Antimicrobial Reviews
Ceftaroline Activity Tested Against Bacterial Isolates From Pediatric Patients Results from the Assessing Worldwide Antimicrobial Resistance and Evaluation Program for the United States (2011–2012) Helio S. Sader, MD, PhD, Rodrigo E. Mendes, PhD, David J. Farrell, PhD, Robert K. Flamm, PhD, and Ronald N. Jones, MD
Background: Ceftaroline, the active form of ceftaroline fosamil, is a cephalosporin with broad-spectrum bactericidal activity against resistant Grampositive organisms, including methicillin-resistant Staphylococcus aureus, ceftriaxone-resistant Streptococcus pneumoniae and many Enterobacteriaceae species. Ceftaroline fosamil is approved in the United States for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in adults. Methods: A total of 5291 consecutive unique pediatric patient strains of clinical significance were collected from 157 US medical centers. The isolates were identified locally and forwarded to a central monitoring laboratory for reference antimicrobial susceptibility testing. S. pneumoniae isolates from the 2011 to 2012 respiratory season were serotyped. Susceptibility results were analyzed according to patient age as follows: ≤1 years old (yo; 1857 strains); 2–5 (1342); 6–12 (1281) and 13–17 (811). Results: Methicillin-resistant Staphylococcus aureus rates were slightly lower in isolates from patients 13–17 yo (39.9%) compared with other age groups (48.2–51.5%), and ceftaroline was consistently active against S. aureus isolates from all 4 age groups [minimal inhibitory concentration (MIC50/90): 0.25–05/1 μg/mL; 99.8–100.0% susceptible]. Overall, 99.8% of methicillin-resistant Staphylococcus aureus were ceftaroline susceptible (MIC50/90: 0.5/1 μg/mL). All S. pneumoniae strains (1178) were ceftaroline susceptible (MIC50/90: ≤0.015/0.12 μg/mL), whereas ceftriaxone susceptibility varied from only 84.8 (≤1 yo) to 89.7% (13–17 yo). 19A was the most frequent serotype identified among S. pneumoniae and these isolates exhibited low susceptibility to ceftriaxone (42.4%) and most other antimicrobials tested. The highest ceftaroline MIC among Haemophilus influenzae (587 strains) was 0.12 μg/mL (100.0% susceptible), and β-lactamase production rates varied from 24.2 (13–17 yo) to 30.1% (6–12 yo); 27.9% overall. Ceftaroline was also active against β-hemolytic streptococci (556 strains, highest MIC, 0.06 μg/mL). Extended-spectrum β-lactamase (ESBL)-phenotype rates among Escherichia coli/Klebsiella spp. were 6.0/5.1, 11.0/11.5, 5.1/8.3 and 11.4/14.7% for the ≤1, 2–5, 6–12 and 13–17 yo age groups, respectively. Ceftaroline exhibited good activity against non-ESBL phenotype strains of E. coli and Klebsiella spp. (MIC90: 0.25 μg/mL for both organisms), but had limited activity against ESBL-producing strains. Accepted for publication January 26, 2014. From the JMI Laboratories, North Liberty, IA This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design of the study, but had no involvement in the collection, analysis, and interpretation of data, Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Helio S. Sader, MD, PhD, JMI Laboratories, 345 Beaver Kreek Ctr, Ste A, North Liberty, IA 52317. E-mail: helio-sader@ jmilabs.com. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3308-0837 DOI: 10.1097/INF.0000000000000307
Conclusion: Ceftaroline demonstrated potent in vitro activity when tested against S. aureus, S. pneumoniae, H. influenzae, β-hemolytic streptococci and non-ESBL-phenotype E. coli and Klebsiella spp. strains isolated from pediatric patients, independent of patient age. Key Words: Ceftaroline, AWARE, MRSA, Streptococcus pneumoniae (Pediatr Infect Dis J 2014;33:837–842)
A
ntimicrobial resistance has been the subject of increasing concern to pediatricians, and it remains a major focus of clinical and microbiology research for pediatric infectious diseases specialists.1,2 The major challenges to pediatricians are antimicrobial resistance among organisms causing community-acquired respiratory tract infections and among infections acquired in the healthcare setting. Moreover, the emergence and dissemination of community-associated (CA), methicillin-resistant Staphylococcus aureus (MRSA) represent another important challenge for those physicians treating children.3,4 Although much has been reported about antimicrobial susceptibility in the pediatric population, considerably less is understood regarding resistance profile patterns by pediatric patient age groupings. Ceftaroline, the active metabolite of ceftaroline fosamil, is a parenteral cephalosporin with potent activity against Gram-positive organisms, including MRSA and multidrug-resistant (MDR) Streptococcus pneumoniae, and common Gram-negative bacilli, but not those producing extended-spectrum β-lactamases (ESBLs).5–7 Ceftaroline fosamil is approved by the US Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSI) in adults, including ABSSSI caused by MRSA.8 It is also approved by the European Medicines Agency for similar indications.9 As part of the Assessing Worldwide Antimicrobial Resistance Evaluation Program, a global ceftaroline surveillance study, we evaluated the activity of ceftaroline tested against contemporary pathogens causing infections in pediatric patients at US hospitals (2011–2012).
MATERIALS AND METHODS Organism Collection Nearly 5300 consecutive unique pediatric patient isolates of clinical significance (Table, Supplemental Digital Content 1, http:// links.lww.com/INF/B844) were collected from 157 US medical centers as part of the Assessing Worldwide Antimicrobial Resistance Evaluation Program.10 The participant centers were distributed across all 9 US Census Regions, with 7–31 medical centers per region. These organisms were collected from January 2011 to December 2012. Susceptibility results were analyzed according to patient age as follows: ≤1 years old (yo; 1857 strains); 2–5 yo
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(1342); 6–12 yo (1281) and 13–17 yo (811). Species identification was performed at the participant center and confirmed by the monitoring laboratory (JMI Laboratories, North Liberty, IA), when necessary using Matrix-assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry from the Bruker Daltonics MALDI Biotyper (Billerica, MA), following manufacturer instructions.
Susceptibility Testing Methods Broth microdilution tests conducted according to the Clinical and Laboratory Standards Institute (CLSI) methods were performed to determine antimicrobial susceptibility of ceftaroline and selected comparator antimicrobials.11 Validated MIC panels were manufactured by ThermoFisher Scientific (Cleveland, OH). S. aureus and Enterobacteriaceae strains were tested in c ation-adjusted MuellerHinton broth (CA-MHB), fastidious streptococci were tested in CA-MHB supplemented with 2.5–5% lysed horse blood and Haemophilus spp. strains were tested in Haemophilus Test Medium according to CLSI document recommendations.11 E. coli and Klebsiella spp. isolates were grouped as “ESBL-phenotype” and “non-ESBL-phenotype” based on the CLSI screening criteria for ESBL production.12 Those isolates with positive ESBL screening test (ie, MIC of >1 μg/mL for ceftazidime and/or ceftriaxone and/or aztreonam) were categorized as “ESBL-phenotype” for the purpose of susceptibility testing result analysis. Although other β-lactamases, such as AmpC and Klebsiella pneumoniae carbapenemases, may also produce an “ESBL-phenotype”, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum β-lactam compounds and other drug classes. Concurrent quality control testing was performed to assure proper test conditions and procedures.11 Susceptibility percentages and validation of quality control results were based on CLSI guidelines and susceptibility breakpoints (M100-S23).12
Serotyping Determination All S. pneumoniae isolates collected from July 2011 to June 2012 (2011–2012 respiratory season) from lower respiratory tract or blood were serotyped. Isolates were subjected to polymerase chain reaction assays for amplification of the cpsB gene as previously described by Leung et al.13 Amplicons were sequenced on both strands and the nucleotide sequences were analyzed using the Lasergene software package (DNASTAR, Madison, WI). Sequences were compared with others available via Pubmed (http://www.ncbi. nlm.nih.gov/blast/). Because of sequence homology among certain serotypes, those showing nucleotide sequence similarity >99% were grouped (eg, 9V/9A, 7F/7A, 11A/11D, 15A/15F, 22F/22A, 15B/15C). All isolates determined to be serogroup 6 by polymerase chain reaction and sequencing analysis were subjected to multiplex polymerase chain reaction assays for confirmation and discrimination purposes (between 6A/6B and 6C/6D).14 Those determined to be serogroups 6A/6B, 6C/6D, 7C/7B/40, 7F/7A, 9N/9L and 9V/9A were selected for further capsular swelling methods to determine serotype within these serogroups. Capsular swelling methods were performed according to manufacturer’s instructions (Miravista; Indianapolis, IN).
RESULTS Bacterial isolates collection included S. aureus (2117 strains, 47.4% MRSA), S. pneumoniae [1178; 15.7% penicillin-non-susceptible (MIC, ≥4 μg/mL)], Haemophilus influenzae (587), β-hemolytic streptococci (556), Escherichia coli (464; 7.8% ESBL-phenotype) and Klebsiella spp. (389; 7.2% ESBL-phenotype). The isolates were from skin and soft tis sue infections (37.0%), community-acquired respiratory tract
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infections (23.1%), pneumonia in hospitalized patients (17.2%), bloodstream infections (10.0%), urinary tract infection (5.0%) and other sites (7.6%). Ceftaroline was consistently active against S. aureus isolates from all 4 monitored age groups [minimal inhibitory concentration (MIC50/90): 0.25–05/1 μg/mL; 99.8–100.0% susceptibility]. Overall, 99.8% of MRSA were susceptible to ceftaroline (MIC50/90: 0.5/1 μg/mL; Tables, Supplemental Digital Content 1 and 2, http:// links.lww.com/INF/B844 and http://links.lww.com/INF/B845). MRSA rates were slightly lower among isolates from patients 13–17 yo (39.9%) compared with other age groups (48.2–51.5%). Also, susceptibility to levofloxacin was lower in S. aureus isolates from patients 2–5 yo (67.6%) compared with other age groups (74.0–76.7%). Susceptibility rates to erythromycin, clindamycin, tetracycline and trimethoprim/sulfamethoxazole for S. aureus did not vary significantly across tabulated age groups (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). When tested against methicillin-susceptible S. aureus, ceftaroline (MIC50 and MIC90: 0.25 μg/mL) was 16-fold more active than ceftriaxone (MIC50 and MIC90: 4 μg/mL; data not shown). All S. pneumoniae strains (1178) were ceftaroline susceptible (MIC50/90: ≤0.015/0.12 μg/mL; Table, Supplemental Digital Content 1, http://links.lww.com/INF/B844), whereas ceftriaxone susceptibility varied from only 84.8 (≤1 yo) to 89.7% (13–17 yo; Table, Supplemental Digital Content 3, http://links.lww.com/INF/ B846). In general, susceptibility rates for all comparator agents were slightly lower among S. pneumoniae isolates from the youngest patients (≤1 yo; Table, Supplemental Digital Content 3, http:// links.lww.com/INF/B846). Ceftaroline was highly active against penicillin-non-susceptible S. pneumoniae (MIC, ≥4 μg/mL; 185 strains) with MIC50 and MIC90 values of 0.25 μg/mL (100.0% susceptibility; Table, Supplemental Digital Content 1, http://links. lww.com/INF/B844), whereas ceftriaxone (MIC50 and MIC90: 2 μg/mL; 20.5% susceptibility), amoxicillin/clavulanate (3.2%), erythromycin (0.5%), clindamycin (6.5%), tetracycline (8.1%) and trimethoprim/sulfamethoxazole (2.2%) displayed very limited activity and low susceptibility rates against these organisms (data not shown). Ceftaroline was 8-fold more active than ceftriaxone (MIC90: 2 μg/mL) when tested against penicillin-susceptible (MIC50/90: ≤0.015/0.12 and ≤0.06/1 μg/mL, respectively) and penicillin-non-susceptible S. pneumoniae strains (MIC50/90: 0.25/0.25 and 2/2 μg/mL, respectively; data not shown). The serogroups/types detected among S. pneumoniae isolates in each age group are displayed in Figure 1. Twenty-nine serogroups/types were observed among 179 isolates tested, with frequencies varying from 18.4% (19A, 33 occurrences) to 0.6% (6B, 9L, 16F, 23F, 24A/B/F, 34, 38/25A/25F and nontypeable, with 1 occurrence each). The PCV7-associated serotypes accounted for 5.0% of the isolates, and only serotypes 19F (3.9%), 6B (0.6%) and 23F (0.6%) were detected. Serotype 19A was the most prevalent type observed overall, as well as among age groups ≤1, 2–5 and 6–12 yo. Other PCV13-associated serotypes observed in this study were serotypes 3 (6.1%) and 7F (1.1%). The most common non-PCV13-associate serogroups/types were 35B [8.9% overall and the most common among age group 13–17 yo (20.0%)], 15B/C (6.7%) and 23A (6.1%). Antimicrobial susceptibility varied markedly among serotypes, with the least ceftriaxone-susceptible serotypes being 19A (MIC50/90: 2/2 μg/mL; 42.4% susceptible), 6C (MIC50: 0.5 μg/mL; 88.9% susceptible) and 35B (MIC50/90: 1/1 μg/mL; 100.0% susceptible; Table, Supplemental Digital Content 4, http://links.lww.com/ INF/B847). Serotype 19A isolates also showed low susceptibility to penicillin (MIC50/90: 4/8 μg/mL; 24.2% susceptible), erythromycin (MIC50/90: >16/>16 μg/mL; 21.2% susceptible), clindamycin © 2014 Lippincott Williams & Wilkins
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(MIC50/90: >2/>2 μg/mL; 27.3% susceptible) and trimethoprim/ sulfamethoxazole (MIC50/90: >4/>4 μg/mL; 15.2% susceptible; data not shown), but were very susceptible to ceftaroline (MIC50/90: 0.12/0.25 μg/mL; 100.0% susceptible; Table, Supplemental Digital Content 4, http://links.lww.com/INF/B847). The highest ceftaroline MIC observed among H. influenzae (587 strains) was 0.12 μg/mL (100.0% susceptibility), and β-lactamase production rates varied from 24.2 (13–17 yo) to 30.1%
Ceftaroline
(6–12 yo); 27.9% overall (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). All isolates were also susceptible to ceftriaxone and levofloxacin, whereas susceptibility to clarithromycin varied more widely from 76.4% (6 – 12 yo) to 90.3% (13–17 yo; Table, Supplemental Digital Content 3, http://links.lww.com/ INF/B846). Ceftaroline was also active against β-hemolytic streptococci (556 strains; highest MIC at 0.06 μg/mL). All β-hemolytic streptococcal strains were susceptible to ceftaroline, ceftriaxone
FIGURE 1. Distribution of serogroups/types among S. pneumoniae strains isolated from lower respiratory tract and bacteremia during the 2011–2012 respiratory season for patients ≤1 (1A), 2–5 (1B), 6–12 (1C) and 13–17 (1D) yo. © 2014 Lippincott Williams & Wilkins
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FIGURE 1. (Continued) and penicillin, but susceptibility to clindamycin ranged from 79.1% (2 – 5 yo) to 94.4% (6 – 12 yo), and susceptibility to erythromycin varied from 54.1 (2–5 yo) to 85.8% (5–12 yo; Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). ESBL-phenotype rates were 5.1 (6–12 yo) to 11.4% (13–17 yo) among E. coli, and ranged from 5.1 (≤1 yo) to 14.7% (13–17 yo) for Klebsiella spp. (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). Ceftaroline exhibited very good activity against non-ESBL-phenotype strains of E. coli
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and Klebsiella spp. (MIC90: 0.25 μg/mL for both organisms), but very limited coverage of ESBL-producing strains (Tables, Supplemental Digital Content 1 and 2, http://links.lww.com/INF/ B844 and http://links.lww.com/INF/B845).
DISCUSSION Pediatricians are facing increasing antimicrobial resistance among common pathogens responsible for healthcare-associated as © 2014 Lippincott Williams & Wilkins
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well as community-associated ABSSSI and community-acquired respiratory tract infections in children, particularly for S. aureus and S. pneumoniae.1,3,4 As S. aureus represents a major cause of ABSSSI and bloodstream infections, it also is an important cause of pneumonia in children.15,16 Before the late 1990s, MRSA infections were confined largely to patients who had known exposures to the healthcare setting, but the emergence and rapid dissemination of CA-MRSA drastically changed the epidemiology of S. aureus infection in the United States.3,17,18 CA-MRSA in the United States was first identified in children in the upper Midwest region.19 Since that time, many areas in the United States have experienced substantial increases in the colonization and the incidence of MRSA infection among healthy children.16 Moreover, the initial CA-MRSA strains were generally susceptible to numerous antimicrobial agents compared with traditional hospital-acquired MRSA strains, but variants of USA300 CA-MRSA having MDR patterns have become more common.20,21 Although a large number of studies have investigated the antimicrobial susceptibility of S. aureus, very little is understood about resistance profiles indexed by patient age group.22 The results of the present study illustrated some variations in the S. aureus susceptibility patterns according to age group, but consistent activity of ceftaroline when tested against S. aureus isolates from all 4 age groups. In addition to potent activity against MRSA (MIC50/90: 05/1 μg/mL; 99.5–100.0% susceptibility), ceftaroline was 16-fold more active than ceftriaxone when tested against methicillin-susceptible S. aureus.6,10 S. pneumoniae accounts for more than half of community-acquired bacterial pneumonia and approximately one-third of acute bacterial rhinosinusitis in children.1 H. influenzae is the second most frequent bacterial cause of respiratory tract infection in children. This latter organism is responsible for 20–30% of bacterial rhinosinusitis and one- to two-thirds of otitis media and childhood pneumonia.1 Community-acquired bacterial pneumonia in children has traditionally been treated with ceftriaxone or an oral second- or third-generation cephalosporin15; however, resistance to those agents has escalated in recent years among S. pneumoniae.23–26 The results presented here are in agreement with those published earlier by showing very potent ceftaroline activity against S. pneumoniae and H. influenzae.6 Although susceptibility rates for comparator agents, including ceftriaxone, were lower among S. pneumoniae isolates from patients ≤1 yo compared with the other age groups; ceftaroline displayed remarkable activity (MIC50/90: ≤0.015/0.12 μg/mL) and complete coverage (100.0% susceptibility) against S. pneumoniae isolated from all pediatric age groups. Furthermore, ceftaroline was highly active against S. pneumoniae isolates serotype 19A, which was the predominant and most drug-resistant serotype (only 42.4% susceptible to ceftriaxone) identified during the 2011–2012 respiratory season in the present study. ESBL rates for E. coli and Klebsiella spp. varied by age group, being generally lower in the ≤1 and 6–12 yo groups and higher in the 2–5 and 13–17 yo groups, and similar variation was observed in the in vitro activity of the cephalosporins (ceftaroline, ceftriaxone and ceftazidime) and piperacillin/tazobactam, that is, higher susceptibility rates in the ≤1 yo and 6–12 yo groups. These findings reflect the limited activity of these β-lactam compounds when tested against ESBL screen-positive Enterobacteriaceae.12,27,28 In summary, ceftaroline demonstrated potent activity when tested against contemporary S. aureus, S. pneumoniae, H. influenzae, β-hemolytic streptococci and non-ESBL-phenotype E. coli and Klebsiella spp. strains isolated from pediatric patients, a level of potency equal or significantly superior to currently available β-lactams. These in vitro data support the further clinical development of ceftaroline © 2014 Lippincott Williams & Wilkins
Ceftaroline
for treatment of infection in children, especially those infections caused by MRSA and MDR S. pneumoniae.
ACKNOWLEDGMENTS The authors would like to thank Dr. Michael R. Jacobs for performing the capsular swelling serotyping. This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design of the study, but had no involvement in the collection, analysis, and interpretation of data, Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc. JMI Laboratories, Inc. has received research and educational grants in 2012-2014 from – Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, ThermoFisher, Venatorx, Vertex, Waterloo and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regards to speakers bureaus and stock options-none to declare. REFERENCES 1. Jacobs MR, Dagan R. Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges. Semin Pediatr Infect Dis. 2004;15:5–20. 2. Versporten A, Sharland M, Bielicki J, et al.; ARPEC Project Group Members. The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J. 2013;32:e242–e253. 3. Long CB, Madan RP, Herold BC. Diagnosis and management of community-associated MRSA infections in children. Expert Rev Anti Infect Ther. 2010;8:183–195. 4. Kaplan SL. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Semin Pediatr Infect Dis. 2006;17:113–119. 5. Critchley IA, Eckburg PB, Jandourek A, et al. Review of ceftaroline fosamil microbiology: integrated FOCUS studies. J Antimicrob Chemother. 2011;66 Suppl 3:iii45–iii51. 6. Frampton JE. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Drugs. 2013;73:1067–1094. 7. Lodise TP, Low DE. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs. 2012;72:1473–1493. 8. Teflaro® Package Insert. Teflaro® Package Insert. 2012. Available at: http:// www.accessdata.fda.gov/drugsatfda_docs/label/2013/200327s009lbl.pdf. Accessed August 2013. 9. ZinforoTM Package Insert. ZinforoTM Package Insert. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ Information/human/002252/WC500132586.pdf. Accessed January 2013. 10. Farrell DJ, Castanheira M, Mendes RE, et al. 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 (Suppl 3):S206-S214. 11. CLSI. M07-A9. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard. Ninth edition. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. 12. CLSI. M100-S23. Performance Standards for Antimicrobial Susceptibility Testing: 23rd Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2013. 13. Leung MH, Bryson K, Freystatter K, et al. Sequetyping: serotyping Streptococcus pneumoniae by a single PCR sequencing strategy. J Clin Microbiol. 2012;50:2419–2427. 14. Pai R, Gertz RE, Beall B. Sequential multiplex PCR approach for determining capsular serotypes of Streptococcus pneumoniae isolates. J Clin Microbiol. 2006;44:124–131.
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15. Bradley JS, Byington CL, Shah SS, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53:617–630. 16. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–687. 17. Hinckley J, Allen PJ. Community-associated MRSA in the pediatric primary care setting. Pediatr Nurs. 2008;34:64–71. 18. Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother. 2009;64:441–446. 19. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593–598. 20. Diep BA, Chambers HF, Graber CJ, et al. Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann Intern Med. 2008;148:249–257. 21. Leclercq R. Epidemiological and resistance issues in multidrug-resistant staphylococci and enterococci. Clin Microbiol Infect. 2009;15:224–231. 22. Sader HS, Flamm RK, Farrell DJ, et al. Activity analyses of staphylococcal isolates from pediatric, adult, and elderly patients: AWARE Ceftaroline Surveillance Program. Clin Infect Dis. 2012;55(Suppl 3):S181–S186.
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23. Jacobs MR, Good CE, Windau AR, et al. Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother. 2010;54:2716–2719. 24. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents. 2010;36:197–204. 25. Jones RN, Sader HS, Mendes RE, et al. Update on antimicrobial susceptibility trends among Streptococcus pneumoniae in the United States: report of ceftaroline activity from the SENTRY Antimicrobial Surveillance Program (1998–2011). Diagn Microbiol Infect Dis. 2013;75:107–109. 26. Pfaller MA, Farrell DJ, Sader HS, et al. AWARE ceftaroline surveillance program (2008–2010); trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012;55 (Suppl 3):S187–S193. 27. Castanheira M, Farrell SE, Deshpande LM, et al. Prevalence of β-lactamase-encoding genes among Enterobacteriaceae bacteremia isolates collected in 26 U.S. hospitals: report from the SENTRY Antimicrobial Surveillance Program (2010). Antimicrob Agents Chemother. 2013;57:3012–3020. 28. Flamm RK, Sader HS, Farrell DJ, et al. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother. 2012;56:2933–2940.
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Ceftaroline Activity Tested Against Bacterial Isolates From Pediatric Patients Results from the Assessing Worldwide Antimicrobial Resistance and Evaluation Program for the United States (2011–2012) Helio S. Sader, MD, PhD, Rodrigo E. Mendes, PhD, David J. Farrell, PhD, Robert K. Flamm, PhD, and Ronald N. Jones, MD
Background: Ceftaroline, the active form of ceftaroline fosamil, is a cephalosporin with broad-spectrum bactericidal activity against resistant Grampositive organisms, including methicillin-resistant Staphylococcus aureus, ceftriaxone-resistant Streptococcus pneumoniae and many Enterobacteriaceae species. Ceftaroline fosamil is approved in the United States for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in adults. Methods: A total of 5291 consecutive unique pediatric patient strains of clinical significance were collected from 157 US medical centers. The isolates were identified locally and forwarded to a central monitoring laboratory for reference antimicrobial susceptibility testing. S. pneumoniae isolates from the 2011 to 2012 respiratory season were serotyped. Susceptibility results were analyzed according to patient age as follows: ≤1 years old (yo; 1857 strains); 2–5 (1342); 6–12 (1281) and 13–17 (811). Results: Methicillin-resistant Staphylococcus aureus rates were slightly lower in isolates from patients 13–17 yo (39.9%) compared with other age groups (48.2–51.5%), and ceftaroline was consistently active against S. aureus isolates from all 4 age groups [minimal inhibitory concentration (MIC50/90): 0.25–05/1 μg/mL; 99.8–100.0% susceptible]. Overall, 99.8% of methicillin-resistant Staphylococcus aureus were ceftaroline susceptible (MIC50/90: 0.5/1 μg/mL). All S. pneumoniae strains (1178) were ceftaroline susceptible (MIC50/90: ≤0.015/0.12 μg/mL), whereas ceftriaxone susceptibility varied from only 84.8 (≤1 yo) to 89.7% (13–17 yo). 19A was the most frequent serotype identified among S. pneumoniae and these isolates exhibited low susceptibility to ceftriaxone (42.4%) and most other antimicrobials tested. The highest ceftaroline MIC among Haemophilus influenzae (587 strains) was 0.12 μg/mL (100.0% susceptible), and β-lactamase production rates varied from 24.2 (13–17 yo) to 30.1% (6–12 yo); 27.9% overall. Ceftaroline was also active against β-hemolytic streptococci (556 strains, highest MIC, 0.06 μg/mL). Extended-spectrum β-lactamase (ESBL)-phenotype rates among Escherichia coli/Klebsiella spp. were 6.0/5.1, 11.0/11.5, 5.1/8.3 and 11.4/14.7% for the ≤1, 2–5, 6–12 and 13–17 yo age groups, respectively. Ceftaroline exhibited good activity against non-ESBL phenotype strains of E. coli and Klebsiella spp. (MIC90: 0.25 μg/mL for both organisms), but had limited activity against ESBL-producing strains. Accepted for publication January 26, 2014. From the JMI Laboratories, North Liberty, IA This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design of the study, but had no involvement in the collection, analysis, and interpretation of data, Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Helio S. Sader, MD, PhD, JMI Laboratories, 345 Beaver Kreek Ctr, Ste A, North Liberty, IA 52317. E-mail: helio-sader@ jmilabs.com. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3308-0837 DOI: 10.1097/INF.0000000000000307
Conclusion: Ceftaroline demonstrated potent in vitro activity when tested against S. aureus, S. pneumoniae, H. influenzae, β-hemolytic streptococci and non-ESBL-phenotype E. coli and Klebsiella spp. strains isolated from pediatric patients, independent of patient age. Key Words: Ceftaroline, AWARE, MRSA, Streptococcus pneumoniae (Pediatr Infect Dis J 2014;33:837–842)
A
ntimicrobial resistance has been the subject of increasing concern to pediatricians, and it remains a major focus of clinical and microbiology research for pediatric infectious diseases specialists.1,2 The major challenges to pediatricians are antimicrobial resistance among organisms causing community-acquired respiratory tract infections and among infections acquired in the healthcare setting. Moreover, the emergence and dissemination of community-associated (CA), methicillin-resistant Staphylococcus aureus (MRSA) represent another important challenge for those physicians treating children.3,4 Although much has been reported about antimicrobial susceptibility in the pediatric population, considerably less is understood regarding resistance profile patterns by pediatric patient age groupings. Ceftaroline, the active metabolite of ceftaroline fosamil, is a parenteral cephalosporin with potent activity against Gram-positive organisms, including MRSA and multidrug-resistant (MDR) Streptococcus pneumoniae, and common Gram-negative bacilli, but not those producing extended-spectrum β-lactamases (ESBLs).5–7 Ceftaroline fosamil is approved by the US Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSI) in adults, including ABSSSI caused by MRSA.8 It is also approved by the European Medicines Agency for similar indications.9 As part of the Assessing Worldwide Antimicrobial Resistance Evaluation Program, a global ceftaroline surveillance study, we evaluated the activity of ceftaroline tested against contemporary pathogens causing infections in pediatric patients at US hospitals (2011–2012).
MATERIALS AND METHODS Organism Collection Nearly 5300 consecutive unique pediatric patient isolates of clinical significance (Table, Supplemental Digital Content 1, http:// links.lww.com/INF/B844) were collected from 157 US medical centers as part of the Assessing Worldwide Antimicrobial Resistance Evaluation Program.10 The participant centers were distributed across all 9 US Census Regions, with 7–31 medical centers per region. These organisms were collected from January 2011 to December 2012. Susceptibility results were analyzed according to patient age as follows: ≤1 years old (yo; 1857 strains); 2–5 yo
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(1342); 6–12 yo (1281) and 13–17 yo (811). Species identification was performed at the participant center and confirmed by the monitoring laboratory (JMI Laboratories, North Liberty, IA), when necessary using Matrix-assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry from the Bruker Daltonics MALDI Biotyper (Billerica, MA), following manufacturer instructions.
Susceptibility Testing Methods Broth microdilution tests conducted according to the Clinical and Laboratory Standards Institute (CLSI) methods were performed to determine antimicrobial susceptibility of ceftaroline and selected comparator antimicrobials.11 Validated MIC panels were manufactured by ThermoFisher Scientific (Cleveland, OH). S. aureus and Enterobacteriaceae strains were tested in c ation-adjusted MuellerHinton broth (CA-MHB), fastidious streptococci were tested in CA-MHB supplemented with 2.5–5% lysed horse blood and Haemophilus spp. strains were tested in Haemophilus Test Medium according to CLSI document recommendations.11 E. coli and Klebsiella spp. isolates were grouped as “ESBL-phenotype” and “non-ESBL-phenotype” based on the CLSI screening criteria for ESBL production.12 Those isolates with positive ESBL screening test (ie, MIC of >1 μg/mL for ceftazidime and/or ceftriaxone and/or aztreonam) were categorized as “ESBL-phenotype” for the purpose of susceptibility testing result analysis. Although other β-lactamases, such as AmpC and Klebsiella pneumoniae carbapenemases, may also produce an “ESBL-phenotype”, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum β-lactam compounds and other drug classes. Concurrent quality control testing was performed to assure proper test conditions and procedures.11 Susceptibility percentages and validation of quality control results were based on CLSI guidelines and susceptibility breakpoints (M100-S23).12
Serotyping Determination All S. pneumoniae isolates collected from July 2011 to June 2012 (2011–2012 respiratory season) from lower respiratory tract or blood were serotyped. Isolates were subjected to polymerase chain reaction assays for amplification of the cpsB gene as previously described by Leung et al.13 Amplicons were sequenced on both strands and the nucleotide sequences were analyzed using the Lasergene software package (DNASTAR, Madison, WI). Sequences were compared with others available via Pubmed (http://www.ncbi. nlm.nih.gov/blast/). Because of sequence homology among certain serotypes, those showing nucleotide sequence similarity >99% were grouped (eg, 9V/9A, 7F/7A, 11A/11D, 15A/15F, 22F/22A, 15B/15C). All isolates determined to be serogroup 6 by polymerase chain reaction and sequencing analysis were subjected to multiplex polymerase chain reaction assays for confirmation and discrimination purposes (between 6A/6B and 6C/6D).14 Those determined to be serogroups 6A/6B, 6C/6D, 7C/7B/40, 7F/7A, 9N/9L and 9V/9A were selected for further capsular swelling methods to determine serotype within these serogroups. Capsular swelling methods were performed according to manufacturer’s instructions (Miravista; Indianapolis, IN).
RESULTS Bacterial isolates collection included S. aureus (2117 strains, 47.4% MRSA), S. pneumoniae [1178; 15.7% penicillin-non-susceptible (MIC, ≥4 μg/mL)], Haemophilus influenzae (587), β-hemolytic streptococci (556), Escherichia coli (464; 7.8% ESBL-phenotype) and Klebsiella spp. (389; 7.2% ESBL-phenotype). The isolates were from skin and soft tis sue infections (37.0%), community-acquired respiratory tract
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infections (23.1%), pneumonia in hospitalized patients (17.2%), bloodstream infections (10.0%), urinary tract infection (5.0%) and other sites (7.6%). Ceftaroline was consistently active against S. aureus isolates from all 4 monitored age groups [minimal inhibitory concentration (MIC50/90): 0.25–05/1 μg/mL; 99.8–100.0% susceptibility]. Overall, 99.8% of MRSA were susceptible to ceftaroline (MIC50/90: 0.5/1 μg/mL; Tables, Supplemental Digital Content 1 and 2, http:// links.lww.com/INF/B844 and http://links.lww.com/INF/B845). MRSA rates were slightly lower among isolates from patients 13–17 yo (39.9%) compared with other age groups (48.2–51.5%). Also, susceptibility to levofloxacin was lower in S. aureus isolates from patients 2–5 yo (67.6%) compared with other age groups (74.0–76.7%). Susceptibility rates to erythromycin, clindamycin, tetracycline and trimethoprim/sulfamethoxazole for S. aureus did not vary significantly across tabulated age groups (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). When tested against methicillin-susceptible S. aureus, ceftaroline (MIC50 and MIC90: 0.25 μg/mL) was 16-fold more active than ceftriaxone (MIC50 and MIC90: 4 μg/mL; data not shown). All S. pneumoniae strains (1178) were ceftaroline susceptible (MIC50/90: ≤0.015/0.12 μg/mL; Table, Supplemental Digital Content 1, http://links.lww.com/INF/B844), whereas ceftriaxone susceptibility varied from only 84.8 (≤1 yo) to 89.7% (13–17 yo; Table, Supplemental Digital Content 3, http://links.lww.com/INF/ B846). In general, susceptibility rates for all comparator agents were slightly lower among S. pneumoniae isolates from the youngest patients (≤1 yo; Table, Supplemental Digital Content 3, http:// links.lww.com/INF/B846). Ceftaroline was highly active against penicillin-non-susceptible S. pneumoniae (MIC, ≥4 μg/mL; 185 strains) with MIC50 and MIC90 values of 0.25 μg/mL (100.0% susceptibility; Table, Supplemental Digital Content 1, http://links. lww.com/INF/B844), whereas ceftriaxone (MIC50 and MIC90: 2 μg/mL; 20.5% susceptibility), amoxicillin/clavulanate (3.2%), erythromycin (0.5%), clindamycin (6.5%), tetracycline (8.1%) and trimethoprim/sulfamethoxazole (2.2%) displayed very limited activity and low susceptibility rates against these organisms (data not shown). Ceftaroline was 8-fold more active than ceftriaxone (MIC90: 2 μg/mL) when tested against penicillin-susceptible (MIC50/90: ≤0.015/0.12 and ≤0.06/1 μg/mL, respectively) and penicillin-non-susceptible S. pneumoniae strains (MIC50/90: 0.25/0.25 and 2/2 μg/mL, respectively; data not shown). The serogroups/types detected among S. pneumoniae isolates in each age group are displayed in Figure 1. Twenty-nine serogroups/types were observed among 179 isolates tested, with frequencies varying from 18.4% (19A, 33 occurrences) to 0.6% (6B, 9L, 16F, 23F, 24A/B/F, 34, 38/25A/25F and nontypeable, with 1 occurrence each). The PCV7-associated serotypes accounted for 5.0% of the isolates, and only serotypes 19F (3.9%), 6B (0.6%) and 23F (0.6%) were detected. Serotype 19A was the most prevalent type observed overall, as well as among age groups ≤1, 2–5 and 6–12 yo. Other PCV13-associated serotypes observed in this study were serotypes 3 (6.1%) and 7F (1.1%). The most common non-PCV13-associate serogroups/types were 35B [8.9% overall and the most common among age group 13–17 yo (20.0%)], 15B/C (6.7%) and 23A (6.1%). Antimicrobial susceptibility varied markedly among serotypes, with the least ceftriaxone-susceptible serotypes being 19A (MIC50/90: 2/2 μg/mL; 42.4% susceptible), 6C (MIC50: 0.5 μg/mL; 88.9% susceptible) and 35B (MIC50/90: 1/1 μg/mL; 100.0% susceptible; Table, Supplemental Digital Content 4, http://links.lww.com/ INF/B847). Serotype 19A isolates also showed low susceptibility to penicillin (MIC50/90: 4/8 μg/mL; 24.2% susceptible), erythromycin (MIC50/90: >16/>16 μg/mL; 21.2% susceptible), clindamycin © 2014 Lippincott Williams & Wilkins
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(MIC50/90: >2/>2 μg/mL; 27.3% susceptible) and trimethoprim/ sulfamethoxazole (MIC50/90: >4/>4 μg/mL; 15.2% susceptible; data not shown), but were very susceptible to ceftaroline (MIC50/90: 0.12/0.25 μg/mL; 100.0% susceptible; Table, Supplemental Digital Content 4, http://links.lww.com/INF/B847). The highest ceftaroline MIC observed among H. influenzae (587 strains) was 0.12 μg/mL (100.0% susceptibility), and β-lactamase production rates varied from 24.2 (13–17 yo) to 30.1%
Ceftaroline
(6–12 yo); 27.9% overall (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). All isolates were also susceptible to ceftriaxone and levofloxacin, whereas susceptibility to clarithromycin varied more widely from 76.4% (6 – 12 yo) to 90.3% (13–17 yo; Table, Supplemental Digital Content 3, http://links.lww.com/ INF/B846). Ceftaroline was also active against β-hemolytic streptococci (556 strains; highest MIC at 0.06 μg/mL). All β-hemolytic streptococcal strains were susceptible to ceftaroline, ceftriaxone
FIGURE 1. Distribution of serogroups/types among S. pneumoniae strains isolated from lower respiratory tract and bacteremia during the 2011–2012 respiratory season for patients ≤1 (1A), 2–5 (1B), 6–12 (1C) and 13–17 (1D) yo. © 2014 Lippincott Williams & Wilkins
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FIGURE 1. (Continued) and penicillin, but susceptibility to clindamycin ranged from 79.1% (2 – 5 yo) to 94.4% (6 – 12 yo), and susceptibility to erythromycin varied from 54.1 (2–5 yo) to 85.8% (5–12 yo; Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). ESBL-phenotype rates were 5.1 (6–12 yo) to 11.4% (13–17 yo) among E. coli, and ranged from 5.1 (≤1 yo) to 14.7% (13–17 yo) for Klebsiella spp. (Table, Supplemental Digital Content 3, http://links.lww.com/INF/B846). Ceftaroline exhibited very good activity against non-ESBL-phenotype strains of E. coli
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and Klebsiella spp. (MIC90: 0.25 μg/mL for both organisms), but very limited coverage of ESBL-producing strains (Tables, Supplemental Digital Content 1 and 2, http://links.lww.com/INF/ B844 and http://links.lww.com/INF/B845).
DISCUSSION Pediatricians are facing increasing antimicrobial resistance among common pathogens responsible for healthcare-associated as © 2014 Lippincott Williams & Wilkins
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well as community-associated ABSSSI and community-acquired respiratory tract infections in children, particularly for S. aureus and S. pneumoniae.1,3,4 As S. aureus represents a major cause of ABSSSI and bloodstream infections, it also is an important cause of pneumonia in children.15,16 Before the late 1990s, MRSA infections were confined largely to patients who had known exposures to the healthcare setting, but the emergence and rapid dissemination of CA-MRSA drastically changed the epidemiology of S. aureus infection in the United States.3,17,18 CA-MRSA in the United States was first identified in children in the upper Midwest region.19 Since that time, many areas in the United States have experienced substantial increases in the colonization and the incidence of MRSA infection among healthy children.16 Moreover, the initial CA-MRSA strains were generally susceptible to numerous antimicrobial agents compared with traditional hospital-acquired MRSA strains, but variants of USA300 CA-MRSA having MDR patterns have become more common.20,21 Although a large number of studies have investigated the antimicrobial susceptibility of S. aureus, very little is understood about resistance profiles indexed by patient age group.22 The results of the present study illustrated some variations in the S. aureus susceptibility patterns according to age group, but consistent activity of ceftaroline when tested against S. aureus isolates from all 4 age groups. In addition to potent activity against MRSA (MIC50/90: 05/1 μg/mL; 99.5–100.0% susceptibility), ceftaroline was 16-fold more active than ceftriaxone when tested against methicillin-susceptible S. aureus.6,10 S. pneumoniae accounts for more than half of community-acquired bacterial pneumonia and approximately one-third of acute bacterial rhinosinusitis in children.1 H. influenzae is the second most frequent bacterial cause of respiratory tract infection in children. This latter organism is responsible for 20–30% of bacterial rhinosinusitis and one- to two-thirds of otitis media and childhood pneumonia.1 Community-acquired bacterial pneumonia in children has traditionally been treated with ceftriaxone or an oral second- or third-generation cephalosporin15; however, resistance to those agents has escalated in recent years among S. pneumoniae.23–26 The results presented here are in agreement with those published earlier by showing very potent ceftaroline activity against S. pneumoniae and H. influenzae.6 Although susceptibility rates for comparator agents, including ceftriaxone, were lower among S. pneumoniae isolates from patients ≤1 yo compared with the other age groups; ceftaroline displayed remarkable activity (MIC50/90: ≤0.015/0.12 μg/mL) and complete coverage (100.0% susceptibility) against S. pneumoniae isolated from all pediatric age groups. Furthermore, ceftaroline was highly active against S. pneumoniae isolates serotype 19A, which was the predominant and most drug-resistant serotype (only 42.4% susceptible to ceftriaxone) identified during the 2011–2012 respiratory season in the present study. ESBL rates for E. coli and Klebsiella spp. varied by age group, being generally lower in the ≤1 and 6–12 yo groups and higher in the 2–5 and 13–17 yo groups, and similar variation was observed in the in vitro activity of the cephalosporins (ceftaroline, ceftriaxone and ceftazidime) and piperacillin/tazobactam, that is, higher susceptibility rates in the ≤1 yo and 6–12 yo groups. These findings reflect the limited activity of these β-lactam compounds when tested against ESBL screen-positive Enterobacteriaceae.12,27,28 In summary, ceftaroline demonstrated potent activity when tested against contemporary S. aureus, S. pneumoniae, H. influenzae, β-hemolytic streptococci and non-ESBL-phenotype E. coli and Klebsiella spp. strains isolated from pediatric patients, a level of potency equal or significantly superior to currently available β-lactams. These in vitro data support the further clinical development of ceftaroline © 2014 Lippincott Williams & Wilkins
Ceftaroline
for treatment of infection in children, especially those infections caused by MRSA and MDR S. pneumoniae.
ACKNOWLEDGMENTS The authors would like to thank Dr. Michael R. Jacobs for performing the capsular swelling serotyping. This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design of the study, but had no involvement in the collection, analysis, and interpretation of data, Scientific Therapeutics Information, Inc., provided editorial coordination, which was funded by Forest Research Institute, Inc. JMI Laboratories, Inc. has received research and educational grants in 2012-2014 from – Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, ThermoFisher, Venatorx, Vertex, Waterloo and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regards to speakers bureaus and stock options-none to declare. REFERENCES 1. Jacobs MR, Dagan R. Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges. Semin Pediatr Infect Dis. 2004;15:5–20. 2. Versporten A, Sharland M, Bielicki J, et al.; ARPEC Project Group Members. The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J. 2013;32:e242–e253. 3. Long CB, Madan RP, Herold BC. Diagnosis and management of community-associated MRSA infections in children. Expert Rev Anti Infect Ther. 2010;8:183–195. 4. Kaplan SL. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Semin Pediatr Infect Dis. 2006;17:113–119. 5. Critchley IA, Eckburg PB, Jandourek A, et al. Review of ceftaroline fosamil microbiology: integrated FOCUS studies. J Antimicrob Chemother. 2011;66 Suppl 3:iii45–iii51. 6. Frampton JE. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Drugs. 2013;73:1067–1094. 7. Lodise TP, Low DE. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs. 2012;72:1473–1493. 8. Teflaro® Package Insert. Teflaro® Package Insert. 2012. Available at: http:// www.accessdata.fda.gov/drugsatfda_docs/label/2013/200327s009lbl.pdf. Accessed August 2013. 9. ZinforoTM Package Insert. ZinforoTM Package Insert. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ Information/human/002252/WC500132586.pdf. Accessed January 2013. 10. Farrell DJ, Castanheira M, Mendes RE, et al. 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 (Suppl 3):S206-S214. 11. CLSI. M07-A9. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard. Ninth edition. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. 12. CLSI. M100-S23. Performance Standards for Antimicrobial Susceptibility Testing: 23rd Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2013. 13. Leung MH, Bryson K, Freystatter K, et al. Sequetyping: serotyping Streptococcus pneumoniae by a single PCR sequencing strategy. J Clin Microbiol. 2012;50:2419–2427. 14. Pai R, Gertz RE, Beall B. Sequential multiplex PCR approach for determining capsular serotypes of Streptococcus pneumoniae isolates. J Clin Microbiol. 2006;44:124–131.
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15. Bradley JS, Byington CL, Shah SS, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53:617–630. 16. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–687. 17. Hinckley J, Allen PJ. Community-associated MRSA in the pediatric primary care setting. Pediatr Nurs. 2008;34:64–71. 18. Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother. 2009;64:441–446. 19. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593–598. 20. Diep BA, Chambers HF, Graber CJ, et al. Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann Intern Med. 2008;148:249–257. 21. Leclercq R. Epidemiological and resistance issues in multidrug-resistant staphylococci and enterococci. Clin Microbiol Infect. 2009;15:224–231. 22. Sader HS, Flamm RK, Farrell DJ, et al. Activity analyses of staphylococcal isolates from pediatric, adult, and elderly patients: AWARE Ceftaroline Surveillance Program. Clin Infect Dis. 2012;55(Suppl 3):S181–S186.
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23. Jacobs MR, Good CE, Windau AR, et al. Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother. 2010;54:2716–2719. 24. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents. 2010;36:197–204. 25. Jones RN, Sader HS, Mendes RE, et al. Update on antimicrobial susceptibility trends among Streptococcus pneumoniae in the United States: report of ceftaroline activity from the SENTRY Antimicrobial Surveillance Program (1998–2011). Diagn Microbiol Infect Dis. 2013;75:107–109. 26. Pfaller MA, Farrell DJ, Sader HS, et al. AWARE ceftaroline surveillance program (2008–2010); trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012;55 (Suppl 3):S187–S193. 27. Castanheira M, Farrell SE, Deshpande LM, et al. Prevalence of β-lactamase-encoding genes among Enterobacteriaceae bacteremia isolates collected in 26 U.S. hospitals: report from the SENTRY Antimicrobial Surveillance Program (2010). Antimicrob Agents Chemother. 2013;57:3012–3020. 28. Flamm RK, Sader HS, Farrell DJ, et al. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother. 2012;56:2933–2940.
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