Antimicrobial Original Research Paper
Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience Ananthakrishnan Ramani1, George Udeani2, John Evans3, Alena Jandourek4, Phillip Cole4, Alexander Smith4, H. David Friedland4 1
Mountainview Medical Practice (Columbia Memorial Hospital), Catskill, NY, USA, 2Christus Spohn Hospital Corpus Christi Shoreline, TX, USA, 3Christus Spohn Hospital Alice, TX, USA, 4Cerexa Inc., Oakland, CA, USA The Clinical Assessment Program and TeflaroH Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and §2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs secondline therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.
Keywords: Community-acquired bacterial pneumonia, CABP, Ceftaroline fosamil, CAPTURE, registry
Introduction The burden of community-acquired bacterial pneumonia (CABP) is considerable in the US, accounting for 5– 10 million cases diagnosed1 and over 1.1 million patients hospitalized each year. Community-acquired bacterial pneumonia is associated with significant morbidity, mortality, and hospital costs.1,2 Commonly, typical bacterial pathogens associated with CABP include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. Less common etiologic organisms are Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Citrobacter freundii.3,4 The majority of cases of CABP occur in adults aged 65 years and older and, due to the growing elderly population, the incidence of CABP is increasing.3 In addition, the emergence of resistant strains of bacterial pathogens renders successful treatment more problematic.5,6 With an increase in multidrug-resistant (MDR) organisms, particularly S. pneumoniae and the emerging importance of S. aureus, there is a need for new treatment options. Ceftaroline, a broad-spectrum cephalosporin active in vitro against a range of Gram-positive and common Gram-negative bacteria,
Correspondence to: Alena Jandourek, Cerexa, Inc., Oakland, CA, USA. Email: [email protected]
ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947814Y.0000000184
is a viable option for treating patients with these organisms.6,7 Ceftaroline is active in vitro against resistant phenotypes commonly isolated in CABP, including penicillin-resistant S. pneumoniae (PRSP), multidrug-resistant S. pneumoniae, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S. aureus (VRSA).7–9 Ceftaroline has the same bactericidal mode of action of other beta-lactam antibiotics, preventing bacterial cell wall biosynthesis through irreversible binding to penicillin-binding proteins (PBPs).10 A particular advantage of ceftaroline is high affinity for PBP2x in S. pneumoniae, PBP2a in MRSA, and PBPs 1 and 3 in E. coli.11,12 Ceftaroline fosamil (Teflaro), the pro-drug of ceftaroline, was approved by the US Food and Drug Administration (FDA) in October 2010 for the treatment of CABP and acute bacterial skin and skin structure infections (ABSSSIs) and is approved for similar indications in Europe.13 It is administered as an intravenous (iv) infusion and is well tolerated, with a safety profile reflective of the cephalosporin class.14 The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Study data for the treatment of CABP are presented here.
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Methods Study design
Data analysis and clinical outcome
The study period reported reviews data collected from August 2011 through February 2013. This study included eligible patients, aged 18 years or over, with clinical signs or symptoms consistent with a lower respiratory tract infection and radiologic confirmation of CABP. Patients were identified through a sequential review of charts randomly ordered from pharmacy lists at participating institutions. Eligible patients received §2 consecutive doses of ceftaroline fosamil between August 2011 and July 2012 or, following a study protocol amendment, §4 consecutive doses of ceftaroline fosamil thereafter. Charts were excluded from patients with additional or underlying infections (except for bacteremia associated with CABP). In addition, patients’ data were excluded where the information on dosing was missing or if data had already been extracted for this study. This registry study was approved by each institution’s ethics committee and conducted in compliance with the International Conference on Harmonization E6 Good Clinical Practice guidance.15
Statistical analyses were performed on the data using SASH Version 9.2. The data were summarized using descriptive statistics, including demographic data, disease and pathogen characteristics, antibiotic usage, clinical outcome, and hospital discharge. Numeric data were summarized with a mean, SD, and median values where relevant and categorical data were presented by frequency and percentage. Evaluable patients were those for whom a clinical outcome could be determined. Clinical outcome (success or failure) was determined based on the reason for discontinuation of ceftaroline fosamil treatment. Clinical success was defined as clinical cure with no further need for antibiotic or clinical improvement with switch to oral antibiotic. Clinical failure was defined as discontinuation due to an adverse event or insufficient therapeutic effect and switch to another iv antibiotic. In some cases, following a review of information where the patient was confirmed to be improving upon discontinuation of ceftaroline fosamil (with no evidence of failure), clinical outcome was deemed as successful.
Data collection For each eligible patient chart, demographic data were extracted, alongside data on relevant medical history, bacterial pathogens, location of care, and clinical signs and symptoms at the time of diagnosis and at the end of ceftaroline fosamil treatment. Data were also extracted on the use of other antibiotics before or concurrent with the administration of ceftaroline fosamil. Information on the response to treatment with ceftaroline fosamil was collected. The study protocol amendment in July 2012 allowed for additional data to be collected for subsequent patients. These included additional data on ceftaroline fosamil dosages, dosing frequencies, as well as further information associated with patient discharge including discharge destination, readmission within 30 days of discharge, and reason for readmission.
Results Patient and disease characteristics A total of 418 patients diagnosed with CABP across 33 centers comprised the enrolled population. From these, sufficient data to determine clinical outcome were available for 398 patients comprising the evaluable population, the population of focus for all subsequent summaries. Patients were equally divided between genders and had a mean (6SD) age of 63.5 years (617.8); 49% were aged §65 years. Patients received ceftaroline fosamil in either a general hospital ward (64%) or an intensive care unit (ICU; 35%). In addition, two patients received outpatient parenteral antibiotic therapy (OPAT) or home iv therapy, and data on the location of treatment of two further patients were missing (Table 1).
Table 1 Baseline demographic data for community-acquired bacterial pneumonia (CABP) patients and location of care Demographics
General ward (n5256)
Gender n (%) Male Female Age group (years), n (%) Under 40 40–65 65–80 Over 80 Age at baseline (years) Mean (SD) Median (range) BMI Number of patients Mean (SD) Median (range)
115 (45) 141 (55) 25 95 71 65
(10) (37) (28) (25)
64.7 (17.9) 66.0 (23–99) 237 28.3 (10.2) 25.9 (13.5–95.3)
ICU (n5138)
All patients (n5398)*
82 (59) 56 (41)
199 (50) 199 (50)
15 64 33 26
41 161 105 91
(11) (46) (24) (19)
61.6 (17.3) 61.0 (19–96) 129 29.9 (10.5) 27.3 (16.2–84.2)
(10) (41) (26) (23)
63.5 (17.8) 64.0 (19–99) 370 28.9 (10.2) 26.5 (13.5–95.3)
*Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
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Figure 1 Clinical signs and symptoms on day of diagnosis and at end of treatment.
Relevant medical history was recorded in 76% of patients diagnosed with CABP, primarily structural lung disease (41%), followed by smoking, prior pneumonia, gastroesophageal reflux, and congestive heart failure (20–29%), (Table 2). At diagnosis, 86% of patients had two or more signs and symptoms of CABP including dyspnea, cough, abnormal auscultatory findings, sputum production, pleuritic chest pain, and cyanosis (Fig. 1). Each sign and symptom showed marked reduction at the end of ceftaroline fosamil treatment. Pathogens were recovered from 40% of patients. The most frequently isolated pathogen was S. aureus accounting for 22% of the overall pathogens with 16% MRSA and 6% methicillin-susceptible S. aureus (MSSA). The numbers of other isolated pathogens were small and included S. pneumoniae (4%), E. coli (2%), and K. pneumoniae (2%).
Antibiotic usage Patients received ceftaroline fosamil as either first(18%) or second-line treatment (82%), and as either monotherapy (34%) or concurrent therapy (66%). Before administration of ceftaroline fosamil, 37% of patients in the evaluable population had received other cephalosporins, as shown in Table 3. Prior antibiotics were more likely to be used in the ICU than in the general hospital wards, especially
Use of ceftaroline fosamil for treatment of CABP
glycopeptides. The frequency of concurrent antibiotic use was similar in the ICU and general hospitals wards. The most common antibiotics administered concurrently with ceftaroline fosamil included macrolides (24%) and quinolones (22%), (Table 3). Analysis of data collected since July 2012 revealed that 77% of patients received 600 mg ceftaroline fosamil, with all but one patient receiving this on a 12-hour dosing regimen. Other doses used were likely reductions in dosing due to renal impairment and included 200 mg (3%), 300 mg (8%), or 400 mg (17%), all at 12-hourly intervals. As renal function may be dynamic some patients may have had a dose adjustment during treatment. The mean duration of ceftaroline treatment was 6.1 days (SD64.3; range, 1–44.0); 33% of patients received ceftaroline fosamil for 5–7 days, and 25% for .7 days. Seven patients (2%) discontinued treatment because of adverse events.
Clinical outcome and patient disposition The overall clinical success rate of ceftaroline fosamil was 79%. Clinical success was found to be independent of age (79–81% across all age groups shown in Table 1). Clinical success rates among patients with relevant medical history were: structural lung disease (83%), history of smoking (84%), prior pneumonia (83%), gastroesophageal reflux (79%), congestive heart failure (80%), stroke (78%), and alcoholism (70%). Among those patients with a positive S. aureus culture, the clinical success rate was 68% (58/85). Clinical success among those with MRSA was 66% (42/64); those with MSSA, 74% (17/23); and those with S. pneumoniae, 88% (14/16). The clinical success rate was 78% with ceftaroline fosamil monotherapy and 80% with concurrent therapy. Patients who required a change from their previously received antibiotics had a similar rate of clinical success, compared with those patients who received ceftaroline fosamil as their first-line treatment (80 and 79% respectively).
Table 2 Relevant medical history by location of care General hospital wards (N5256) n (%) Any relevant medical history Structural lung disease Smoking Current smoker Past smoker Prior pneumonia Gastroesophageal reflux Congestive heart failure Stroke Alcoholism
190 102 70 31 39 72 61 49 21 15
(74) (40) (27) (12) (15) (28) (24) (19) (8) (6)
ICU (N5138) n (%) 107 58 43 25 18 25 30 30 10 12
All patients (N5398)* n (%)
(78) (42) (31) (18) (13) (18) (22) (22) (7) (9)
301 162 114 56 58 98 92 80 32 27
(76) (41) (29) (14) (15) (25) (23) (20) (8) (7)
* Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing. Lung cancer and chronic sinusitis recorded for ,5% of patients overall.
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Table 3 Antibiotic usage by location of care General hospital wards (N5256) n (%)
ICU (N5138) n (%)
Patients receiving other antibiotics before ceftaroline fosamil treatment (.5% of all patients) All antibiotics 205 (80) 120 (87) Other cephalosporins 96 (38) 51 (37) Quinolones 68 (27) 51 (37) Glycopeptides 61 (24) 55 (40) Macrolides 64 (25) 39 (28) Penicillins 40 (16) 35 (25) Patients receiving other antibiotics concurrently with ceftaroline fosamil (.5% of all patients) All antibiotics 168 (66) 95 (69) Macrolides 65 (25) 29 (21) Quinolones 52 (20) 36 (26) Glycopeptides 20 (8) 21 (15) Other cephalosporins 15 (6) 13 (9) Penicillins 16 (6) 8 (6)
All patients (N5398)* n (%)
328 (82) 147 (37) 121 (30) 117 (29) 104 (26) 76 (19) 264 94 89 41 28 24
(66) (24) (22) (10) (7) (6)
* Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
Overall, clinical success was 85% among patients in general hospital wards and 68% among those in the ICU. Clinical success by subgroup was higher for patients in general hospital wards (81–88%) than for ICU patients (61–72%), irrespective of ceftaroline fosamil usage as first- or second-line, and as monotherapy or concurrent therapy (Table 4). The majority of patients who were treated in general hospital wards were either discharged home (71%) or another healthcare facility (27%). The majority of patients treated in the ICU were discharged to another healthcare facility (50%) or home (39%). Eight patients died, two in the general hospital ward and six in the ICU, and discharge information was not available for 12 patients.
Discussion The treatment of CABP is complex due to a range of factors including co-morbidities, severity of infection, and the etiologic microorganism. The response to antibiotic therapy requires consideration of the presence of underlying infections, the patient’s age and immune status, and co-morbidities such as structural lung disease or congestive heart failure. More recently, the use of severity assessment scores such as the PIRO (predisposition, insult, response, and organ dysfunction) score has been proposed for the prediction of clinical outcome.16,17 These scores suggest that not
only co-morbidities, immune status, and age should be taken into account during the determination of treatment choice and regimen, but that consideration of factors such as high bacterial load, length of stay in the ICU, and days of mechanical ventilation are of value.2,16,17 Analysis of the data from this study in patients with CABP including those with underlying co-morbidities revealed a high rate of clinical success (79%) with ceftaroline fosamil treatment. A lower rate of clinical success was seen among those patients with a history of alcoholism compared with other co-morbidities, although the number of patients with alcohol abuse was low (,7%). This is not unexpected, given that the association between alcohol abuse and severe lung injury is well documented.18 Lower rates of clinical success in ICUs compared with general hospital wards are common, despite an even distribution of comorbidities,2,16,17 and a consistent finding is that patients with more severe disease have worse outcomes. Early studies of patients diagnosed with CABP treated with a range of antibiotics such as beta-lactam antibiotics, macrolides, or quinolones reported clinical success rates of 70 and 85%.19,20 However, the emergence of multiple antibiotic resistance strains has impacted the choice of antibiotic therapy employed.19,21
Table 4 Clinical success by location of care General hospital wards (N5256) n (%)
Ceftaroline fosamil usage Overall First-line therapy Second- or salvage therapy Monotherapy Concurrent therapy
218/256 43/51 175/205 71/88 147/168
(85) (84) (85) (81) (88)
ICU (N5138) n (%) 94/138 11/18 83/120 31/43 63/95
(68) (61) (69) (72) (66)
All patients (N5398)* n (%) 316/398 54/69 258/325 102/131 210/263
(79) (78) (79) (79) (80)
*Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
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Ceftaroline fosamil offers a broad spectrum of activity against the etiologic agents of CABP, e.g., PRSP, and has activity against MRSA which is reported as a causative agent of bacterial pneumonia.22,23 The rate of MRSA recovery in the CAPTURE study was considerably higher than that reported by Moran et al. (2012), (16 vs 2.4%). In our study, ceftaroline fosamil was often found in clinical use for the treatment of S. aureus in CABP, although it is not approved for MRSA in this indication. Integrated analysis of two randomized, double-blind, multicenter phase III studies for community-acquired pneumonia, FOCUS 1 and 2, demonstrates that the clinical cure rates for the ceftaroline group were numerically higher than those for a comparison group treated with ceftriaxone (84 vs 78%; difference: 6.7%; 95% confidence interval, 1.6–11.8%).14 These studies excluded patients with pneumonia due to MRSA as the comparator ceftriaxone did not provide coverage for this pathogen. In addition, ceftaroline fosamil was well tolerated with minimal adverse events being reported.14,24–26 A recent review article suggested that the treatment of CABP with dual therapy was more effective than monotherapy.27 Data analyzed in this study, however, suggest that the use of ceftaroline fosamil as monotherapy or together with other antibiotics is equally effective. The data from this study suggest that ceftaroline fosamil is also effective when used as second-line therapy due possibly to a failing regimen. The identification of causative organisms generally remains unconfirmed due to the widespread empiric use of antibiotics for the treatment of CABP.28 Additionally, it is often difficult to obtain adequate respiratory specimens and prior antibacterial therapy may adversely affect pathogen recovery. For these reasons, together with the lack of commercial testing, information on the susceptibility of bacterial isolates in this study to ceftaroline is limited. Pathogen recovery in the CAPTURE study was low and this is consistent with what is seen in clinical practice. In contrast to the types of pathogens reported in clinical practice, however, was the high rate of S. aureus (especially MRSA) isolates relative to S. pneumoniae; this is likely due to the majority of patients in this study being treated with ceftaroline fosamil as a second-line agent. Registry studies like CAPTURE have limitations, such as variable reporting of microbiology results in patient charts from various study centers without further central laboratory confirmation, the use of different types of charts and documentation by the study centers, and the lack of a randomized design that includes a comparator arm to allow for statistical inference. Such registry studies, however, have the potential to provide useful information on the contemporary use of antibiotics, including their
Use of ceftaroline fosamil for treatment of CABP
spectrum of use, duration of treatment, effectiveness, and cost.29 In the CAPTURE study, ceftaroline fosamil was often found to be used for the treatment of CABP with high clinical success rates. The data from CAPTURE support data from clinical trials and show that ceftaroline fosamil is an important antibiotic for the treatment of CABP in patients presenting with a range of co-morbidities, a highlevel of acuity, and for patients who have had prior antibiotic therapy. In summary, with a safety profile reflective of the cephalosporin class of antibiotics and in vitro activity against multidrug-resistant strains of S. pneumoniae and S. aureus including MRSA and VRSA,5 ceftaroline fosamil is an effective treatment option for CABP, and these CAPTURE data support more clinical studies in the area of CABP due to MRSA.
Disclaimer Statements Contributors All authors meet the criteria for authorship; all authors have participated in the development of this manuscript and all have approved the version submitted. Funding Forest Laboratories, Inc. Conflicts of interest A. Ramani, G. Udeani, and J. Evans are study investigators for CAPTURE, the ceftaroline fosamil study funded by Forest Labs, Inc. A. Ramani has received consultancy fees (speaker and advisory board) from Forest Labs, Inc. A. Jandourek, P. Cole, A. Smith, and H. D. Friedland are employees of Cerexa Inc., a wholly-owned subsidiary of Forest Labs, Inc. Micron Research Ltd provided writing and editorial services, funded by Forest Labs, Inc. Ethics approval This registry study was approved by each institution’s ethics committee and conducted in compliance with the International Conference on Harmonisation E6 Good Clinical Practice guidance.
References 1 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72. 2 Johnstone J, Mandell L. Guidelines and quality measures: do they improve outcomes of patients with community-acquired pneumonia? Infect Dis Clin North Am. 2013;27(1):71–86. 3 Marrie TJ. Epidemiology, pathogenesis and microbiology of community acquired pneumonia in adults. In: Bartlett JG, editor. Waltham, MA: UpToDate; 2013. http://www.uptodate. com/contents/epidemiology-pathogenesis-and-microbiology-ofcommunity-acquired-pneumonia-in-adults?source5search_ result&search5epidemiologyzpneumonia&selectedTitle51y150. 4 Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V, Limbago B, et al. Prevalence of methicillin-resistant Staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis. 2012;54(8):1126–33. 5 Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Leven M, et al. Guidelines for the management of adult lower respiratory
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7
8
9
10 11 12
13 14
15
16
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tract infections – full version. Clin Microbiol Infect. 2011;17(S6):E1–59. Ishikawa T, Matsunaga N, Tawada H, Kuroda N, Nakayama Y, Ishibashi Y, et al. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem. 2003;11(11):2427–37. Sader HS, Fritsche TR, Kaniga K, Ge Y, Jones RN. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Agents Chemother. 2005;49(8):3501– 12. Farrell DJ, Castanheira M, Mendes RE, Sader HS, Jones RN. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: a review of published studies and the AWARE Surveillance Program (2008–2010). Clin Infect Dis. 2012;55(S3):S206–14. Richter SS, Heilmann KP, Dohrn CL, Riahi F, Costello AJ, Kroeger JS, et al. Activity of ceftaroline and epidemiologic trends in Staphylococcus aureus isolates collected from 43 medical centers in the United States in 2009. Antimicrob Agents Chemother. 2011;55(9):4154–60. Tipper DJ. Mode of action of beta-lactam antibiotics. Pharmacol Ther. 1985;27(1):1–35. Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2010;65(4):713–6. Kosowski-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2010;54(5):1670–7. Forest Laboratories, Inc. Teflaro package insert. New York, NY: Forest Laboratories, Inc.; 2010. Available from: http:// www.frx.com/pi/Teflaro_pi.pdf File T. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis. 2010;51:1395–405. International Conference on Harmonisation E6 Good Clinical Practice guidance. Drug Information Branch (HFD-210), Center for Drug Evaluation and Research (CDER), 5600 Fishers Lane, Rockville, MD 20857. 1976; Available from: http://www.fda.gov/cder/guidance/index.htm Pereira JM, Moreno RP, Matos R, Rhodes A, Martin-Loeches I, Cecconi M, et al. Severity assessment tools in ICU patients
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18 19
20
21
22
23 24
25
26
27 28
29
with 2009 influenza A (H1N1) pneumonia. ESICM H1N1 Registry Steering Committee; ESICM H1N1 Registry Contributors. Clin Microbiol Infect. 2012;18(10):1040–8. Rello J, Rodriguez A, Lisboa T, Gallego M, Lujan M, Wunderink R. PIRO score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia. Crit Care Med. 2009;37:456–62. Kershaw CD, Guidot DM. Alcoholic lung disease. Alcohol Res Health. 2008;31:66–75. Aspa J, Rajas O, Rodriguez de Castro F, Huertas MC, Borderı´as L, Cabello FJ, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. Eur Respir J. 2006;27(5):1010–9. Spellberg B, Talbot GH, Brass EP, Bradley JS, Boucher HW, Gilbert DN. Recommended design features of future clinical trials of antibacterial agents for community-acquired pneumonia. Clin Infect Dis. 2008;47:S249–65. Maselli DJ, Fernandez JF, Whong CY, Echevarria K, Nambiar AM, Anzueto A, et al. Clinical evaluation of the role of ceftaroline in the management of community acquired bacterial pneumonia. Infect Drug Resist. 2012;5:43–51. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008;47(S5):S378–85. Nakou A, Woodhead M, Torres A. MRSA as a cause of community-acquired pneumonia. Eur Resp J. 2009;34(5):1013–4. Kanafani ZA, Corey GR. Ceftaroline: a cephalosporin with expanded Gram-positive activity. Future Microbiol. 2009;4(1):25– 33. File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis. 2012;55(S3):S173–80. Rank DR, Friendland HD, Laudano JB. Integrated safety summary of FOCUS 1 and FOCUS 2 trials: phase III randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother. 2011;66(S3):53–9. Caballero J, Rello J. Combination antibiotic therapy for community-acquired pneumonia. Ann Intensive Care. 2011;1:48–55. Carbonara S. Critical review of guidelines for communityacquired pneumonia in immunocompetent adults. Hot Top Respir Med. 2009;10:23–42. Thadhani R, Tonelli M. Cohort studies: marching forward. Clin J Am Soc Nephrol. 2006;1:1117–23.
Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience Ananthakrishnan Ramani1, George Udeani2, John Evans3, Alena Jandourek4, Phillip Cole4, Alexander Smith4, H. David Friedland4 1
Mountainview Medical Practice (Columbia Memorial Hospital), Catskill, NY, USA, 2Christus Spohn Hospital Corpus Christi Shoreline, TX, USA, 3Christus Spohn Hospital Alice, TX, USA, 4Cerexa Inc., Oakland, CA, USA The Clinical Assessment Program and TeflaroH Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and §2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs secondline therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.
Keywords: Community-acquired bacterial pneumonia, CABP, Ceftaroline fosamil, CAPTURE, registry
Introduction The burden of community-acquired bacterial pneumonia (CABP) is considerable in the US, accounting for 5– 10 million cases diagnosed1 and over 1.1 million patients hospitalized each year. Community-acquired bacterial pneumonia is associated with significant morbidity, mortality, and hospital costs.1,2 Commonly, typical bacterial pathogens associated with CABP include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. Less common etiologic organisms are Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Citrobacter freundii.3,4 The majority of cases of CABP occur in adults aged 65 years and older and, due to the growing elderly population, the incidence of CABP is increasing.3 In addition, the emergence of resistant strains of bacterial pathogens renders successful treatment more problematic.5,6 With an increase in multidrug-resistant (MDR) organisms, particularly S. pneumoniae and the emerging importance of S. aureus, there is a need for new treatment options. Ceftaroline, a broad-spectrum cephalosporin active in vitro against a range of Gram-positive and common Gram-negative bacteria,
Correspondence to: Alena Jandourek, Cerexa, Inc., Oakland, CA, USA. Email: [email protected]
ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947814Y.0000000184
is a viable option for treating patients with these organisms.6,7 Ceftaroline is active in vitro against resistant phenotypes commonly isolated in CABP, including penicillin-resistant S. pneumoniae (PRSP), multidrug-resistant S. pneumoniae, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant S. aureus (VRSA).7–9 Ceftaroline has the same bactericidal mode of action of other beta-lactam antibiotics, preventing bacterial cell wall biosynthesis through irreversible binding to penicillin-binding proteins (PBPs).10 A particular advantage of ceftaroline is high affinity for PBP2x in S. pneumoniae, PBP2a in MRSA, and PBPs 1 and 3 in E. coli.11,12 Ceftaroline fosamil (Teflaro), the pro-drug of ceftaroline, was approved by the US Food and Drug Administration (FDA) in October 2010 for the treatment of CABP and acute bacterial skin and skin structure infections (ABSSSIs) and is approved for similar indications in Europe.13 It is administered as an intravenous (iv) infusion and is well tolerated, with a safety profile reflective of the cephalosporin class.14 The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Study data for the treatment of CABP are presented here.
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Methods Study design
Data analysis and clinical outcome
The study period reported reviews data collected from August 2011 through February 2013. This study included eligible patients, aged 18 years or over, with clinical signs or symptoms consistent with a lower respiratory tract infection and radiologic confirmation of CABP. Patients were identified through a sequential review of charts randomly ordered from pharmacy lists at participating institutions. Eligible patients received §2 consecutive doses of ceftaroline fosamil between August 2011 and July 2012 or, following a study protocol amendment, §4 consecutive doses of ceftaroline fosamil thereafter. Charts were excluded from patients with additional or underlying infections (except for bacteremia associated with CABP). In addition, patients’ data were excluded where the information on dosing was missing or if data had already been extracted for this study. This registry study was approved by each institution’s ethics committee and conducted in compliance with the International Conference on Harmonization E6 Good Clinical Practice guidance.15
Statistical analyses were performed on the data using SASH Version 9.2. The data were summarized using descriptive statistics, including demographic data, disease and pathogen characteristics, antibiotic usage, clinical outcome, and hospital discharge. Numeric data were summarized with a mean, SD, and median values where relevant and categorical data were presented by frequency and percentage. Evaluable patients were those for whom a clinical outcome could be determined. Clinical outcome (success or failure) was determined based on the reason for discontinuation of ceftaroline fosamil treatment. Clinical success was defined as clinical cure with no further need for antibiotic or clinical improvement with switch to oral antibiotic. Clinical failure was defined as discontinuation due to an adverse event or insufficient therapeutic effect and switch to another iv antibiotic. In some cases, following a review of information where the patient was confirmed to be improving upon discontinuation of ceftaroline fosamil (with no evidence of failure), clinical outcome was deemed as successful.
Data collection For each eligible patient chart, demographic data were extracted, alongside data on relevant medical history, bacterial pathogens, location of care, and clinical signs and symptoms at the time of diagnosis and at the end of ceftaroline fosamil treatment. Data were also extracted on the use of other antibiotics before or concurrent with the administration of ceftaroline fosamil. Information on the response to treatment with ceftaroline fosamil was collected. The study protocol amendment in July 2012 allowed for additional data to be collected for subsequent patients. These included additional data on ceftaroline fosamil dosages, dosing frequencies, as well as further information associated with patient discharge including discharge destination, readmission within 30 days of discharge, and reason for readmission.
Results Patient and disease characteristics A total of 418 patients diagnosed with CABP across 33 centers comprised the enrolled population. From these, sufficient data to determine clinical outcome were available for 398 patients comprising the evaluable population, the population of focus for all subsequent summaries. Patients were equally divided between genders and had a mean (6SD) age of 63.5 years (617.8); 49% were aged §65 years. Patients received ceftaroline fosamil in either a general hospital ward (64%) or an intensive care unit (ICU; 35%). In addition, two patients received outpatient parenteral antibiotic therapy (OPAT) or home iv therapy, and data on the location of treatment of two further patients were missing (Table 1).
Table 1 Baseline demographic data for community-acquired bacterial pneumonia (CABP) patients and location of care Demographics
General ward (n5256)
Gender n (%) Male Female Age group (years), n (%) Under 40 40–65 65–80 Over 80 Age at baseline (years) Mean (SD) Median (range) BMI Number of patients Mean (SD) Median (range)
115 (45) 141 (55) 25 95 71 65
(10) (37) (28) (25)
64.7 (17.9) 66.0 (23–99) 237 28.3 (10.2) 25.9 (13.5–95.3)
ICU (n5138)
All patients (n5398)*
82 (59) 56 (41)
199 (50) 199 (50)
15 64 33 26
41 161 105 91
(11) (46) (24) (19)
61.6 (17.3) 61.0 (19–96) 129 29.9 (10.5) 27.3 (16.2–84.2)
(10) (41) (26) (23)
63.5 (17.8) 64.0 (19–99) 370 28.9 (10.2) 26.5 (13.5–95.3)
*Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
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Figure 1 Clinical signs and symptoms on day of diagnosis and at end of treatment.
Relevant medical history was recorded in 76% of patients diagnosed with CABP, primarily structural lung disease (41%), followed by smoking, prior pneumonia, gastroesophageal reflux, and congestive heart failure (20–29%), (Table 2). At diagnosis, 86% of patients had two or more signs and symptoms of CABP including dyspnea, cough, abnormal auscultatory findings, sputum production, pleuritic chest pain, and cyanosis (Fig. 1). Each sign and symptom showed marked reduction at the end of ceftaroline fosamil treatment. Pathogens were recovered from 40% of patients. The most frequently isolated pathogen was S. aureus accounting for 22% of the overall pathogens with 16% MRSA and 6% methicillin-susceptible S. aureus (MSSA). The numbers of other isolated pathogens were small and included S. pneumoniae (4%), E. coli (2%), and K. pneumoniae (2%).
Antibiotic usage Patients received ceftaroline fosamil as either first(18%) or second-line treatment (82%), and as either monotherapy (34%) or concurrent therapy (66%). Before administration of ceftaroline fosamil, 37% of patients in the evaluable population had received other cephalosporins, as shown in Table 3. Prior antibiotics were more likely to be used in the ICU than in the general hospital wards, especially
Use of ceftaroline fosamil for treatment of CABP
glycopeptides. The frequency of concurrent antibiotic use was similar in the ICU and general hospitals wards. The most common antibiotics administered concurrently with ceftaroline fosamil included macrolides (24%) and quinolones (22%), (Table 3). Analysis of data collected since July 2012 revealed that 77% of patients received 600 mg ceftaroline fosamil, with all but one patient receiving this on a 12-hour dosing regimen. Other doses used were likely reductions in dosing due to renal impairment and included 200 mg (3%), 300 mg (8%), or 400 mg (17%), all at 12-hourly intervals. As renal function may be dynamic some patients may have had a dose adjustment during treatment. The mean duration of ceftaroline treatment was 6.1 days (SD64.3; range, 1–44.0); 33% of patients received ceftaroline fosamil for 5–7 days, and 25% for .7 days. Seven patients (2%) discontinued treatment because of adverse events.
Clinical outcome and patient disposition The overall clinical success rate of ceftaroline fosamil was 79%. Clinical success was found to be independent of age (79–81% across all age groups shown in Table 1). Clinical success rates among patients with relevant medical history were: structural lung disease (83%), history of smoking (84%), prior pneumonia (83%), gastroesophageal reflux (79%), congestive heart failure (80%), stroke (78%), and alcoholism (70%). Among those patients with a positive S. aureus culture, the clinical success rate was 68% (58/85). Clinical success among those with MRSA was 66% (42/64); those with MSSA, 74% (17/23); and those with S. pneumoniae, 88% (14/16). The clinical success rate was 78% with ceftaroline fosamil monotherapy and 80% with concurrent therapy. Patients who required a change from their previously received antibiotics had a similar rate of clinical success, compared with those patients who received ceftaroline fosamil as their first-line treatment (80 and 79% respectively).
Table 2 Relevant medical history by location of care General hospital wards (N5256) n (%) Any relevant medical history Structural lung disease Smoking Current smoker Past smoker Prior pneumonia Gastroesophageal reflux Congestive heart failure Stroke Alcoholism
190 102 70 31 39 72 61 49 21 15
(74) (40) (27) (12) (15) (28) (24) (19) (8) (6)
ICU (N5138) n (%) 107 58 43 25 18 25 30 30 10 12
All patients (N5398)* n (%)
(78) (42) (31) (18) (13) (18) (22) (22) (7) (9)
301 162 114 56 58 98 92 80 32 27
(76) (41) (29) (14) (15) (25) (23) (20) (8) (7)
* Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing. Lung cancer and chronic sinusitis recorded for ,5% of patients overall.
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Use of ceftaroline fosamil for treatment of CABP
Table 3 Antibiotic usage by location of care General hospital wards (N5256) n (%)
ICU (N5138) n (%)
Patients receiving other antibiotics before ceftaroline fosamil treatment (.5% of all patients) All antibiotics 205 (80) 120 (87) Other cephalosporins 96 (38) 51 (37) Quinolones 68 (27) 51 (37) Glycopeptides 61 (24) 55 (40) Macrolides 64 (25) 39 (28) Penicillins 40 (16) 35 (25) Patients receiving other antibiotics concurrently with ceftaroline fosamil (.5% of all patients) All antibiotics 168 (66) 95 (69) Macrolides 65 (25) 29 (21) Quinolones 52 (20) 36 (26) Glycopeptides 20 (8) 21 (15) Other cephalosporins 15 (6) 13 (9) Penicillins 16 (6) 8 (6)
All patients (N5398)* n (%)
328 (82) 147 (37) 121 (30) 117 (29) 104 (26) 76 (19) 264 94 89 41 28 24
(66) (24) (22) (10) (7) (6)
* Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
Overall, clinical success was 85% among patients in general hospital wards and 68% among those in the ICU. Clinical success by subgroup was higher for patients in general hospital wards (81–88%) than for ICU patients (61–72%), irrespective of ceftaroline fosamil usage as first- or second-line, and as monotherapy or concurrent therapy (Table 4). The majority of patients who were treated in general hospital wards were either discharged home (71%) or another healthcare facility (27%). The majority of patients treated in the ICU were discharged to another healthcare facility (50%) or home (39%). Eight patients died, two in the general hospital ward and six in the ICU, and discharge information was not available for 12 patients.
Discussion The treatment of CABP is complex due to a range of factors including co-morbidities, severity of infection, and the etiologic microorganism. The response to antibiotic therapy requires consideration of the presence of underlying infections, the patient’s age and immune status, and co-morbidities such as structural lung disease or congestive heart failure. More recently, the use of severity assessment scores such as the PIRO (predisposition, insult, response, and organ dysfunction) score has been proposed for the prediction of clinical outcome.16,17 These scores suggest that not
only co-morbidities, immune status, and age should be taken into account during the determination of treatment choice and regimen, but that consideration of factors such as high bacterial load, length of stay in the ICU, and days of mechanical ventilation are of value.2,16,17 Analysis of the data from this study in patients with CABP including those with underlying co-morbidities revealed a high rate of clinical success (79%) with ceftaroline fosamil treatment. A lower rate of clinical success was seen among those patients with a history of alcoholism compared with other co-morbidities, although the number of patients with alcohol abuse was low (,7%). This is not unexpected, given that the association between alcohol abuse and severe lung injury is well documented.18 Lower rates of clinical success in ICUs compared with general hospital wards are common, despite an even distribution of comorbidities,2,16,17 and a consistent finding is that patients with more severe disease have worse outcomes. Early studies of patients diagnosed with CABP treated with a range of antibiotics such as beta-lactam antibiotics, macrolides, or quinolones reported clinical success rates of 70 and 85%.19,20 However, the emergence of multiple antibiotic resistance strains has impacted the choice of antibiotic therapy employed.19,21
Table 4 Clinical success by location of care General hospital wards (N5256) n (%)
Ceftaroline fosamil usage Overall First-line therapy Second- or salvage therapy Monotherapy Concurrent therapy
218/256 43/51 175/205 71/88 147/168
(85) (84) (85) (81) (88)
ICU (N5138) n (%) 94/138 11/18 83/120 31/43 63/95
(68) (61) (69) (72) (66)
All patients (N5398)* n (%) 316/398 54/69 258/325 102/131 210/263
(79) (78) (79) (79) (80)
*Data included from two patients who received care in an outpatient parenteral antibiotic therapy (OPAT) unit or at home, and two further patients for whom information on the location of care was missing.
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Ceftaroline fosamil offers a broad spectrum of activity against the etiologic agents of CABP, e.g., PRSP, and has activity against MRSA which is reported as a causative agent of bacterial pneumonia.22,23 The rate of MRSA recovery in the CAPTURE study was considerably higher than that reported by Moran et al. (2012), (16 vs 2.4%). In our study, ceftaroline fosamil was often found in clinical use for the treatment of S. aureus in CABP, although it is not approved for MRSA in this indication. Integrated analysis of two randomized, double-blind, multicenter phase III studies for community-acquired pneumonia, FOCUS 1 and 2, demonstrates that the clinical cure rates for the ceftaroline group were numerically higher than those for a comparison group treated with ceftriaxone (84 vs 78%; difference: 6.7%; 95% confidence interval, 1.6–11.8%).14 These studies excluded patients with pneumonia due to MRSA as the comparator ceftriaxone did not provide coverage for this pathogen. In addition, ceftaroline fosamil was well tolerated with minimal adverse events being reported.14,24–26 A recent review article suggested that the treatment of CABP with dual therapy was more effective than monotherapy.27 Data analyzed in this study, however, suggest that the use of ceftaroline fosamil as monotherapy or together with other antibiotics is equally effective. The data from this study suggest that ceftaroline fosamil is also effective when used as second-line therapy due possibly to a failing regimen. The identification of causative organisms generally remains unconfirmed due to the widespread empiric use of antibiotics for the treatment of CABP.28 Additionally, it is often difficult to obtain adequate respiratory specimens and prior antibacterial therapy may adversely affect pathogen recovery. For these reasons, together with the lack of commercial testing, information on the susceptibility of bacterial isolates in this study to ceftaroline is limited. Pathogen recovery in the CAPTURE study was low and this is consistent with what is seen in clinical practice. In contrast to the types of pathogens reported in clinical practice, however, was the high rate of S. aureus (especially MRSA) isolates relative to S. pneumoniae; this is likely due to the majority of patients in this study being treated with ceftaroline fosamil as a second-line agent. Registry studies like CAPTURE have limitations, such as variable reporting of microbiology results in patient charts from various study centers without further central laboratory confirmation, the use of different types of charts and documentation by the study centers, and the lack of a randomized design that includes a comparator arm to allow for statistical inference. Such registry studies, however, have the potential to provide useful information on the contemporary use of antibiotics, including their
Use of ceftaroline fosamil for treatment of CABP
spectrum of use, duration of treatment, effectiveness, and cost.29 In the CAPTURE study, ceftaroline fosamil was often found to be used for the treatment of CABP with high clinical success rates. The data from CAPTURE support data from clinical trials and show that ceftaroline fosamil is an important antibiotic for the treatment of CABP in patients presenting with a range of co-morbidities, a highlevel of acuity, and for patients who have had prior antibiotic therapy. In summary, with a safety profile reflective of the cephalosporin class of antibiotics and in vitro activity against multidrug-resistant strains of S. pneumoniae and S. aureus including MRSA and VRSA,5 ceftaroline fosamil is an effective treatment option for CABP, and these CAPTURE data support more clinical studies in the area of CABP due to MRSA.
Disclaimer Statements Contributors All authors meet the criteria for authorship; all authors have participated in the development of this manuscript and all have approved the version submitted. Funding Forest Laboratories, Inc. Conflicts of interest A. Ramani, G. Udeani, and J. Evans are study investigators for CAPTURE, the ceftaroline fosamil study funded by Forest Labs, Inc. A. Ramani has received consultancy fees (speaker and advisory board) from Forest Labs, Inc. A. Jandourek, P. Cole, A. Smith, and H. D. Friedland are employees of Cerexa Inc., a wholly-owned subsidiary of Forest Labs, Inc. Micron Research Ltd provided writing and editorial services, funded by Forest Labs, Inc. Ethics approval This registry study was approved by each institution’s ethics committee and conducted in compliance with the International Conference on Harmonisation E6 Good Clinical Practice guidance.
References 1 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72. 2 Johnstone J, Mandell L. Guidelines and quality measures: do they improve outcomes of patients with community-acquired pneumonia? Infect Dis Clin North Am. 2013;27(1):71–86. 3 Marrie TJ. Epidemiology, pathogenesis and microbiology of community acquired pneumonia in adults. In: Bartlett JG, editor. Waltham, MA: UpToDate; 2013. http://www.uptodate. com/contents/epidemiology-pathogenesis-and-microbiology-ofcommunity-acquired-pneumonia-in-adults?source5search_ result&search5epidemiologyzpneumonia&selectedTitle51y150. 4 Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V, Limbago B, et al. Prevalence of methicillin-resistant Staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis. 2012;54(8):1126–33. 5 Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Leven M, et al. Guidelines for the management of adult lower respiratory
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6
7
8
9
10 11 12
13 14
15
16
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tract infections – full version. Clin Microbiol Infect. 2011;17(S6):E1–59. Ishikawa T, Matsunaga N, Tawada H, Kuroda N, Nakayama Y, Ishibashi Y, et al. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem. 2003;11(11):2427–37. Sader HS, Fritsche TR, Kaniga K, Ge Y, Jones RN. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Agents Chemother. 2005;49(8):3501– 12. Farrell DJ, Castanheira M, Mendes RE, Sader HS, Jones RN. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: a review of published studies and the AWARE Surveillance Program (2008–2010). Clin Infect Dis. 2012;55(S3):S206–14. Richter SS, Heilmann KP, Dohrn CL, Riahi F, Costello AJ, Kroeger JS, et al. Activity of ceftaroline and epidemiologic trends in Staphylococcus aureus isolates collected from 43 medical centers in the United States in 2009. Antimicrob Agents Chemother. 2011;55(9):4154–60. Tipper DJ. Mode of action of beta-lactam antibiotics. Pharmacol Ther. 1985;27(1):1–35. Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2010;65(4):713–6. Kosowski-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2010;54(5):1670–7. Forest Laboratories, Inc. Teflaro package insert. New York, NY: Forest Laboratories, Inc.; 2010. Available from: http:// www.frx.com/pi/Teflaro_pi.pdf File T. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis. 2010;51:1395–405. International Conference on Harmonisation E6 Good Clinical Practice guidance. Drug Information Branch (HFD-210), Center for Drug Evaluation and Research (CDER), 5600 Fishers Lane, Rockville, MD 20857. 1976; Available from: http://www.fda.gov/cder/guidance/index.htm Pereira JM, Moreno RP, Matos R, Rhodes A, Martin-Loeches I, Cecconi M, et al. Severity assessment tools in ICU patients
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VOL .
26
NO .
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17
18 19
20
21
22
23 24
25
26
27 28
29
with 2009 influenza A (H1N1) pneumonia. ESICM H1N1 Registry Steering Committee; ESICM H1N1 Registry Contributors. Clin Microbiol Infect. 2012;18(10):1040–8. Rello J, Rodriguez A, Lisboa T, Gallego M, Lujan M, Wunderink R. PIRO score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia. Crit Care Med. 2009;37:456–62. Kershaw CD, Guidot DM. Alcoholic lung disease. Alcohol Res Health. 2008;31:66–75. Aspa J, Rajas O, Rodriguez de Castro F, Huertas MC, Borderı´as L, Cabello FJ, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. Eur Respir J. 2006;27(5):1010–9. Spellberg B, Talbot GH, Brass EP, Bradley JS, Boucher HW, Gilbert DN. Recommended design features of future clinical trials of antibacterial agents for community-acquired pneumonia. Clin Infect Dis. 2008;47:S249–65. Maselli DJ, Fernandez JF, Whong CY, Echevarria K, Nambiar AM, Anzueto A, et al. Clinical evaluation of the role of ceftaroline in the management of community acquired bacterial pneumonia. Infect Drug Resist. 2012;5:43–51. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008;47(S5):S378–85. Nakou A, Woodhead M, Torres A. MRSA as a cause of community-acquired pneumonia. Eur Resp J. 2009;34(5):1013–4. Kanafani ZA, Corey GR. Ceftaroline: a cephalosporin with expanded Gram-positive activity. Future Microbiol. 2009;4(1):25– 33. File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis. 2012;55(S3):S173–80. Rank DR, Friendland HD, Laudano JB. Integrated safety summary of FOCUS 1 and FOCUS 2 trials: phase III randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother. 2011;66(S3):53–9. Caballero J, Rello J. Combination antibiotic therapy for community-acquired pneumonia. Ann Intensive Care. 2011;1:48–55. Carbonara S. Critical review of guidelines for communityacquired pneumonia in immunocompetent adults. Hot Top Respir Med. 2009;10:23–42. Thadhani R, Tonelli M. Cohort studies: marching forward. Clin J Am Soc Nephrol. 2006;1:1117–23.
