are reported also separately. It remains unclear whether radiological response was an independent outcome or not


Low risk

Quote: “Double-blind study”. “Placebotablets used” Comment: although the description of the blinding was incomplete, this domain was


127

Stefansson 1998

(Continued)

graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described Incomplete outcome data addressed? Low risk (Clinical efficacy outcomes)

Missing data: 10/185 (5%) in cefuroxime axetil group and 6/185 (3%) in clarithromycin group at 11 to 13 days (primary outcome) Comment: this assessment has been based on the numbers given in a table. Although the corresponding exact numbers given in the text were slightly different, this domain was graded ’low’ risk of bias because the missing data rate is marginal


Low risk



Low risk



Unclear risk


Sterkers 1997 Methods

Randomised, unblinded design. Diagnosis by symptoms (duration not described) and fluid or opacity on radiograph. Clinical cure defined as disappearance of purulent nasal discharge. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 13%

Participants

Multicentre, but settings not described. Mean age approximately 41; 178 men and 280 women. Country - France

Interventions

3 treatment arms: (only group 1 - the standard dosing and group 3 used in the analysis) Group 1: ceftibuten 400 mg once daily for 8 days Group 2: ceftibuten 200 mg twice daily for 8 days Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily Adjuvant treatments not described

Outcomes

Overall, clinical and radiographic outcomes reported on day 10 in 400 out of 458 randomised participants (in 134 participants out of 152 in ceftibuten 400 mg once daily group; 138 out of 157 in ceftibuten 200 mg twice daily group and 128 out of 149


128

Sterkers 1997

(Continued)

participants in amoxicillin-clavulanate group); 50 excluded post-randomisation due to negative radiograph. Second follow-up on day 40 after randomisation Notes

Funding source not identified

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical and radiographic responses, and adverse affects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk



Total missing data 13% on day 10 and 14% on day 40 Comment: no description of reasons for missing data across groups


Unclear risk



Unclear risk



Unclear risk

Funding source not identified


129

Steurer 2000 Methods

Randomised, investigator-blinded trial. Diagnosis by clinical signs and symptoms, confirmed by a radiograph (criteria not specified). Sinus aspirate and culture (1 or more pathogens were isolated from the maxillary sinus aspirates of 66% participants). Clinical cure defined dichotomously - “cure” or “failure”. Compliance not reported. Proportion of randomised participants without known clinical outcome was not reported. Study reported only clinical cure rates for intention-to-treat population (all randomised participants) and for “evaluable” population (participants all of whose clinical and microbial data were available). The data from this study were not used in the meta-analyses of this review because all non-cures in the ITT population (11%) were categorised as failures in analyses (it remains unclear how many responses were true failures in each group and how much was missing data); the missing data in the “evaluable” population was high (52%)

Participants

Participants recruited from 16 medical centres throughout Europe. Setting not described. Mean age 31; 336 men, 233 women. ENT co-morbidity not reported

Interventions

3 treatment arms Group 1: cefdinir 600 mg daily, 10 days Group 2: cefdinir 300 mg twice daily, 10 days Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily, 10 days Topical nasal decongestants with xylomethazoline, oxymethazoline or naphazoline were permitted but not prescribed

Outcomes

Study did not report description of missing data. Study reported only clinical cure rates for intention-to-treat population and all clinical responses were known only for “evaluable” populations. Clinical outcomes for “evaluable population” were reported on day 17 to 25 and on day 31 to 35 in 295 out of 569 randomised participants (in 93 participants out of 182 in cefdinir 600 mg once daily group, in 96 out of 198 in cefdinir 300 mg twice daily group and in 106 out of 189 participants in amoxicillin-clavulanate group) . Radiographic outcomes reported on day 17 to 25 for 295. Bacteriological outcomes reported in 248

Notes

Study sponsored by a pharmaceutical company

Risk of bias Bias




Quote: “For each study centre an independent randomized schedule was prepared”


Quote: “Study monitored by a pharmaceutical company. Medication was dispensed by a third person and all records concerning medications were kept in a separate location”

Low risk


130

Steurer 2000

(Continued)


Low risk



High risk

Quote: “Participants were given consecutive patient numbers after screening. As this was investigator-blinded study, medication was dispensed by a third person and all records concerning medications were kept in a separate location. The participants were instructed not to reveal the type of medication to the investigator” Comment: no blinding of the participants


Missing data: 89/182 (49%) in cefdinir 600 mg once daily group, 102/198 (52%) in cefdinir 300 mg twice daily group, and 83/189 (44%) in amoxicillin-clavulanate group on day 17 to 25 Comment: missing data rate over 20%


Low risk



Low risk



High risk

Study sponsored by a pharmaceutical company


131

Sydnor 1992 Methods

Randomised, single-blind (investigator). Diagnosis was confirmed by a clinical diagnosis of acute sinusitis and a radiograph consistent with sinusitis (showing mucosal thickening at a minimum). A bacteriologic culture of aspirated maxillary sinus fluid; evaluable patients were required to have positive cultures of pathogens susceptible to both study antibiotics. Clinical cure was not defined. Compliance with therapy was not reported. Total proportion of the participants without known clinical outcome 62%. Participants were excluded mostly due to bacteriologic reasons; exclusions because of other reasons marginal 2%

Participants

The study setting was not well described. Participants’ mean age was approximately 38 (range 18 to 78); 39 men and 74 women. Country - USA

Interventions

2 treatment arms Group 1: loracarbef 400 mg twice daily for 7 to 10 days Group 2: amoxicillin clavulanate 500 mg/125 mg 3 times daily for 7 to 10 days No information provided on symptomatic medication for sinusitis

Outcomes

Clinical outcomes were assessed on day 7 to 13 in 43 of 113 randomised participants (in 22 out of 59 participants in loracarbef group and in 21 out of 54 participants in amoxicillin-clavulanate group). Second follow-up at 1 to 2 weeks after the conclusion of therapy for those participants with favourable symptomatic responses at the first followup. Radiographic outcomes were not reported; bacteriological outcomes were reported for 28 participants

Notes

Study supported by grants from a pharmaceutical company. 1 of the authors was affiliated to the same pharmaceutical company

Risk of bias Bias






Unclear risk



Low risk

Outcomes reported: clinical and bacteriologic responses, and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


High risk

Quote: “Investigator-blinded”



Exclusions from analyses: bacteriologic reasons 36/59 in loracarbef group and 32/ 54 in amoxicillin clavulanate group; other exclusions 1 (2%) and 1 (2%) of participants, respectively. (Bacteriologic reasons included resistant causative organ132

Sydnor 1992

(Continued)

isms, negative pre-therapy cultures for pathogens, and no or low colony counts on pre-therapy isolates) Comment: the bacteriologic reasons were seen not to cause bias. Other missing data marginal Free of other bias? Baseline comparability

Low risk



Unclear risk



High risk

Study supported by grants from a pharmaceutical company. 1 of the authors was affiliated to the same pharmaceutical company

Upchurch 2006 Methods

Randomised, double-blind design. Diagnosis by clinical signs and symptoms > 7 days but < 28 days, confirmed by radiograph showing air fluid level, opacification and/or at least 6 mm mucosal thickening. Clinical outcomes were assessed by an investigator and clinical cure was defined as resolution or improvement of clinical symptoms and signs such that no additional antimicrobial treatment was necessary. Treatment compliance 91%. Proportion of the participants included in the efficacy-valid population was 78% on day 17 to 31

Participants

Multicentre trial (57 centres) in USA and Canada. 1099 outpatients, 481 male and 618 women. Participants were 43 years old on average (range 15 to 90). 37% of participants had a history of allergic rhinitis

Interventions

3 treatment arms: Group 1: faropenem medoxomil 300 mg twice daily for 7 days Group 2: faropenem medoxomil 300 mg twice daily for 10 days Group 3: cefuroxime axetil 250 mg twice daily for 10 days Oral or nasal decongestants or antihistamines were allowed; systemic or topical corticosteroids not permitted

Outcomes

Study reported clinical cure rates for intention-to-treat and efficacy-valid populations. However, only efficacy-valid population could be used as basis for clinical failure rate calculating in this review because true failures were not reported and both indeterminate and missing responses were included in failures in ITT analyses. Clinical outcomes for efficacy-valid population were assessed on day 17 to 31 in 861 out of 1106 randomised participants (in 295 out of 370 participants in faropenem medoxomil for 7 days group, in 280 out of 365 participants in faropenem medoxomil for 10 days group, and in 286 out of 371 participants in cefuroxime axetil group). Efficacy-valid population was defined as participants who met inclusion criteria, had radiologically confirmed sinusitis, study


133

Upchurch 2006

(Continued)

drug given for a minimum of 72 hours for participants considered treatment failures and a minimum of 5 days to be a treatment success, adequate adherence documented with over 80% of medication, absence of any protocol violation influencing treatment efficacy, and no essential data missing or indeterminate. Second follow-up 28 to 38 days post-treatment. Radiographic outcomes not reported Notes

Funding for trial provided by a pharmaceutical company

Risk of bias Bias




Quote: “Participants were randomly assigned in a 1:1:1, double-blind fashion by using a computer-generated random code to one of three oral-treatment groups”


Unclear risk



Low risk



Low risk

Quote: “Double-blind study”. “Because faropenem medoxomil could not be encapsulated, a double-dummy design was used to maintain blinding”. “Matching placebocapsules used” Comment: although the description of blinding was incomplete (no description of investigator blinding), this domain was graded ’low’ risk of bias because the study was reported to be double-blind and blinding method was partly described


Missing data: 75/370 (20%) in faropenem medoxomil for 7 days group, 85/365 (23%) in faropenem medoxomil for 10 days group and 85/371 (23%) in cefuroxime axetil group on day 17 to 31 Comment: missing data rate over 20%


Quote: “Demographic and baseline medical characteristics for the efficacy-valid population were generally consistent with those of the intent-to-treat population” Comment: although data on baseline com-

Low risk


134

Upchurch 2006

(Continued)

parability were only shown for the ITT population (not separately for efficacyvalid population), this domain was graded ’low’ risk of bias because the authors stated that also the efficacy-valid groups were comparable Free of other bias? Co-interventions

Low risk



High risk

Funding for trial provided by a pharmaceutical company

van Buchem 1997 Methods

Randomised, double-blind design. Diagnosis made clinically (the mean duration of the symptomatic period before treatment was 2.2 weeks), confirmed by radiograph showing > 5 mm mucosal thickening, opacity or air-fluid level. Clinical cure was not defined. Treatment compliance reported as 98% assessed by pills taking by participants. Proportion of the participants without known or reported clinical outcome 4% on day 14

Participants

Participants were recruited from community-based, general medical practices. Mean age was 34; 79 men and 135 women. ENT co-morbidity was assessed; approximately 12% had allergic disease. Country - The Netherlands

Interventions

2 treatment arms Group 1: placebo 3 times daily for 7 days Group 2: amoxicillin 750 mg 3 times daily for 7 days Adjuvant therapy with oxymetazoline steam inhalation (duration not specified). Paracetamol as needed

Outcomes

Clinical and radiographic outcomes were assessed on day 14 for 206 out of 214 participants randomised (in 105 out of 108 participants in antibiotic group and in 101 out of 106 participants in placebo group). Long-term relapse rates during 1 year. Bacteriological outcomes were not assessed

Notes


Risk of bias Bias


Random sequence generation (selection Low risk bias) Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement Quote: “The randomization of allocation of the amoxycillin or placebo (distributed 135

van Buchem 1997

(Continued)

in identical bottles) was computer generated” Allocation concealment (selection bias)

Low risk

Quote: “Randomisation of patients was carried out and capsules were provided by the hospital pharmacy in the hospital were patients were to see the ENT specialist. The code of the allocation schedule was kept in the office of the head of the hospital pharmacy, and was broken prematurely only if a severe clinical development or severe adverse effects occurred” Comment: central allocation


Low risk

Outcomes reported: clinical and radiological responses, relapses, chronic evolution and adverse effects Comment: prespecified outcomes (in methods) were reported in prespecified way


Low risk

Quote: “Neither the pharmacist’s assistant who distributed the bottles (identical bottles for both groups), the patient, nor the ENT specialist was aware of the nature of the medication”


Missing data: 2.7% (3/108) in antibiotic group and 4.7% (5/106) in placebo group at 14 days Comment: marginal missing data rate


Low risk



Low risk



Unclear risk



136

von Sydow 1995 Methods

Randomised, double-blind design. Diagnosis based on clinical symptoms and radiograph showing air-fluid level or opacity (verified by sinus aspiration). Failure defined as clinical signs and sinus X-ray points unchanged or worsened. Treatment compliance not reported. Proportion of the participants without known or reported clinical outcome 10%

Participants

Participants recruited from academic affiliated, otolaryngology practices. Mean age 33 (range 18 to 78); 149 men and 137 women. ENT co-morbidity was not assessed. Countries - Sweden, Finland, Norway

Interventions

2 treatment arms Group 1: cefpodoxime proxetil 200 mg twice daily for 10 days Group 2: amoxicillin 750 mg twice daily for 10 days All participants received xylometazoline (nasal decongestant) for up to 7 days

Outcomes

Clinical outcomes were assessed on day 11 to 20 in 258 out of 286 participants randomised (in 130 out of 143 participants in cefpodoxime proxetil group and in 128 out of 143 participants in amoxicillin group). Bacteriological outcomes reported in 150 participants

Notes

Study was financially supported by a pharmaceutical company. 1 of the authors had affiliation to pharmaceutical company

Risk of bias Bias






Unclear risk



High risk

Outcomes reported: clinical response (including radiological findings), bacteriological response for 150 participants and adverse effects Comment: in the protocol it is stated that the second follow-up would be at days 28 to 35. Those results are, however, not reported


Unclear risk

Quote: “Double-blind, double-dummy study” Comment: no description of the blinding procedure



Missing data: 13/143 (9.1%) in cefpodoxime proxetil group and 15/143 (10.5%) in amoxicillin group Comment: although description of the reasons for the missing data by group was un137

von Sydow 1995

(Continued)

clear this domain was graded ’low’ risk of bias because the total missing data rate was moderate and balanced Free of other bias? Baseline comparability

Low risk



Low risk



High risk

Study was financially supported by a pharmaceutical company. 1 of the authors had affiliation to a pharmaceutical company

ABMS: acute bacterial maxillary sinusitis BID: twice daily CT: computerised tomography (scan) ENT: ear, nose and throat ITT: intention-to-treat mITT: modified intention-to-treat

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Agbim 1974

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before study entry not reported). Results not reported separately for participants with acute sinusitis

Alvart 1992

Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30

Axelsson 1971

Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes

Axelsson 1973

Antibiotic versus antibiotic - study design. Not randomised study

Axelsson 1975

Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes, only radiological outcomes

Axelsson 1981


Bandak 1999

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before study entry not reported)


138

(Continued)

Beatson 1985

Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition reported for acute sinusitis)

Bockmeyer 1994

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before study entry not reported; bacteriological specimens taken from nasal discharge)

Brodie 1989

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis mainly by clinical signs and symptoms but the minimum duration of those before study entry not reported)

Brook 2006

Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes

Bucher 2003

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings; only 32% of participants had symptoms for 7 days or longer before study entry)

Carenfelt 1975

Antibiotic versus antibiotic - study design. Random allocation not stated

Casiano 1991

Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute sinusitis

Correa 1986

Antibiotic versus antibiotic - study design. Clinical outcomes measured are clinical plus bacteriological; they are not separated individually

De Abate 1992

Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition reported for acute sinusitis)

De Sutter 2002

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings; about 50% of participants with symptoms less than 7 days at study entry). The information obtained from the authors

Edelstein 1993

Antibiotic versus antibiotic - study design. Approximately 50% of participants with acute exacerbation of chronic sinusitis. Results not reported separately for acute maxillary sinusitis

Ekedahl 1987

Antibiotic versus antibiotic - study design. No clinical outcomes Insufficient information on intervention groups

Elies 2001

Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled; proportion of included complicated cases (frontal sinusitis or pansinusitis) was not reported

Falser 1988

Antibiotic versus antibiotic - study design including participants with otitis and sinusitis. Results not reported separately for participants with sinusitis

Federspil 1983

Antibiotic versus antibiotic - study design. Mixed ENT infections. Sample size for acute sinusitis < 30


139

(Continued)

Felstead 1991

Antibiotic versus antibiotic - study design. The criteria for diagnosis of acute maxillary sinusitis not clearly stated

Fiscella 1991

Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30 (the total number of the participants was > 30, but about 50% of participants had acute exacerbation of chronic sinusitis)

Freche 1988

Antibiotic versus antibiotic - study design. The definition of acute maxillary sinusitis unclear

Gananca 1973

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (definition of sinusitis by clinical signs and symptoms or by X-ray not reported; bacteriological specimens taken from purulent nasal discharge, site not specified)

Gananca 1977

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings without detailed description of signs and symptoms and duration)

Garcia 1998


Gladkov 1979

Antibiotic versus dexamethazone and formaldehyde - study design. Randomisation not stated. Sample size for acute sinusitis < 30

Goumas 1997

Antibiotic versus antibiotic - study design. Quasi-randomised design

Gurdogan 2001


Gwaltney 1981

Antibiotic versus antibiotic - study design. Randomised trial for some of the participants. Out of 113 participants randomised only 32 had outcomes reported. Uncertain if outcomes relate only to those randomised

Hansen 2000

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings; at least 50% of participants had symptoms lasting for 6 days or less at study entry)

Hebblethwaite 1987

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis insufficiently stated

Henry 1999a

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (the duration of symptoms before study entry not reported; the diagnosis in 30% of participants not confirmed by X-ray)

Henry 1999b

Antibiotic versus antibiotic - study design. Unclear data, contradictory results in table and text

Husfeldt 1993


Jeppesen 1970

Antibiotic versus placebo - study design. Quasi-randomised design. Puncture and irrigation (every second day) used as co-intervention. Sample size for acute maxillary sinusitis < 30

Johnson 1999

Antibiotic versus antibiotic - study design. Approximately 30% of participants had acute exacerbation of chronic sinusitis. Results not reported separately for acute maxillary sinusitis


140

(Continued)

Karpov 1998

Antibiotic versus antibiotic - study design Puncture used as co-intervention

Klein 1998


Lacroix 2002

Study mainly designed to identify signs to predict the presence of bacteria in acute rhinosinusitis (including common cold and acute sinusitis). Inclusion criteria for the study did not fulfil the inclusion criteria for this review (69% of patients had other URTIs than sinusitis confirmed by X-ray; median duration of clinical symptoms 4 days for all randomised patients; data not reported separately for patients with acute sinusitis)

Li 2000

Antibiotic versus antibiotic - study design. Approximately 67% of participants had chronic sinusitis. Randomisation unclear

Lopez 1975

Sample size for acute sinusitis < 30 (7 participants)

Luchikhin 2005

Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30

Mannhardt 1980

Antibiotic versus antibiotic - study design. Mixed sample of acute (n = 30) and chronic (n = 22) sinusitis. Only combined results are reported

Manzini 1993

Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary sinusitis

Marchi 1990


Marcolino 1999

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (clinical symptoms lasting at least 4 weeks)

Mesure 1973

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (no definition of acute maxillary sinusitis). Sample size for acute sinusitis < 30

Mira 2001

Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30. Insufficient information on diagnostic criteria for acute maxillary sinusitis

Miyamoto 2005

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)

Moorhouse 1985

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)

Norrelund 1978

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)

Olsson 1976

Antibiotic versus antibiotic - study design. Questionable random allocation. Sample size for acute sinusitis < 30

Osman 1983

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis not stated


141

(Continued)

Pallestrini 1995


Panosetti 1992

Antibiotic versus antibiotic - study design. Hospitalised participants, ENT ward

Peyramond 1991

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis on clinical basis; duration of symptoms before study entry not stated)

Piragine 1988

Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30 (7 participants)

Podvinec 1982

Antibiotic versus antibiotic - study design. Mixed sample of acute (< 80%) and chronic sinusitis. Results not reported separately

Polonovski 2006

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis on clinical basis, median duration of symptoms 4 days before study entry)

Quick 1973

Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis < 30

Quick 1975

Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis < 30

Rantanen 1973

Antibiotic versus no antibiotic - study design. Study design not suitable for this review because weekly irrigation was used as co-intervention. Random allocation not stated

Rechtweg 2004


Riedel 1987

Study design comparing antibiotic + serrapeptase versus serrapeptase. Not a randomised study

Rimmer 1997

Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for sinusitis

Roenning 1987

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review Overall clinical outcomes not reported

Sabater 1995

Antibiotic versus antibiotic - study design. Assessment of the study was based on the abstract. Additional information was requested from the authors to assess the adequacy of the study for this review but the authors were not able to deliver the necessary information

Salmi 1986


Salmi 1993

Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Sample size for acute sinusitis < 30. Insufficient information on diagnostic criteria for acute maxillary sinusitis

Schering-Plough 2003

Unpublished study (assessment of the study based on the study synopsis which was obtained from the pharmaceutical company). The study was a randomised clinical trial comparing intranasal corticosteroid with antibiotic and placebo. In the synopsis, definition of outcome and data were not in a usable form for this review


142

(Continued)

Serra 2007

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (sinusitis not defined by clinical signs and symptoms; microbiological evaluation reported to be based on specimens taken by swab without specification of where they were taken from)

Spindler 1985

Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (criteria for acute sinusitis not reported)

Stahl 1989

Antibiotic versus antibiotic - study design. Included also other URTI than sinusitis. Inclusion criteria for this review not fulfilled: criteria for acute sinusitis not reported, the proportion of participants with chronic sinusitis > 20% and clinical outcomes for acute sinusitis not reported separately

Stalman 1997a

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings; duration of symptoms reported to have lasted at least 5 days). Additional information was requested from the authors about the proportion of the participants with symptoms for less than 7 days but the authors were not able to deliver the information

Strachunskii 1993


Sydnor 1989

Antibiotic versus antibiotic - study design. No clinical outcomes

Söderström 1991

Antibiotic versus antibiotic - study design. Clinical outcomes not measured for sinusitis (included also other URTI)

Taub 1967

RCT comparing bromelains + antibiotics to antibiotics Diagnostic criteria for sinusitis not stated. Sample size for acute maxillary sinusitis < 30

Varonen 2003a

Antibiotics versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (about 27% of participants with symptoms for less than 6 days at study entry. Ultrasound positive about 50% of participants)

von Sydow 1984

Antibiotic versus antibiotic - study design. Insufficient information (for example, the follow-up time and duration of the therapy were not stated)

Wallace 1985

Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Insufficient information on diagnostic criteria for acute maxillary sinusitis

Weis 1998

Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before study entry not reported)

Westerman 1975

Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary sinusitis

Williamson 2007

Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis based on clinical findings; only 57% of participants had symptoms for 7 days or longer at study entry). The information was obtained from the authors


143

(Continued)

Young 2003

The study design mainly intended to examine the diagnostic indicators for acute bacterial rhinosinusitis than comparing antibiotic versus placebo. Diagnostic criteria for acute sinusitis did not fulfil the inclusion criteria for this review (diagnosis by clinical signs and symptoms; median duration of symptoms 4 days)

Zbären 1983

Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30

RCT: randomised controlled trial URTI: upper respiratory tract infection


144

DATA AND ANALYSES

Comparison 1. Antibiotics versus placebo

Outcome or subgroup title 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up 3 Clinical failure defined as a lack of full recovery at 7 to 15 days of follow-up 4 Clinical failure defined as a lack of full recovery at 16 to 60 days of follow-up 5 Relapse rates after 60 days 6 Drop-outs due to adverse effects

No. of studies

No. of participants

5

1058

2

Statistical method

Effect size

Risk Ratio (M-H, Random, 95% CI)

0.66 [0.47, 0.94]

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

5

680


0.73 [0.63, 0.85]

1

169


0.63 [0.38, 1.05]

1 9

214 1818

Risk Ratio (M-H, Fixed, 95% CI) Peto Odds Ratio (Peto, Fixed, 95% CI)

1.25 [0.72, 2.19] 1.40 [0.60, 3.25]

Comparison 2. Cephalosporin/macrolide versus amoxicillin-clavulanate

Outcome or subgroup title 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up 3 Drop-outs due to adverse effects (cephalosporins) 4 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up 5 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up 6 Drop-outs due to adverse effects (macrolides)

No. of studies

No. of participants

6

1887


1.37 [1.04, 1.80]

7

1415


1.08 [0.85, 1.37]

9

2973

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.32 [0.21, 0.49]

7

1807


0.83 [0.62, 1.13]

4

908


0.85 [0.57, 1.27]

8

2550


0.47 [0.30, 0.72]

Statistical method


Effect size

145

Comparison 3. Non-penicillin antibiotics versus beta-lactamase sensitive penicillins

Outcome or subgroup title 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up 3 Drop-outs due to adverse effects

No. of studies

No. of participants

7

1083


0.70 [0.47, 1.06]

1

436


0.67 [0.37, 1.20]

7

1208


0.58 [0.25, 1.35]

Statistical method

Effect size

Comparison 4. Tetracyclines versus mixed classes of antibiotics

Outcome or subgroup title 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up 2 Drop-outs due to adverse effects

No. of studies

No. of participants

5

807


1.09 [0.70, 1.71]

5

854


0.73 [0.33, 1.60]

Statistical method


Effect size

146

Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. Review:

Antibiotics for acute maxillary sinusitis in adults

Comparison: 1 Antibiotics versus placebo Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up

Study or subgroup

Antibiotics

Placebo

Risk Ratio MH,Random,95% CI

Weight


n/N

n/N

Haye 1998

6/86

9/82

12.3 %

0.64 [ 0.24, 1.71 ]

Lindbaek 1996

2/83

5/44

4.7 %

0.21 [ 0.04, 1.05 ]

Lindbaek 1998

5/42

3/21

6.8 %

0.83 [ 0.22, 3.16 ]

Meltzer 2005

18/250

27/244

37.0 %

0.65 [ 0.37, 1.15 ]

van Buchem 1997

18/105

23/101

39.3 %

0.75 [ 0.43, 1.31 ]

Total (95% CI)

566

492

100.0 %

0.66 [ 0.47, 0.94 ]

Total events: 49 (Antibiotics), 67 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 2.29, df = 4 (P = 0.68); I2 =0.0% Test for overall effect: Z = 2.33 (P = 0.020) Test for subgroup differences: Not applicable

0.01

0.1

Favours antibiotics

1

10

100

Favours placebo

Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. Review:


Comparison: 1 Antibiotics versus placebo Outcome: 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up

Study or subgroup

Hadley 2010 Haye 1998

Antibiotics

Placebo

n/N

n/N

Risk Ratio

Risk Ratio

19/73

19/45

0.62 [ 0.37, 1.03 ]

9/87

10/82

0.85 [ 0.36, 1.98 ]

M-H,Fixed,95% CI

0.01

0.1

Favours antibiotics


1

10

M-H,Fixed,95% CI

100

Favours placebo

147

Analysis 1.3. Comparison 1 Antibiotics versus placebo, Outcome 3 Clinical failure defined as a lack of full recovery at 7 to 15 days of follow-up. Review:


Comparison: 1 Antibiotics versus placebo Outcome: 3 Clinical failure defined as a lack of full recovery at 7 to 15 days of follow-up

Study or subgroup

Antibiotics

Placebo


Weight


n/N

n/N

Haye 1998

36/86

55/82

21.3 %

0.62 [ 0.47, 0.84 ]

Lindbaek 1996

51/83

39/44

35.4 %

0.69 [ 0.57, 0.85 ]

Lindbaek 1998

27/42

12/21

11.1 %

1.13 [ 0.73, 1.74 ]

Merenstein 2005

24/56

35/60

14.6 %

0.73 [ 0.51, 1.06 ]

van Buchem 1997

37/105

48/101

17.6 %

0.74 [ 0.53, 1.03 ]

Total (95% CI)

372

308

100.0 %

0.73 [ 0.63, 0.85 ]

Total events: 175 (Antibiotics), 189 (Placebo) Heterogeneity: Tau2 = 0.01; Chi2 = 5.18, df = 4 (P = 0.27); I2 =23% Test for overall effect: Z = 3.98 (P = 0.000070) Test for subgroup differences: Not applicable

0.01

0.1

Favours antibiotics

1

10

100

Favours placebo


148

Analysis 1.4. Comparison 1 Antibiotics versus placebo, Outcome 4 Clinical failure defined as a lack of full recovery at 16 to 60 days of follow-up. Review:


Comparison: 1 Antibiotics versus placebo Outcome: 4 Clinical failure defined as a lack of full recovery at 16 to 60 days of follow-up

Study or subgroup

Haye 1998

Total (95% CI)

Antibiotics

Placebo

n/N

n/N

Risk Ratio

Weight

18/87

27/82

100.0 %

0.63 [ 0.38, 1.05 ]

87

82

100.0 %

0.63 [ 0.38, 1.05 ]

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 18 (Antibiotics), 27 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.77 (P = 0.077) Test for subgroup differences: Not applicable

0.01

0.1

1

Favours antibiotics

10

100

Favours placebo

Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days. Review:


Comparison: 1 Antibiotics versus placebo Outcome: 5 Relapse rates after 60 days

Study or subgroup

Antibiotics

Placebo

n/N

n/N

Risk Ratio

Weight

van Buchem 1997

23/108

18/106

100.0 %

1.25 [ 0.72, 2.19 ]

Total (95% CI)

108

106

100.0 %

1.25 [ 0.72, 2.19 ]

M-H,Fixed,95% CI


Total events: 23 (Antibiotics), 18 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.80 (P = 0.42) Test for subgroup differences: Not applicable

0.01

0.1

Favours antibiotics

1

10

100

Favours placebo


149

Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 Drop-outs due to adverse effects. Review:


Comparison: 1 Antibiotics versus placebo Outcome: 6 Drop-outs due to adverse effects

Study or subgroup

Peto Odds Ratio

Peto Odds Ratio

Antibiotics

Placebo

n/N

n/N

Axelsson 1970

0/35

0/32

0.0 [ 0.0, 0.0 ]

Garbutt 2012

1/85

0/81

7.05 [ 0.14, 355.67 ]

Hadley 2010

3/251

1/123

1.43 [ 0.18, 11.64 ]

Haye 1998

0/87

0/82

0.0 [ 0.0, 0.0 ]

Lindbaek 1996

3/86

0/44

4.64 [ 0.42, 51.71 ]

Lindbaek 1998

3/46

0/22

4.59 [ 0.39, 53.49 ]

Meltzer 2005

5/251

6/252

0.83 [ 0.25, 2.75 ]

Merenstein 2005

0/67

0/68

0.0 [ 0.0, 0.0 ]

van Buchem 1997

0/105

1/101

0.13 [ 0.00, 6.56 ]

Total (95% CI)

1013

805

1.40 [ 0.60, 3.25 ]

Peto,Fixed,95% CI

Peto,Fixed,95% CI

Total events: 15 (Antibiotics), 8 (Placebo) Heterogeneity: Chi2 = 4.64, df = 5 (P = 0.46); I2 =0.0% Test for overall effect: Z = 0.77 (P = 0.44) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours antibiotics


1

10 100 1000 Favours placebo

150

Analysis 2.1. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up

Study or subgroup

Cephalosporins n/N

n/N

Adelglass 1998b

15/108

9/111

12.3 %

1.71 [ 0.78, 3.75 ]

Gehanno 1998

13/121

6/115

8.7 %

2.06 [ 0.81, 5.24 ]

Gwaltney 1997

49/474

44/491

50.5 %

1.15 [ 0.78, 1.70 ]

8/85

5/77

6.6 %

1.45 [ 0.50, 4.24 ]

23/134

14/128

19.8 %

1.57 [ 0.85, 2.91 ]

Sydnor 1992

2/22

2/21

2.2 %

0.95 [ 0.15, 6.17 ]

Total (95% CI)

944

943

100.0 %

1.37 [ 1.04, 1.80 ]

Pessey 1996 Sterkers 1997

Amox-clav


Weight


Total events: 110 (Cephalosporins), 80 (Amox-clav) Heterogeneity: Tau2 = 0.0; Chi2 = 2.14, df = 5 (P = 0.83); I2 =0.0% Test for overall effect: Z = 2.24 (P = 0.025) Test for subgroup differences: Not applicable

0.01

0.1

Favours ceph

1

10

100

Favours amox-clav


151

Analysis 2.2. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up. Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up

Study or subgroup

Cephalosporins n/N

n/N

Adelglass 1998b

18/100

16/99

14.9 %

1.11 [ 0.60, 2.06 ]

Camacho 1992

17/115

22/124

16.6 %

0.83 [ 0.47, 1.49 ]

Gehanno 1998

21/119

13/111

13.6 %

1.51 [ 0.79, 2.86 ]

Olmo 1994

1/26

0/22

0.6 %

2.56 [ 0.11, 59.75 ]

Pessey 1996

15/85

12/77

11.6 %

1.13 [ 0.57, 2.27 ]

Russell 1997

27/146

30/135

25.9 %

0.83 [ 0.52, 1.32 ]

Sterkers 1997

25/133

16/123

16.8 %

1.45 [ 0.81, 2.57 ]

724

691

100.0 %

1.08 [ 0.85, 1.37 ]

Total (95% CI)

Amox-clav


Weight


Total events: 124 (Cephalosporins), 109 (Amox-clav) Heterogeneity: Tau2 = 0.0; Chi2 = 4.31, df = 6 (P = 0.63); I2 =0.0% Test for overall effect: Z = 0.62 (P = 0.53) Test for subgroup differences: Not applicable

0.01

0.1

Favours ceph

1

10

100

Favours amox-clav


152

Analysis 2.3. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 3 Drop-outs due to adverse effects (cephalosporins). Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 3 Drop-outs due to adverse effects (cephalosporins)

Study or subgroup

Peto Odds Ratio

Peto Odds Ratio

Cephalosporins

Amox-clav

n/N

n/N

Adelglass 1998b

3/140

9/138

0.35 [ 0.11, 1.10 ]

Camacho 1992

1/157

2/160

0.52 [ 0.05, 5.05 ]

Gehanno 1998

2/123

1/118

1.88 [ 0.19, 18.24 ]

Gwaltney 1997

8/585

30/603

0.31 [ 0.16, 0.60 ]

Olmo 1994

0/25

0/22

0.0 [ 0.0, 0.0 ]

Pessey 1996

0/87

6/82

0.12 [ 0.02, 0.61 ]

Russell 1997

1/158

7/161

0.22 [ 0.05, 0.89 ]

Sterkers 1997

3/152

5/149

0.59 [ 0.14, 2.39 ]

Sydnor 1992

1/59

6/54

0.20 [ 0.04, 0.92 ]

1486

1487

0.32 [ 0.21, 0.49 ]

Total (95% CI)

Peto,Fixed,95% CI

Peto,Fixed,95% CI

Total events: 19 (Cephalosporins), 66 (Amox-clav) Heterogeneity: Chi2 = 5.30, df = 7 (P = 0.62); I2 =0.0% Test for overall effect: Z = 5.18 (P < 0.00001) Test for subgroup differences: Not applicable

0.01

0.1

Favours ceph


1

10

100

Favours amox-clav

153

Analysis 2.4. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 4 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 4 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up

Study or subgroup

Macrolides

Amox-clav



n/N

n/N

2/29

3/27

0.62 [ 0.11, 3.43 ]

Clement 1998

19/151

6/82

1.72 [ 0.72, 4.14 ]

Dubois 1993

4/132

9/128

0.43 [ 0.14, 1.36 ]

Gehanno 1996a

19/134

19/129

0.96 [ 0.53, 1.73 ]

Henry 2003

30/269

39/259

0.74 [ 0.47, 1.15 ]

Klapan 1999

0/47

0/47

0.0 [ 0.0, 0.0 ]

Riffer 2005

4/188

6/185

0.66 [ 0.19, 2.29 ]

950

857

0.83 [ 0.62, 1.13 ]

Chatzimanolis 1998

Total (95% CI)

Total events: 78 (Macrolides), 82 (Amox-clav) Heterogeneity: Tau2 = 0.0; Chi2 = 4.63, df = 5 (P = 0.46); I2 =0.0% Test for overall effect: Z = 1.18 (P = 0.24) Test for subgroup differences: Not applicable

0.01

0.1

Favours macrolide


1

10

100

Favours amox-clav

154

Analysis 2.5. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 5 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 5 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up

Study or subgroup

Macrolide

Amoxicillin-clavulan


Weight


n/N

n/N

Clement 1998

17/136

12/74

34.8 %

0.77 [ 0.39, 1.53 ]

Desrosiers 2008

14/123

14/125

33.3 %

1.02 [ 0.51, 2.04 ]

1/43

4/46

3.5 %

0.27 [ 0.03, 2.30 ]

12/184

13/177

28.3 %

0.89 [ 0.42, 1.89 ]

486

422

100.0 %

0.85 [ 0.57, 1.27 ]

Klapan 1999 Riffer 2005

Total (95% CI)

Total events: 44 (Macrolide), 43 (Amoxicillin-clavulan) Heterogeneity: Tau2 = 0.0; Chi2 = 1.46, df = 3 (P = 0.69); I2 =0.0% Test for overall effect: Z = 0.80 (P = 0.42) Test for subgroup differences: Not applicable

0.01

0.1

Favours macrolide

1

10

100

Favours amox-clav


155

Analysis 2.6. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 6 Drop-outs due to adverse effects (macrolides). Review:


Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate Outcome: 6 Drop-outs due to adverse effects (macrolides)

Study or subgroup

Peto Odds Ratio

Peto Odds Ratio

Macrolides

Amox-clav

n/N

n/N

0/31

3/29

0.12 [ 0.01, 1.18 ]

Clement 1998

0/165

2/89

0.06 [ 0.00, 1.05 ]

Desrosiers 2008

5/145

9/148

0.56 [ 0.19, 1.64 ]

Dubois 1993

7/246

7/251

1.02 [ 0.35, 2.95 ]

Gehanno 1996a

5/145

4/139

1.20 [ 0.32, 4.53 ]

Henry 2003

7/312

28/313

0.28 [ 0.14, 0.56 ]

Klapan 1999

0/50

0/50

0.0 [ 0.0, 0.0 ]

Riffer 2005

4/221

6/216

0.65 [ 0.19, 2.27 ]

1315

1235

0.47 [ 0.30, 0.72 ]

Chatzimanolis 1998

Total (95% CI)

Peto,Fixed,95% CI

Peto,Fixed,95% CI

Total events: 28 (Macrolides), 59 (Amox-clav) Heterogeneity: Chi2 = 9.91, df = 6 (P = 0.13); I2 =39% Test for overall effect: Z = 3.47 (P = 0.00052) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours macrolide


1

10 100 1000 Favours amox-clav

156

Analysis 3.1. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. Review:


Comparison: 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up

Study or subgroup

Non-penicillin

Penicillin class


Weight


n/N

n/N

5/55

7/61

14.0 %

0.79 [ 0.27, 2.35 ]

Haye 1996

6/220

11/214

17.4 %

0.53 [ 0.20, 1.41 ]

Huck 1993

11/44

8/37

26.0 %

1.16 [ 0.52, 2.57 ]

Karma 1991

3/32

3/35

7.1 %

1.09 [ 0.24, 5.04 ]

Mattucci 1986

0/25

1/22

1.7 %

0.29 [ 0.01, 6.89 ]

Nyffenegger 1991

2/40

7/40

7.3 %

0.29 [ 0.06, 1.29 ]

von Sydow 1995

9/130

15/128

26.6 %

0.59 [ 0.27, 1.30 ]

Total (95% CI)

546

537

100.0 %

0.70 [ 0.47, 1.06 ]

Calhoun 1993

Total events: 36 (Non-penicillin), 52 (Penicillin class) Heterogeneity: Tau2 = 0.0; Chi2 = 4.07, df = 6 (P = 0.67); I2 =0.0% Test for overall effect: Z = 1.69 (P = 0.092) Test for subgroup differences: Not applicable

0.01

0.1

Favours non-pen

1

10

100

Favours pen-class


157

Analysis 3.2. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. Review:


Comparison: 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins Outcome: 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up

Study or subgroup

Haye 1996

Total (95% CI)

Non-penicillin

Penicillin class

n/N

n/N

Risk Ratio

Weight

17/220

25/216

100.0 %

0.67 [ 0.37, 1.20 ]

220

216

100.0 %

0.67 [ 0.37, 1.20 ]

M-H,Fixed,95% CI


Total events: 17 (Non-penicillin), 25 (Penicillin class) Heterogeneity: not applicable Test for overall effect: Z = 1.35 (P = 0.18) Test for subgroup differences: Not applicable

0.01

0.1

Favours non-pen

1

10

100

Favours pen-class


158

Analysis 3.3. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 3 Drop-outs due to adverse effects. Review:


Comparison: 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins Outcome: 3 Drop-outs due to adverse effects

Study or subgroup

Peto Odds Ratio

Peto Odds Ratio

Non-penicillin

Penicillin class

n/N

n/N

2/70

3/72

0.68 [ 0.12, 4.04 ]

Haye 1996

0/221

0/217

0.0 [ 0.0, 0.0 ]

Huck 1993

0/54

1/54

0.14 [ 0.00, 6.82 ]

Karma 1991

0/50

1/50

0.14 [ 0.00, 6.82 ]

Mattucci 1986

2/29

2/29

1.00 [ 0.13, 7.49 ]

Nyffenegger 1991

0/40

0/40

0.0 [ 0.0, 0.0 ]

von Sydow 1995

4/140

7/142

0.58 [ 0.17, 1.92 ]

Total (95% CI)

604

604

0.58 [ 0.25, 1.35 ]

Calhoun 1993

Peto,Fixed,95% CI

Peto,Fixed,95% CI

Total events: 8 (Non-penicillin), 14 (Penicillin class) Heterogeneity: Chi2 = 1.37, df = 4 (P = 0.85); I2 =0.0% Test for overall effect: Z = 1.27 (P = 0.20) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours non-pen


1

10 100 1000 Favours pen-class

159

Analysis 4.1. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. Review:


Comparison: 4 Tetracyclines versus mixed classes of antibiotics Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up

Study or subgroup

Tetracyclines

Mixed group


Weight


n/N

n/N

Arndt 1994

1/26

1/28

2.7 %

1.08 [ 0.07, 16.35 ]

Boezeman 1988

5/15

3/12

13.7 %

1.33 [ 0.40, 4.49 ]

Mattucci 1986

0/25

1/22

2.0 %

0.29 [ 0.01, 6.89 ]

Otte 1983

6/17

4/14

18.3 %

1.24 [ 0.43, 3.53 ]

SSG 1993

23/323

22/325

63.3 %

1.05 [ 0.60, 1.85 ]

406

401

100.0 %

1.09 [ 0.70, 1.71 ]

Total (95% CI)

Total events: 35 (Tetracyclines), 31 (Mixed group) Heterogeneity: Tau2 = 0.0; Chi2 = 0.85, df = 4 (P = 0.93); I2 =0.0% Test for overall effect: Z = 0.38 (P = 0.70) Test for subgroup differences: Not applicable

0.01

0.1

Favours tetracycline

1

10

100

Favours mixed group


160

Analysis 4.2. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 2 Drop-outs due to adverse effects. Review:


Comparison: 4 Tetracyclines versus mixed classes of antibiotics Outcome: 2 Drop-outs due to adverse effects

Study or subgroup

Peto Odds Ratio

Peto Odds Ratio

Tetracycline

Mixed group

n/N

n/N

Arndt 1994

0/35

3/35

0.13 [ 0.01, 1.27 ]

Boezeman 1988

0/18

0/15

0.0 [ 0.0, 0.0 ]

Mattucci 1986

2/29

2/29

1.00 [ 0.13, 7.49 ]

Otte 1983

0/17

0/14

0.0 [ 0.0, 0.0 ]

SSG 1993

9/330

10/332

0.90 [ 0.36, 2.25 ]

429

425

0.73 [ 0.33, 1.60 ]

Total (95% CI)

Peto,Fixed,95% CI

Peto,Fixed,95% CI

Total events: 11 (Tetracycline), 15 (Mixed group) Heterogeneity: Chi2 = 2.52, df = 2 (P = 0.28); I2 =21% Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours tetracycline

1

10 100 1000 Favours mixed group

ADDITIONAL TABLES Table 1. Collected information from placebo-controlled studies

Study

Comparison

Diagnostic method

Day assessed

Axelsson 1970 (Sweden)

Penicillin V (400 mg 3 times daily for 10 days) + nasal decongestant (oxymetazoline) versus oxymetazoline

Patients 10 with clinically suspected sinusitis were radiologically examined; only participants with secretion

Missing data

FR1 con- FR1 an- FR + I2 FR + I2 trol tibiotics control antibiotics

Side effects

7%

31%

Penicillin: 8% Control: 6%


46%

72%

83%

161

Table 1. Collected information from placebo-controlled studies

(Continued)

included Garbutt 2012 (USA)

AmoxClin10; icillin (500 ical symp- 28 mg 3 times toms > 7 daily for 10 days, purudays) ver- lent nasal sus placebo discharge, Acfacial pain etaminophen, guaifenesin, dextromethorphan hydrobromide and pseudoephedrine prescribed to be used as needed

8%; 4%

InforInfor80%; mation not mation not 92% available available

78%; 85%

Amoxicillin: 16% Placebo: 14%

Hadley 2010 (USA)

Moxifloxacin (400 mg once daily for 5 days) versus placebo Oral or nasal decongestants or antihistamines, corticosteroid nasal sprays and bronchoinhalants (if in stable use) allowed

6%; 6%

InforInfor67%; mation not mation not 58% available available

78%, 74%

Moxifloxacin: 14% Placebo: 7%

33%; 67%

93%; 90%

Azithromycin: 28% Placebo:

Haye 1998 Azithro(Norway) mycin (500 mg once daily for 3 days)

Isolation 6 to 8; of 20 to 26 pathogenic bacteria from the sinus secretion was a prerequisite

Clinical 10 to 12; 0.6%; symptoms 23 to 27 0% lasting 11 to 29 days (symp-


58%; 79%

89%; 88%

162


(Continued)

versus placebo

toms: purulent secretion, maxillary sinus tenderness and/or pain); radiograph taken to exclude patients with more than 6 mm mucosal thickening, complete opacity or air-fluid level

18%

Lindbaek 1996 (Norway)

Penicillin V (1320 mg 3 times daily for 10 days) , or amoxicillin (500 mg 3 times daily for 10 days) versus placebo. Nasal decongestants and analgesics were allowed but not prescribed in all groups

Clin10 ical symptoms lasting at least 8 days; computer tomography showing opacity or fluidlevel

2%

11%

Penicillin: 31%, Amoxicillin: 45%

89%

Penicillin: 97%, Amoxicillin: 98%

Penicillin: 59% Amoxicillin: 56% Placebo: 36%

Lindbaek 1998 (Norway)

Penicillin V (1320 mg 3 times daily for 10 days)

Clin10 ical symptoms lasting at least

7%

43%

Penicillin: 30% Amoxicillin:

86%

Penicillin: 91% Amoxicillin:

Information not available


163


, or amoxicillin (500 mg 3 times daily for 10 days) versus placebo. Nasal decongestants and analgesics were allowed but not prescribed in all groups

8 days; computer tomography showing mucosal thickening of 5 mm or more in any sinus without opacity or fluidlevel

Meltzer 2005 (14 countries, not specified)

Amoxicillin (500 mg 3 times daily for 10 days) versus placebo Concomitant medications not allowed

Clinical signs and symptoms lasting at least 7 but less than 29 days (rhinorrhoea, postnasal drip, nasal congestion/stuffiness, sinus headache, and facial pain/ pressure/ tenderness on palpation over the paranasal sinuses)

Merenstein 2005 (USA)

Amoxicillin (500 mg twice daily for 10 days) ver-

Clin14 ical symptoms > 7 days, purulent nasal

During the 1.8% 15-day treatment phase

14%

(Continued)

41%

86%

InforInfor89% mation not mation not available available

93%

42%


57%

Treatmentemergent adverse effects Amoxicillin: 34% Placebo: 38%

InforInforAmoximation not mation not cillin: 23% available available Placebo: 12%

164


(Continued)

sus placebo discharge, Over-the- facial pain counter medications were allowed in both groups van Buchem 1997 (the Netherlands)

1 FR 2 FR

Amoxicillin (750 mg 3 times daily for 7 days) versus placebo Adjuvant therapy with oxymetazoline steam inhalation (duration not specified) . Paracetamol as needed

The mean 14 duration of the symptomatic period before treatment 2.2 weeks; radiograph showing > 5 mm mucosal thickening, opacity or airfluid level

4%

52%

65%

77%

83%

Amoxicillin: 28% Placebo: 9%

= full recovery. + I = full recovery + improvement.


165

APPENDICES Appendix 1. MEDLINE (Ovid) search strategy 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

exp Sinusitis/ sinusit*.tw. or/1-2 exp Anti-Bacterial Agents/ antibiotic*.tw,nm. or/4-5 3 and 6 randomized controlled trial.pt. controlled clinical trial.pt. randomized.ab. placebo.ab. clinical trials as topic.sh. randomly.ab. trial.ti. 8 or 9 or 10 or 11 or 12 or 13 or 14 (animals not (humans and animals)).sh. 15 not 16 7 and 17

Appendix 2. Embase.com search strategy #11. #7 AND #10 #10. #8 OR #9 #9. random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR ’cross-over’:ab,ti OR factorial*:ab,ti OR (doubl* NEAR/1 blind*):ab,ti OR (singl* NEAR/1 blind*):ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti #8. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp #7. #3 AND #6 #6. #4 OR #5 #5. antibiotic*:ab,ti #4. ’antibiotic agent’/exp #3. #1 OR #2 #2. sinusit*:ab,ti #1. ’sinusitis’/exp

Appendix 3. SIGLE search strategy keyword: sinusit* AND Subject collection: 06 - Biological and medical sciences


166

Appendix 4. Search strategy for ongoing trials acute maxillary sinusitis AND antibiotics

Appendix 5. Details of previous searches

Review update 2011 In the 2011 review update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1), which contains the Cochrane Acute Respiratory Infections Group’s Specialised Register, MEDLINE (2007 to March Week 2, 2010) and EMBASE (2007 to March 2010) and the System for Information on Grey Literature in Europe (SIGLE) (1976 to August 2009). We used the following search terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precisionmaximising version (2008 revision); Ovid format (Lefebvre 2011). The search terms were adapted to search EMBASE (Appendix 2). To locate unpublished literature, the search of SIGLE was carried out on the OpenSIGLE (http://opensigle.inist.fr/) (Appendix 3). MEDLINE (Ovid) 1. exp Sinusitis/ 2. sinusit*.tw. 3. or/1-2 4. exp Anti-Bacterial Agents/ 5. antibiotic*.tw,nm. 6. or/4-5 7. 3 and 6 8. randomized controlled trial.pt. 9. controlled clinical trial.pt. 10. randomized.ab. 11. placebo.ab. 12. clinical trials as topic.sh. 13. randomly.ab. 14. trial.ti. 15. 8 or 9 or 10 or 11 or 12 or 13 or 14 16. (animals not (humans and animals)).sh. 17. 15 not 16 18. 7 and 17 We used the function for finding related articles in PubMed for those already identified placebo-controlled trials to track down additional, relevant articles. We reviewed reference lists of the identified new trials and four systematic reviews considering placebo-controlled study designs (Falagas 2008a; Gwaltney 2004; Rosenfeld 2007; Young 2008) for additional, appropriate studies. There were no language or publication restrictions.

Review update 2008 In the review version 2008, we used a revised, more specific strategy (compared to review version 2003) to search for trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); MEDLINE (1950 to May 2007) and EMBASE (1974 to June 2007). In the revised strategy “antibiotics” was used as an additional keyword and “anti-bacterial agents” as an exploded MeSH term in addition to “sinusitis”. The MEDLINE search terms were run over CENTRAL and adapted for EMBASE. MEDLINE (OVID) 1 exp SINUSITIS/ 2 sinusitis.mp. 3 or/1-2 4 exp Anti-Bacterial Agents/ 5 antibiotic$.mp. 6 or/4-5 Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

167

7 3 and 6 8 RANDOMIZED CONTROLLED TRIAL.pt. 9 CONTROLLED CLINICAL TRIAL.pt. 10 RANDOMIZED CONTROLLED TRIALS.sh. 11 RANDOM ALLOCATION.sh. 12 DOUBLE BLIND METHOD.sh. 13 SINGLE-BLIND METHOD.sh. 14 or/8-13 15 Animals/ 16 human.sh. 17 15 not 16 18 14 not 17 19 CLINICAL TRIAL.pt. 20 exp Clinical Trials/ 21 (clin$ adj25 trial$).ti,ab. 22 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 23 PLACEBOS.sh. 24 placebo$.ti,ab. 25 random$.ti,ab. 26 or/19-25 27 26 not 17 28 18 or 27 29 7 and 28 The function for finding related articles in PubMed was used for those already identified placebo-controlled trials so as to track down additional, relevant articles. Reference lists from the already identified trials and nine systematic reviews considering placebo-controlled study designs (Benninger 2000; de Bock 1997; de Ferranti 1998; Ioannidis 2001; Ioannidis 2002; Ip 2005; Linder 2003; Low 1997; Stalman 1997b) were reviewed for additional, appropriate studies. Included and excluded trials in the previous version were rechecked by using the revised inclusion criteria for this review. A search of the database ’System for Information on Grey Literature in Europe (SIGLE)’ was intended, but the database was not available via the Internet in November 2005. For the review version 2003 pharmaceutical companies that manufacture antibiotics used in the treatment of acute sinusitis had been contacted and data and references from all published and unpublished trials on acute sinusitis were requested. Further, three experts in the field had been contacted and asked to review the bibliography of the initial review (1999) for completeness.

Appendix 6. Results of the earlier searches

Review update 2011 In the 2011 update, the total number of the records considered from all updates was 2209 including 2036 records from the earlier searches and 173 records from the 2010 update search. Of the total 2209 records, we rejected 1923 records as definitely not meeting the inclusion criteria simply on the basis of title or abstract or because they were duplicates. Altogether 286 full-text reports were obtained. From these 286 reports, 128 were clearly irrelevant for this review leaving 158 reports for final assessment. The main reasons for irrelevance were: trials without control group, studies with treatments other than antibiotic, studies comparing same classes of antibiotics and studies regarding children. Over all updates, there were in total 158 reports to be considered in detail. Additional information was needed from four studies with antibiotic versus placebo comparisons to assess whether they meet the inclusion criteria for this review (Meltzer 2005; Schering-Plough 2003; Stalman 1997a; Williamson 2007). Finally we considered 62 reports representing 59 individual studies eligible for inclusion in the review. Compared to the 2008 update, two new antibiotic versus antibiotic studies were included. Eighty-nine studies with 96 reports were excluded.

Review update 2008 Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

168

The electronic search based on the revised search strategy in the update 2008 produced 2030 records, many of which were duplicates. Of these, 1761 records were rejected as definitely not meeting the inclusion criteria simply on the basis of title or abstract. Duplicates were omitted. Checking the lists of the included and excluded studies in the previous version of the review (version 2003), reviewing reference lists from the already identified trials and systematic reviews and using the function for finding related articles in PubMed yielded six more appropriate trials. Altogether 269 full-text reports were obtained. All non-English language reports were translated to assess the studies. The review authors could read reports in German, Russian and Scandinavian languages. Outside translators were consulted to identify and assess the reports in Portuguese, Spanish, French, Chinese and Japanese. From these 269 reports, 117 were clearly irrelevant for this review. The main reasons for exclusion were: trials without control group, studies with other treatment than antibiotic, studies comparing same classes of antibiotics and studies regarding children. In total there were 152 reports to be considered in detail. From these, 60 reports representing 57 individual studies were considered eligible for inclusion in the review. Six of the 57 included studies compared antibiotic treatment to placebo. The remaining 51 studies compared different classes of antibiotics.

FEEDBACK

Antibiotics for acute maxillary sinusitis

Summary There are 4 primary questions to be answered by this systematic review: 1) Is antibiotic therapy effective for acute sinusitis? 2) Which antibiotic is most effective? 3) What is the best duration for antibiotic therapy? 4) Is there a change in the efficacy of antibiotics over time? Question 1 Firstly, all 4 questions are clinically important. But it is paramount to recognize the interrelationships of all 4 questions, such that, if the answer to the first question is negative, the value of the other answers is significantly diminished. It is therefore essential to include all the evidence unless the exclusion is completely justified. On the efficacy of antibiotics for acute sinusitis, there are only 6 published randomised clinical trials with control groups: Axelsson 1970, Gananca 1973, Wald 1986, Lindbaek 1996, van Buchen 1997, and Stalman 1997. I agree that the Wald study involving children and the Gananca study from Brazil should be excluded. Gananca trial had only 50 subjects, with 50% more patients in the antibiotic group after randomisation. It also had extreme differences in cure rates between antibiotic and placebo groups (15/30 versus 0/20). The last 3 trials on this list, according to the recent meta-analysis by de Ferranti et al (BMJ 1998;317:632-7), received a quality score of 5 by the Jadad scale (a maximum score indicating highest quality). The Axelsson study had a score of 1. The Williams et al answered this first question, “Is antibiotic therapy effective?”, by excluding Stalman 1997 (with quality score of 5) and by doubling the control group populations in Axelsson 1970 (n=34) and in Lindbaek 1996 (n=44). This artificially created population of 156 controls from 78 real controls would inflate the contributions of those 2 trials on the outcome. The exclusion of those true placebo-controls in Stalman 1997 (n=94), while adding 78 phantom controls, is not a reasonable approach to answer the antibiotic efficacy question for sinusitis. The Stalman study was excluded, according to the author’s, because it did not use radiographic images for diagnosis. The same is true however for the included Axelsson study. Though Axelsson et al took several different radiographic views of sinuses, they did not describe a radiographic criteria for diagnosis. Moreover, the relationship between radiograms, even the more advanced images of paranasal sinuses obtained by computed tomography (CT scan), and the clinical description of sinusitis is extremely poor. The 1997 study of Bhattaharyya et al involving 586 patients (the largest published data set) failed to find any correlation between CT scan results and patient described symptoms of sinusitis (See Arch. Otolaryngol. 1997;123:1189-92). Also note that Williams et al argue that the cure rate differences between Lindbaek and van Buchem were probably related to the diagnostic criteria. That is, a diagnosis confirmed by CT scan is more likely associated with bacterial sinusitis than a diagnosis by radiography. This new theory of differential diagnosis of bacterial sinusitis however is not supported by any published data. Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

169

To be consistent, either both Axelsson and Stalman should be included, or both should be excluded. If they are both excluded, then the meta-analysis of Williams et al on the efficacy of antibiotics for sinusitis would depend on only 2 placebo controlled trials - Lindbaek 1996 and van Buchem 1997 - with opposite conclusions. The Lindbaek study was terminated early with 130 patients instead of the original sample size of 180 subjects. This was done without correction and without predefined stopping rules. Also, the randomisation was in a most unusual fashion for a modern clinical trial using dice. Lindbeak et al do not provide a table, as customary, showing the baseline patient characteristics at entry indicating their randomisation was effective. In contrast to those deficits, van Buchem reports this baseline information about randomisation and an analysis of prognostic factors on the outcome. It shows that initial severity of sinusitis does not change the results. The van Buchem study has a much higher quality and reliability than the Lindbaek trial. If the entire evidence has to be based on combining or contrasting only those 2 trials, then conclusion has to follow the van Buchem results. Most important, the Stalman trial which was published 9 months later completely supports the van Buchem results. Among the 3 trials with Jadad score of 5, reasonable people can easily conclude that van Buchem and Stalman clearly show that antibiotics for acute sinusitis are not effective; and, Lindbaek et al is an outlier. Lindbaek’s efficacy claim based on one endpoint (cure) is not sustained by his second endpoint (improvement). This inconsistent outcome and those basic problems associated with early termination and poor randomisation perhaps is why Lindbaek results are not replicated by the last 2 trials (van Buchem and Stalman). I suggest however that we include all 4 clinical trials to combine results and estimate a pooled efficacy. As such, even this would yield still a meager sample size, a total of 648 subjects with only 278 controls. Consequently, this is the entire dataset we have to establish the scientific evidence-base in justifying 15 million antibiotic prescriptions in the U.S. for sinusitis. Instead of finding excuses to exclude the few controls in this limited database, we should savor them. The answer to the first question, then, is a simple pooling of the results from those 4 clinical trials: Axelsson 1970 (n=112), Lindbaek 1996 (n=130), van Buchem 1997 (n=214), and Stalman 1997(n=192). In all sinusitis trials the primary outcome measures of at 10-14 days are subjective. Outcomes are not based on some “Gold Standard” but study-variant definitions of cure and success (cure/improvement) by each investigator. Those primary data unfortunately are not based on objective endpoints. A well defined diagnostic criteria, such as combining radiographs with symptoms, validated against a standard is lacking. I argue that if the entry includes radiograms to make the diagnosis of sinusitis, then to be consistent for at least in defining cure, the primary endpoint should also include both measures (e.g.. combination of normal radiograph with symptom free status). If both measures are not negative, then improvement (or scaled improvement) is the only logical alternative. Without a normal radiogram, cured diagnosis would be in contradiction with the entry criteria. Regardless of these problems associated with an objective and study invariant outcome, the combined results from 4 trials are as follows: Cure Controls: 10/34 + 5/44 + 53/106 + 56/94 = 124/278 or 44.6% Antibiotics: 27/78 + 32/86 + 68/108 + 59/98 = 186/370 or 50.3% Success Controls: 23/34 + 39/44 + 78/106 + 80/94 = 220/278 or 79.1% Antibiotics: 51/78 + 81/86 + 87/108 + 83/98 = 302/370 or 81.6% Antibiotic-placebo rate difference in cure is 5.7% (OR=1.26) and the rate difference in success is 2.5% (OR=1.17). These marginal differences, neither statistically nor clinically significant, indicate the lack of efficacy of antibiotic therapy for the treatment of acute paranasal sinusitis. The methods used by Williams et al in their meta-analysis therefore must be re-examined. Relying on magical statistical packages, with interesting inclusions and exclusions, can sometimes lead to positively misleading results. As in this case, claiming antibiotic efficacy for sinusitis is not a reasonable conclusion but perhaps an artifact of meta-analysis. The answer to this first question, “Are antibiotics for acute sinusitis effective?”, therefore is negative. Question 2 Now the second question, which antibiotic is most effective, is a less important scientific issue. Notwithstanding, in real life clinical practice, this question continues to be a primary issue because of the ongoing campaign of promoting newer, wider spectrum antibiotics for sinusitis with higher costs. Though there is no clinical trial which exclusively has focused on bacterial sinusitis caused by resistant bacteria, and which has shown the benefit of such drugs, the emergence of multi-drug resistant bacteria is always cited to advocate those wide spectrum drugs. Therefore, the second part of the Williams meta-analysis is clinically most significant. Using a large sample size, Williams et al (n=7330 patients in 32 trials) show that there is no superior antibiotic. This result supports the earlier findings of de Bock 1997 (n=3358 patients in 16 trials) and de Ferranti 1998 (n=2717 patients in 27 trials) meta-analyses. The ineffectiveness of wide spectrum drugs are based on a wide collection of clinical trials. In fact, among those 3 meta-analyses, Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

170

the inclusion of the same trials are not common. The number of trials commonly inclusive between meta-analyses are: Williams de Ferranti (13/47), Williams - de Bock (3/45), and de Ferranti - de Bock (5/39). This diversity in inclusion/exclusion indicates the arbitrary nature of selection of trials included in meta-analyses while supporting the robustness of conclusions. Note also that this result, ineffectiveness of wide spectrum antibiotics for sinusitis, is consistent with the meta-analysis findings in acute otitis media. It is a logical result since acute otitis media in general has the same pathogenic bacterial spectrum as acute sinusitis. There is however an interesting point to consider. If the antibiotics are not better than placebo, then it is logical not to find a superior antibiotic for sinusitis. Unless each new antibiotic is concurrently matched with a placebo control in the primary clinical trial, it would be impossible to show the usefulness of new, wide spectrum antibiotics. Without such data, I think it is irresponsible to advocate wide spectrum antibiotics for sinusitis. I hope that Williams et al would reduce the complexity of their presentation to make this point by decreasing the number of figures and by selecting a single primary endpoint to display. I suggest success (cure/improvement) as the measure of choice as I discussed above. The remaining measures can be simply stated as not being different with some odds ratios or rate differences. Also, those redundant figures with confidence intervals all over the place, are they necessary? It only illustrates that poor evidence is being included in the meta-analysis. I suggest that their Summary figure should also include sample sizes, exclude tetracycline’s, include duration of therapy analysis (short versus long), and finally include some cumulative meta-analysis to indicate change in efficacy over time. Question 3 Authors conclude in recommending 10-days of amoxicillin therapy for acute sinusitis but do not provide evidence-based arguments for selecting this particular duration of therapy. This is not scientific and somewhat odd, because a few years ago, Dr.Williams published arguably the best study showing that 3-days of antibiotic therapy is as good as the standard 10-days of therapy (See JAMA 1995;273: 1015-21). A recent review by Pichichero and Cohen (Pediatr Infect Dis J 1997;16:680-95) indicates that there are at least 5 published studies involving adult patients which show that short duration therapy is as effective as long duration therapy. I suggest Williams et al provide a meta-analysis to answer this question or explain why such combination of data is not possible. This part on duration of therapy I think is extremely important. Question 4 The recent increase in the prevalence of multi-drug resistant bacteria is clearly shown to be changing rapidly and is caused by the misuse or overuse of antibiotics. However, the research about the change of efficacy of antibiotics in vivo for common respiratory diseases is lacking. This is an important question. I am not sure how it can be answered. The approach taken by Williams et al seems a reasonable one, but I doubt that it can really answer the question of changing antibiotic efficacy for sinusitis. The change in efficacy over time perhaps can be best approached by using a cumulative meta-analysis (See N Eng J Med 1992;327:24854, JAMA 1992;268:240-8). Williams et al state that they have performed such a cumulative meta-analysis as well as a meta-regression. However, they do not show those results. I think the cumulative meta-analysis involving 32 trials in some chronological order (by the date of the trial, and not the publication date) would be an excellent figure to make the point. We must also keep in mind another possibility. The lack of change in efficacy over time, suggesting that the emergence of drug resistant bacteria had no effect, could be simply untrue but related to the ineffectiveness of antibiotics for sinusitis in general. With $2 billion over the counter medications, 15 million antibiotic prescriptions, 17 million office visits, 300,000 endoscopic sinus surgeries, and 37 million Americans suffering from chronic sinus disease, this is not a trivial healthcare issue. If the Cochrane is going to enter a systematic review in it’s library, it should be based on the best evidence and analysis. William et al require many changes and much improvement before it is suitable for the Cochrane database. I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.

Reply Dr. Cantekin identifies the question - “are antibiotics more effective than placebo for acute sinusitis” as critically important but disagrees with a number of our methods for answering this question. We will address each point. First, it is stated that the control populations are double counted. This is an important and difficult methodological issue that occurs when trials have more than two treatment arms. It was only problematic for the Lindbaek trial, which had amoxicillin, penicillin and placebo arms. To avoid “double counting,” we analysed the amoxicillin and penicillin trials separately, thereby including the control populations only once in each of these separate analyses. Second, it is argued that the Stalman trial should be included in the analysis. We agree that the Stalman study is high quality, but it was excluded because it lacked a diagnostic radiographic or sinus puncture. Our review was restricted to studies enrolling adult subjects with Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

171

sinusitis as determined by clinical symptoms and either an abnormal radiographic or sinus aspiration (the Stalman study used neither). Because clinical symptoms alone lead to relatively high rates of misclassification, we thought the requirement for an objective measure (x-ray or aspiration) was important. Studies with high rates of misclassification may include large proportions of subjects without bacterial sinusitis, leading to a negative result because antibiotics are unlikely to help allergic or viral rhinosinusitis. These criteria were applied to all studies considered for inclusion. Although we excluded studies without a diagnostic criterion standard, authors of other literature syntheses on this topic have used more liberal inclusion criteria by dropping the requirement for an objective measure of sinusitis. Their results were consistent with our findings (risk ratio to prevent clinical failure 0.54, 95% CI 0.37 to 0.79)1 . Third, simple pooling is suggested as an appropriate method for combining trial results. We disagree. Simple pooling (as opposed to meta-analytic techniques), can lead to biased results for a variety of reasons. These include bias if there is imbalance in the number of subjects in treatment arms, underestimation of the variance, and inappropriate weighting of small and large trials. Further, it is not possible to evaluate heterogeneity through simple pooling. Next, the reviewer reaches the conclusion that antibiotics are no more effective than placebo. Although the trials are few, and the results limited to patients with maxillary sinusitis confirmed radiographically or by aspiration, we interpret the current evidence as showing that penicillin is more effective than placebo and that there are similar, but more heterogeneous findings for amoxicillin. The reviewer asks for a single endpoint to simplify the presentation. We agree that it increases the complexity of the presentation to consider both clinical cure and clinical cure or improvement. However, we think that these two clinical outcomes give information that is worth the additional complexity. As clinicians, we think it is useful to be able to tell patients that on average 50% will be well and 75% will feel substantially better within the next 10 days. The issue of cumulative meta-analysis is important. We report the findings of these results without showing the forest plots because of limitations of the software. For newer non-penicillins versus penicillins, there was no effect over time for clinical cure (P = 0.17) or for clinical cure or improvement (P = 0.60). It is difficult to draw robust conclusions from this analysis because clinically important changes (other than bacterial resistance) may affect the results. The reviewer asks for an analysis addressing the duration of treatment. We agree that treatment duration is a clinically important issue. In fact we completed a study showing therapeutic equivalency for three versus 10 days of TMP/SMX2 . This study was excluded from the current literature synthesis because it was a within-class antibiotic comparison (not eligible). Four other studies compared two antibiotics with differing duration of treatment. Three of these compared two different antibiotics for differing duration making it difficult to isolate treatment duration as the key variable. Only one study compared two durations for the same antibiotic (cefixime four versus 10 days) and found similar efficacy. Because of differing pharmacokinetics and tissue penetration, we do not think it is wise to generalise results about TMP/SMX and cefixime to antibiotics in general. Readers should incorporate these findings cautiously. Because study duration was not one of our study questions, we have not done a systematic search to identify relevant literature. We will consider adding this question to future reviews. We strongly endorse the reviewer’s call for more clinical trials in this area, particularly with placebo control and look forward to other readers’ comments.

Reference list 1 de

Ferranti SD, Ioannidis JPA, Lau j, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. BMJ 1998;317:632-637 2 Williams JW, Jr., Holleman DR, Jr., Samsa GP, Simel DL. Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole for acute maxillary sinusitis. JAMA 1995; 273:1015-1021. I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms. John W. Williams Jr Contributors Erdem Cantekin This response was originally added to the Cochrane Review in 2000.


172

Amoxicillin results for cure

Summary The heterogeneity in this outcome may be explained by the choice of cure as your outcome measure. You are pooling relative benefit instead of relative risk. If the outcome is entered as failure to cure the heterogeneity disappears and the pooled RR is significant even with a random model. RR = 0.68 (95% CI 0.55 to 0.83). In my view it is therefore wrong to conclude that Amoxicillin does not have significant benefit in maxillary sinusitis. I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of my criticisms.

Reply The current author group has analysed the data differently to the earlier authors group. Unlike the previous version, in the metaanalyses the data of all placebo-controlled studies were combined across antibiotic classes. In the new analyses pooled risk ratios using the clinical failure rate as an outcome measure were calculated. The new meta-analyses results do not have any statistically significant heterogeneity between the individual study results. The data of all placebo-controlled studies were combined despite which antibiotic was used because it was anticipated that there would be only a few placebo-controlled studies available in the analyses. Further, it was presumed that researchers in different countries had had local reasons for selecting particular antibiotics for their trials, taking into account for example, local resistance rates to antibiotics among community-acquired pathogens. This reply was added 9 October 2007.

Contributors Christopher Cates This feedback comment was posted 1999.

Antibiotics for acute maxillary sinusitis, 27 September 2010

Summary Dear Authors, The Cochrane Report on “acute maxillary rhinosinusitis” is not very helpful for GPs because it is misleading in some points: A) Most of the relevant studies are ruled out by not fulfilling the inclusion criterion “Duration of symptoms > 1 week”. But “Acute maxillary sinusitis as defined by: a history of URTI lasting 7 to 30 days...”. But there are important issues besides diagnostic via duration of sickness and CT findings. B) For 5 of the remaining 6 placebo-controlled RCTs used for the meta-analyses, the external validity is weak. For practical applicability it is not so important to know if there might be any subgroups in acute rhinosinusitis that profit from antibiotics. Rather, we need results from trials with completely realistic practice conditions. Mixed inclusion criteria for meta-analyses are therefore questionable. * X-ray or CT is not routinely accessible in general practice nor indicated for diagnosis of acute rhinosinusitis. As stated in the report “In the referral guidelines for imaging of the European Commission, radiograph is not indicated as a routine diagnostic method (ECRP 2007)”. The results of the following studies are therefore not applicable: Axelsson 1970, Lindbaek 1996a+b, Lindbaek 1998a+b, van Buchem 1997. * The Haye-trial used x-ray to exclude those with positive findings. As there has been yet no general-practice-based-trial to prove that these findings would be a good reason for antibiotics anyway, this filter criterion seems not only artificial but also deletes the practical use. C) Most of the Cochrane-report is concerned with the comparative trials. But very few of these studies applied any of the successful diagnostic criteria (see below) - so unequivocal results were likely to result. In fact, my main point is that for us GPs it is very important to keep in mind the special prevalences, supplies and priorities of primary care.Thus we focused our german DEGAM (German Society of General Practitioners) guideline “akute rhinosinusitis” (http:/ Antibiotics for acute maxillary sinusitis in adults (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

173

/www.degam-leitlinien.de/) on primary care. We grouped the evidence from diagnostic and therapeutic clinical trials in the categories “predominantly primary care/secondary care/unknown setting”. (The guideline included literature on sinusitis until April 2007 - the trials of Haye and Merenstein were not included). Evaluating literature on acute rhinosinusitis in adults, this focus leads to interesting discoveries: 1. In primary care, antibiotics proved only helpful when a technical diagnostic test was added to clinical evaluation: CT (Lindbaek 1996) / nasal swabs + culture (Kaiser 2001) / CRP (Hansen 2000); trials with clinical evaluation only (Stalman 1997, Bucher 2003, Merenstein 2005) or added plain-x-ray (van Buchem 1997, Rantanen 1973, Norrelund 1978, Kristo 2005) or added ultrasound (Laine 1998, Varonen 2000, Varonen 2003) were negative. 2. Strikingly, in secondary care (ENT) studies with CE plus plain x-ray were significantly positive (Axelsson 1970, Wald 1976) 3. Comparative studies showed no significant difference between various types of antibiotics (Stalman 1997, de Ferranti 1998, de Bock 1997, Williams 2000, Piccirillo 2001) 4. Nearly all trials with positive effect of corticoid nasal spray for acute rhinosinusitis were done by allergologists (Sinusitis Study Group) - thus making confounding by allergies likely. The above findings might be explained by combining the following observations: 1. In cases of acute maxillary sinusitis the prevalence of pathogenic bacteria in sinus puncture differs by setting: 34% in primary care (Hansen 1995, van Buchem 1995) / ENT 45% (Axelsson 1973) / soldiers 72-78% (Savolainen 1997, Penttil? 1997) - the latter probably due to endemic spreads of hemophilus influenzae. 2. Diagnostic tests can moderately “raise” the prevalence of bacterial vs viral infections. Positive Likelihood-ratios for diagnostic test are approximately 4 for CT (Hansen 1995) / plain X-ray 3,4 (Vaaronen 2000) / ultrasound 2,8 (Vaaronen 2000) / clinical test 1-2 (Hansen 1995) and 2.1-3.3 for CRP (Lindbaek 1996) 3. Calculating post-test prevalence by applying LR to pre-test prevalence suggests that antibiotic trials were only significantly positive when post-test bacterial prevalence was > 60% (probably due to relatively small trials) Comment: In a health system with immediate direct accessibility to specialists (like in Germany), the study results suggest that primary care guidelines should be applied for example by ENT-specialists when involved directly. Referred patients would probably merit from secondary care guideline. Because of interpretation of mixed data, we discarded the use of the results of the preceding Cochrane-report of Williams “Antibiotics for acute maxillary sinusitis”. Conclusion: after reading your interesting report, I would summarize the primary-care-related evidence on antibiotics for acute rhinosinusitis as follows * Antibiotics + referral if complications are suspected * Antibiotics with small proven effect if symptoms >7days (Merenstein 2005, ?Haye?) * Antibiotics with small proven effect if symptoms

Are antibiotics indicated for acute sinusitis?

Azithromycin and amoxicillin in the treatment of acute maxillary sinusitis.

Bacteria in chronic maxillary sinusitis.

Diagnosing maxillary sinusitis.

Diagnosing maxillary sinusitis.

Diagnosing maxillary sinusitis.

Diagnosing maxillary sinusitis.

[Unilateral maxillary sinusitis].

Maxillary sinusitis with pulmonary tuberculosis.

Sinusitis of the maxillary antrum.

Maxillary sinusitis diagnosed by ultrasound.

Histopathological observations in chronic maxillary sinusitis.

Maxillary sinus hypoplasia masquerading as chronic sinusitis.

[Differential diagnosis of chronic maxillary sinusitis].

Systemic corticosteroids for acute sinusitis.

Intranasal steroids for acute sinusitis.

IRAK4 gene polymorphism and odontogenic maxillary sinusitis.

Maxillary sinusitis from dental osseointegrated implants.

Long-term outcomes of endoscopic maxillary mega-antrostomy for refractory chronic maxillary sinusitis.

Acute bacterial maxillary sinusitis: results of U.S. and European comparative therapy trials.

Pharmacokinetic study of cefaclor in chronic maxillary sinusitis.

A-mode ultrasound of maxillary sinusitis in children.

Penetration of erythromycin stearate into maxillary sinus mucosa and secretion in chronic maxillary sinusitis.

Treatment of acute maxillary sinusitis. IV. Ampicillin, cephradine and erythromycinestolate with and without irrigation.