Diagnostic Microbiology and Infectious Disease 78 (2014) 437–442

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Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE program, 2009–2011 Robert K. Flamm ⁎, Helio S. Sader, Ronald N. Jones JMI Laboratories, North Liberty, IA 52317, USA

a r t i c l e

i n f o

Article history: Received 25 September 2013 Received in revised form 22 October 2013 Accepted 27 October 2013 Available online 6 November 2013 Keywords: Ceftaroline USA AWARE S. pneumoniae

a b s t r a c t The Assessing Worldwide Antimicrobial Resistance Evaluation Program monitors the activity of ceftaroline and comparator agents tested against pathogens causing either respiratory or skin and soft tissue infections. A total of 7733 isolates from patients in 80 medical centers across the United States (USA) identified as respiratory tract pathogens by the infection type and/or specimen site recorded by the submitting laboratory during 2009–2011 were evaluated. There were 3360 isolates of Streptococcus pneumoniae, 1799 Haemophilus influenzae, 1087 Staphylococcus aureus, 678 Moraxella catarrhalis, 459 Klebsiella pneumoniae, 223 Escherichia coli, and 127 Klebsiella oxytoca. Annual penicillin resistance among S. pneumoniae ranged from 21.9 to 24.3%. All S. pneumoniae strains were inhibited at a ceftaroline MIC of ≤0.5 μg/mL with 100.0% of isolates categorized as susceptible. Ceftaroline was 16-fold more active than ceftriaxone and 32-fold more active than amoxicillinclavulanate against penicillin-resistant pneumococci. Only 49.8% of the penicillin-resistant isolates were susceptible to ceftriaxone. There were a total of 1087 S. aureus (48.9% methicillin-resistant S. aureus [MRSA]) isolates, and the yearly MRSA rate ranged from 47.9 to 49.7%. The ceftaroline MIC50/90 for S. aureus was at 0.25/ 1 μg/mL; 98.2% susceptible and no resistant strains (≥4 μg/mL). Ceftaroline activity against methicillinsusceptible S. aureus (MSSA) isolates (MIC50 and MIC90, 0.25 and 0.25 μg/mL, respectively; 100% susceptible) was 2- to 4-fold greater than for MRSA (MIC50/90, 0.5/1 μg/mL; 96.2% susceptible). The ceftriaxone MIC90 for MSSA was 4 μg/mL. Ceftaroline was active against H. influenzae (MIC50/90 ≤0.015/0.03 μg/mL; 100.0% susceptible) and against M. catarrhalis (MIC50/90, 0.06/0.12 μg/mL). Ceftaroline was active against non– extended spectrum β-lactamase (ESBL) phenotype strains of Enterobacteriaceae but not against ESBL-positive phenotype strains. In summary, ceftaroline was highly active against a large collection of bacterial pathogens isolated from patients with respiratory tract infections in the USA during 2009 through 2011. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Community-acquired respiratory tract infections or those occurring after hospitalization may be caused by bacteria resistant to some or many available therapies (Critchley et al., 2011; Jones et al., 2010; Jones et al., 2011). As such, the choice of the appropriate initial empiric therapy is important to minimize morbidity and mortality (File, 2006; File and Marrie, 2010; Kollef et al., 2005). In spite of the increasing concern over the emergence of antimicrobial resistance, there have been relatively few new antibacterial agents licensed for use for the treatment of respiratory tract infections in the United States (USA) and/or Europe. Only 2 new agents have been approved in the USA for the treatment of bacterial pneumonia recently telavancin in 2013 and ceftaroline fosamil (hereafter referred to as ceftaroline) in 2010 (Teflaro® Package Insert, 2012; VIBATIV Package Insert, 2013). Bacterial causes of lower respiratory tract infections often include Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, and enteric bacilli (File and Marrie, 2010; ⁎ Corresponding author. Tel.: +1-319-665-3370; fax: +1-319-665-3371. E-mail address: robert-fl[email protected] (R.K. Flamm). 0732-8893/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.diagmicrobio.2013.10.020

Jones et al., 2011; Rank et al., 2011). Ceftaroline is a recently approved agent, which has been shown to be effective against S. pneumoniae, S. aureus (methicillin-susceptible [MSSA] isolates only), H. influenzae, Klebsiella pneumoniae, K. oxytoca, and Escherichia coli in CABP (Teflaro® Package Insert, 2012). It has also been approved for use in the treatment of acute bacterial skin and skin structure infections caused by S. aureus (including methicillin-resistant [MRSA] and MSSA isolates), Streptococcus pyogenes, Streptococcus agalactiae, E. coli, K. pneumoniae, and K. oxytoca (Teflaro® Package Insert, 2012). Further, ceftaroline has documented in vitro activity against drug-resistant S. pneumoniae and S. aureus including MRSA (Biek et al., 2010; Farrell et al., 2012; Flamm et al., 2012; Jacobs et al., 2010; Jones et al., 2011; Karlowsky et al., 2011; Laudano, 2011; McGee et al., 2009; Morrissey and Leakey, 2012; Pfaller et al., 2012; Saravolatz et al., 2010; Vidaillac et al., 2010; Versalovic et al., 2011). The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Program monitors the activity of ceftaroline and comparator agents tested against pathogens causing either respiratory or skin and soft tissue infections (Farrell et al., 2012; Flamm et al., 2012; Pfaller et al., 2012; Sader et al., 2012). The program is in its fifth year for the USA, providing longitudinal information on antimicrobial

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Table 1 Activity of ceftaroline and comparator antimicrobial agents when tested against contemporary respiratory tract pathogens from USA medical centers (2009–2011). Organism (no. tested)/ antimicrobial agents S. aureus (1087) Ceftaroline Oxacillin Ceftriaxone Amoxicillin/clavulanate Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin MRSA (532) Ceftaroline Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin MSSA (555) Ceftaroline Ceftriaxone Erythromycin Clindamycin Levofloxacin Trimethoprim/sulfamethoxazole Tetracycline Tigecyclineb Linezolid Vancomycin Daptomycin S. pneumoniae (3360) Ceftaroline Penicillinc Penicillind Ceftriaxone Amoxicillin/clavulanate Meropenem Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline Tigecyclineb Trimethoprim/sulfamethoxazole Vancomycin S. pneumoniae PenR (791) Ceftaroline Penicillinc Penicillind Ceftriaxone Amoxicillin/clavulanate Meropenem Erythromycin Clindamycin Levofloxacin Linezolid Tetracycline Tigecyclineb Trimethoprim/sulfamethoxazole Vancomycin H. influenzae (1799) Ceftaroline Ampicillin Ceftriaxone Cefuroxime Amoxicillin/clavulanate Tetracycline

CLSIa %S/%I/%R

MIC (μg/mL) MIC50

MIC90

Range

0.25 2 4 2 N2 ≤0.25 ≤0.5 ≤0.5 ≤2 0.06 1 1 0.25

1 N2 N8 N8 N2 N2 N4 ≤0.5 ≤2 0.25 2 1 0.5

0.03–2 ≤0.25–N2 0.5–N8 ≤1–N8 ≤0.25–N2 ≤0.25–N2 ≤0.5–N4 ≤0.5–N2 ≤2–N8 ≤0.03–0.5 0.25–N8 ≤0.12–2 ≤0.06–1

98.2/1.8/51.1/0.0/48.9 51.1/0.0/48.9 51.1/0.0/48.9 36.5/2.2/61.3 76.2/0.2/23.6 53.7/1.2/45.1 97.7/0.0/2.3 95.5/0.4/4.1 100.0/-/99.6/0.0/0.4 100.0/0.0/0.0 100.0/-/-

0.5 N2 ≤0.25 N4 ≤0.5 ≤2 0.06 1 1 0.25

1 N2 N2 N4 ≤0.5 ≤2 0.25 2 1 0.5

0.12–2 ≤0.25–N2 ≤0.25–N2 ≤0.5–N4 ≤0.5–N2 ≤2–N8 ≤0.03–0.5 0.5–N8 0.5–2 0.12–1

96.2/3.8/7.9/1.7/90.4 58.8/0.0/41.2 17.5/1.5/81.0 96.8/0.0/3.2 93.0/0.4/6.6 100.0/-/99.2/0.0/0.8 100.0/0.0/0.0 100.0/-/-

0.25 4 ≤0.25 ≤0.25 ≤0.5 ≤0.5 ≤2 0.06 1 1 0.25

0.25 4 N2 ≤0.25 4 ≤0.5 ≤2 0.25 2 1 0.5

0.03–1 0.5–16 ≤0.25–N2 ≤0.25–N2 ≤0.5–N4 ≤0.5–N2 ≤2–N8 ≤0.03–0.5 0.25–2 ≤0.12–2 ≤0.06–1

100.0/-/99.6/0.4/0.0 64.0/2.7/33.3 92.8/0.5/6.7 88.5/0.9/10.6 98.6/0.0/1.4 97.8/0.4/1.8 100.0/-/100.0/0.0/0.0 100.0/0.0/0.0 100.0/-/-

≤0.015 ≤0.06 ≤0.06 ≤0.25 ≤1 ≤0.12 ≤0.25 ≤0.25 1 1 ≤2 ≤0.03 ≤0.5 ≤1

0.12 4 4 2 8 1 N2 N1 1 1 N8 0.06 N2 1

≤0.015–0.5 ≤0.06–N4 ≤0.06–N4 ≤0.25–8 ≤1–N8 ≤0.12–2 ≤0.25–N2 ≤0.25–N1 ≤0.5–N4 ≤0.12–4 ≤2–N8 ≤0.03–0.25 ≤0.5–N2 ≤1–1

100.0/-/84.2/13.8/1.9 54.5/22.0/23.5 88.0/10.2/1.8 80.9/4.0/15.1 74.4/10.8/14.8 55.6/0.4/44.0 77.2/0.5/22.3 98.8/0.0/1.2 N99.9/-/73.3/0.4/26.3 96.2/-/64.2/8.4/27.4 100.0/-/-

0.12 4 4 2 8 1 N2 N1 1 0.5 N8 ≤0.03 N2 ≤1

0.25 4 4 2 8 1 N2 N1 1 1 N8 0.06 N2 ≤1

0.03–0.5 2–N4 2–N4 ≤0.25–8 ≤1–N8 ≤0.12–2 ≤0.25–N2 ≤0.25–N1 ≤0.5–N4 0.25–2 ≤2–N8 ≤0.03–0.25 ≤0.5–N2 ≤1

100.0/-/32.7/59.2/8.1 0.0/0.0/100.0 49.8/42.5/7.7 19.8/16.4/63.8 3.3/36.1/60.6 9.5/0.2/90.3 36.9/0.5/62.6 98.4/0.1/1.5 100.0/-/33.1/0.1/66.8 94.2/-/19.5/2.5/78.0 100.0/-/-

≤0.015 ≤1 ≤0.25 ≤2 ≤1 ≤2

0.03 N8 ≤0.25 ≤2 ≤1 ≤2

≤0.015–0.5 ≤1–N8 ≤0.25–0.5 ≤2–8 ≤1–8 ≤2–N8

100.0/-/73.0/0.9/26.1 100.0/-/99.6/0.4/0.0 99.9/0.0/0.1 98.7/0.1/1.2

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Table 1 (continued) Organism (no. tested)/ antimicrobial agents Trimethoprim/sulfamethoxazole Azithromycin Levofloxacin β-lactamase positive (480) Ceftaroline Ceftriaxone Cefuroxime Amoxicillin/clavulanate Tetracycline Trimethoprim/sulfamethoxazole Azithromycin Levofloxacin β-lactamase negative (1319) Ceftaroline Ceftriaxone Cefuroxime Amoxicillin/clavulanate Tetracycline Trimethoprim/ sulfamethoxazole Azithromycin Levofloxacin M. catarrhalis (678) Ceftaroline Ceftriaxone Amoxicillin/clavulanate Tetracycline Trimethoprim/ sulfamethoxazole Levofloxacin E. coli (223) Ceftaroline Ceftazidime Ceftriaxone Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb Non-ESBL E. coli (178) Ceftaroline Ceftazidime Ceftriaxone Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb ESBL-positive E. coli (45) Ceftaroline Ceftazidime Ceftriaxone Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb K. pneumoniae (459) Ceftaroline Ceftazidime Ceftriaxone Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb Non-ESBL K. pneumoniae (375) Ceftaroline Ceftazidime Ceftriaxone

CLSIa %S/%I/%R

MIC (μg/mL) MIC50

MIC90

≤0.5 1 0.5

N2 2 0.5

Range ≤0.5–N2 ≤0.5–N4 ≤0.5–0.5

74.9/2.5/22.6 98.6/-/100.0/-/-

≤0.015 ≤0.25 ≤2 ≤1 ≤2 ≤0.5 1 ≤0.5

0.06 ≤0.25 ≤2 2 ≤2 N2 2 ≤0.5

≤0.015–0.5 ≤0.25 ≤2–8 ≤1–8 ≤2–N8 ≤0.5–N2 ≤0.5–N4 ≤0.5

100.0/-/100.0/-/99.8/0.2/0.0 99.8/0.0/0.2 96.0/0.7/3.3 76.7/1.6/21.7 98.3/-/100.0/-/-

≤0.015 ≤0.25 ≤2 ≤1 ≤2 ≤0.5

≤0.015 ≤0.25 ≤2 ≤1 ≤2 N2

≤0.015–0.12 ≤0.25–0.5 ≤2–8 ≤1–4 ≤2–N8 ≤0.5–N2

100.0/-/100.0/-/99.5/0.5/0.0 100.0/0.0/0.0 99.6/0.0/0.4 74.3/2.7/23.0

1 0.5

2 0.5

≤0.5–N4 ≤0.5–0.5

98.7/-/100.0/-/-

0.06 ≤0.25 ≤1 ≤2 ≤0.5

0.12 0.5 ≤1 ≤2 ≤0.5

≤0.015–1 ≤0.25–8 ≤1 ≤2–8 ≤0.5–N2

-/-/99.9/-/100.0/0.0/0.0 99.9/0.0/0.1 95.0/3.2/1.8

≤0.5

≤0.5

≤0.5–1

100.0/-/-

0.25 0.25 ≤0.25 2 ≤0.12 ≤0.5 ≤2 ≤2 0.12

N16 16 N8 32 ≤0.12 N4 N8 N8 0.25

≤0.015–N16 ≤0.015–N32 ≤0.25–N8 ≤0.5–N64 ≤0.12–0.5 ≤0.5–N4 ≤2–N8 ≤2–N8 0.06–0.5

72.6/3.7/23.8 86.5/1.8/11.7 81.2/0.9/17.9 89.2/3.2/7.6 100.0/0.0/0.0 54.7/1.4/43.9 84.8/1.7/13.5 64.1/0.0/35.9 100.0/0.0/0.0

0.12 0.25 ≤0.25 2 ≤0.12 ≤0.5 ≤2 ≤2 0.12

1 0.5 ≤0.25 8 ≤0.12 N4 N8 N8 0.25

≤0.015–32 ≤0.015–1 ≤0.25–1 ≤0.5–N64 ≤0.12 ≤0.5–N4 ≤2–N8 ≤2–N8 0.06–0.5

89.9/3.8/6.2 100.0/0.0/0.0 100.0/0.0/0.0 93.8/2.3/3.9 100.0/0.0/0.0 66.3/1.7/32.0 86.5/1.7/11.8 70.8/0.0/29.2 100.0/0.0/0.0

N16 16 N8 8 ≤0.12 N4 ≤2 N8 0.12

N16 N32 N8 N64 ≤0.12 N4 N8 N8 0.25

0.25–N16 0.25–N32 0.12–N8 1–N64 ≤0.12–0.5 ≤0.5–N4 ≤2–N8 ≤2–N8 0.06–0.5

4.4/2.3/93.3 33.3/8.9/57.8 6.7/4.4/88.9 71.1/6.7/22.2 100.0/0.0/0.0 8.9/0.0/91.1 77.8/2.2/20.0 37.8/0.0/62.2 100.0/0.0/0.0

0.12 0.25 ≤0.25 4 ≤0.12 ≤0.5 ≤2 ≤2 0.25

N16 N32 N8 N64 ≤0.12 N4 8 N8 1

0.03–N16 0.03–N32 ≤0.25–N8 ≤0.5–N64 ≤0.12–N8 ≤0.5–N4 ≤2–N8 ≤2–N8 0.06–N4

76.0/4.6/19.4 83.0/0.4/16.6 82.4/0.3/17.2 85.4/3.1/11.5 93.7/0.2/6.1 83.7/1.5/14.8 89.3/2.9/7.8 77.6/5.8/16.6 97.0/2.6/0.4

0.12 0.12 ≤0.25

0.5 0.5 ≤0.25

0.03–4 0.03–1 ≤0.25–1

93.1/5.7/1.3 100.0/0.0/0.0 100.0/0.0/0.0 (continued on next page)

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Table 1 (continued) Organism (no. tested)/ antimicrobial agents Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb ESBL-positive K. pneumoniae (84) Ceftaroline Ceftazidime Ceftriaxone Piperacillin/tazobactam Meropenem Levofloxacin Gentamicin Tetracycline Tigecyclineb a b c d

CLSIa %S/%I/%R

MIC (μg/mL) MIC50 4 ≤0.12 ≤0.5 ≤2 ≤2 0.25 N16 N32 N8 N64 ≤0.12 N4 8 4 0.5

MIC90 16 ≤0.12 ≤0.5 ≤2 N8 1 N16 N32 N8 N64 N8 N4 N8 N8 1

Range ≤0.5–N64 ≤0.12–0.25 ≤0.5–N4 ≤2–N8 ≤2–N8 0.06–N4

98.1/1.4/0.5 100.0/0.0/0.0 97.3/1.2/1.6 98.9/0.6/0.5 82.4/3.5/14.1 97.6/2.2/0.3

2–N16 1–N32 0.25–N8 1–N64 ≤0.12–N8 ≤0.5–N4 ≤2–N8 ≤2–N8 0.12–N4

0.0/0.0/100.0 7.1/2.4/90.5 3.6/2.4/94.0 28.6/10.7/60.7 65.5/1.2/33.3 22.6/3.6/73.8 46.4/13.1/40.5 56.0/16.6/27.4 94.0/4.8/1.2

Criteria as published by the CLSI (2013). USA-FDA breakpoints were applied (Tygacil Package Insert, 2011). Criteria as published by the CLSI (2013) for 'Penicillin parenteral (non-meningitis)'. Criteria as published by the CLSI (2013) for 'Penicillin oral (penicillin V)'.

activity. As it is prudent to monitor any new agent after regulatory approval, this program is ongoing. In this report, we present the results of the 2009–2011 surveillance years for 7733 isolates from 80 different medical centers across the USA. 2. Materials and methods 2.1. Medical centers Isolates were collected from patients of all ages (range b1 year to N90 years of age) in 80 different medical centers: number of centers (year): 50 (2009), 64 (2010), and 66 (2011) located in each of the USA Census regions. The numbers of centers for each USA census region during the 3-year period ranged per year from 5–6 centers (Northeast), 6–8 (Mid-Atlantic), 8–12 (East North Central), 6– 8 (West North Central), 6–9 (South Atlantic), 4–6 (East North Central), 3–9 (West South central), 3–5 (Mountain), and 7–10 (Pacific). A total of 39 individual sites were able to participate all 3 years. 2.2. Organism collection The study protocol predetermined the target pathogens and the numbers of organisms which were to be collected. The study focus was on antibiotic susceptibility of select respiratory tract pathogens, which commonly occur in community-acquired pneumonia excluding atypical pathogens. A total of 7733 isolates were selected from the AWARE Program, which were identified as respiratory tract pathogens based on the infection type (respiratory tract) and/or specimen site (examples include: sputum, lower respiratory tract, tracheal aspirate, bronchoalveolar lavage, etc.) recorded by the submitting laboratory. Submitting laboratories followed their local standard operating procedures for identification. Isolates were submitted to the coordinating laboratory (JMI Laboratories, North Liberty, IA, USA) for confirmatory identification and susceptibility testing. Confirmatory identification was performed using reference-quality methods for microbial identification. This included identification by classical manual methods (2011) and the commercial Vitek®2 system, supported by DNA sequencing-based 16S RNA methods, as needed. There were 3360 (43.5%) isolates of S. pneumoniae, 1799 (23.3%) of H. influenzae, 1087 (14.1%) of S. aureus, 678 (8.8%) of M. catarrhalis, 459 (5.9%) of K. pneumoniae, 223 (2.9%) of E. coli, and 127 (1.6%) of K. oxytoca.

2.3. Susceptibility testing Susceptibility testing for ceftaroline and comparator agents was performed by reference broth microdilution at the coordinating laboratory (JMI Laboratories, North Liberty, IA, USA) for all organisms using custom dry-form panels produced by Thermo Fisher (formerly TREK Diagnostics, Cleveland, OH, USA) following Clinical and Laboratory Standards Institute (CLSI) methods (CLSI, 2012). The medium used was cation-adjusted Mueller-Hinton broth, supplemented with 2.5–5% lysed horse blood for streptococci. Haemophilus spp. were tested in Haemophilus Test Medium (CLSI, 2012). M. catarrhalis and H. influenzae were also tested in frozen-form reference panels (1 panel per isolate) produced at JMI Laboratories. Comparators were selected according to organism group (S. aureus, S. pneumoniae, H. influenzae, M. catarrhalis, and Enterobactericeae), and each organism was tested against multiple MIC panels. CLSI interpretations were based on criteria described in M100-S23 (CLSI, 2013). USA-FDA breakpoints were used for tigecycline in the absence of CLSI interpretations (Tygacil Package Insert, 2011). An extended spectrum β-lactamase (ESBL) phenotype screen was performed as per CLSI guidelines (CLSI, 2013). Concurrent quality control (QC) testing was performed to assure proper test conditions and procedures. QC strains included: S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, S. pneumoniae ATCC 49619, H. influenzae ATCC 49247 and 49766, E. coli ATCC 25922 and 35218, and Pseudomonas aeruginosa ATCC 27853. All QC results were within published CLSI ranges (CLSI, 2013). 3. Results Among 3360 S. pneumoniae isolates, 738 (22.0%) exhibited penicillin-intermediate susceptibility (Pen-I; MIC, 0.12-1 μg/mL), and 791 (23.5%) were penicillin-resistant (Pen-R, MIC, ≥2 μg/mL) (Table 1). Annual penicillin resistance ranged from 21.9 to 24.3% (Table 2). All S. pneumoniae strains were inhibited at a ceftaroline MIC of ≤0.5 μg/mL and categorized as susceptible (Table 1). Ceftaroline activity, as for other β-lactams, differed based on penicillin susceptibility. Ceftaroline MIC values for penicillin-intermediate strains were 4- to 8-fold higher than those of penicillin-susceptible strains and were 8- to 16- fold higher for penicillin-resistant strains (Table 1; data not shown). Ceftaroline was 8-fold more active than ceftriaxone and 32-fold more active than amoxicillin-clavulanate against penicillin-

R.K. Flamm et al. / Diagnostic Microbiology and Infectious Disease 78 (2014) 437–442 Table 2 Antimicrobial resistant phenotypes stratified by year of occurrence. Organism/antimicrobial

MRSAa Penicillin-resistant S. pneumoniaea Ceftriaxone non-susceptible S. pneumoniaea β-lactamase–positive H. influenzaea β-lactamase–positive M. catarrhalisa ESBL-phenotype E. colib ESBL-phenotype K. pneumoniaeb

% (no. of isolates tested) 2009

2010

2011

49.7 21.9 13.5 23.2 95.3 13.0 19.6

47.9 23.8 10.8 28.1 97.8 31.4 10.4

48.7 24.3 11.9 27.1 98.1 21.6 21.2

(382) (844) (844) (357) (233) (77) (112)

(190) (863) (863) (670) (178) (35) (106)

(515) (1653) (1652) (772 (267) (111) (241)

a

Criteria as published by the CLSI (2013). Percentage of isolates with positive ESBL screening test, i.e., MIC of ≥2 μg/mL for ceftazidime and/or ceftriaxone and/or aztreonam (CLSI, 2013). b

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mL; Table 1). The percentage of ESBL-positive phenotype K. pneumoniae strains varied from 10.4% in 2010 to 21.2% in 2011 (Table 2). Only meropenem (93.7% susceptible) and tigecycline (97.0% susceptible) showed a high level of activity (N90%) against K. pneumoniae (Table 1). Ceftaroline was active against the non-ESBL phenotype K. pneumoniae strains (MIC range, 0.03–4 μg/mL; MIC50/90, 0.12/0.5 μg/mL) (Table 1). Susceptibility rates were generally lower for agents against ESBL phenotype K. pneumoniae than for non-ESBL phenotype strains (Table 1). Unlike in E. coli where levofloxacin resistance was high in the non-ESBL phenotype and higher yet in the ESBL phenotype, levofloxacin resistance in K. pneumoniae resided mostly in the ESBL-positive phenotype strains, 73.8% compared to the non-ESBL phenotype strains (1.6%). 4. Discussion

resistant isolates. Only 49.8% of the penicillin-resistant pneumococcal isolates were susceptible to ceftriaxone (Table 1). There were 1087 S. aureus (48.9% MRSA) isolates from respiratory tract infections (Table 1). The yearly MRSA rate ranged from 47.9 to 49.7% (Table 2). A total of 426 strains were isolated from patients within 48 hours of hospitalization (community-acquired), and 226, after 48 hours of hospitalization (nosocomial acquired); the remaining isolates could not be classified into either group due to limited demographic information (data not shown). The MRSA rate for community-acquired S. aureus was 45.1%, and for the nosocomially acquired isolates, 57.1% (data not shown). The ceftaroline MIC50/90 for all S. aureus was at 0.25/1 μg/mL; 98.2% susceptible (CLSI, 2013), and no resistant strains (≥4 μg/mL; Table 1). Ceftaroline activity against MSSA isolates (MIC50 and MIC90, 0.25 μg/mL; 100% susceptible) was 2to 4-fold greater than for MRSA (MIC50/90, 0.5/1 μg/mL; 96.2% susceptible) (Table 1). Ceftaroline was 16-fold more active than ceftriaxone when tested against MSSA. Most agents tested against MSSA exhibited a high rate of susceptibility (N90%; Table 1); except erythromycin and levofloxacin (64.0 and 88.5%, respectively). Against all S. aureus, daptomycin (MIC50/90, 0.25/0.5 μg/mL; 100.0% susceptible), vancomycin (MIC50/90, 1/1 μg/mL; 100.0% susceptible), linezolid (MIC50/90, 1/2 μg/mL; 99.6% susceptible), tigecycline (MIC50/90, 0.06/ 0.25 μg/mL) and ceftaroline (MIC50/90, 0.25/1 μg/mL; 98.2% susceptible) were the most active agents. Ceftaroline was very active against all 1799 H. influenzae. The MIC50/90 was ≤0.015/0.03 μg/mL (100.0% susceptible) with the highest MIC value at 0.5 μg/mL (Table 1). H. influenzae was generally susceptible (N90%) to most agents tested except for trimethoprimsulfamethoxazole (74.9% susceptible) and ampicillin (Table 1). A total of 26.7% of H. influenzae were β-lactamase positive (ranging from 23.2 to 28.1% annually), and the ceftaroline MIC90 was 4-fold higher for the β-lactamase–positive than for β-lactamase–negative strains (0.06 and ≤0.015 μg/mL, respectively; Tables 1 and 2). Ceftaroline was also active against M. catarrhalis (97.1% β-lactamase positive; MIC50/90, 0.06/0.12 μg/mL; Table 1). There were 223 E. coli, 45 (20.2%) of which were an ESBL phenotype (Tables 1 and 2). The E. coli ESBL-positive phenotype ranged from 13.0 to 31.4% annually with the highest percentage occurring in 2010, when there was a small number of isolates sampled (35). The ceftaroline MIC range for all E. coli was ≤0.015 to N16 μg/mL with 72.6% of the isolates exhibiting susceptibility (CLSI, 2013) to ceftaroline at ≤0.5 μg/mL (Table 1). All E. coli were susceptible to meropenem; however, susceptibility to levofloxacin was low at 54.7% (Table 1). Ceftaroline was active against the non-ESBL phenotype E. coli with a MIC50/90 at 0.12/1 μg/mL; 89.9% susceptible (Table 1). Other agents such as ampicillin-sulbactam (46.1%), tetracycline (70.8%), and levofloxacin (66.3%) showed poor activity against the non-ESBL phenotype strains (data not shown). Against K. pneumoniae (459; 18.3% ESBL phenotype), ceftaroline exhibited an MIC range of 0.03 to N16 μg/mL (MIC50/90, 0.12/N16 μg/

In this study, ceftaroline was shown to be highly active against a large collection of Gram-positive and Gram-negative respiratory tract pathogens from patients in the USA (2009 through 2011). Although nearly one-fourth (23.5%) of the S. pneumoniae isolates were resistant to penicillin, none were resistant to ceftaroline. Ceftriaxone susceptibility was less than 90%; yearly rates of ceftriaxone non-susceptibility ranged from 10.8 to 13.5%. Only 49.8% of the penicillin-resistant strains were ceftriaxone susceptible. Ceftaroline activity, as for other β-lactams, decreased as penicillin MIC values increased; however, no pneumococcal isolate exhibited a ceftaroline MIC higher than 0.5 μg/mL. Approximately 50% of S. aureus were MRSA (yearly MRSA rate ranged from 47.9 to 49.7%). The MRSA rate for community-acquired S. aureus collected in this study was lower (45.1%) than for those isolates, which were nosocomially acquired (57.1%). Ceftaroline was more active against MSSA isolates (MIC50 and MIC90, 0.25 μg/mL; 100% susceptible) than against MRSA (MIC50/90, 0.5/1 μg/mL; 96.2% susceptible). All isolates, which exhibited an MIC value that was above the ceftaroline applied susceptible interpretive breakpoint (CLSI, 2013; Teflaro® Package Insert, 2012), had an MIC value at 2 μg/mL (CLSI intermediate category). Susceptibility of MSSA to most agents tested was N90% except for erythromycin and levofloxacin. There were a number of agents, which showed activity against both MRSA and MSSA including daptomycin, vancomycin, linezolid, tigecycline, and ceftaroline. Of those agents, only tigecycline and ceftaroline also have activity against Gram-negative CABP pathogens. Ceftaroline was highly active against the Gram-negative respiratory pathogens such as H. influenzae and M. catarrhalis including βlactamase–positive strains. Although MIC values were slightly higher for β-lactamase–positive H. influenzae (MIC90, 0.06 μg/mL) than for βlactamase–negative strains (≤0.015 μg/mL), all isolates remained susceptible to ceftaroline. For the Enterobacteriaceae, ceftaroline was active against non-ESBL phenotype strains (MIC50/90 at 0.12/1 μg/mL; 89.9% susceptible), but not against ESBL-positive phenotype strains. In previous reports based on isolates from the USA from a variety of infection types including bloodstream, respiratory tract, acute bacterial skin and skin structure, urinary tract, and other miscellaneous infections, it was shown that the highest MIC value for MSSA was 1 μg/mL (MIC90, 0.25 μg/mL) and for MRSA, 2 μg/mL (MIC90, 1 μg/mL) (Farrell et al., 2012; Flamm et al., 2012). These values were similar to those seen in the current study for S. aureus from respiratory tract infections. For S. pneumoniae from medical centers in the USA, ceftaroline was previously shown to be 16-fold more active than ceftriaxone with the highest MIC value for ceftaroline at 0.5 μg/mL (Farrell et al., 2012; Pfaller et al., 2012). In the current study of respiratory tract isolates collected from USA medical centers during 2009–2011, all S. pneumoniae isolates also tested at ≤0.5 μg/mL (100.0% susceptible). In summary, ceftaroline demonstrated in vitro activity against this collection of contemporary Gram-positive and Gram-negative pathogens from the USA associated with respiratory tract infections. During the period 2009 through 2011 of this study, no S. pneumoniae

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nor H. influenzae isolates with MIC values N0.5 μg/mL (CLSI susceptible breakpoint) were detected nor were any S. aureus with an MIC value at N2 μg/mL. Continued surveillance activities are warranted to track the potent activity of ceftaroline and other antimicrobial agents, which could be applied for the treatment of lower respiratory tract infections, thus assuring that contemporary information is available to address the evolving issues of bacterial antimicrobial resistance. Acknowledgment This study at JMI Laboratories was supported by an Educational/ Research Grant from Forest/Cerexa, and JMI Laboratories received compensation fees for services in relation to preparing the manuscript, which was funded by Forest/Cerexa. JMI Laboratories, Inc., has received research and educational grants in 2010–2012 from Achaogen, Aires, American Proficiency Institute, Anacor, Astellas, AstraZeneca, bioMerieux, Cempra, Cerexa, Contrafect, Cubist, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, ThermoFisher, and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regard to speakers bureaus and stock options, none to declare. References Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broadspectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother 2010;65(Suppl 4):iv9–iv16. Clinical and Laboratory Standards Institute (CLSI). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition, M07-A9. Wayne, PA: CLSI; 2012. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing: 23rd informational supplement (M100-S23). Wayne, PA: CLSI; 2013. 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(Suppl 3):iii45–51. 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(Suppl 3):S206–14. File Jr TM. Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia. Clin Microbiol Infect 2006;12(Suppl 3):31–41. File Jr TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010;122:130–41.

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