Abstract
A total of 84,704 isolates were collected from 191 medical centers in 2009 to 2013 and tested for susceptibility to ceftaroline and comparator agents by broth microdilution methods. Ceftaroline inhibited all Staphylococcus aureus isolates at ≤2 μg/ml and was very active against methicillin-resistant strains (MIC at which 90% of the isolates tested are inhibited [MIC90], 1 μg/ml; 97.6% susceptible). Among Streptococcus pneumoniae isolates, the highest ceftaroline MIC was 0.5 μg/ml, and ceftaroline activity against the most common Enterobacteriaceae species (MIC50, 0.12 μg/ml; 78.9% susceptible) was similar to that of ceftriaxone (MIC50, ≤0.25 μg/ml; 86.8% susceptible).
TEXT
Ceftaroline fosamil (Teflaro), the prodrug of ceftaroline, was approved in 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to susceptible isolates of Staphylococcus aureus (including methicillin-susceptible [MSSA] and -resistant [MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca. Ceftaroline fosamil was also approved for community-acquired bacterial pneumonia (CABP) due to Streptococcus pneumoniae (including cases with concurrent bacteremia), S. aureus (MSSA only), Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E. coli (1–3).
An antimicrobial resistance surveillance program, known as the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) Program, was designed to monitor the activity of ceftaroline and comparator agents (4). This program provides contemporary and longitudinal information on the activity of this agent against relevant pathogens. Previous reports from the AWARE program have provided analyses of ceftaroline activity against bacterial isolates recovered from indicated sites of infections (ABSSSI and CAPB) during the initial years of the program (5, 6) as well as resistant subsets of organisms from indicated species (4, 7, 8). In this report, we summarized the results of 5 years (2009 to 2013) of the AWARE Program in the United States.
A total of 84,704 bacterial isolates were collected from clinical infections, as defined by local clinical criteria. The isolates were collected from January 2009 to December 2013 from 191 medical centers distributed across all nine U.S. census regions, and target numbers of strains for each of the requested bacterial species/genus were predetermined by study protocol. Only isolates deemed clinically relevant by the submitting laboratory were included in the investigation. If multiple isolates of the same organism (species) were collected multiple times during the same infection episode, the investigator was instructed to provide only the first isolate. The isolates were from skin and skin structure infections (27,395; 32.3%), respiratory tract infections (23,931; 28.3%), bloodstream infections (17,685; 20.9%), urinary tract infections (7,814; 9.2%), intra-abdominal infections (1,521; 1.8%), and infections at other sites (6,358; 7.5%). Isolates were sent to the coordinator laboratory (JMI Laboratories, North Liberty, IA, USA) for reference susceptibility testing. Only one strain per patient infection episode was included in the surveillance.
Isolates were tested for susceptibility to ceftaroline and multiple comparator agents by reference broth microdilution methods as described by Clinical and Laboratory Standards Institute (CLSI) standard M07-A9 (9), and CLSI interpretations were based on M100-S24 and M45-A2 breakpoints (9, 10). Ceftaroline and comparator agents were tested simultaneously using the same bacterial inoculum and testing reagents. Isolates with positive extended-spectrum β-lactamase (ESBL) screening test results, i.e., MICs 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 KPC, may also produce an ESBL phenotype, these strains were grouped together because they usually demonstrate resistance to various broad-spectrum β-lactam compounds (10). K. pneumoniae isolates with MICs of >1 μg/ml for meropenem or imipenem isolated in 2009, 2010, 2012, and 2013 (all years except 2011) were screened for blaKPC by PCR as previously described (11, 12). Streptococcal isolates were tested in Mueller-Hinton broth supplemented with 2.5 to 5% lysed horse blood, and Haemophilus species isolates were tested in Haemophilus test medium (HTM), whereas all other organisms were tested in cation-adjusted Mueller-Hinton broth. Concurrent testing of quality control (QC) strains ensured proper test conditions.
Staphylococcus aureus and coagulase-negative staphylococci (CoNS) were particularly susceptible to ceftaroline, with MICs at which 90% of the isolates tested were inhibited (MIC90s) of 1 and 0.5 μg/ml, respectively. Ceftaroline inhibited 98.8% of S. aureus strains at the susceptible breakpoint of ≤1 μg/ml (Table 1). Rates of susceptibility to levofloxacin and clindamycin were 60.2 and 71.1%, respectively, according to CLSI breakpoints. Rates of susceptibility to daptomycin, linezolid, tigecycline, and vancomycin were >99.9% (data not shown).
TABLE 1.
Summary of ceftaroline activity tested against 84,704 bacterial isolates from U.S. medical centers (2009 to 2013)
| Organisma | Total no. of isolates | No. of isolates (cumulative %) inhibited at ceftaroline MIC (μg/ml) of: |
MIC50 | MIC90 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | ||||
| Staphylococcus aureus | 25,192 | 4 (0.0) | 9 (0.1) | 64 (0.3) | 1,193 (5.0) | 11,035 (48.8) | 6,931 (76.4) | 5,656 (98.8) | 300 (100.0) | 0.5 | 1 | ||||
| MSSA | 12,678 | 4 (0.0) | 9 (0.1) | 64 (0.6) | 1,183 (9.9) | 10,832 (95.4) | 583 (>99.9) | 3 (100.0) | 0.25 | 0.25 | |||||
| MRSA | 12,514 | 10 (0.1) | 203 (1.7) | 6,348 (52.4) | 5,653 (97.6) | 300 (100.0) | 0.5 | 1 | |||||||
| Coagulase-negative staphylococci | 3,379 | 32 (0.9) | 90 (3.6) | 683 (23.8) | 513 (39.0) | 1,184 (74.0) | 788 (97.4) | 79 (99.7) | 10 (100.0) | 0.25 | 0.5 | ||||
| Streptococcus pneumoniae | 10,096 | 6,186 (61.3) | 902 (70.2) | 916 (79.3) | 1,441 (93.6) | 573 (99.2) | 78 (100.0) | ≤0.015 | 0.12 | ||||||
| Penicillin S (MIC, ≤2 μg/ml) | 8,937 | 6,186 (69.2) | 902 (79.3) | 907 (89.5) | 907 (99.6) | 33 (>99.9) | 2 (100.0) | ≤0.015 | 0.12 | ||||||
| Penicillin I (MIC, 4 μg/ml) | 1,042 | 8 (0.8) | 531 (51.7) | 467 (96.5) | 36 (100.0) | 0.12 | 0.25 | ||||||||
| Penicillin R (MIC, ≥8 μg/ml) | 117 | 1 (0.9) | 3 (3.4) | 73 (65.8) | 40 (100.0) | 0.25 | 0.5 | ||||||||
| Ceftriaxone non-S (MIC, ≥2 μg/ml) | 952 | 1 (0.1) | 3 (0.4) | 5 (0.8) | 365 (39.3) | 501 (91.9) | 77 (100.0) | 0.25 | 0.25 | ||||||
| Viridans group streptococci | 2,332 | 1,136 (48.7) | 747 (80.7) | 250 (91.5) | 91 (95.4) | 49 (97.5) | 43 (99.3) | 16 (100.0) | 0.03 | 0.06 | |||||
| Beta-hemolytic streptococci | 5,679 | 5,162 (90.9) | 497 (99.6) | 19 (>99.9) | 1 (100.0) | ≤0.015 | ≤0.015 | ||||||||
| Streptococcus pyogenes | 2,166 | 2,155 (99.5) | 8 (99.9) | 2 (100.0) | 1 (100.0) | ≤0.015 | ≤0.015 | ||||||||
| Streptococcus agalactiae | 2,873 | 2,465 (85.8) | 405 (99.9) | 3 (100.0) | ≤0.015 | 0.03 | |||||||||
| Enterococcus faecalis | 2,315 | 3 (0.1) | 12 (0.6) | 49 (2.8) | 582 (27.9) | 1,092 (75.1) | 229 (85.0) | 305 (98.1) | 31 (99.5) | 12 (100.0) | 2 | 8 | |||
| Enterobacteriaceae | 25,139 | 139 (0.6) | 1,251 (5.5) | 6,443 (31.2) | 6,578 (57.3) | 3,259 (70.3) | 2,161 (78.9) | 1,294 (84.0) | 453 (85.8) | 301 (87.0) | 273 (88.1) | 303 (89.3) | 2,684 (100.0) | 0.12 | >16 |
| Escherichia coli | 8,287 | 76 (0.9) | 744 (9.9) | 2,645 (41.8) | 2,164 (67.9) | 902 (78.8) | 480 (84.6) | 223 (87.3) | 86 (88.3) | 55 (89.0) | 60 (89.7) | 58 (90.4) | 794 (100.0) | 0.12 | 16 |
| Non-ESBL phenotype | 7,306 | 76 (1.0) | 744 (11.2) | 2,643 (47.4) | 2,151 (76.8) | 882 (88.9) | 461 (95.2) | 212 (98.1) | 72 (99.1) | 35 (99.6) | 16 (99.8) | 10 (99.9) | 4 (100.0) | 0.12 | 0.5 |
| ESBL phenotype | 981 | 2 (0.2) | 13 (1.5) | 20 (3.6) | 19 (5.5) | 11 (6.6) | 14 (8.1) | 20 (10.1) | 44 (14.6) | 48 (19.5) | 790 (100.0) | >16 | >16 | ||
| Klebsiella spp. | 7,381 | 34 (0.5) | 263 (4.0) | 2,198 (33.8) | 2,110 (62.4) | 963 (75.4) | 514 (82.4) | 207 (85.2) | 60 (86.0) | 60 (86.8) | 55 (87.6) | 51 (88.3) | 866 (100.0) | 0.12 | >16 |
| Non-ESBL phenotype | 6,298 | 34 (0.5) | 263 (4.7) | 2,197 (39.6) | 2,107 (73.1) | 962 (88.3) | 508 (96.4) | 187 (99.4) | 21 (99.7) | 10 (99.9) | 3 (99.9) | 3 (100.0) | 3 (100.0) | 0.12 | 0.5 |
| ESBL phenotype | 1,083 | 1 (0.1) | 3 (0.4) | 1 (0.5) | 6 (1.0) | 20 (2.9) | 39 (6.5) | 50 (11.1) | 52 (15.9) | 48 (20.3) | 863 (100.0) | >16 | >16 | ||
| Klebsiella pneumoniae | 5,833 | 31 (0.5) | 220 (4.3) | 1,952 (37.8) | 1,689 (66.7) | 536 (75.9) | 320 (81.4) | 162 (84.2) | 53 (85.1) | 51 (86.0) | 47 (86.8) | 36 (87.4) | 736 (100.0) | 0.12 | >16 |
| Klebsiella oxytoca | 1,548 | 3 (0.2) | 43 (3.0) | 246 (18.9) | 421 (46.1) | 427 (73.6) | 194 (86.2) | 45 (89.1) | 7 (89.5) | 9 (90.1) | 8 (90.6) | 15 (91.6) | 130 (100.0) | 0.25 | 4 |
| Proteus mirabilis | 1,883 | 2 (0.1) | 35 (2.0) | 650 (36.5) | 771 (77.4) | 184 (87.2) | 97 (92.4) | 37 (94.3) | 17 (95.2) | 8 (95.6) | 4 (95.9) | 14 (96.6) | 64 (100.0) | 0.12 | 0.5 |
| Non-ESBL phenotype | 1,547 | 2 (0.1) | 29 (2.0) | 584 (39.8) | 649 (81.7) | 161 (92.1) | 77 (97.1) | 29 (99.0) | 13 (99.8) | 1 (99.9) | 1 (99.9) | 1 (100.0) | 0.12 | 0.25 | |
| ESBL phenotype | 80 | 5 (6.3) | 3 (10.0) | 13 (26.3) | 59 (100.0) | >16 | >16 | ||||||||
| Enterobacter cloacae | 2,465 | 12 (0.5) | 35 (1.9) | 112 (6.5) | 622 (31.7) | 695 (59.9) | 309 (72.4) | 95 (76.3) | 39 (77.8) | 25 (78.9) | 33 (80.2) | 52 (82.3) | 436 (100.0) | 0.25 | >16 |
| Enterobacter aerogenes | 894 | 3 (0.3) | 21 (2.7) | 309 (37.2) | 268 (67.2) | 58 (73.7) | 32 (77.3) | 17 (79.2) | 11 (80.4) | 11 (81.7) | 9 (82.7) | 22 (85.1) | 133 (100.0) | 0.12 | >16 |
| Morganella morganii | 911 | 8 (0.9) | 74 (9.0) | 253 (36.8) | 182 (56.8) | 74 (64.9) | 57 (71.1) | 26 (74.0) | 24 (76.6) | 22 (79.0) | 23 (81.6) | 23 (84.1) | 145 (100.0) | 0.12 | >16 |
| Citrobacter koseri | 514 | 3 (0.6) | 7 (1.9) | 156 (32.3) | 251 (81.1) | 31 (87.2) | 41 (95.1) | 13 (97.7) | 2 (98.1) | 2 (98.4) | 1 (98.6) | 1 (98.8) | 6 (100.0) | 0.12 | 0.5 |
| Citrobacter freundii | 574 | 1 (0.2) | 11 (2.1) | 146 (27.5) | 211 (64.3) | 61 (74.9) | 9 (76.5) | 4 (77.2) | 5 (78.0) | 6 (79.1) | 18 (82.2) | 102 (100.0) | 0.25 | >16 | |
| Serratia marcescens | 1,378 | 1 (0.1) | 1 (0.1) | 3 (0.4) | 71 (5.5) | 467 (39.4) | 541 (78.7) | 134 (88.4) | 47 (91.8) | 45 (95.1) | 24 (96.8) | 44 (100.0) | 1 | 4 | |
| Proteus vulgaris | 305 | 3 (1.0) | 7 (3.3) | 8 (5.9) | 41 (19.3) | 50 (35.7) | 53 (53.1) | 30 (63.0) | 25 (71.1) | 14 (75.7) | 17 (81.3) | 57 (100.0) | 1 | >16 | |
| Providencia spp. | 547 | 1 (0.2) | 67 (12.4) | 101 (30.9) | 53 (40.6) | 29 (45.9) | 53 (55.6) | 73 (68.9) | 46 (77.3) | 41 (84.8) | 23 (89.0) | 23 (93.2) | 37 (100.0) | 0.5 | 16 |
| Pseudomonas aeruginosa | 4,115 | 4 (0.1) | 19 (0.6) | 46 (1.7) | 104 (4.2) | 260 (10.5) | 781 (29.5) | 1,150 (57.4) | 1,751 (100.0) | 16 | >16 | ||||
| Acinetobacter baumannii | 632 | 3 (0.5) | 19 (3.5) | 72 (14.9) | 86 (28.5) | 63 (38.4) | 17 (41.1) | 372 (100.0) | >16 | >16 | |||||
| Haemophilus influenzae | 3,906 | 3,403 (87.1) | 386 (97.0) | 87 (99.2) | 22 (99.8) | 6 (99.9) | 2 (100.0) | ≤0.015 | 0.03 | ||||||
| β-Lactamase negative | 2,921 | 2,701 (92.5) | 202 (99.4) | 16 (99.9) | 2 (100.0) | ≤0.015 | ≤0.015 | ||||||||
| β-Lactamase positive | 985 | 702 (71.3) | 184 (89.9) | 71 (97.2) | 20 (99.2) | 6 (99.8) | 2 (100.0) | ≤0.015 | 0.06 | ||||||
| Haemophilus parainfluenzae | 408 | 354 (86.8) | 29 (93.9) | 10 (96.3) | 8 (98.3) | 2 (98.8) | 3 (99.5) | 1 (99.8) | 1 (100.0) | ≤0.015 | 0.03 | ||||
| Moraxella catarrhalis | 1,511 | 185 (12.2) | 379 (37.3) | 481 (69.2) | 354 (92.6) | 100 (99.2) | 10 (99.9) | 2 (100.0) | 0.06 | 0.12 | |||||
Abbreviations: S, susceptible; I, intermediate; R, resistant; ESBL, extended-spectrum β-lactamase.
The overall methicillin-resistant S. aureus (MRSA) rate was 49.7%, varying from a low of 46.0% in 2009 to a high of 50.5% in 2010, with no trend toward increase or decrease during the study period (Table 2). Overall, 97.6% of MRSA isolates (12,514 strains tested) were susceptible to ceftaroline (MIC50/90, 0.5/1 μg/ml; highest MIC, 2 μg/ml [Table 1]). When tested against MSSA, ceftaroline (MIC50 and MIC90, 0.25 μg/ml [Table 1]) was 16-fold more potent than ceftriaxone (MIC50 and MIC90, 4 μg/ml [data not shown]).
TABLE 2.
Yearly frequency of selected resistance phenotypes
| Resistance phenotype | Frequency (%) |
|||||
|---|---|---|---|---|---|---|
| 2009 | 2010 | 2011 | 2012 | 2013 | Overall | |
| MRSA | 46.0 | 50.5 | 49.7 | 47.3 | 49.9 | 49.7 |
| Ceftaroline-NSa S. aureus | 1.6 | 0.8 | 1.2 | 1.3 | 1.3 | 1.2 |
| Ceftriaxone-NS S. pneumoniae (MIC, ≥2 μg/ml) | 12.7 | 10.6 | 11.6 | 9.2 | 6.5 | 9.4 |
| Penicillin-NS S. pneumoniae (MIC, ≥4 μg/ml) | 16.0 | 14.6 | 14.8 | 10.2 | 7.2 | 11.5 |
| Ceftriaxone-NS Enterobacteriaceae | 10.9 | 11.5 | 14.0 | 13.8 | 13.4 | 13.2 |
| ESBL-phenotype E. coli | 9.9 | 11.9 | 12.1 | 11.9 | 12.3 | 11.8 |
| ESBL-phenotype K. pneumoniae | 14.5 | 12.3 | 15.5 | 16.0 | 17.0 | 15.7 |
| Meropenem-NS K. pneumoniae | 5.4 | 4.1 | 5.1 | 6.2 | 6.8 | 5.9 |
| β-Lactamase-positive H. influenzae | 23.7 | 27.8 | 27.0 | 23.3 | 23.8 | 25.2 |
NS, nonsusceptible.
Ceftaroline (MIC50/90, ≤0.015/0.12 μg/ml) inhibited all (100.0%) 10,096 S. pneumoniae strains at the MIC of ≤0.5 μg/ml, which is the susceptible breakpoint established by the CLSI and U.S. FDA (3, 10), and showed potent activity against ceftriaxone-nonsusceptible (MIC, ≥2 μg/ml) strains (n = 952; ceftaroline MIC50 and MIC90, 0.25 μg/ml). When tested against penicillin-resistant (MIC, ≥8 μg/ml) strains (n = 117), ceftaroline (MIC50/90, 0.25/0.5 μg/ml [Table 1]) was 8- to 16-fold more potent than ceftriaxone (MIC50/90, 2/8 μg/ml [data not shown]). The overall rate of ceftriaxone-nonsusceptible S. pneumoniae was 9.4% and decreased gradually during the study period from 12.7% in 2009 to 6.5% in 2013 (Table 2). Penicillin-nonsusceptible S. pneumoniae rates showed a similar trend toward lower rates, varying from 16.0% in 2009 to 7.2% in 2013 (Table 2).
Ceftaroline demonstrated potent activity against beta-hemolytic streptococci (MIC50 and MIC90, ≤0.015 μg/ml; highest MIC, 0.12 μg/ml; 100.0% susceptible) and viridans group streptococci (MIC50/90, 0.03/0.06 μg/ml; highest MIC, 1 μg/ml) but exhibited limited activity against Enterococcus faecalis (MIC50/90, 2/8 μg/ml [Table 1]).
Ceftaroline activity against Enterobacteriaceae strains (n = 25,139; MIC50/90, 0.12/>32 μg/ml; 78.9% susceptible [Tables 1 and 2]) was similar to those of ceftriaxone (MIC50/90, ≤0.25/8 μg/ml; 86.8% susceptible [data not shown]) and ceftazidime (MIC50/90, 0.12/8 μg/ml; 89.7% susceptible [data not shown]). Non-ESBL-phenotype strains were generally susceptible to ceftaroline (MIC50/90, 0.12/0.25 to 0.5 μg/ml; 95.2 to 97.1% susceptible), whereas ESBL screen-positive strains exhibited elevated ceftaroline MIC values (MIC50, >16 μg/ml [Table 1]). The prevalence of ceftriaxone-nonsusceptible Enterobacteriaceae increased from 10.9 to 11.5% in 2009 to 2010 to 13.4 to 14.0% in 2011 to 2013 (Table 2).
ESBL phenotypes were observed in 11.8% of E. coli and 15.7% of K. pneumoniae isolates overall. Among E. coli isolates, the ESBL phenotype rate increased from 9.9% in 2009 to 11.9% in 2010 but showed only minor variations (11.9 to 12.3%) in the following 4 years (2010 to 2013 [Table 2]). In contrast, ESBL phenotype rates increased from 14.5% in 2009 to 17.0% in 2013 among K. pneumoniae isolates (Table 2), and all cephalosporins showed limited activity against ESBL-phenotype strains (data not shown).
Among 284 carbapenem-nonsusceptible K. pneumoniae isolates screened for blaKPC, 266 (93.4%) were positive, and the number of medical centers with KPC-producing strains increased from 9 and 12 in 2009 and 2010, respectively, to 25 and 23 in 2012 and 2013, respectively. Thus, these results indicate that the yearly increase of K. pneumoniae with ESBL phenotype and the corresponding increase of meropenem-nonsusceptible strains were mainly due to the dissemination of KPC-producing strains in some geographic regions (Table 2) (11, 12).
Ceftaroline inhibited all (100.0%) H. influenzae strains (n = 3,906) at MICs of 0.5 μg/ml or less (Table 1). Overall, 25.2% of H. influenzae strains were β-lactamase producers, with rates varying from a low of 23.3% in 2012 to a high of 27.8% in 2010 and no trend toward increase or decrease during the study period (Table 2). Ceftaroline was also active against Haemophilus parainfluenzae (MIC50/90, ≤0.015/0.03 μg/ml) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 μg/ml) strains, independent of β-lactamase production (Table 1).
Ceftaroline represents a new class of cephalosporin with anti-MRSA activity. Favorable features of ceftaroline include avid binding to penicillin-binding proteins 2a and 2x of MRSA and penicillin-resistant S. pneumoniae, respectively, and lack of antagonism with other agents used in combination (4, 13, 14). Numerous published studies confirm the potent activity of ceftaroline against S. aureus and S. pneumoniae, including multidrug-resistant strains, such as S. aureus with decreased susceptibility to linezolid, daptomycin, or vancomycin and emerging S. pneumoniae serotypes 19A, 35B, and 6C (7, 8, 15). The data presented here provide further documentation of the excellent activity of ceftaroline when tested against significant collections of contemporary U.S. isolates. We evaluated ceftaroline activity against 25,192 S. aureus and 10,096 S. pneumoniae contemporary clinical isolates collected from 191 U.S. medical centers distributed throughout all nine census regions, and ceftaroline was active against 98.8% of S. aureus and all (100.0%) of the S. pneumoniae isolates at the respective susceptible breakpoints. It is important to note that all ceftaroline-nonsusceptible S. aureus (all MRSA) isolates exhibited ceftaroline MIC values only 1 doubling dilution higher than the susceptible breakpoint (i.e., 2 μg/ml, intermediate), and no ceftaroline-resistant S. aureus isolate was detected during these 5 years of surveillance in the United States. Furthermore, Monte Carlo simulations using ceftaroline pharmacokinetic and pharmacodynamic properties have indicated that target attainment rates (stasis or 1 log10 CFU/g bacterial cell kill) remained >95% up to an MIC of 2 μg/ml, suggesting clinical efficacy in treating ABSSSI against strains up to this MIC (16).
Ceftaroline also demonstrated potent and consistent (2009 to 2013) in vitro activity against large collections of beta-hemolytic streptococci (n = 5,679; MIC90, ≤0.015 μg/ml), viridans group streptococci (n = 2,332; MIC90, 0.06 μg/ml), coagulase-negative staphylococci (CoNS) (n = 3,379; MIC90, 0.5 μg/ml), H. influenzae (n = 3,906; MIC90, 0.03 μg/ml), M. catarrhalis (n = 1,511; MIC90, 0.12 μg/ml), and non-ESBL-phenotype strains of Enterobacteriaceae (n = 15,151; MIC90, 0.25 to 0.5 μg/ml). These results are similar to those of previous publications and indicate that ceftaroline in vitro activity against key bacterial species remained stable since its approval for clinical use in the United States in 2010 (17). These results, coupled with the documented efficacy of ceftaroline fosamil in the treatment of serious infections (1, 2, 18), make this agent particularly attractive in the initial management of CABP and ABSSI patients requiring hospitalization.
ACKNOWLEDGMENTS
This study performed at JMI Laboratories was supported in part 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 the sponsor.
We thank all AWARE participants for providing bacterial isolates for this surveillance program.
This study was supported by Cerexa, Inc., a wholly owned subsidiary of Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design and decision to present these results. Forest Laboratories, Inc., had no involvement in the collection, analysis, and interpretation of data. JMI Laboratories, Inc., has also received research and educational grants in 2012 to 2014 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cubist, Daiichi, Dipexium, Durata, Fedora, 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, and Waterloo. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, and Theravance. In regards to speakers bureaus and stock options, there are none to declare.
REFERENCES
- 1.Corey GR, Wilcox M, Talbot GH, Friedland HD, Baculik T, Witherell GW, Critchley I, Das AF, Thye D. 2010. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 51:641–650. doi: 10.1086/655827. [DOI] [PubMed] [Google Scholar]
- 2.File TM Jr, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley I, Thye D. 2010. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 51:1395–1405. doi: 10.1086/657313. [DOI] [PubMed] [Google Scholar]
- 3.Forest Pharmaceuticals, Inc. 2012. Teflaro package insert. Forest Pharmaceuticals, Inc, St. Louis, MO: http://www.frx.com/pi/Teflaro_pi.pdf. [Google Scholar]
- 4.Farrell DJ, Castanheira M, Mendes RE, Sader HS, Jones RN. 2012. 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 55(Suppl 3):S206–S214. doi: 10.1093/cid/cis563. [DOI] [PubMed] [Google Scholar]
- 5.Flamm RK, Sader HS, Jones RN. 2014. Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE program, 2009–2011. Diagn Microbiol Infect Dis 78:437–442. doi: 10.1016/j.diagmicrobio.2013.10.020. [DOI] [PubMed] [Google Scholar]
- 6.Pfaller MA, Flamm RK, Sader HS, Jones RN. 2014. Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2009–2011). Diagn Microbiol Infect Dis 78:422–428. doi: 10.1016/j.diagmicrobio.2013.08.027. [DOI] [PubMed] [Google Scholar]
- 7.Sader HS, Flamm RK, Jones RN. 2013. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. Antimicrob Agents Chemother 57:3178–3181. doi: 10.1128/AAC.00484-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Flamm RK, Sader HS, Farrell DJ, Jones RN. 2014. Antimicrobial activity of ceftaroline tested against drug resistant subsets of Streptococcus pneumoniae from U.S. medical centers. Antimicrob Agents Chemother 58:2468–2471. doi: 10.1128/AAC.02557-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Clinical and Laboratory Standards Institute. 2012. M07-A9 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—9th ed. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 10.Clinical and Laboratory Standards Institute. 2014. M100-S24 Performance standards for antimicrobial susceptibility testing: 24th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 11.Castanheira M, Farrell SE, Deshpande LM, Mendes RE, Jones RN. 2013. 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 57:3012–3020. doi: 10.1128/AAC.02252-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Castanheira M, Farrell SE, Krause KM, Jones RN, Sader HS. 2014. Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother 58:833–838. doi: 10.1128/AAC.01896-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kosowska-Shick K, McGhee PL, Appelbaum PC. 2010. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother 54:1670–1676. doi: 10.1128/AAC.00019-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Vidaillac C, Leonard SN, Sader HS, Jones RN, Rybak MJ. 2009. In vitro activity of ceftaroline alone and in combination against clinical isolates of resistant gram-negative pathogens, including beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 53:2360–2366. doi: 10.1128/AAC.01452-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Mendes RE, Costello AJ, Jacobs MR, Biek D, Critchley IA, Jones RN. 2014. Serotype distribution and antimicrobial susceptibility of USA Streptococcus pneumoniae isolates collected prior to and post introduction of 13-valent pneumococcal conjugate vaccine. Diagn Microbiol Infect Dis 80:19–25. doi: 10.1016/j.diagmicrobio.2014.05.020. [DOI] [PubMed] [Google Scholar]
- 16.Drusano GL. 2010. Pharmacodynamics of ceftaroline fosamil for complicated skin and skin structure infection: rationale for improved anti-methicillin-resistant Staphylococcus aureus activity. J Antimicrob Chemother 65(Suppl 4):iv33–iv39. doi: 10.1093/jac/dkq253. [DOI] [PubMed] [Google Scholar]
- 17.Flamm RK, Sader HS, Farrell DJ, Jones RN. 2012. 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 56:2933–2940. doi: 10.1128/AAC.00330-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shirley DA, Heil EL, Johnson JK. 2013. Ceftaroline fosamil: a brief clinical review. Infect Dis Ther 2:95–110. doi: 10.1007/s40121-013-0010-x. [DOI] [PMC free article] [PubMed] [Google Scholar]