International Journal of Antimicrobial Agents 45(S1) (2015) S1–S14

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Managing skin and soft-tissue infection and nosocomial pneumonia caused by MRSA: a 2014 follow-up survey Matthew Dryden a, *, Arjana Tambic Andrasevic b , Matteo Bassetti c , Emilio Bouza d , Jean Chastre e,f , Mo Baguneid g , Silvano Esposito h , Helen Giamarellou i , Inge Gyssens j,k,l , Dilip Nathwani m , Serhat Unal n , Andreas Voss o , Mark Wilcox p a

Department of Microbiology and Communicable Diseases, Royal Hampshire County Hospital, Romsey Road, Winchester, Hampshire SO22 5DG, UK Department of Clinical Microbiology, University Hospital for Infectious Diseases, Zagreb, Croatia Santa Maria della Misericordia University Hospital, Udine, Italy d ´n, University of Madrid, Madrid, Spain Division of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Mara˜ no e Service de R´eanimation M´edicale, Institut de Cardiologie, Groupe Hospitalier Piti´e-Salpêtri`ere, Paris, France f Assistance Publique-Hˆ opitaux de Paris, University of Paris VI (Universit´e Pierre et Marie Curie), Paris, France g University of Salford, University Hospital of South Manchester NHS Foundation Trust, Salford, Manchester, UK h Department of Infectious Diseases, University of Salerno, Salerno, Italy i 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece j Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands k Canisius–Wilhelmina Hospital, Nijmegen, The Netherlands l Hasselt University, Hasselt, Belgium m Infection Unit, Ninewells Hospital and Medical School, Dundee, UK n Department of Infectious Diseases, Medical Faculty, Hacettepe University, Ankara, Turkey o Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands p Department of Microbiology, Old Medical School, Leeds Teaching Hospitals, Leeds, UK b c

ARTICLE INFO

ABSTRACT

Keywords: Antibiotic management Complicated skin and soft-tissue infection Europe Infection Meticillin-resistant Staphylococcus aureus Nosocomial pneumonia

As a follow-up to our 2009 survey, in order to explore opinion and practice on the epidemiology and management of meticillin-resistant Staphylococcus aureus (MRSA) in Europe, we conducted a second survey to elicit current opinions on this topic, particularly around antibiotic choice, dose, duration and route of administration. We also aimed to further understand how the management of MRSA has evolved in Europe during the past 5 years. Members of an expert panel of infectious diseases specialists convened in London (UK) in January 2014 to identify and discuss key issues in the management of MRSA. Following this meeting, a survey was developed comprising 36 questions covering a wide range of topics on MRSA complicated skin and soft-tissue infection and nosocomial pneumonia management. The survey instrument, a web-based questionnaire, was sent to the International Society of Chemotherapy for distribution to registered European infection societies and their members. This article reports the survey results from the European respondents. At the time of the original survey, the epidemiology of MRSA varied significantly across Europe and there were differing views on best practice. The current findings suggest that the epidemiology of healthcare-associated MRSA in Europe is, if anything, even more polarised, whilst communityacquired MRSA has become much more common. However, there now appears to be a much greater knowledge of current treatment/management options, and antimicrobial stewardship has moved forward considerably in the 5 years since the last survey. © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction In 2009, we surveyed European physicians about their opinions and practice on the epidemiology and management of meticillin-resistant Staphylococcus aureus (MRSA) infections [1]. The epidemiology of MRSA varied significantly across Europe at that time and there * Corresponding author. Tel.: +44 1962 828398. E-mail address: [email protected] (M. Dryden)

were differing views on treatment and the role of the limited novel antibiotics, namely linezolid, tigecycline and daptomycin. Five years ago, the incidence of healthcare-associated MRSA (HA-MRSA) was very high; however, there was evidence to suggest that the epidemiology of HA-MRSA was changing [2]. At that time, community-acquired MRSA (CA-MRSA) was very rare in Europe, unlike in North America where it was the most common cause of community-acquired skin and soft-tissue infection [3–5]. Following

0924-8579/ © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

S2

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

the dramatic rise in community-acquired cases across North America, there was concern that Europe might experience the same phenomenon. If this did occur, the survey respondents felt that there would be a considerable shift in community antibiotic use in Europe. Today, the epidemiology of HA-MRSA in Europe is, if anything, even more polarised, with significant reductions in HA-MRSA in some European countries [6] and persisting high levels of HA-MRSA in others [7]. The incidence is also directly proportional to the volume of antibiotic usage across the continent [8], providing potent support for the development of effective pan-European antimicrobial stewardship programmes. Although CA-MRSA played only a minor role in Europe 5 years ago, it has become more common, as originally feared [9]. Many strains may persist and cause recurrent infection, as well as being highly pathogenic by virtue of eliciting the Panton–Valentine leukocidin (PVL) cytotoxin. These strains may exhibit some interesting and challenging epidemiology, with some strains emerging in livestock [10] and others dispersing widely around the world. Treatment of MRSA has largely focused on the use of glycopeptides, with many older antibiotics, such as doxycycline, trimethoprim/ sulfamethoxazole (SXT), clindamycin, fusidic acid and rifampicin being used for outpatients and those with minor infections. However, there is now a wealth of knowledge regarding the use of linezolid [7] and daptomycin in MRSA [11], whilst our knowledge of tigecycline is gradually increasing [12–15], and many other novel antibiotics will soon become available or are currently under development, i.e. ceftaroline, tedizolid, dalbavancin and oritavancin. The objectives of this survey were: (i) to explore current opinion and practice on MRSA complicated skin and soft-tissue infections (cSSTIs) and MRSA nosocomial pneumonia (NP) in Europe and, where possible, to compare the results with the findings of the survey 5 years ago; (ii) to review current physician opinion on practical and controversial questions around antibiotic choice, dose, duration and route of administration; (iii) to try and understand any developments and evolution in the management of MRSA infections in Europe over the past 5 years; and (iv) to support antibiotic stewardship.

3. Results 3.1. Demographic characteristics of survey participants The survey was publicised by the ISC to European societies of microbiology and infectious diseases, but it was not possible to establish how many potential respondents were contacted. In total, there were 430 survey respondents across all countries, of whom 350 (81.4%) were based in Europe. The results of this survey are based on the European respondents only. The majority of European respondents were from Italy (32.4%), the UK (23.3%), Turkey (18.5%) and France (12.4%), with a smaller number of respondents from a wide range of other countries including Bosnia and Herzegovina, Greece, Germany and The Netherlands. The main specialties were infectious diseases (43.7%) and clinical microbiology (26.6%) (Table 1). In general, hospitals were the predominant place of work, although a small proportion of the respondents were from private care. Table 1 Demographic characteristics of the survey respondents (Questions 1 and 2) Characteristic

Response [n (%)]

Specialty a

350

Infectious diseases

153 (43.7)

Clinical microbiology

93 (26.6)

Laboratory-based microbiology

32 (9.1)

Pharmacy/pharmacology

5 (1.4)

Intensive care

12 (3.4)

Internal medicine

16 (4.6)

Surgery

6 (1.7)

Respiratory disease

6 (1.7)

Primary care

1 (0.3)

Haematology/oncology

1 (0.3)

Other

25 (7.1)

a Participants could choose more than one specialty.

2. Materials and methods 3.2. Epidemiology 2.1. Development of the survey Members of an expert panel of infectious diseases specialists convened in London (UK) in January 2014 with the aim of identifying key current issues in the management of MRSA for a survey to capture the full diversity of opinion and practice within the European community. Following this meeting, a survey comprising 36 questions covering a wide range of topics on MRSA cSSTI and NP management was developed. 2.2. Survey administration Following the development of these questions, a web-based questionnaire (Survey Monkey; http://www.surveymonkey.com) was sent to the International Society of Chemotherapy (ISC) in April 2014 for distribution to registered European infection societies; the societies, in turn, distributed the questionnaire to their members. 2.3. Analysis Responses were collated and analysed by the group (all responses were anonymous). Simple counts and proportions were calculated based on the number of respondents answering each question (not all participants responded to each question, and respondents could provide more than one answer for some questions).

3.2.1. Background Over the past 10 years there have been notable changes in the epidemiology of MRSA in Europe, with some countries experiencing a fall and others a rise in the rates of invasive MRSA [2]. Recent data submitted to the European Antimicrobial Resistance Surveillance Network (EARS-Net) by 28 participating countries suggest that MRSA accounts for 17.8% of all invasive S. aureus isolates [2]. The percentage of isolates reported as MRSA ranges from 0.7% (Sweden) to 53.9% (Romania), with a high variability between different countries [2]. Globally, S. aureus is the most common cause of cSSTIs [7,16]. According to the SENTRY Antimicrobial Surveillance Program, S. aureus is the predominant pathogen across North America, Latin America and Europe, although rates of S. aureus vary among these continents, with North America having the highest prevalence [17]. In Europe, S. aureus represents > 70% of all isolates [18], with ca. 25% meticillinresistant strains. However, the proportion of patients with pneumonia in which MRSA is the causative micro-organism varies considerably from location to location [19], according to individual predisposing conditions and local epidemiology. Although MRSA is an uncommon cause of community-acquired pneumonia (< 0.6–6%), the incidence of MRSA both in healthcare-associated pneumonia and hospitalacquired pneumonia can be quite variable [20]. MRSA carriage rates vary widely in hospitalised patients across the world [21]. Although there are currently few data on the rates of colonisation, these rates are important because they reflect the

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

incidence of clinical infection with this organism; high carriage rates are likely to reflect higher infection rates for all infections with MRSA. In the 1980s and early 1990s, cases of MRSA infection among patients without healthcare risk factors for MRSA were reported from several countries. The term CA-MRSA was used to distinguish these strains from classic HA-MRSA strains. CA-MRSA strains differ from HA-MRSA strains both by epidemiological features and genotype; moreover, they may carry specific virulence factors, such as PVL [22,23]. CA-MRSA also has the propensity to cause recurrent infection and outbreaks in families and populations that tend to be otherwise healthy young patients [22,24]. With the exception of Greece and Romania, CA-MRSA prevalence in Europe is lower than in the USA; however, a changing trend in CA-MRSA epidemiology in Europe has been described, with USA300 now the most frequent clone [23]. In the UK, predominant clones of CA-MRSA have been derived from many geographical sources [9]. 3.2.2. Questions 3.2.2.1. What proportion of patients in your practice are colonised with MRSA? Responses. Overall the majority of respondents (39.6%) answered that, in their clinical practice, fewer than 5% of patients were colonised with MRSA. Across all countries, only 3% of respondents reported seeing > 25% of patients colonised with MRSA; however, in Greece and Italy between 8 and 10% of respondents said they saw > 25% of patients with MRSA. Discussion points. Colonisation with MRSA can lead to onward transmission of MRSA to other patients and healthcare workers, with high carriage rates likely to lead to more infections with MRSA. Therefore, institutions or units with high rates of MRSA will probably need to offer empirical treatment to cover MRSA in patients with infections such as cSSTI and NP, at least until microbiology results demonstrate that MRSA is not involved. Areas with low rates of MRSA do not generally need to include empirical coverage against MRSA unless the patient is known to have been colonised, recently infected or is at high risk for MRSA infection. 3.2.2.2. Have you seen an increase in community-acquired MRSA in your clinical practice in the last 5 years? Responses. Approximately one-half of all respondents (47.7%) had seen an increase in the number of patients presenting with CA-MRSA in their clinical practice over the past 5 years. Discussion points. There is evidence to suggest that the epidemiology of CA-MRSA infection in some European countries could be changing [25,26]. Data from the current survey suggest that CA-MRSA infection may be increasing in some counties, including Greece, Italy, the UK and Turkey. The increase in CA-MRSA in the UK appears to reflect the arrival of multiple strains from different regions of the world [9]. Travel to high-prevalence areas is a risk factor for infection and thus a contributing factor in the intercontinental spread of CA-MRSA [27,28]. HA-MRSA also has a tendency to spill over into the community, which may account for the higher incidence of MRSA in the community in some countries, e.g. Portugal and Italy [29]. This reversal of epidemiology will make it harder to distinguish between CA-MRSA and HA-MRSA. 3.2.2.3. How often do you see patients with MRSA complicated skin and soft-tissue infections in your clinical practice? Responses. Approximately one in five participants (20.6%) reported they saw more than one patient with MRSA cSSTI per week; however, the majority of respondents (73.3%) said that the number of patients with MRSA cSSTI visiting their clinic was still very low, with fewer than one patient per week.

S3

Discussion points. Staphylococcus aureus continues to be the most important and most frequently observed pathogen in cSSTI; however, the proportion of MRSA strains varied depending on the country and clinical setting. The real impact of MRSA and the decision to treat it empirically should, therefore, be based on local surveillance data. 3.2.2.4. How often do you see patients with MRSA nosocomial pneumonia in your clinical practice? Responses. Less than 25% of respondents reported seeing more than one case of MRSA NP per month; respondents who saw more cases per month appeared to be primarily from those countries where MRSA rates are increasing, i.e. Italy, Turkey and Greece. Discussion points. Based on these findings, the incidence of MRSA NP appears to be uncommon in Europe, with the majority of respondents (70.9%) seeing less than one case of MRSA in their clinical practice each month, except where the incidence of colonisation is higher. 3.3. Treatment management of MRSA complicated skin and soft-tissue infection 3.3.1. Background Administration of appropriate initial antibiotic therapy with an agent that is active against the causative pathogen is a cornerstone in the management of cSSTIs. Currently there are six antibiotics approved by the European Medicines Agency (EMA) for the treatment of cSSTIs due to MRSA, namely vancomycin, teicoplanin, linezolid, daptomycin, tigecycline [1] and, more recently, ceftaroline. The timing of when effective treatment is initiated for these infections is important for patient outcomes, as failure to give antibiotics within 8 h of presentation is associated with prolonged patient hospitalisation [30]. Although Gram-positive organisms such as S. aureus and/or haemolytic streptococci are the major pathogens causing cSSTIs on the extremities and the trunk [31,32], Gram-negative coverage is often required in the empirical treatment of certain cSSTIs, such as some surgical infections, pre-treated diabetic foot infections and major abscesses in the perirectal area. Furthermore, postoperative SSTIs that occur after surgery on the intestinal tract or female genital tract, and incisions in the perineum or axilla, have a high probability of having mixed Gram-positive and Gramnegative flora both with facultative and anaerobic organisms, whilst animal and human bite wounds can contain Pasteurella spp. or Capnocytophaga canimorsus [33]. As such, empirical antibacterial therapy against Gram-negative pathogens should be guided by expected pathogens, local/regional susceptibility profiles, patient risk factors (immunosuppression) and diagnostic procedure reports, i.e. the Gram stain of wound discharge or exudate [34]. In recent years, serious cSSTIs caused by multidrug-resistant (MDR) non-fermentative Gram-negative bacilli and Enterobacteriaceae have become more common [35]. The Infectious Diseases Society of America (IDSA) recommends systemic antibiotic treatment, in addition to incision and drainage, for patients with severe or extensive disease (e.g. multiple abscesses) or with rapid disease progression and associated cellulitis, signs and symptoms of systemic illness, associated co-existing conditions or immunosuppression, very young age or advanced age, an abscess in an area difficult to drain (e.g. face, hands or genitalia), associated septic phlebitis or an abscess that does not respond to incision and drainage alone [36]. Options from the IDSA guideline include the following: intravenous (i.v.) vancomycin; oral (p.o.) or i.v. linezolid 600 mg twice daily; daptomycin 6 mg/kg/dose i.v. once daily; telavancin 10 mg/kg/dose i.v. once daily; and clindamycin 600 mg i.v. or p.o. three times a day [36].

S4

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

40.0%

34.5%

30.0% 20.7% 20.0%

20.3% 12.9%

10.0%

6.0%

3.0%

1.3%

0.9%

0.4%

e

m ox az ol e Co -tr i

Ce fta ro lin

er O th

e Ti ge cy cl in

Cl in

da m yc in

ne zo lid Li

n an i Te ic op l

om yc in Da pt

Va nc om yc in

0.0%

Fig. 1. If available, what would be your initial i.v. treatment of choice for a patient with a complicated skin and soft-tissue infection caused by MRSA? (Please select a response.)

3.3.2.1. In your clinical practice, in what proportion of patients with complicated skin and soft-tissue infections would you use initial MRSA coverage?

Although vancomycin was selected by the majority of respondents, teicoplanin is also frequently used; however, due to its long halflife, teicoplanin is more likely to be used for outpatient parenteral antibiotic therapy (OPAT). Of the remaining treatment options, telavancin currently is not yet available in Europe and does not have an indication for cSSTI in this region, whilst i.v. linezolid is probably not used as much as the oral preparation (the oral route is the key advantage of this agent due to the 100% bioavailability of the drug). In addition, there is now also an increasing amount of real-life data for tigecycline in the treatment of cSSTI caused by MRSA [14]. Infections whose aetiology might include MRSA and Gram-negative organisms can be treated with tigecycline or ceftaroline; however, tigecycline has also demonstrated activity against extended-spectrum b-lactamase (ESBL)- and carbapenemase-producing Enterobacteriaceae.

Responses. Only 20% of respondents said they would cover MRSA in > 50% of their empirical cSSTI treatment; the majority (40.4%) said they would use MRSA coverage in fewer than 25% of cases.

3.3.2.4. Do you routinely use combination therapy to treat proven MRSA complicated skin and soft-tissue infections?

Oral antibiotics have been used in the outpatient setting for less severe SSTIs due to MRSA, but their efficacy has not been well studied [37]. There is a strong argument for using effective oral therapy early and limiting the requirement for hospital admission [38,39]. In addition to SXT and linezolid, other oral options include clindamycin, tetracycline, rifampicin, fusidic acid and, occasionally, quinolones [40–43], if the isolate is sensitive. It is expected that tedizolid will be available in Europe soon. 3.3.2. Questions

Discussion points. The perception of the role of MRSA and its impact in cSSTI varies considerably between countries and settings. This reflects the highly varied epidemiology of MRSA within Europe. Patients with MRSA infections require different empirical treatment than those with non-MRSA infections, and yet accurate tools to aid in stratifying the risk for an MRSA cSSTI are still lacking. 3.3.2.2. In your clinical practice, in what proportion of patients with complicated skin and soft-tissue infections would you use initial Gram-negative coverage? Responses. Of 232 responses, ca. 50% said they used initial Gramnegative coverage in < 25% of patients with cSSTIs; 10% of respondents said they used it in > 75% of patients with cSSTI. Discussion points. There is no absolute rule on the proportion of patients that require empirical Gram-negative treatment. This is a clinical judgement based on the type of cSSTI. The proportion will depend, among other determinants, on the infection site, type of infection and host factors. The responses are concordant with the proportion of one-quarter of patients with Gram-negative coverage included in clinical trials. 3.3.2.3. If available, what would be your initial i.v. treatment of choice for a patient with a complicated skin and softtissue infection caused by MRSA? Responses. Of 232 responses, more than one-half of the respondents said the glycopeptides (34.5% vancomycin, 20.3% teicoplanin) were their preferred initial treatment for a cSSTI caused by MRSA. Daptomycin was preferred by 20.7% and i.v. linezolid by 12.9% of the respondents (Fig. 1). Discussion points. As with the previous survey, glycopeptides remain the standard first-line treatment for cSSTI caused by MRSA in Europe.

Responses. More than one-half of the respondents said they never routinely used combination therapy in cSSTIs. However, notably 30.6% of respondents said they would use rifampicin in combination with another antibiotic; 20.7% would use rifampicin in combination with a glycopeptide (vancomycin/teicoplanin) (Fig. 2). Discussion points. Almost one-third of respondents say they would routinely use rifampicin in combination with other agents in the treatment of cSSTIs; however, the practice of adding rifampicin in the absence of a foreign body or biofilm is not advised in any guideline. Thus, this practice deviates considerably from international recommendations. 3.3.2.5. In your opinion, if oral antibiotic treatment is acceptable for the initial treatment of confirmed MRSA complicated skin and soft-tissue infections, which would be your preferred treatment option? Responses. Oral linezolid was the preferred antibiotic for this indication (31.9%), followed by clindamycin (13.7%) and SXT (11.1%). Nineteen percent of respondents did not think that oral treatment was appropriate for the initial treatment of cSSTIs due to MRSA (Fig. 3). Discussion points. Oral antibiotic treatment together with surgical drainage may be appropriate for the initial treatment of mild-tomoderate cSSTIs due to MRSA. Where an oral antibiotic is deemed appropriate, and in keeping with the previous survey findings, linezolid appears to be the preferred oral antibiotic of choice for the initial empirical treatment of cSSTIs due to MRSA. 3.3.2.6. In your opinion, what is the optimal duration of therapy for most patients with MRSA complicated skin and softtissue infections? Responses. Most respondents (70%) believed that 10 days was the optimum duration of therapy for patients with cSSTIs due to MRSA.

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

Ceftaroline + rifampicin

S5

0.0%

Daptomycin + rifampicin

2.6%

Linezolid + rifampicin

3.0% 4.3%

Co-trimoxazole + rifampicin

6.9%

Other

8.2%

Vancomycin/teicoplanin + aminoglycoside

20.7%

Vancomycin/teicoplanin + rifampicin

54.3%

I don’t routinely use combination therapy 0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

Fig. 2. Do you routinely use combination therapy to treat proven MRSA complicated skin and soft-tissue infections? (Please select a response.)

Cloxacillin Moxifloxacin/levofloxacin

0.4% 4.0% 5.8%

Other

6.2%

Doxycycline

8.0%

Rifampicin + fusidic acid

11.1%

Co-trimoxazole

13.7%

Clindamycin I don’t think that oral antibiotic treatment is acceptable

19.0% 31.9%

Linezolid 0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

Fig. 3. In your opinion, if oral antibiotic treatment is acceptable for the initial treatment of confirmed MRSA complicated skin and soft-tissue infections, which would be your preferred treatment option? (Please select a response.)

Discussion points. These findings suggest that many patients are being treated for too long. Unnecessary usage of antibiotics is one of the key factors driving antibiotic resistance. For cSSTIs due to MRSA, current evidence and guidelines support a shorter period of treatment. Longer courses (10–14 days) should only be considered in patients with a slow clinical response.

Despite a number of studies indicating that glycopeptide (vancomycin and teicoplanin) MICs may have an impact on treatment outcomes, there is little evidence that MIC creep causes problems in the treatment of cSSTIs [51]. 3.4.2. Questions

3.4. Minimum inhibitory concentrations (MICs) in clinical practice

3.4.2.1. In your practice, do you routinely have MIC values available?

3.4.1. Background

Responses. Of the respondents, 76.6% confirmed that MIC values were routinely available in their practice.

In patients with MRSA infections, high vancomycin MICs appear to be predictive of therapeutic failure [44], with several studies suggesting that reduced vancomycin susceptibility (MIC  2 mg/L) is associated with higher rates of treatment failure and/or mortality [45–47]; however, there is some debate over this association, with evidence to suggest otherwise [48]. According to both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI), it is not possible to determine the sensitivity of staphylococci to vancomycin by disk diffusion; as such, it is mandatory to test sensitivity to vancomycin by determining the MIC. MICs can be obtained using agar or broth dilution or by the Etest (gradient diffusion) method, and differences in methodology are well known to affect the MICs [49]. Broth microdilution (BMD) is a EUCAST reference method; however, in routine diagnostics MICs are most frequently determined using automated systems or the Etest method. Vancomycin MICs from automated testing tend to have lower values than those obtained by BMD, whilst those obtained by Etest demonstrate higher values [49,50].

Discussion points. Clinicians should be aware that if sensitivity of staphylococci to vancomycin is tested, MICs are readily available in the laboratory. However, the correlation between vancomycin MIC methodologies remains suboptimal. Usually there is only 1 dilution difference between the methods, but because of the narrow therapeutic window of vancomycin, this may also be relevant. It seems that most studies evaluating the impact of vancomycin MICs on clinical outcomes use the Etest methodology [52]. 3.4.2.2. In patients with MRSA complicated skin and soft-tissue infections, at which vancomycin MIC would you replace vancomycin with an alternative antibiotic? Responses. There was a wide distribution of answers; however, 61.2% of respondents were in favour of replacing vancomycin when MICs were 1.5–2.0 mg/L. Discussion points. It is evident from the wide distribution of answers that prescribers may be unaware of the phenomenon or the importance of vancomycin MIC creep in MRSA strains or do not believe

S6

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

80.0% 68.6%

70.0% 60.0%

54.9%

50.0% 40.0% 30.0% 17.6%

20.0%

6.7%

10.0% 0.0% Complicated skin and soft-tissue infections

Nosocomial pneumonia

None of the above

I don’t know

Fig. 4. Are elevated minimum inhibitory concentrations of vancomycin (MIC 1.5 or 2) clinically important for you in the following indications? (Please select all that apply.)

this is a real issue. Despite an increase in vancomycin MICs in recent years, vancomycin still appears to be the antibiotic of choice for patients with cSSTIs due to MRSA. An MIC of 4.0 mg/L is indicative of a vancomycin-intermediate S. aureus (VISA) strain and thus excludes therapy with vancomycin. In these cases, an alternative lipopeptide or lipoglycopeptide antibiotic such as daptomycin, telavancin or linezolid should be considered [53]. However, the wide distribution of answers in response to this question suggests a lack of clarity on the importance of vancomycin MICs, probably due to the absence of clear scientific evidence on the relationship of MIC with clinical outcome. It also highlights the importance of having organised national laboratory and clinically oriented surveys to establish the frequency of vancomycin MIC creep in different settings (countries, and regions or possibly specific institutions) so that specific guidelines can be developed. 3.4.2.3. In patients with a reduced susceptibility to vancomycin, what would be your preferred treatment for MRSA complicated skin and soft-tissue infections? Responses. More than 95% of the respondents said they would change the antibiotic if the infecting agent had a reduced susceptibility to vancomycin. Approximately 60% preferred linezolid or daptomycin, with 7.8% preferring teicoplanin. Discussion points. Although the importance of reduced susceptibility to vancomycin in the treatment of MRSA SSTIs is not clear, there are alternative antibiotics available for this indication. Daptomycin and linezolid appear to be the preferred antibiotics. 3.4.2.4. In which indication/s are elevated minimum inhibitory concentrations of vancomycin (MIC 1.5 or 2) clinically important for you? Responses. Of the respondents, 68.6% considered elevated MICs of vancomycin (MIC of 1.5 mg/L or 2 mg/L) clinically important in the case of NP and 54.9% in the case of cSSTI (Fig. 4). Discussion points. Elevated MICs of vancomycin appear to be most important in the treatment of MRSA NP (ca. 70%); however, > 50% of respondents also considered them important in the treatment of MRSA cSSTIs. 3.5. Treatment management of nosocomial pneumonia 3.5.1. Background NP caused by MRSA is frequently associated with poor outcomes and lengthy clinical resolution despite appropriate therapy. The current mainstay in MRSA NP treatment is therapy with vancomycin or linezolid. It has been suggested that, due to the low tissue concentration in

the lungs, vancomycin alone may be a suboptimal therapeutic option for MRSA NP; however, there appears to be no consensus on the efficacy of combination therapy over monotherapy in these patients. The use of vancomycin or linezolid in combination with rifampicin, a bactericidal antistaphylococcal drug with good tissue penetration, is common clinical practice in some institutions despite contradictory and confusing data from in vitro and animal studies [54–65]. There is also little supportive evidence of combination therapy with vancomycin in intensive care unit (ICU) patients with pneumonia caused by MRSA or in other severe MRSA infections [62]. In accordance with the guidelines, most experts recommend prolonging the duration of antimicrobial therapy to 10–14 days in patients with MRSA NP. However, this approach may favour the emergence of MDR strains, expose patients to unnecessary antibiotic toxicity and increase costs, without improving outcomes [66–68]. Furthermore, in a subgroup analysis of 42 patients with microbiologically proven MRSA pneumonia who were included in a large, multicentre, randomised controlled trial comparing two durations of therapy for ventilator-associated pneumonia (VAP), the clinical outcomes of patients who received appropriate empirical therapy for 8 days were similar to those of patients who received therapy for 15 days, casting some doubt on the necessity for prolonging therapy to such an extent in that type of infection [20]. Whether using a drug with better pulmonary penetration than vancomycin, such as linezolid, may allow a reduction in duration of therapy is unknown at present. Furthermore, the risk of MRSA VAP depends on the local epidemiology, not only within a country but also within individual units. If there is a high rate of MRSA colonisation and transmission within a unit, efforts need to be made to improve infection prevention and, if needed, to ensure anti-MRSA treatment is included in all empirical therapy of VAP. Surveillance cultures may also help guide therapy. Many clinicians prefer to customise antibiotic duration based on the clinical course of the disease, as determined by improvement in the PaO2 /FiO2 (partial pressure of oxygen/fraction of inspired oxygen) ratio and/or the clinical pulmonary score, and/or using serial determinations of a biomarker such as procalcitonin (PCT) or C-reactive protein (CRP). The rationale for using a biomarker to tailor antibiotic treatment duration relies on evidence that the inflammatory response is often proportional to infection severity [69]. When that response is absent or low, it might be logical to discontinue antibiotics earlier [70,71]. Thus, adapting antimicrobial treatment duration to PCT kinetics seems reasonable and has been demonstrated as useful in several randomised trials [72,73]. Unfortunately, only a few patients with MRSA infection were included in these studies, making it difficult to draw a firm conclusion for this subset of patients. A large majority of patients with healthcare-associated pneumonia or hospital-acquired pneumonia require an i.v. line, particularly for initial administration of antibiotics. If oral treatment is to be used,

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

S7

Table 2 In your opinion, how does combination therapy compare with monotherapy for the treatment of patients with MRSA nosocomial pneumonia? (Please select the three most relevant responses.) Answer options

Response [n (%)] (N = 224)

More effective than monotherapy

69 (30.8)

Increases the risk of toxicity

101 (45.1)

Not enough evidence for routine use

125 (55.8)

Glycopeptides alone do NOT provide adequate therapy for serious infections

69 (30.8)

Less likely for resistance to develop

58 (25.9)

Shortens duration of treatment

28 (12.5)

Other

26 (11.6)

patients must first demonstrate that they are haemodynamically stable, are able to ingest oral medication and have no problems with antimicrobial absorption. Suitable oral antibiotics should have a very high (> 90%) oral bioavailability, be effective against the causative pathogen and demonstrate good penetration at the focus of the infection. Linezolid fulfils this profile and, following oral administration, has been shown to penetrate the epithelial lining of healthy volunteers by ca. 400% (compared with 206% in bronchoscopy patients with respiratory disease and 104% in critically ill patients with VAP) [19,74–77]. 3.5.2. Questions 3.5.2.1. For a patient with clinical pneumonia and MRSA isolated from the upper respiratory tract, would you treat with antibiotics that cover MRSA? Responses. The majority of respondents (82.4%) said they would treat a patient with clinical pneumonia and MRSA isolated from the upper respiratory tract with antibiotics that cover MRSA. These findings appear to be in agreement with the current evidence. The pathogens in a lower respiratory tract infection must be influenced by microbial carriage in the upper respiratory tract, thus MRSA colonisation of the upper respiratory tract is an indication to cover for MRSA in patients with pneumonia. 3.5.2.2. In a patient presenting with SUSPECTED MRSA nosocomial pneumonia, what would be your preferred empirical treatment for covering MRSA? Responses. Approximately one-half of the respondents selected linezolid as their drug of choice; of the remainder, many preferred to use vancomycin (alone or in combination with rifampicin). Discussion points. The presence of MDR pathogens and MRSA risk factors are important considerations when selecting patients for empirical MRSA coverage of pneumonia. Currently, the preferred drug of choice for patients with suspected MRSA pneumonia is linezolid, followed by vancomycin. 3.5.2.3. In a patient presenting with CONFIRMED MRSA nosocomial pneumonia, what would be your preferred treatment for covering MRSA? Responses. Overall, 59.5% of the respondents said that linezolid would be their drug of choice in a patient presenting with confirmed MRSA NP. Only 26.8% of the respondents said they would use vancomycin or a combination of vancomycin and rifampicin. Discussion points. Unless contraindicated, linezolid is the preferred drug of choice by most respondents for patients with confirmed MRSA pneumonia. These findings are in line with those of the previous survey. Other new drugs are not appropriate (daptomycin) or have not been adequately assessed (tigecycline and ceftaroline).

3.5.2.4. In your opinion, how does combination therapy compare with monotherapy for the treatment of patients with MRSA nosocomial pneumonia? Responses. Only 30.8% of the respondents thought that combination therapy was more effective than monotherapy in this setting. The majority (55.8%) indicated that there was not enough evidence for its routine use, whilst 45.1% were concerned that combination therapy may increase the risk of toxicity. Furthermore, 30.8% of respondents believed that glycopeptides alone did not provide adequate therapy in this setting (Table 2). Discussion points. Interestingly, a similar number of respondents in the current survey compared with the 2009 survey [1] thought that combination therapy was more effective than monotherapy (30.8% vs. 40%) despite limited evidence to support the adjunctive use of rifampicin or any other antimicrobial agent to treat MRSA pneumonia. This may reflect the lack of confidence in glycopeptides as a single agent in this indication. Combination therapy may increase drug interactions and adverse effects and lead to rifampicin resistance when this antibiotic is used to overcome the potential limitations of glycopeptides. Further research is required before combination therapy can be recommended for treating patients with MRSA NP. 3.5.2.5. In your opinion, what is the optimal duration of therapy for most patients with MRSA nosocomial pneumonia? Responses. There was a general lack of consensus on the optimal duration of therapy of MRSA pneumonia. Although 46% of the respondents felt that the optimal duration of therapy was 11–14 days, 34% thought the treatment duration should be limited to 8–10 days and 5% suggested 4–7 days (Fig. 5). Discussion points. The majority of respondents thought 11–14 days was the optimal duration of treatment, which is in line with current evidence/guidelines for uncomplicated MRSA pneumonia [78–80]. However, compared with the previous survey in 2009 [1], a much larger proportion of respondents said that the optimal duration of treatment should be reduced to < 10 days. Customising the duration of therapy appears to be a promising strategy that could lead to avoiding the overuse of antibiotics while preserving outcomes. 3.5.2.6. How do you decide on the optimal duration of treatment in patients with MRSA nosocomial pneumonia? Responses. There was a general consensus that the decision for discontinuing antimicrobial therapy in patients with MRSA pneumonia cannot be based only on recommendations in the current guidelines (8.4%), the clinical course of the disease (15%) or the kinetics of biomarkers such as CRP and PCT (5.3%), but should take into consideration all of the above (69.2%). Discussion points. For uncomplicated MRSA pneumonia, current guidelines and evidence support a treatment duration of 10–14 days [66,81,82]. Customising the duration of therapy appears to be

S8

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

50.0%

46.0%

40.0% 33.6% 30.0%

20.0% 12.8% 10.0%

5.3% 2.2%

0.0% 4 to 7 days

8 to 10 days

11 to 14 days

15 to 28 days

I don't know

Fig. 5. In your opinion, what is the optimal duration of therapy for most patients with MRSA nosocomial pneumonia? (Please select a response.)

Table 3 If your answer to Question 3.5.2.7 is ‘no’, what type of patients with a clinical suspicion of ventilator-associated pneumonia would you treat with an antimicrobial agent active against MRSA? (Please select all that apply.) Answer options

Response [n (%)] (N = 177)

Patients previously colonised or with a current MRSA infection

139 (78.5)

Patients with prior hospitalisation in high-risk settings, such as nursing homes, with high (> 20%) local MRSA prevalence

102 (57.6)

Patients with late-onset infection and/or prior antimicrobial treatment when intensive care unit MRSA prevalence is high (> 20%)

116 (65.5)

Patients with multiple recent prior antimicrobial treatments

50 (28.2)

None of the above, I would wait for culture results

15 (8.5)

I don’t know

5 (2.8)

a promising strategy that could lead to avoiding the overuse of antibiotics while preserving outcomes. The value of using specific clinical factors and/or biomarkers in customising the duration of antibiotic therapy remains to be better demonstrated in clinical trials. 3.5.2.7. Should all patients for whom there is a clinical suspicion of ventilator-associated pneumonia be treated with an antimicrobial agent active against MRSA? Responses. Of the respondents, 68.3% said they would not treat all patients for whom there was a clinical suspicion of VAP with an antimicrobial agent active against MRSA. Discussion points. Corresponding to the feedback from the previous survey [1], the majority of respondents said they would not routinely cover MRSA in empirical treatment of VAP. 3.5.2.8. If your answer to Question 3.5.2.7 is ‘no’, what type of patients with a clinical suspicion of ventilator-associated pneumonia would you treat with an antimicrobial agent active against MRSA? Responses. Overall, a large number of respondents said they would routinely cover MRSA in the following patient populations: patients who had been previously colonised with MRSA or who had a current MRSA infection (78.5%); patients with late-onset infection and/or prior antimicrobial treatment when the ICU MRSA prevalence is high (65.5%); and patients who had previously been hospitalised in a high-risk setting (57.6%) (Table 3). Discussion points. Again, in line with feedback from the previous survey, patients with a clinical suspicion of VAP should be treated with an antimicrobial agent active against MRSA if they have previously been or are currently colonised with MRSA. In addition, patients in ICUs or nursing homes with a high risk/prevalence of MRSA infection should prompt strong consideration of treatment covering MRSA.

3.5.2.9. Would you use oral antibiotics in a patient with nosocomial pneumonia in your practice? Responses. Only 7% of respondents said they would use oral antibiotics to treat NP from the very first dose; however, 63% said they would use oral treatment once the patient improves. Remarkably, 27.6% of the respondents would not use oral agents at any time and would not consider de-escalation. Discussion points. Oral treatment from the initial first dose appears to be used by only a small minority of physicians. Whilst the pharmacokinetics of linezolid permit early de-escalation and, theoretically, the possibility of using the drug orally at the very first dose, many patients will be given an initial i.v. dose with de-escalation 2–5 days after the beginning of treatment [83]. Oral antibiotic treatment of NP should only be considered when patients are stable and when the right conditions are present. 3.6. Intravenous-to-oral switch and discharge 3.6.1. Background Early-switch programmes promote the switching of patients from i.v. to oral antibiotic therapies. These programmes are beneficial [80,84–87] as they facilitate earlier discharge from hospital [38] and enable patients to finish their treatment at home. Furthermore, they require few additional resources and are considered to be relatively low-cost, high-impact antimicrobial stewardship strategies [88]. Early-switch programmes are regarded as having the greatest potential benefit on the management of MRSA infections, particularly complicated skin and skin-structure infections [18]. Findings from the previous survey, published in 2010 [1], confirmed the predominant criteria used by clinicians for i.v.-to-oral switch in patients with MRSA infections. These criteria are generally widely accepted [39] and have been used to assess early switch opportunities against real-world practice for hospitalised patients with proven cSSTI due to MRSA in Europe [89]. The influential role of specific protocols to

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

S9

7.0% 14.0% 43.2% Complete the treatment with an i.v. course Switch to Outpatient Parenteral Antibiotic Therapy (OPAT) 35.8%

Switch to oral treatment Switch to oral and discharge (if no other barriers to discharge)

Fig. 6. Once the patient (with complicated skin and soft-tissue infection) is stable, what would you do next? (Please select a response.)

drive this practice has also been raised but was not formally assessed in the previous survey. A separate analysis [79] from the above real-world study [89] sought information about a range of organisational factors and showed significant variation in the availability of an early-switch protocol. Of 341 sites, 82.9% had antibiotic steering committees, but only 23.7% had i.v.-to-oral switch antibiotic protocols for MRSA. With high demand for hospital beds in many countries and, indeed, for the greater welfare of patients, discharging patients who are clinically stable appears to be good clinical practice [38]. For patients who have received i.v. treatment, have had documented clinical improvement and who are able to tolerate oral therapy, the aim should be step-down (streamline) therapy to the oral route as soon as possible. In choosing an appropriate step-down oral antibiotic, the same active antibiotic in oral form and high bioavailability should be considered. Antibiotics in this group include SXT, linezolid and tedizolid, once available. In a recent retrospective observational medical chart review of patients in 12 European countries, Eckmann et al. [79] have shown that 32.7% of all hospitalised patients with MRSA were discharged home on an MRSA-active drug. Of these, 42.1% received linezolid, 18.8% clindamycin, 14% quinolones and 11.9% SXT. This clearly points to the important role of oral step-down therapy with highly bioavailable agents in the context of this disease area. Interestingly, in another European study [90] that examined the management of all cSSTIs across Europe in 2010–2011, there were no clear data regarding what treatment patients received following discharge, although 14.1% of patients did receive some type of ‘home-based care after discharge’ for a median duration of 15 days. It is unclear whether this includes oral antibiotic therapy. As previously mentioned, oral therapy for the treatment of MRSA pneumonia is considered primarily as a de-escalation strategy. In a retrospective cohort study, a significantly higher rate of the composite outcome of clinical success was observed among patients treated with linezolid compared with vancomycin when combined i.v. and oral therapy was used [91]. Also, SXT can prevent the development of MRSA VAP in patients with severe burns [92]. Data regarding the oral use of drugs such as clindamycin, doxycycline, rifampicin, moxifloxacin and minocycline as oral antistaphylococcal agents in pneumonia are almost non-existent. 3.6.2. Questions 3.6.2.1. Do you have an i.v.-to-oral switch protocol in your hospital? Responses. In the current questionnaire, only 52.2% of respondents were aware of their local i.v.-to-oral switch protocols. Discussion points. These findings suggest that there is a need to improve availability and implementation of early-switch protocols.

3.6.2.2. Do you have a discharge protocol in your hospital for continuing antibiotic treatment (of complicated skin and soft-tissue infections/nosocomial pneumonia) out of hospital? Responses. Answers were split fairly evenly; 46.1% of respondents confirmed that their hospital had a discharge protocol for continuing antibiotic treatment out of hospital, 47.7% said they did not and 6.2% were not sure if they did or did not have a discharge protocol. Discussion points. It appears that nearly one-half of all those questioned in the current survey do have some formal process for discharge planning, either through continuing oral or i.v. (OPAT) treatment in the community. These findings are very different from those observed in the pan-European study by Eckmann et al. [79] in which only 12.9% had early discharge protocols for cSSTI due to MRSA. This may reflect the work that has been done in recent years on the development of OPAT and early discharge programmes [38,93]. 3.6.2.3. Once the patient (with complicated skin and soft-tissue infection) is stable, what would you do next? Responses. Approximately one in five respondents (21%) said that once the patient was stable they would complete the treatment with the same i.v. antibiotic (7% in hospital, 14% in an OPAT programme); however, the majority of respondents (79%) favoured step-down oral therapy (Fig. 6). Discussion points. Once the patient with proven cSSTI due to MRSA has been stabilised it may be appropriate to switch to oral therapy, for which there is a large number of treatment options available. 3.6.2.4. What proportion of your stable patients (with complicated skin and soft-tissue infections/nosocomial pneumonia) do you discharge on antibiotics? Responses. The majority of respondents (27.7%) said they would discharge more than 10–25% of cases on antibiotics; however, 25.7% said they were unsure. Discussion points. The response to this question again reflects an increasing acceptance of i.v.-to-oral switch, OPAT and early discharge. However, there is still room for further education and development in this area. 3.6.2.5. For those patients that you discharge during the course of antibiotic treatment, what proportion would be on oral treatment? Responses. In the current survey, 52.4% of respondents said they would discharge 50–100% of cases on oral therapy; 18.8% said they would do so in < 25% of cases (Fig. 7). Discussion points. As previously shown, these responses confirm that the use of oral medication at discharge is a common practice amongst infectious diseases specialists.

S10

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

37.2%

40.0% 30.0% 20.0% 10.0% 0.0%

16.8%

15.2% 12.0%

12.0%

>10–25%

>25–50%

6.8%

≤10%

>50–75%

>75–100%

I don't know

Fig. 7. For those patients that you discharge during the course of antibiotic treatment, what proportion would be on oral treatment? (Please select a response.)

Physician familiarity

6.2%

Cost of drug acquistion

6.6%

Potential for drug interactions

17.1%

Possibility of oral switch Drug cost Rapidity of antibiotic action

30.7% 34.2% 39.3%

Pharmacokinetics/pharmacodynamics

52.9% 58.4%

Toxicity/adverse events Patient factors: age, comorbidity, previous antibiotics, severity

69.3% 79.0%

Severity of infection

93.0%

Clinical efficacy

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% Fig. 8. Which are the five factors that most influence your choice of antibiotic?

3.6.2.6. If oral drugs are acceptable and the isolate is susceptible to the drug, which oral treatments would you consider for the treatment of MRSA nosocomial pneumonia infections?

3.7. General management of MRSA infections

resistance of local circulating strains; the type, site and severity of infection; and patient factors (age, liver disease or chronic kidney disease), which may contribute to increased drug toxicity. The inexorable growth in healthcare costs is forcing decisionmakers to try to extract greater value from healthcare resources. Between 1998 and 2008, in 15 European countries acute-care hospital bed capacity per 100,000 patients fell on average by 18% [96]. During this same period, in 12 European countries there was an average reduction in hospital LOS of 2 days, resulting in a mean hospital LOS of 6.5 days [96]. A decrease both in acute-care hospital bed capacity and hospital LOS could indicate a significant pressure on inpatient bed capacity [96]. The contribution of LOS as a key driver of the costs of healthcare-associated infections is well known [97], despite significant methodological limitations in their measurement and interpretation [98].

3.7.1. Background

3.7.2. Questions

The choice of antibiotic is an important consideration in the management of MRSA infections. A number of older drugs, such as SXT and doxycycline, have been used in the oral treatment of uncomplicated SSTI; however, there are no randomised trial data to provide evidential support. For complicated infections, glycopeptides are the accepted first-choice treatment, although the newer drugs with more acceptable administration are non-inferior in efficacy. In addition, the correct dosing schedule should be used to achieve successful treatment and to avoid the consequences of increased antibiotic resistance [94]. Inappropriate empirical antibiotic therapy in patients with MRSA bacteraemia is associated with a significant increase in mortality, prolonged length of stay (LOS) and increased hospital costs [95]. Clinicians starting a drug therapy on the basis of empirical choice should consider the possibility of multidrug

3.7.2.1. Which are the five factors which most influence your choice of antibiotic?

Responses. From the treatment list provided, 66% of the participants said they would select linezolid as an oral agent to treat MRSA pneumonia, whilst SXT and clindamycin were considered in some situations. Discussion points. Although there is no firm evidence to support the use of oral drugs from the very first dose in the treatment of NP, the bioavailability, pharmacokinetics and potency of linezolid support early oral treatment and rapid de-escalation.

Responses. Clinical efficacy of the antibiotic (93.0%) and severity of infection (79.0%) appear to be the two most important factors influencing the choice of antibiotic agent (93% of responses). In addition, patient factors such as age, co-morbidity and previous antibiotic use (69.3%), toxicity/adverse events caused by antibiotics (58.4%) and the pharmacokinetic/pharmacodynamic drug proprieties (52.9%) were also important (Fig. 8). Discussion points. As would be expected, and in line with findings of the previous survey in 2009 [1], clinical efficacy appears to be the most important factor influencing the choice of antibiotic agent among respondents. It is also interesting to note that drug-related costs were

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

None of the above

S11

4.7% 17.8%

Enhanced patient satisfaction

20.2%

Drug cost

27.3%

Reduced time in ICU

34.4%

Improved quality of life (e.g. QALY)

43.1%

Reduced overall cost of episode of infection

53.0%

Reduced duration of i.v. therapy Reduced length of hospital stay 0.0%

82.6% 20.0%

40.0%

60.0%

80.0%

100.0%

Fig. 9. What are the top health economic factors that most influence your antibiotic choice for the management of MRSA infections? (Please select the three most important factors for you.) [QALY, quality-adjusted life year.]

not a major concern to physicians, although budget-holders may have a different view. These findings suggest that the factors determining the choice of antibiotic in patients with MRSA have not changed over time. 3.7.2.2. What are the top health economic factors that most influence your antibiotic choice for the management of MRSA infections? Responses. Reducing LOS (82.6%) and reducing the duration of i.v. therapy (53.0%) were the two most important health economic factors in decision-making. Reducing the overall cost of infection was also a key goal for 43.1% of respondents (Fig. 9). Discussion points. In keeping with the previous survey [1], reducing LOS and reducing the duration of i.v. therapy were the two most important health economic factors in decision-making. The value of reducing LOS [99,100] with a view to improving the efficiency of healthcare delivery is well known [101]. The latter cost-efficiency strategy is well recognised as an approach in healthcare where more patients can receive care with the same investment in fixed costs [101]. The integration of such information in diagnosis-related groups (DRGs) is becoming increasingly common in Europe, as they provide incentives for hospitals to limit the services per patient and to treat more patients [102]. The survey data support the prominence of simple health economic parameters in clinical decision-making, although reducing the overall cost of an episode of infection remains a key goal. There is no doubt that reducing LOS would also significantly contribute to cost reduction [97], but the complexities of measuring this and interpreting it in a meaningful way are challenging. 4. Discussion This survey follows on from the original survey conducted in 2009 [1] and takes a European perspective on the role and management of MRSA in cSSTI and NP infections. Both surveys were carried out using SurveyMonkey, a web-based questionnaire; however, unlike the previous survey, and due to reasons of data protection, publicity was kindly provided by the ISC. The ISC informed all of their Europeanassociated societies, who in turn contacted their members. Whilst we appreciate that this approach may have resulted in some bias, as it relied on the enthusiasm of the associated societies, it should be noted that this survey had approximately the same number of European respondents as did the previous survey. Five years ago there was concern amongst clinicians and the scientific community over the prevalence of HA-MRSA across the continent and the possible rise in CA-MRSA; however, since then we have seen considerable changes in the epidemiology of MRSA. The predominant clone of HA-MRSA has peaked and is now in decline,

particularly across northern Europe; with no immediate replacement, the incidence of HA-MRSA has fallen. Despite falling rates of HA-MRSA across Europe, there still appears to be a North–South divide, with higher rates of HA-MRSA observed in the south of Europe compared with the north [2]. This is a more marked polarisation in epidemiology than was seen in the last survey. Although CA-MRSA has become more prevalent (the predominant clone being USA300), it has not increased to the extent that was first feared; however, these community strains, which are readily transmissible and can cause persistent or recurrent infection, may be causing more disease than is currently recognised. They may also be more pathogenic. Production of PVL is not easily detected in routine laboratories and there is likely to be under-reporting of PVL-producing meticillin-susceptible S. aureus and MRSA. Reference facilities for monitoring the epidemiology of S. aureus are available in some countries, but consideration of a central European surveillance laboratory or participating laboratories with regular submission of staphylococcal strains from every country would be helpful. Since publication of the previous survey [1] in 2010 a number of new antibiotics to treat MRSA have become available. However, despite a lack of clarity around the significance of MIC creep and its relationship to clinical outcome, the glycopeptides remain the predominant drug class. This lack of clarity persists and the clinical evidence is contradictory. It is no surprise, therefore, that respondents in the survey had different views on the significance of rising glycopeptide MICs. There appears, however, to be a consensus that for soft-tissue infection or pneumonia caused by microbes with glycopeptide MICs 2 mg/L, an alternative treatment should be sought. Based on the current survey findings, clinical efficacy appears to be the main driving influence behind the physician’s choice of antibiotic, with cost the least important consideration; however, this view is unlikely to reflect those of the budget-holders. Unfortunately this question does not reflect the complexity of the issue. Physicians want patients to get better and for this their paramount concern is for an effective treatment; however, based on current evidence, all the recently developed antibiotics have been shown to be noninferior to standard treatment (usually glycopeptides with or without a combined Gram-negative agent). Thus, based on the criterion that all new antibiotics are equal, budget-holders will say the least costly agent must be used. Despite this, it is clear that each of the newer agents has a role in specific patient populations. For example, linezolid is the only one of these agents that has demonstrated efficacy as an oral preparation; as such, linezolid has been shown to significantly reduce the requirement for i.v. administration and also the hospital LOS [103]. Whilst this distinction has been recognised by the survey respondents, it is also clear that they may not fully appreciate the potential of

S12

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

this advantage. Tigecycline and ceftaroline have both been shown to cover resistant Gram-negative pathogens (as well as MRSA) and thus may be useful in patients with intolerance [15,104]. Ceftaroline is the first b-lactam active against MRSA, and daptomycin has found a niche in bacteraemic patients and patients with endocarditis, although there is no clear evidence of its superiority [105,106]. In addition to these newer drugs, it is clear that the older antibiotics such as SXT, doxycycline/minocycline and clindamycin still have an important role to play in treatment, in particular in uncomplicated CA-MRSA infections. In the past 5 years a considerable amount of work also has been undertaken to try and shorten the length of antibiotic courses and to avoid potentiating antibiotic selection pressure. It is likely that more work will need to be done on this as well as on developing predictive biomarkers to support antibiotic cessation. Antimicrobial stewardship has moved forwards in the 5 years since the last survey. Familiarity with concepts of i.v.-to-oral switch, OPAT treatment and early discharge has increased, and some respondents were aware of local guidelines and standards in these areas, although further education and training is likely to be welcomed. Earlier oral switch may help reduce costs by reducing hospital LOS. The current survey identified that there are disparate views on the duration of therapy in cSSTIs and in pneumonia. There is also widespread use of combination therapy with glycopeptides despite the lack of evidence for its use. This leaves scope for further European development of antimicrobial stewardship and ‘bundles’ or standards to improve the quality of prescribing and improve the ‘patient journey’. Whilst this survey has limitations in terms of the number of respondents and the range of European countries involved, it nevertheless provides a contemporary view of the management of MRSA infections in parts of Europe. This is important for the future of clinical practice because the survey highlights that empirical treatment to cover MRSA in cSSTI and pneumonia depends on physician assessment based on the likelihood of previous MRSA colonisation or on local epidemiology of the local rate and transmission of MRSA. This is as it should be because the epidemiology of MRSA varies considerably across Europe and local expert knowledge of surveillance and antimicrobial resistance is crucial for local guidelines. The survey has demonstrated that there is now much wider knowledge around the different agents available to treat MRSA infection, and a greater interest in dose, duration, early discharge and antibiotic stewardship, all of which are important factors for the future of clinical practice in the management of infection. Acknowledgments : The Chair (M. Dryden) and authors would like to thank all of the participants for their response to the survey. Editorial support for the supplement was provided by L. Prevost at PAREXEL and was funded by Pfizer International Operations. Competing interests : M. Dryden is General Secretary of the British Society for Antimicrobial Chemotherapy (BSAC) and has received honoraria for lectures and advisory boards from Pfizer, Bayer, AstraZeneca, Basilea and Cubist; A. Tambic Andrasevic is on the guideline committee of the Croatian Interdisciplinary Section for Antibiotic Resistance Control (ISKRA) and has received honoraria for lectures and advisory boards from Pfizer and Xellia; M. Bassetti serves on scientific advisory boards for AstraZeneca, Bayer, Cubist, Pfizer, MSD, Tetraphase and Astellas Pharma Inc. and has received funding for travel or speaker honoraria from Algorithm, Angelini, Astellas Pharma Inc., AstraZeneca, Cubist, Pfizer, MSD, Gilead Sciences, Novartis, Ranbaxy and Teva; E. Bouza has received consulting and/or speaker honoraria from Astellas, Baxter, Gilead, Janssen, McDonalds, Novartis, Optimer, Pfizer and Wyeth Lederle and has received research support from Novartis, Pfizer and Schering-Plough; J. Chastre has received honoraria for lectures and advisory boards from Pfizer, Bayer, Astellas, Cubist-Trius, Basilea and Aridis; M. Baguneid has received honoraria for lectures and advisory boards from Pfizer;

S. Esposito has served on scientific boards for Basilea, MSD and Pfizer; H. Giamarellou is the National Focal Point for antimicrobial resistance at the European Centre for Disease Prevention and Control (Stockholm, Sweden) as well as President of the Executive Committee of the Hellenic Society of Chemotherapy and has received honoraria for lectures and advisory boards from Astellas, Novartis and Pfizer; I. Gyssens is on the Guideline Committee of the Dutch Working Party on Antibiotic Policy (SWAB) and is a member of the ESCMID Study Group for Antibiotic Policies (ESGAP); recent and relevant commercial relationships include research grant recipient from Bayer HealthCare, educational grant recipient from Pfizer and consultancy fees from Pfizer; D. Nathwani is President Elect of the British Society for Antimicrobial Chemotherapy (BSAC) and Chair of the Scottish Antimicrobial Prescribing Group and has served on advisory boards and received honoraria for lectures and research grants from AstraZeneca, Astellas, Basilea, Bayer, Cubist, Durata, Pfizer and The Medicines Company; S. Unal has served on scientific advisory boards for Gilead Sciences, MSD and Pfizer and has received consultancy fees from GSK and Pfizer; A. Voss is a board member of the International Society of Chemotherapy (ISC) and the Infection Control African Network (ICAN) and has received honoraria, travel support ´ and/or advisory board fees from 3M, Astellas, bioMerieux, CareFusion, Deb and Pfizer; M. Wilcox has received consulting fees from Abbott Laboratories, Actelion, Astellas, AstraZeneca, Bayer, Cerexa, Cubist, Durata, The European Tissue Symposium, The Medicines Company, MedImmune, Merck, Motif Biosciences, Nabriva, Optimer, Paratek, Pfizer, Roche, Sanofi-Pasteur, Seres, Summit and Synthetic Biologics, has received lecture fees from Abbott, Alere, Astellas, AstraZeneca and Pfizer and has also received grant support from Abbott, Actelion, ´ Astellas, bioMerieux, Cubist, Da Volterra, The European Tissue Symposium, Merck and Summit. References [1] Dryden M, Andrasevic AT, Bassetti M, Bouza E, Chastre J, Cornaglia G, et al. A European survey of antibiotic management of methicillin-resistant Staphylococcus aureus infection: current clinical opinion and practice. Clin Microbiol Infect 2010;16(Suppl 1):3–30. [2] European Antimicrobial Resistance Surveillance System (EARSS). EARSS annual report 2007. European Centre for Disease Prevention and Control. http://www .ecdc.europa.eu / en / activities / surveillance/ears -net / documents / 2007 _ earss _ annual_report.pdf [accessed 12 January 2015]. [3] Ferry T. Community acquired MRSA in Europe. BMJ 2007;335:947–8. [4] Huang H, Flynn NM, King JH, Monchaud C, Morita M, Cohen SH. Comparisons of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and hospital-associated MRSA infections in Sacramento, California. J Clin Microbiol 2006;44:2423–7. [5] Lloyd-Smith E, Hull MW, Tyndall MW, Zhang R, Wood E, Montaner JS, et al. Community-associated methicillin-resistant Staphylococcus aureus is prevalent in wounds of community-based injection drug users. Epidemiol Infect 2010;138: 713–20. [6] Ellington MJ, Hope R, Livermore DM, Kearns AM, Henderson K, Cookson BD, et al. Decline of EMRSA-16 amongst methicillin-resistant Staphylococcus aureus causing bacteraemias in the UK between 2001 and 2007. J Antimicrob Chemother 2010;65:446–8. [7] Bassetti M, Baguneid M, Bouza E, Dryden M, Nathwani D, Wilcox M. European perspective and update on the management of complicated skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid. Clin Microbiol Infect 2014;20(Suppl 4): 3–18. [8] European Centre for Disease Prevention and Control (ECDC). Surveillance of antimicrobial consumption in Europe 2011. http://www.ecdc.europa.eu / en / publications / Publications / antimicrobial - consumption - europe - surveillance -2011.pdf [accessed 5 January 2014]. [9] Holden MT, Hsu LY, Kurt K, Weinert LA, Mather AE, Harris SR, et al. A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant Staphylococcus aureus pandemic. Genome Res 2013;23:653–64. [10] Price LB, Stegger M, Hasman H, Aziz M, Larsen J, Andersen PS, et al. Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock. MBio 2012;3:pii: e00305-11. [11] Gonzalez-Ruiz A, Beiras-Fernandez A, Lehmkuhl H, Seaton RA, Loeffler J, Chaves RL. Clinical experience with daptomycin in Europe: the first 2.5 years. J Antimicrob Chemother 2011;66:912–9.

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

[12] Bassetti M, Eckmann C, Bodmann KF, Dupont H, Heizmann WR, Montravers P, et al. Prescription behaviours for tigecycline in real-life clinical practice from five European observational studies. J Antimicrob Chemother 2013;68(Suppl 2): ii5–14. ´ [13] Guirao X, Sanchez-Garc´ ıa M, Bassetti M, Bodmann KF, Dupont H, Montravers P, et al. Safety and tolerability of tigecycline for the treatment of complicated skin and soft-tissue and intra-abdominal infections: an analysis based on five European observational studies. J Antimicrob Chemother 2013;68(Suppl 2): ii37–44. [14] Montravers P, Bassetti M, Dupont H, Eckmann C, Heizmann WR, Guirao X, et al. Efficacy of tigecycline for the treatment of complicated skin and soft-tissue infections in real-life clinical practice from five European observational studies. J Antimicrob Chemother 2013;68(Suppl 2):ii15–24. [15] Montravers P, Dupont H, Bedos JP, Bret P. Tigecycline use in critically ill patients: a multicentre prospective observational study in the intensive care setting. Intensive Care Med 2014;40:988–97. [16] Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother 2010;65(Suppl 3):iii35–44. [17] Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Diagn Microbiol Infect Dis 2007;57:7–13. [18] Sader HS, Farrell DJ, Jones RN. Antimicrobial susceptibility of Gram-positive cocci isolated from skin and skin-structure infections in European medical centres. Int J Antimicrob Agents 2010;36:28–32. [19] Chastre J, Blasi F, Masterton RG, Rello J, Torres A, Welte T. European perspective and update on the management of nosocomial pneumonia due to methicillinresistant Staphylococcus aureus after more than 10 years of experience with linezolid. Clin Microbiol Infect 2014;20(Suppl 4):19–36. [20] Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003;290:2588–98. [21] Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006;368:874–85. [22] David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus : epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010;23:616–87. [23] Rolo J, Miragaia M, Turlej-Rogacka A, Empel J, Bouchami O, Faria NA, et al. High genetic diversity among community-associated Staphylococcus aureus in Europe: results from a multicenter study. PLoS One 2012;7:e34768. [24] Stegger M, Wirth T, Andersen PS, Skov RL, De Grassi A, Simões PM, et al. Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus . MBio 2014;5:e01044-14. [25] Cercenado E, Ruiz de Gopegiu E. Community-acquired methicillin-resistant Staphylococcus aureus [in Spanish]. Enferm Infecc Microbiol Clin 2008;26: 19–24. [26] Stefani S, Varaldo PE. Epidemiology of methicillin-resistant staphylococci in Europe. Clin Microbiol Infect 2003;9:1179–86. [27] Dudareva S, Barth A, Paeth K, Krenz-Weinreich A, Layer F, Delere Y, et al. Cases of community-acquired meticillin-resistant Staphylococcus aureus in an asylum seekers centre in Germany, November 2010. Euro Surveill 2011;16(4):pii=19777. [28] Nhan TX, Bes M, Meugnier H, Toko L, Julienne G, Thiolet JM, et al. ST93Queensland community-acquired meticillin-resistant Staphylococcus aureus clone in France: outbreak in a scout camp and sporadic cases, July to August 2012. Euro Surveill 2012;17(44):pii=20307. [29] Giuffre M, Bonura C, Cipolla D, Mammina C. MRSA infection in the neonatal intensive care unit. Expert Rev Anti Infect Ther 2013;11:499–509. [30] Figtree M, Konecny P, Jennings Z, Goh C, Krilis SA, Miyakis S. Risk stratification and outcome of cellulitis admitted to hospital. J Infect 2010;60:431–9. [31] Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004;38:1673–81. [32] Gyssens IC, Dryden M, Kujath P, Nathwani D, Schaper N, Hampel B, et al. A randomized trial of the efficacy and safety of sequential intravenous/ oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections. J Antimicrob Chemother 2011;66:2632–42. [33] Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373–406. [34] Fung HB, Chang JY, Kuczynski S. A practical guide to the treatment of complicated skin and soft tissue infections. Drugs 2003;63:1459–80. [35] Sader HS, Mallick R, Kuznik A, Fritsche TR, Jones RN. Use of in vitro susceptibility and pathogen prevalence data to model the expected clinical success rates of tigecycline and other commonly used antimicrobials for empirical treatment of complicated skin and skin-structure infections. Int J Antimicrob Agents 2007;30:514–20. [36] Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of

[37] [38]

[39]

[40] [41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51] [52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

S13

methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis 2011;52:285–92. Unal S. Treatment options for skin and soft tissue infections: ‘oldies but goldies’. Int J Antimicrob Agents 2009;34(Suppl 1):S20–3. Dryden M, Saeed K, Townsend R, Winnard C, Bourne S, Parker N, et al. Antibiotic stewardship and early discharge from hospital: impact of a structured approach to antimicrobial management. J Antimicrob Chemother 2012;67:2289–96. Nathwani D, Eckmann C, Lawson W, Stephens JM, Macahilig C, Solem CT, et al. Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections. Clin Microbiol Infect 2014;20:993–1000. Drew RH. Emerging options for treatment of invasive, multidrug-resistant Staphylococcus aureus infections. Pharmacotherapy 2007;27:227–49. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006;57:589–608. Kaka AS, Rueda AM, Shelburne SA III, Hulten K, Hamill RJ, Musher DM. Bactericidal activity of orally available agents against methicillin-resistant Staphylococcus aureus . J Antimicrob Chemother 2006;58:680–3. Zervos M. Treatment options for uncomplicated community-acquired skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus : oral antimicrobial agents. Surg Infect (Larchmt) 2008;9(Suppl 1):s29–34. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004;42:2398–402. Choi EY, Huh JW, Lim CM, Koh Y, Kim SH, Choi SH, et al. Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia. Intensive Care Med 2011;37:639–47. Han JH, Mascitti KB, Edelstein PH, Bilker WB, Lautenbach E. Effect of reduced vancomycin susceptibility on clinical and economic outcomes in Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2012;56:5164–70. Tadros M, Williams V, Coleman BL, McGeer AJ, Haider S, Lee C, et al. Epidemiology and outcome of pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) in Canadian hospitals. PLoS One 2013;8:e75171. Kalil AC, Van Schooneveld TC, Fey PD, Rupp ME. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. JAMA 2014;312:1552–64. van Hal SJ, Barbagiannakos T, Jones M, Wehrhahn MC, Mercer J, Chen D, et al. Methicillin-resistant Staphylococcus aureus vancomycin susceptibility testing: methodology correlations, temporal trends and clonal patterns. J Antimicrob Chemother 2011;66:2284–7. Edwards B, Milne K, Lawes T, Cook I, Robb A, Gould IM. Is vancomycin MIC ‘creep’ method dependent? Analysis of methicillin-resistant Staphylococcus aureus susceptibility trends in blood isolates from North East Scotland from 2006 to 2010. J Clin Microbiol 2012;50:318–25. Gould IM. The problem with glycopeptides. Int J Antimicrob Agents 2007;30: 1–3. Mavros MN, Tansarli GS, Vardakas KZ, Rafailidis PI, Karageorgopoulos DE, Falagas ME. Impact of vancomycin minimum inhibitory concentration on clinical outcomes of patients with vancomycin-susceptible Staphylococcus aureus infections: a meta-analysis and meta-regression. Int J Antimicrob Agents 2012;40:496–509. van Hal SJ, Paterson DL. Systematic review and meta-analysis of the significance of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Antimicrob Agents Chemother 2011;55:405–10. Antony SJ. Combination therapy with daptomycin, vancomycin, and rifampin for recurrent, severe bone and prosthetic joint infections involving methicillinresistant Staphylococcus aureus . Scand J Infect Dis 2006;38:293–5. Dworkin R, Modin G, Kunz S, Rich R, Zak O, Sande M. Comparative efficacies of ciprofloxacin, pefloxacin, and vancomycin in combination with rifampin in a rat model of methicillin-resistant Staphylococcus aureus chronic osteomyelitis. Antimicrob Agents Chemother 1990;34:1014–6. Lee DG, Chun HS, Yim DS, Choi SM, Choi JH, Yoo JH, et al. Efficacies of vancomycin, arbekacin, and gentamicin alone or in combination against methicillin-resistant Staphylococcus aureus in an in vitro infective endocarditis model. Antimicrob Agents Chemother 2003;47:3768–73. Lefebvre M, Jacqueline C, Amador G, Le Mabecque V, Miegeville A, Potel G, et al. Efficacy of daptomycin combined with rifampicin for the treatment of experimental meticillin-resistant Staphylococcus aureus (MRSA) acute osteomyelitis. Int J Antimicrob Agents 2010;36:542–4. Mulazimoglu L, Drenning SD, Muder RR. Vancomycin–gentamicin synergism revisited: effect of gentamicin susceptibility of methicillin-resistant Staphylococcus aureus . Antimicrob Agents Chemother 1996;40:1534–5. Palmer SM, Rybak MJ. Pharmacodynamics of once- or twice-daily levofloxacin versus vancomycin, with or without rifampin, against Staphylococcus aureus in an in vitro model with infected platelet–fibrin clots. Antimicrob Agents Chemother 1996;40:701–5.

S14

M. Dryden et al. / International Journal of Antimicrobial Agents 45S1 (2015) S1–S14

[60] Rochon-Edouard S, Pestel-Caron M, Lemeland JF, Caron F. In vitro synergistic effects of double and triple combinations of b-lactams, vancomycin, and netilmicin against methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 2000;44:3055–60. [61] Rose WE, Poppens PT. Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus . J Antimicrob Chemother 2009;63:485–8. [62] Tremblay S, Lau TT, Ensom MH. Addition of rifampin to vancomycin for methicillin-resistant Staphylococcus aureus infections: what is the evidence? Ann Pharmacother 2013;47:1045–54. [63] Watanakunakorn C, Guerriero JC. Interaction between vancomycin and rifampin against Staphylococcus aureus . Antimicrob Agents Chemother 1981;19:1089–91. [64] Watanakunakorn C, Tisone JC. Synergism between vancomycin and gentamicin or tobramycin for methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 1982;22:903–5. [65] Yin LY, Lazzarini L, Li F, Stevens CM, Calhoun JH. Comparative evaluation of tigecycline and vancomycin, with and without rifampicin, in the treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis in a rabbit model. J Antimicrob Chemother 2005;55:995–1002. [66] American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388– 416. [67] Dellit TH, Chan JD, Skerrett SJ, Nathens AB. Development of a guideline for the management of ventilator-associated pneumonia based on local microbiologic findings and impact of the guideline on antimicrobial use practices. Infect Control Hosp Epidemiol 2008;29:525–33. [68] Goldmann DA, Weinstein RA, Wenzel RP, Tablan OC, Duma RJ, Gaynes RP, et al. Strategies to prevent and control the emergence and spread of antimicrobialresistant microorganisms in hospitals. A challenge to hospital leadership. JAMA 1996;275:234–40. [69] Luyt CE, Guerin V, Combes A, Trouillet JL, Ayed SB, Bernard M, et al. Procalcitonin kinetics as a prognostic marker of ventilator-associated pneumonia. Am J Respir Crit Care Med 2005;171:48–53. ¨ [70] Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006;174:84–93. ¨ [71] Christ-Crain M, Muller B. Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J 2007;30:556–73. [72] Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012;55:651–62. ¨ [73] Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2012;9:CD007498. [74] Boselli E, Breilh D, Rimmele T, Djabarouti S, Toutain J, Chassard D, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med 2005;33:1529–33. [75] Conte JE Jr, Golden JA, Kipps J, Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 2002;46:1475–80. [76] Honeybourne D, Tobin C, Jevons G, Andrews J, Wise R. Intrapulmonary penetration of linezolid. J Antimicrob Chemother 2003;51:1431–4. [77] Stein GE, Wells EM. The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus : vancomycin and linezolid. Curr Med Res Opin 2010;26:571–88. ´ [78] Carratala` J, Garcia-Vidal C, Ortega L, Fernandez-Sab e´ N, Clemente M, Albero G, et al. Effect of a 3-step critical pathway to reduce duration of intravenous antibiotic therapy and length of stay in community-acquired pneumonia: a randomized controlled trial. Arch Intern Med 2012;172:922–8. [79] Eckmann C, Lawson W, Nathwani D, Solem CT, Stephens JM, Macahilig C, et al. Antibiotic treatment patterns across Europe in patients with complicated skin and soft-tissue infections due to meticillin-resistant Staphylococcus aureus : a plea for implementation of early switch and early discharge criteria. Int J Antimicrob Agents 2014;44:56–64. [80] Nathwani D, Moitra S, Dunbar J, Crosby G, Peterkin G, Davey P. Skin and soft tissue infections: development of a collaborative management plan between community and hospital care. Int J Clin Pract 1998;52:456–60. [81] Masterton RG, Galloway A, French G, Street M, Armstrong J, Brown E, et al. Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2008;62: 5–34.

[82] Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: diagnosis and treatment. J Crit Care 2008;23:138–47. [83] Dryden MS. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. J Antimicrob Chemother 2011;66(Suppl 4):iv7–15. [84] Cunha BA. Oral antibiotic therapy of serious systemic infections. Med Clin North Am 2006;90:1197–222. [85] Desai M, Franklin BD, Holmes AH, Trust S, Richards M, Jacklin A, et al. A new approach to treatment of resistant Gram-positive infections: potential impact of targeted IV to oral switch on length of stay. BMC Infect Dis 2006;6:94. [86] Parodi S, Rhew DC, Goetz MB. Early switch and early discharge opportunities in intravenous vancomycin treatment of suspected methicillin-resistant staphylococcal species infections. J Manag Care Pharm 2003;9:317–26. [87] Seaton RA, Bell E, Gourlay Y, Semple L. Nurse-led management of uncomplicated cellulitis in the community: evaluation of a protocol incorporating intravenous ceftriaxone. J Antimicrob Chemother 2005;55:764–7. [88] Goff DA, Bauer KA, Reed EE, Stevenson KB, Taylor JJ, West JE. Is the ‘low-hanging fruit’ worth picking for antimicrobial stewardship programs? Clin Infect Dis 2012;55:587–92. [89] Lee SL, Azmi S, Wong PS. Clinicians’ knowledge, beliefs and acceptance of intravenous-to-oral antibiotic switching, Hospital Pulau Pinang. Med J Malaysia 2012;67:190–8. [90] Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F; REACH Study Group. Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010–2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 2013;19:E377–85. [91] Caffrey AR, Morrill HJ, Puzniak LA, LaPlante KL. Comparative effectiveness of linezolid and vancomycin among a national Veterans Affairs cohort with methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy 2014; 34:473–80. [92] Kimura A, Mochizuki T, Nishizawa K, Mashiko K, Yamamoto Y, Otsuka T. Trimethoprim–sulfamethoxazole for the prevention of methicillin-resistant Staphylococcus aureus pneumonia in severely burned patients. J Trauma 1998; 45:383–7. [93] Chapman AL, Seaton RA, Cooper MA, Hedderwick S, Goodall V, Reed C, et al. Good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) in adults in the UK: a consensus statement. J Antimicrob Chemother 2012;67:1053–62. [94] Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000;31(Suppl 4):S131–8. [95] Paul M, Kariv G, Goldberg E, Raskin M, Shaked H, Hazzan R, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2010;65:2658–65. [96] European Hospital and Healthcare Federation. Hospitals in Europe healthcare data. Brussels, Belgium: HOPE Publications; 2011. [97] Plowman RP, Graves N, Griffin M, et al. The socioeconomic burden of hospital acquired infection. London, UK: Public Health Laboratory Service; 1999. [98] Graves N, Harbarth S, Beyersmann J, Barnett A, Halton K, Cooper B. Estimating the cost of health care-associated infections: mind your p’s and q’s. Clin Infect Dis 2010;50:1017–21. [99] Nathwani D. Impact of methicillin-resistant Staphylococcus aureus infections on key health economic outcomes: does reducing the length of hospital stay matter? J Antimicrob Chemother 2003;51(Suppl 2):ii37–44. [100] Nathwani D. Health economic issues in the treatment of drug-resistant serious Gram-positive infections. J Infect 2009;59(Suppl 1):S40–50. [101] Ward WJ Jr, Spragens L, Smithson K. Building the business case for clinical quality. Healthc Financ Manage 2006;60:92–8. [102] Busse R, Geissler A, Aaviksoo A, Cots F, Hakkinen U, Kobel C, et al. Diagnosis related groups in Europe: moving towards transparency, efficiency, and quality in hospitals? BMJ 2013;346:f3197. [103] Itani KM, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 2005;26:442–8. [104] Jones RN, Mendes RE, Sader HS. Ceftaroline activity against pathogens associated with complicated skin and skin structure infections: results from an international surveillance study. J Antimicrob Chemother 2010;65(Suppl 4):iv17–31. [105] Dryden MS. Novel antibiotic treatment for skin and soft tissue infection. Curr Opin Infect Dis 2014;27:116–24. [106] Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus . N Engl J Med 2006;355:653–65.

Managing skin and soft-tissue infection and nosocomial pneumonia caused by MRSA: a 2014 follow-up survey.

As a follow-up to our 2009 survey, in order to explore opinion and practice on the epidemiology and management of meticillin-resistant Staphylococcus ...
227KB Sizes 0 Downloads 8 Views