SUPPLEMENT ARTICLE. Michael A. Pfaller, David J. Farrell, Helio S. Sader, and Ronald N. Jones. JMI Laboratories, North Liberty, Iowa

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1 SUPPLEMENT ARTICLE AWARE Ceftaroline Surveillance Program ( ): Trends in Resistance Patterns Among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States Michael A. Pfaller, David J. Farrell, Helio S. Sader, and Ronald N. Jones JMI Laboratories, North Liberty, Iowa Ceftaroline fosamil, the prodrug form of the active metabolite ceftaroline, is a new broad-spectrum parenteral cephalosporin with antibacterial activity against the prevalent respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Bacterial resistance surveillance (5330 isolates) was conducted in the United States between 2008 and 2010 to assess the in vitro activity of ceftaroline and comparator antibacterial agents against invasive respiratory isolates of S. pneumoniae (3329 isolates), H. influenzae (1545 isolates), and M. catarrhalis (456 isolates). All organisms were cultured from patient infections in 71 US hospital laboratories and were submitted to a central reference monitor for broth microdilution testing by Clinical and Laboratory Standards Institute reference methods. Against S. pneumoniae, ceftaroline inhibited 98.7% of strains at the susceptible breakpoint of 0.25 µg/ml (50% minimum inhibitory concentration [MIC 50 ], 0.01 µg/ml; 90% MIC [MIC 90 ], 0.12 µg/ml) and was 16-fold more active than ceftriaxone (MIC 90, 2 µg/ml). Among 70 ceftriaxone-resistant pneumococcal isolates, all were inhibited by 0.5 µg/ml of ceftaroline. Haemophilus influenzae (MIC 50, µg/ml; MIC 90, µg/ml) and M. catarrhalis (MIC 50, 0.06 µg/ml; MIC 90, 0.12 µg/ml) were very susceptible to ceftaroline regardless of β-lactamase production. Whereas the high-level of activity of ceftaroline was maintained against S. pneumoniae and H. influenzae from 2008 through 2010, increased rates of nonsusceptibility were observed for amoxicillin/clavulanate, erythromycin, and levofloxacin among S. pneumoniae and for trimethoprim/ sulfamethoxazole and azithromycin among H. influenzae. In summary, ceftaroline resistance surveillance (Assessing Worldwide Antimicrobial Resistance Evaluation [AWARE] Program) in the United States ( ) documented in vitro sustained potency and spectrum against Gram-positive and Gram-negative pathogens known to cause community-acquired bacterial pneumonia. Community-acquired bacterial pneumonia (CABP) continues to be a common, expensive to treat, and deadly infectious disease despite the availability of potent antibiotics and effective vaccines [1, 2]. Analysis Correspondence: Michael A. Pfaller, MD, 345 Beaver Kreek Centre, Ste A, North Liberty, IA (michael-pfaller@jmilabs.com). Clinical Infectious Diseases 2012;55(S3):S The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com. DOI: /cid/cis561 of published CABP clinical trials has shown that the most common bacterial pathogens are Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, and some species of Enterobacteriaceae [3]. Streptococcus pneumoniae is the most common pathogen implicated in CABP, and increasing multidrugresistant (MDR) S. pneumoniae (MDRSP) represents a challenge for existing antibacterial agents [4]. In a US surveillance study conducted in 2008, Jones et al [4] found that rates of resistance to erythromycin, Ceftaroline vs Respiratory Tract Pathogens CID 2012:55 (Suppl 3) S187

2 clindamycin, and co-trimoxazole were 37.1%, 20.3%, and 22.5%, respectively, among respiratory isolates of S. pneumoniae. Haemophilus influenzae was also frequently identified among patients hospitalized with CABP [5], and the prevalence of β-lactamase-producing strains was 22% among H. influenzae respiratory isolates in the United States [6]. Likewise, CABP due to S. aureus, including methicillin-resistant S. aureus (MRSA), is increasingly common and carries a high rate of mortality [7]. Initial therapy of CABP should provide broad coverage against common causative organisms, including existing and emerging resistant phenotypes. As such, the initial treatment of CABP requires prescription of empiric combination therapy or the application of an agent with sufficient broad-spectrum coverage to include MDRSP and MRSA. Ceftaroline fosamil (hereafter referred to as ceftaroline) is the prodrug form of the active metabolite ceftaroline, a new broad-spectrum cephalosporin that demonstrates in vitro activity against typical respiratory pathogens, including resistant Gram-positive pathogens such as MDRSP and MRSA and common Gram-negative pathogens such as M. catarrhalis, β-lactamase producing H. influenzae, and many enteric Gram-negative bacilli (Escherichia coli and Klebsiella pneumoniae) [1, 6, 8 11]. Ceftaroline was approved in 2010 by the US Food and Drug Administration (FDA) for the treatment of CABP [12, 13] and acute bacterial skin and skin structure infections (ABSSSIs) [14, 15]. In this article, we review the results of a 3-year ( ) US surveillance study of ceftaroline and comparators tested against a collection of 5330 clinical isolates of S. pneumoniae, H. influenzae, and M. catarrhalis cultured from patient infections (95% respiratory or bloodstream infection isolates) in 71 unique US hospitals. All testing was performed by reference broth microdilution (BMD) methods and categorical interpretations employed Clinical and Laboratory Standards Institute (CLSI) or FDA criteria [16 19]. MATERIALS AND METHODS Surveillance Network and Organisms The bacterial strains were collected from 71 medical centers representing all 9 US Census regions. Among a total of 5330 consecutively collected isolates processed between 2008 and 2010, 5080 (95%) were either respiratory tract or bloodstream infection isolates, including 3329 isolates of S. pneumoniae, 1545 of H. influenzae, and 456 of M. catarrhalis. Each cultured organism was unique (1 isolate per patient per infectious episode). All testing was performed in a central reference laboratory ( JMI Laboratories, North Liberty, Iowa) under Good Laboratory Practices and Clinical Laboratory Improvement Amendments certified conditions. Antimicrobial Susceptibility Testing All organisms were tested for antimicrobial susceptibility by the CLSI BMD method [18]. Validated BMD panels and broth reagents utilized were manufactured by Thermo Fisher Scientific (formerly TREK Diagnostics). Comparator agents included those representing the most common classes of drugs used for treatment of the indicated pathogens for CABP. Ceftaroline and the following comparison agents were tested: ceftazidime, penicillin, ampicillin, amoxicillin/clavulanate, piperacillin/tazobactam, ceftriaxone, cefuroxime, meropenem, tetracycline, tigecycline, trimethoprim/sulfamethoxazole, clindamycin, erythromycin, azithromycin, clarithromycin, levofloxacin, moxifloxacin, vancomycin, and linezolid. Quality control (QC) strains were also tested and results indicated that proper test conditions and procedures were applied [19]. These organisms included the following ATCC QC strains: E. coli ATCC 25922; Pseudomonas aeruginosa ATCC 27853; S. aureus ATCC 29213; Enterococcus faecalis ATCC 29212; H. influenzae ATCC and ATCC 49766; and S. pneumoniae ATCC Susceptibility percentages and validation of QC results were based on breakpoints and ranges obtained from CLSI publications [18 20] (Table 1). Breakpoint criteria for ceftaroline susceptibility were those indicated in the product package insert [16] for S. pneumoniae ( 0.25 µg/ml; no resistant breakpoint) and H. influenzae ( 0.12 µg/ml; no resistant breakpoint). For purposes of this study, we have categorized those strains of S. pneumoniae and H. influenzae for which ceftaroline MIC values were greater than the susceptibility breakpoint as nonsusceptible. No breakpoint has been established for M. catarrhalis. The QC limits for ceftaroline reference tests have been published by the CLSI [19, 21]. Of the QC MIC results, 99.5% were within established ranges. RESULTS Activity Against S. Pneumoniae The activity of ceftaroline and 13 comparator agents against 3329 US isolates of S. pneumoniae are shown in Table 1. Depending on the penicillin breakpoints used, this collection contained up to 21.1% penicillin-resistant strains (using CLSI criteria for penicillin [oral penicillin V]) [19]. Ceftaroline showed very potent activity (MIC 50, µg/ml; MIC 90, 0.12 µg/ml) against penicillin-resistant S. pneumoniae, with 98.7% of all S. pneumoniae isolates inhibited by <0.25 µg/ml. Accordingly, ceftaroline was 8- to >64-fold more active than all comparators with the exception of tigecycline (MIC 90, 0.06 µg/ml). Direct comparison of ceftaroline (MIC 90, 0.12 µg/ml) with ceftriaxone for all S. pneumoniae tested illustrated a 16-fold potency advantage. Among 70 ceftriaxone-resistant strains of S. pneumoniae, all were inhibited by <0.5 µg/ml of ceftaroline. S188 CID 2012:55 (Suppl 3) Pfaller et al

3 Table 1. Activity of Ceftaroline Against Isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis Isolated in the United States in MIC (µg/ml) CLSI a Species (No. Tested) Antimicrobial Agent 50% b 90% b Range %S %R/NS c Streptococcus pneumoniae (3329) Ceftaroline d Ceftriaxone Cefuroxime > Amoxicillin/clavulanate > Penicillin e > Penicillin f > Meropenem Erythromycin 0.25 > > Clindamycin 0.25 > > Levofloxacin > Linezolid >99.9 <0.1 Tetracycline 2 >8 2 > Tigecycline g Trimethoprim/sulfamethoxazole 0.5 >2 0.5 > Vancomycin Haemophilus influenzae All (1545) Ceftaroline d Ceftriaxone Cefuroxime > Ampicillin 1 >8 1 > Amoxicillin/clavulanate Meropenem Azithromycin > Clarithromycin > Levofloxacin Tetracycline > Trimethoprim/sulfamethoxazole 0.5 >2 0.5 > β-lactamase positive (414) Ceftaroline d Ceftriaxone Cefuroxime Ampicillin >8 >8 1 > Amoxicillin/clavulanate Meropenem Azithromycin > Clarithromycin > Levofloxacin Tetracycline > Trimethoprim/sulfamethoxazole 0.5 >2 0.5 > β-lactamase negative (1131) Ceftaroline d Ceftriaxone Cefuroxime > Ampicillin Amoxicillin/clavulanate Meropenem Azithromycin > Clarithromycin > Levofloxacin Tetracycline > Trimethoprim/sulfamethoxazole 0.5 >2 0.5 > Ceftaroline vs Respiratory Tract Pathogens CID 2012:55 (Suppl 3) S189

4 Table 1 continued. MIC (µg/ml) CLSI a Species (No. Tested) Antimicrobial Agent 50% b 90% b Range %S %R/NS c Moraxella catarrhalis (443) Ceftaroline d Ceftriaxone Cefuroxime > Amoxicillin/clavulanate Penicillin >4 > > h Erythromycin > Levofloxacin Tetracycline Trimethoprim/sulfamethoxazole > Abbreviations: CLSI, Clinical and Laboratory Standards Institute; MIC, minimum inhibitory concentration; NS, nonsusceptible (used when susceptibility category was the only category assigned by CLSI); R, resistant; S, susceptible. a Criteria as published by CLSI, 2012 [19]. b Minimum inhibitory concentration encompassing 50% and 90% of isolates tested, respectively. c Percent of isolates for which the MIC is greater than the susceptibility breakpoint are categorized as NS. d Food and Drug Administration breakpoints were applied when available [16]. Streptrococcus pneumoniae, susceptibility 0.25 µg/ml, no R or I (intermediate) category; H. influenzae, susceptibility 0.12 µg/ml, no R or I category. e Criteria as published by the CLSI for penicillin parenteral (non-meningitis) [19]. f Criteria as published by the CLSI for penicillin (oral penicillin V) [19]. g Food and Drug Administration breakpoints were applied when available [17]. h Based on β-lactamase production. Similar to ceftriaxone, all of the β-lactams as well as tetracycline, trimethoprim/sulfamethoxazole, clindamycin, and erythromycin had compromised coverage of these contemporary US isolates of S. pneumoniae (Table 1). Amoxicillin/clavulanate (83.0%) and penicillin (85.2%) exhibited low susceptibility rates. Only the fluoroquinolones (levofloxacin [99.2% susceptibility], vancomycin [100.0% susceptibility], and linezolid [>99.9% susceptibility]) showed comparably high in vitro activity at currently applied breakpoints (Table 1). Activity Against H. Influenzae and M. Catarrhalis Ceftaroline demonstrated potent activity against 1545 isolates of H. influenzae (MIC 50, µg/ml; MIC 90, µg/ml) regardless of the β-lactamase capability of the tested strains (Table 1). All but 2 strains of H. influenzae were inhibited by 0.12 µg/ml of ceftaroline. This degree of activity and coverage (99.9% susceptibility) was comparable to that of amoxicillin/clavulanate (99.9% susceptibility), ceftriaxone (100.0% susceptibility), cefuroxime (99.2% susceptibility), meropenem (100.0% susceptibility), tetracycline (98.7% susceptibility), azithromycin (98.7% susceptibility), and levofloxacin (100.0% susceptibility) (see Table 1). When tested against M. catarrhalis (443 isolates), ceftaroline demonstrated a potency that was comparable to that observed against S. pneumoniae (MIC 90, 0.12 µg/ml) (Table 1). All isolates except 1 (MIC, 1 µg/ml) were inhibited at a ceftaroline concentration of 0.25 µg/ml. Other tested antimicrobial agents had comparable activity at utilized breakpoints [19, 20] with complete or nearly complete ( 94.4% susceptibility) coverage for amoxicillin/clavulanate, ceftriaxone, cefuroxime, tetracycline, trimethoprim/sulfamethoxazole, erythromycin, and levofloxacin (Table 1). β-lactamase production was detected in M. catarrhalis isolates at a rate of 96.4%. Three-Year ( ) Trends in Decreased Susceptibility or Resistance Among US Isolates of S. Pneumoniae and H. Influenzae The frequency of nonsusceptibility for ceftaroline against both S. pneumoniae and H. influenzae was extremely low (1.2% 1.5% and 0.0% 0.3%, respectively) and did not change significantly over the 3-year monitored interval (Table 2). Similarly, the rates of resistance for most of the comparators remained stable for both organisms, with the exception of slight increases in resistance for erythromycin (38.4% to 41.7%) and levofloxacin (0.6% to 1.09%) for S. pneumoniae and trimethoprim/ sulfamethoxazole (19.4% to 24.4%) and azithromycin (0.8% to 1.4%) for H. influenzae (Table 2). DISCUSSION Ceftaroline fosamil represents a new class of cephalosporin with anti-mrsa activity [10, 22] largely due to its truly S190 CID 2012:55 (Suppl 3) Pfaller et al

5 Table 2. Trends in Nonsusceptibility to Ceftaroline and Comparators Among US Isolates of Streptococcus pneumoniae and Haemophilus influenzae, % NS by Year (No. Tested) a Species Antimicrobial Agent unique expanded Gram-positive activity against MRSA and MDRSP. Numerous published studies confirm a consensus MIC 90 value of µg/ml against S. pneumoniae, withthe highest MIC result rarely exceeding 0.5 µg/ml [1, 6, 8, 23 29]. These results were obtained from pneumococci collected from throughout the world, including the United States. The data presented herein provide further documentation of the excellent activity of ceftaroline when tested against significant collections of contemporary US pneumococcal isolates. Other compounds that exhibited excellent activity against pneumococci in the present study included levofloxacin (99.2% susceptible), linezolid (>99.9% susceptible), and vancomycin (100.0% susceptible). Many of the published reports have emphasized the potent activity of ceftaroline against penicillin-resistant, cefotaximeresistant, and MDR isolates of S. pneumoniae, including emerging serotype 19A strains [23, 24, 27, 30, 31]. Other pathogens associated with CABP, including H. influenzae and M. catarrhalis, are also inhibited by ceftaroline at concentrations <0.5 µg/ml (Table 1). Notably, ceftaroline exhibits high activity against respiratory isolates of S. aureus (97.0% of strains inhibited by 1 µg/ml) and non extended-spectrum Streptococcus pneumoniae Ceftaroline b 1.2 (894) 1.5 (1235) 1.2 (1200) Ceftriaxone 9.2 (894) 12.8 (1235) 10.2 (1200) Amoxicillin/clavulanate 16.7 (894) 17.5 (1235) 16.9 (1200) Penicillin c 13.5 (894) 16.0 (1235) 14.6 (1200) Penicillin d 41.7 (894) 40.7 (1235) 43.5 (1200) Erythromycin 38.4 (894) 38.9 (1235) 41.7 (1200) Levofloxacin 0.6 (894) 0.7 (1235) 1.0 (1200) Trimethoprim/sulfamethoxazole 33.7 (894) 34.4 (1235) 33.3 (1200) Haemophilus influenzae Ceftaroline b 0.0 (381) 0.0 (394) 0.3 (770) Ceftriaxone b 0.0 (381) 0.0 (394) 0.0 (770) Amoxicillin/clavulanate 0.3 (381) 0.3 (394) 0.0 (770) Ampicillin 27.3 (381) 23.1 (394) 27.4 (770) Azithromycin b 0.8 (381) 1.5 (394) 1.4 (770) Clarithromycin 23.1 (381) 35.6 (394) 21.3 (770) Levofloxacin b 0.0 (381) 0.0 (394) 0.0 (770) Trimethoprim/sulfamethoxazole 19.4 (381) 24.4 (394) 23.8 (770) Abbreviation: NS, nonsusceptibility. a Criteria as published by the Clinical and Laboratory Standards Institute (CLSI). b No criteria for resistant or intermediate has been assigned by CLSI Percentage of isolates for which the minimum inhibitory concentration is greater than the susceptibility breakpoint are categorized as NS. For ceftaroline, the Food and Drug Administration breakpoints were applied [16]. c Criteria as published by the CLSI for penicillin parenteral (non-meningitis) [19]. d Criteria as published by the CLSI for penicillin (oral penicillin V) [19]. β-lactamase phenotypes of E. coli and K. pneumoniae (>90.0% of strains inhibited by 0.5 µg/ml) [6]. Ceftaroline has some activity against anaerobic bacteria, although it has little or no activity against Clostridium difficile, Bacteroides fragilis, or Prevotella spp. [32]. Although it is generally well tolerated, minor adverse events have included rash, nausea, vomiting, diarrhea, headache, and tendon pain [32]. The favorable features of ceftaroline include avid binding to penicillin-binding protein 2a and 2 ( penicillin-binding proteins) of MRSA and MDRSP, respectively [1, 8], minimal disruption of normal bowel flora [32], lack of antagonism with other agents used in combination [33], and an in vitro postantibiotic effect against Gram-positive pathogens of 1 2 hours duration [34]. These features, coupled with documented efficacy of ceftaroline fosamil in the treatment of serious CABP [2, 13], make this agent particularly attractive in the initial management of CABP patients requiring hospitalization and infected with potentially refractory pathogens such as MDRSP [35]. Presently, many of these types of serious CABP infections have required combination empiric or directed therapies [36, 37], whereas ceftaroline fosamil may be applied as a single Ceftaroline vs Respiratory Tract Pathogens CID 2012:55 (Suppl 3) S191

6 treatment entity. Clinical application of ceftaroline fosamil in the United States for the treatment of CABP will provide an important therapeutic option based on these most recent ( ) surveillance study results (Tables 1 and 2). The continued evolution of respiratory pathogens with reduced susceptibility to established antimicrobial agents makes an agent such as ceftaroline fosamil a particularly welcome addition to our antimicrobial armamentarium. Notes Acknowledgments. We wish to express our appreciation to S. Benning and P. Clark in the preparation of this manuscript and to the following JMI staff members for scientific assistance in performing this study: M. Castanheira, R. Flamm, and G. Moet. This study was supported by Cerexa, Inc, a wholly owned subsidiary of Forest Laboratories, Inc. Cerexa, Inc was involved in the study design and decision to present these results. Cerexa, Inc was not involved in the collection, analysis, or interpretation of data. Scientific Therapeutics Information, Inc provided editorial coordination, which was funded by Forest Research Institute, Inc. Financial support. This study was funded by educational/research grants from Cerexa, Inc. (Oakland, CA), a wholly owned subsidiary of Forest Laboratories, Inc (New York, NY). Supplement sponsorship. This article was published as part of a supplement entitled Ceftaroline Applications for Therapy in the United States, sponsored by Forest Laboratories, Inc (New York, NY). Potential conflicts of interest. All authors: JMI Laboratories, Inc. has received research and educational grants in from Achaogen, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, biomerieux, Cempra, Cerexa, Contrafect, Cubist, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), LegoChem Biosciences Inc, Meiji Seika Kaisha, Merck, Nabriva, Novartis, Paratek, Pfizer (Wyeth), PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co, Theravance, ThermoFisher, TREK Diagnostics, and some other corporations. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Critchley IA, Eckburg PB, Jandourek A, Biek D, Friedland HD, Thye DA. Review of ceftaroline fosamil microbiology: integrated FOCUS studies. J Antimicrob Chemother 2011; 66:iii File TM Jr, Marrie TJ. 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