Abstract
The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program is a sentinel resistance monitoring system designed to track the activity of ceftaroline and comparator agents. In the United States, a total of 8,434 isolates were collected during the 2010 surveillance program from 65 medical centers distributed across the nine census regions (5 to 10 medical centers per region). All organisms were isolated from documented infections, including 3,055 (36.2%) bloodstream infections, 2,282 (27.1%) respiratory tract infections, 1,965 (23.3%) acute bacterial skin and skin structure infections, 665 (7.9%) urinary tract infections, and 467 (5.5%) miscellaneous other infection sites. Ceftaroline was the most potent β-lactam agent tested against staphylococci. The MIC90 values were 1 μg/ml for methicillin-resistant Staphylococcus aureus (MRSA; 98.4% susceptible) and 0.5 μg/ml for methicillin-resistant coagulase-negative staphylococci (CoNS). Ceftaroline was 16- to 32-fold more potent than ceftriaxone against methicillin-susceptible staphylococcal strains. All staphylococcus isolates (S. aureus and CoNS) were inhibited at ceftaroline MIC values of ≤2 μg/ml. Ceftaroline also displayed potent activity against streptococci (MIC90, 0.015 μg/ml for beta-hemolytic streptococci; MIC90, 0.25 μg/ml for penicillin-resistant Streptococcus pneumoniae). Potent activity was also shown against Gram-negative pathogens (Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Furthermore, wild-type strains of Enterobacteriaceae (non-extended-spectrum β-lactamase [ESBL]-producing strains and non-AmpC-hyperproducing strains) were often susceptible to ceftaroline. Continued monitoring through surveillance networks will allow for the assessment of the evolution of resistance as this new cephalosporin is used more broadly to provide clinicians with up-to-date information to assist in antibiotic stewardship and therapeutic decision making.
INTRODUCTION
Aamong the most prescribed antimicrobial agents in the community and hospital settings are β-lactam antibiotics. They have a long history of use, demonstrating both safety and efficacy over a broad range of infections and organisms. However, as frequently occurs with large-scale and long-term use of antimicrobials, there has been a selection for variant strains of bacteria with altered β-lactamases and/or altered drug targets (penicillin binding proteins [PBPs]) (5, 12, 18, 19, 25, 26, 28). This selection has limited the utility of this well-known and versatile class of antibiotics (2, 4, 13, 17, 22, 24).
Multidrug resistance in key bacterial pathogens has been identified as a major public health concern (4, 15). The Infectious Diseases Society of America (IDSA) published a white paper in 2004 (14) and provided an update in 2009 (4) in which it identified a group of organisms designated the ESKAPE pathogens, an acronym that stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella spp., Acinetobacter spp., Pseudomonas spp., and Enterobacter spp. These pathogens were identified as those most urgently requiring new effective therapies, as these bacteria cause severe morbidity and mortality, and there are limited treatment options.
Ceftaroline fosamil (Teflaro) is an N-phosphonoamino water-soluble prodrug cephalosporin with the active form, ceftaroline, possessing broad-spectrum in vitro antimicrobial activity (11). Its bioactive form, ceftaroline, is rapidly released in vivo upon hydrolysis of the phosphonate group (1, 3, 20, 23). The spectrum of activity for ceftaroline includes major pathogens found in acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), including the ESKAPE pathogen S. aureus. Ceftaroline has high affinity for PBP2a, the altered PBP responsible for methicillin and thus β-lactam resistance in S. aureus (3, 16, 20).
Ceftaroline fosamil was approved in 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of ABSSSI due to susceptible isolates of S. aureus (including methicillin-susceptible [MSSA] and -resistant [MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca (11). Ceftaroline fosamil was also approved for CABP due to Streptococcus pneumoniae (including cases with concurrent bacteremia), S. aureus (MSSA only), Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E. coli (11).
A sentinel monitoring system has been designed to track the activity of ceftaroline and comparator agents, known as the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. This program provides contemporary and longitudinal information on the activity of this newly released agent against relevant pathogens. Monitoring provides important data that clinicians may use in their decision-making process in determining appropriate antimicrobial choices. In this report, we present the results from the 2010 U.S. AWARE Program.
MATERIALS AND METHODS
Organism collection.
In 2010, the AWARE program included 65 medical centers in the United States distributed across the nine census regions (5 to 10 medical centers per region). The centers contributed clinical isolates over the time period January through December 2010. Organisms were consecutively collected from clinical infections, and target numbers of strains for each of the requested bacterial species/genera were predetermined by study protocol. Isolates were sent to the central laboratory (JMI Laboratories, North Liberty, IA) for reference susceptibility testing (6–8). Only one strain per patient infection episode was included in the surveillance.
The target numbers of organisms per laboratory site were as indicated: S. aureus, 30; coagulase-negative staphylococci (CoNS), 8; beta-hemolytic streptococci (BHS), 20; S. pneumoniae, 20; viridans group streptococci (VGS), 8; Enterococcus faecalis, 3; E. coli, 10; K. pneumoniae, 10; K. oxytoca, 5; Morganella morganii, 3; H. influenzae, 10; Haemophilus parainfluenzae, 3; and Moraxella catarrhalis, 5. All organisms were isolated from documented infections, including 3,055 (36.2%) bloodstream infections, 2,282 (27.1%) respiratory tract infections (RTI), 1,965 (23.3%) ABSSSI, 665 (7.9%) urinary tract infections (UTI), and 467 (5.5%) miscellaneous other infection sites.
Susceptibility testing.
Isolates were tested for susceptibility to ceftaroline and comparator agents by reference broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) (7). Susceptibility interpretations were based on the CLSI M100-S21 and M45-A documents (6, 8) and on the U.S. FDA package insert labels where CLSI susceptibility was not available (11, 27). Susceptibility results for clindamycin were based on MIC testing without further evaluation for inducibility. Streptococci were tested in Mueller-Hinton broth supplemented with 3 to 5% lysed horse blood, and Haemophilus spp. were tested in Haemophilus test medium, while S. aureus, E. faecalis, and Enterobacteriaceae isolates were tested in cation-adjusted Mueller-Hinton broth. Concurrent testing of quality control (QC) strains ensured proper test conditions. These QC strains included S. aureus ATCC 29213, E. faecalis ATCC 29212, S. pneumoniae ATCC 49619, E. coli ATCC 25922, and H. influenzae ATCC 49247 and 49766. Staphylococci, beta-hemolytic streptococci, S. pneumoniae, and Haemophilus isolates that tested as nonsusceptible to ceftaroline were confirmed by repeat testing. The ESBL-producing phenotype was defined as a MIC of ≥2 μg/ml for ceftazidime, ceftriaxone, or aztreonam (8). The analyses presented in this study addressing ESBL status were derived from this phenotypic definition. No further characterization or confirmation of ESBL status was conducted.
RESULTS
Numbers of target organisms.
The numbers of isolates in 2010 overall for each species/organism group were as indicated: S. aureus, 2,146; CoNS, 486; S. pneumoniae, 1,200; BHS, 1,201; VGS, 492; E. faecalis, 195; E. coli, 657; K. pneumoniae, 653; K. oxytoca, 250; M. morganii, 116; H. influenzae, 770; H. parainfluenzae, 68; M. catarrhalis, 200. The total was 8,434 isolates.
Ceftaroline MIC distributions for key organisms.
MIC distributions for ceftaroline for the main groups and subsets of organisms tested are summarized in Table 1. The in vitro activity of ceftaroline in comparison to those of selected antimicrobial agents tested against isolates from all U.S. census regions combined (all United States) is summarized in Tables 2 to 4.
Table 1.
Frequency of occurrence and cumulative percent distribution of ceftaroline MICs for all AWARE 2010 pathogens
| Organism and subgroup (no. of isolates) | No. of isolates (cumulative %) inhibited at ceftaroline MIC (μg/ml) of: |
MIC50 | MIC90 | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.008 | 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |||
| Staphylococcus aureus (2,146) | 0 (0.0) | 0 (0.0) | 1 (0.0) | 5 (0.3) | 117 (5.7) | 943 (49.7) | 748 (84.5) | 315 (99.2) | 17 (100) | 0.5 | 1 | |||||
| MSSA (1,074) | 0 (0.0) | 0 (0.0) | 1 (0.1) | 5 (0.6) | 117 (11.5) | 924 (97.5) | 27 (100) | 0.25 | 0.25 | |||||||
| MRSA (1,072) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 20 (1.9) | 721 (69.1) | 314 (98.4) | 17 (100) | 0.5 | 1 | |||||
| Coagulase-negative staphylococci (486) | 1 (0.2) | 2 (0.6) | 10 (2.7) | 99 (23.0) | 89 (41.4) | 158 (73.9) | 115 (97.5) | 8 (99.2) | 4 (100) | 0.25 | 0.5 | |||||
| MSCoNS (188) | 1 (0.5) | 2 (1.6) | 10 (6.9) | 96 (58.0) | 67 (93.6) | 12 (100) | 0.06 | 0.12 | ||||||||
| MRCoNS (298) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.0) | 22 (8.4) | 146 (57.4) | 115 (96.0) | 8 (98.7) | 4 (100) | 0.25 | 0.5 | |||||
| Enterococcus faecalis (195) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.5) | 3 (2.1) | 52 (28.7) | 94 (76.9) | 19 (86.7) | 23 (98.5) | 3 (100) | 2 | 8 | ||
| Vancomycin susceptible (188) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.5) | 3 (2.1) | 52 (29.8) | 91 (78.2) | 19 (88.3) | 19 (98.4) | 3 (100) | 2 | 8 | ||
| Vancomycin nonsusceptible (7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (42.9) | 0 (42.9) | 4 (100) | 8 | ||||
| Streptococcus pneumoniae (1,200) | 603 (50.2) | 139 (61.8) | 86 (69.0) | 106 (77.8) | 185 (93.3) | 67 (98.8) | 14 (100) | ≤0.008 | 0.12 | |||||||
| Penicillin susceptible (678) | 595 (87.8) | 64 (97.2) | 13 (99.1) | 6 (100) | ≤0.008 | 0.015 | ||||||||||
| Penicillin intermediate (266) | 8 (3.0) | 75 (31.2) | 73 (58.6) | 92 (93.2) | 17 (99.6) | 1 (100) | 0.03 | 0.06 | ||||||||
| Penicillin resistant (256) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 8 (3.1) | 168 (68.8) | 66 (94.5) | 14 (100) | 0.12 | 0.25 | |||||||
| Viridans group streptococci (492) | 140 (28.5) | 115 (51.8) | 125 (77.2) | 54 (88.2) | 20 (92.3) | 17 (95.7) | 16 (99.0) | 5 (100) | 0.015 | 0.12 | ||||||
| Beta-hemolytic streptococci (1,201) | 589 (49.0) | 515 (91.9) | 87 (99.2) | 9 (99.9) | 1 (100) | 0.015 | 0.015 | |||||||||
| Group A Streptococcus (422) | 405 (96.0) | 13 (99.1) | 2 (99.5) | 1 (99.8) | 1 (100) | ≤0.008 | ≤0.008 | |||||||||
| Group B Streptococcus (576) | 29 (5.0) | 486 (89.4) | 59 (99.7) | 2 (100) | 0.015 | 0.03 | ||||||||||
| Escherichia coli (657) | 1 (0.2) | 2 (0.5) | 77 (12.2) | 235 (47.9) | 145 (70.0) | 65 (79.9) | 32 (84.8) | 17 (87.4) | 9 (88.7) | 5 (89.5) | 9 (90.9) | 3 (91.3) | 4 (91.9) | 53 (100) | 0.12 | 8 |
| Non-ESBL phenotype (579) | 1 (0.2) | 2 (0.5) | 77 (13.8) | 235 (54.4) | 144 (79.3) | 64 (90.3) | 30 (95.5) | 15 (98.1) | 6 (99.1) | 3 (99.7) | 1 (99.8) | 1 (100) | 0.06 | 0.25 | ||
| ESBL phenotype (78) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.3) | 1 (2.6) | 2 (5.1) | 2 (7.7) | 3 (11.5) | 2 (14.1) | 8 (24.4) | 2 (26.9) | 4 (32.1) | 53 (100) | >32 | >32 |
| Klebsiella spp. (903) | 2 (0.2) | 6 (0.9) | 46 (6.0) | 324 (41.9) | 226 (66.9) | 110 (79.1) | 61 (85.8) | 14 (87.4) | 7 (88.2) | 7 (88.9) | 14 (90.5) | 5 (91.0) | 6 (91.7) | 75 (100) | 0.12 | 8 |
| Non-ESBL phenotype (791) | 2 (0.3) | 6 (1.0) | 46 (6.8) | 324 (47.8) | 225 (76.2) | 110 (90.1) | 60 (97.7) | 12 (99.2) | 3 (99.6) | 1 (99.7) | 2 (100) | 0.12 | 0.25 | |||
| ESBL phenotype (112) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.9) | 0 (0.9) | 1 (1.8) | 2 (3.6) | 4 (7.1) | 6 (12.5) | 12 (23.2) | 5 (27.7) | 6 (33.0) | 75 (100) | >32 | >32 |
| Klebsiella pneumoniae (653) | 2 (0.3) | 4 (0.9) | 34 (6.1) | 280 (49.0) | 161 (73.7) | 47 (80.9) | 34 (86.1) | 8 (87.3) | 5 (88.1) | 4 (88.7) | 11 (90.4) | 4 (91.0) | 5 (91.7) | 54 (100) | 0.12 | 8 |
| Klebsiella oxytoca (250) | 0 (0.0) | 2 (0.8) | 12 (5.6) | 44 (23.2) | 65 (49.2) | 63 (74.4) | 27 (85.2) | 6 (87.6) | 2 (88.4) | 3 (89.6) | 3 (90.8) | 1 (91.2) | 1 (91.6) | 21 (100) | 0.25 | 8 |
| Morganella morganii (116) | 0 (0.0) | 0 (0.0) | 11 (9.5) | 25 (31.0) | 28 (55.2) | 9 (62.9) | 10 (71.6) | 3 (74.1) | 1 (75.0) | 2 (76.7) | 4 (80.2) | 0 (80.2) | 3 (82.8) | 20 (100) | 0.12 | >32 |
| Haemophilus influenzae (770) | 520 (67.5) | 164 (88.8) | 63 (97.0) | 17 (99.2) | 4 (99.7) | 1 (99.9) | 1 (100) | ≤0.008 | 0.03 | |||||||
| β-Lactamase negative (556) | 433 (77.9) | 100 (95.9) | 21 (99.6) | 2 (100) | ≤0.008 | 0.015 | ||||||||||
| β-Lactamase positive (214) | 87 (40.7) | 64 (70.6) | 42 (90.2) | 15 (97.2) | 4 (99.1) | 1 (99.5) | 1 (100) | 0.015 | 0.03 | |||||||
| Haemophilus parainfluenzae (68) | 47 (69.1) | 12 (86.8) | 4 (92.6) | 3 (97.1) | 1 (98.5) | 0 (98.5) | 1 (100) | ≤0.008 | 0.03 | |||||||
| Moraxella catarrhalis (200) | 9 (4.5) | 8 (8.5) | 54 (35.5) | 62 (66.5) | 56 (94.5) | 11 (100) | 0.06 | 0.12 | ||||||||
Table 2.
In vitro activity of ceftaroline in comparison to those of selected antimicrobial agents against AWARE 2010 Gram-positive pathogens
| Organism and antimicrobial agent (no. of isolates tested) | MIC (μg/ml) |
CLSI % S/% Ra | ||
|---|---|---|---|---|
| 50% | 90% | Range | ||
| S. aureus (2,146) | ||||
| MSSA (1,074) | ||||
| Ceftarolineb | 0.25 | 0.25 | 0.03–0.5 | 100/—c |
| Ceftriaxone | 4 | 4 | ≤0.06–>8 | 98.0/0.2 |
| Erythromycin | ≤0.25 | >4 | ≤0.25–>4 | 65.3/32.3 |
| Clindamycin | ≤0.25 | ≤0.25 | ≤0.25–>2 | 94.1/5.5 |
| Levofloxacin | ≤0.5 | 4 | ≤0.5–>4 | 88.4/11.0 |
| Linezolid | 1 | 1 | ≤0.12–2 | 100/0.0 |
| Tigecyclined | 0.06 | 0.25 | ≤0.03–0.5 | 100/— |
| Vancomycin | 1 | 1 | 0.25–2 | 100/0.0 |
| MRSA (1,072) | ||||
| Ceftarolineb | 0.5 | 1 | 0.25–2 | 98.4/— |
| Erythromycin | >4 | >4 | ≤0.25–>4 | 10.8/88.5 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 71.4/28.6 |
| Levofloxacin | 4 | >4 | ≤0.5–>4 | 32.4/65.5 |
| Linezolid | 1 | 1 | ≤0.12–4 | 100/0.0 |
| Tigecyclined | 0.06 | 0.25 | ≤0.03–0.5 | 100/— |
| Vancomycin | 1 | 1 | 0.25–2 | 100/0.0 |
| CoNS (486) | ||||
| MSCoNS (188) | ||||
| Ceftarolineb | 0.06 | 0.12 | ≤0.008–0.25 | —/— |
| Ceftriaxone | 2 | 4 | 0.25–8 | 94.1/0.0 |
| Erythromycin | ≤0.25 | >4 | ≤0.25–>4 | 54.3/43.1 |
| Clindamycin | ≤0.25 | 1 | ≤0.25–>2 | 88.8/9.0 |
| Levofloxacin | ≤0.5 | >4 | ≤0.5–>4 | 73.4/25.0 |
| Linezolid | 0.5 | 1 | ≤0.12–1 | 100/0.0 |
| Vancomycin | 1 | 2 | 0.25–2 | 100/0.0 |
| MRCoNS (298) | ||||
| Ceftarolineb | 0.25 | 0.5 | 0.06–2 | —/— |
| Erythromycin | >4 | >4 | ≤0.25–>4 | 23.5/74.2 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 59.7/35.6 |
| Levofloxacin | >4 | >4 | ≤0.5–>4 | 36.6/61.4 |
| Linezolid | 0.5 | 1 | ≤0.12–>8 | 96.6/3.4 |
| Vancomycin | 2 | 2 | 0.25–4 | 100/0.0 |
| Enterococcus faecalis (195) | ||||
| Ceftarolineb | 2 | 8 | 0.25–16 | —/— |
| Ampicillin | ≤1 | 2 | ≤1–4 | 100/0.0 |
| Piperacillin-tazobactam | 4 | 8 | 1–>64 | 100/— |
| Erythromycin | >4 | >4 | ≤0.25–>4 | 12.3/50.3 |
| Quinupristin-dalfopristin | >4 | >4 | ≤0.5–>4 | 0.5/94.4 |
| Vancomycin | 1 | 2 | 0.5–>16 | 96.4/3.6 |
| Teicoplanin | ≤1 | ≤1 | ≤1–>8 | 96.9/3.1 |
| Linezolid | 1 | 1 | 0.5–>8 | 99.5/0.5 |
| Tetracycline | >8 | >8 | ≤0.25–>8 | 23.6/75.4 |
| Levofloxacin | 1 | >4 | ≤0.5–>4 | 69.7/29.2 |
| Viridans group streptococci (492) | ||||
| Ceftarolineb | 0.015 | 0.12 | ≤0.008–1 | —/— |
| Ceftriaxone | 0.12 | 1 | ≤0.06–8 | 92.9/4.1 |
| Penicillin | 0.06 | 1 | ≤0.03–>4 | 74.6/4.3 |
| Erythromycin | 0.5 | >4 | ≤0.25–>4 | 45.7/49.6 |
| Clindamycin | ≤0.25 | 0.5 | ≤0.25–>2 | 89.0/10.0 |
| Levofloxacin | 1 | 2 | ≤0.5–>4 | 92.1/7.1 |
| Linezolid | 1 | 1 | ≤0.12–2 | 100/— |
| Vancomycin | 0.5 | 0.5 | ≤0.12–1 | 100/— |
| Beta-hemolytic streptococci (1,201) | ||||
| Group A (422) | ||||
| Ceftarolineb | ≤0.008 | ≤0.008 | ≤0.008–0.12 | 99.1/— |
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06–0.25 | 100/— |
| Penicillin | ≤0.03 | ≤0.03 | ≤0.03–0.12 | 100/— |
| Erythromycin | ≤0.25 | 2 | ≤0.25–>4 | 87.7/11.6 |
| Clindamycin | ≤0.25 | ≤0.25 | ≤0.25–>2 | 95.3/4.5 |
| Levofloxacin | ≤0.5 | 1 | ≤0.5–>4 | 99.5/0.5 |
| Linezolid | 1 | 1 | ≤0.12–1 | 100/— |
| Vancomycin | 0.25 | 0.5 | ≤0.12–1 | 100/— |
| Group B (576) | ||||
| Ceftarolineb | 0.015 | 0.03 | ≤0.008–0.06 | 99.7/— |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06–0.5 | 100/— |
| Penicillin | ≤0.03 | 0.06 | ≤0.03–0.12 | 100/— |
| Erythromycin | ≤0.25 | >4 | ≤0.25–>4 | 52.1/46.9 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 73.1/26.2 |
| Levofloxacin | ≤0.5 | 1 | ≤0.5–>4 | 99.1/0.9 |
| Linezolid | 1 | 1 | 0.5–2 | 100/— |
| Vancomycin | 0.5 | 0.5 | 0.25–1 | 100/— |
Criteria as published by the CLSI (8). S, susceptible; R, resistant.
U.S. FDA Teflaro product insert (11) breakpoints were applied when available: S. aureus, susceptible, ≤1 μg/ml; S. agalactiae, susceptible, ≤0.03 μg/ml; S. pyogenes, susceptible, ≤0.015 μg/ml.
—, no interpretive breakpoint assignment exists for this agent for this category.
U.S. FDA Tygacil product insert (27) breakpoints were applied when available: S. aureus, susceptible, ≤0.5 μg/ml; Streptococcus spp. other than S. pneumoniae, susceptible, ≤0.25 μg/ml.
Table 4.
In vitro activity of ceftaroline in comparison to those of selected antimicrobial agents against AWARE 2010 fastidious respiratory pathogens
| Organism and antimicrobial agent (no. of isolates tested) | MIC (μg/ml) |
CLSI % S/% Ra | ||
|---|---|---|---|---|
| 50% | 90% | Range | ||
| S. pneumoniae (1,200) | ||||
| Penicillin susceptible (MIC, ≤0.06 μg/ml) (678)b | ||||
| Ceftarolinec | ≤0.008 | 0.015 | ≤0.008–0.06 | 100/—f |
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06–0.5 | 100/0.0 |
| Cefuroxime | ≤0.12 | ≤0.12 | ≤0.12–1 | 100/0.0 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–2 | 100/0.0 |
| Penicillind | ≤0.03 | ≤0.03 | ≤0.03–0.06 | 100/0.0 |
| Tetracycline | 0.5 | 0.5 | ≤0.25–>8 | 96.8/3.2 |
| TMP-SMXe | ≤0.5 | ≤0.5 | ≤0.5–>4 | 91.2/4.4 |
| Erythromycin | ≤0.06 | 4 | ≤0.06–>8 | 86.4/13.0 |
| Clindamycin | ≤0.25 | ≤0.25 | ≤0.25–>1 | 97.2/2.5 |
| Levofloxacin | 1 | 1 | ≤0.5–>4 | 99.3/0.7 |
| Penicillin intermediate (MIC, 0.12–1 μg/ml) (266)b | ||||
| Ceftarolinec | 0.03 | 0.06 | ≤0.008–0.25 | 100/— |
| Ceftriaxone | 0.12 | 0.5 | ≤0.06–4 | 99.6/0.4 |
| Cefuroxime | 0.5 | 4 | ≤0.12–4 | 73.7/10.2 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–4 | 99.2/0.0 |
| Penicillind | 0.25 | 1 | 0.12–1 | 100/0.0 |
| Tetracycline | 0.5 | >8 | ≤0.25–>8 | 60.8/38.9 |
| TMP-SMX | 1 | >4 | ≤0.5–>4 | 48.9/27.1 |
| Erythromycin | 4 | >8 | ≤0.06–>8 | 34.2/65.4 |
| Clindamycin | ≤0.25 | >1 | ≤0.25–>1 | 68.8/30.5 |
| Levofloxacin | 1 | 1 | ≤0.5–>4 | 98.5/1.5 |
| Penicillin resistant (MIC, ≥2 μg/ml) (256)b | ||||
| Ceftarolinec | 0.12 | 0.25 | 0.06–0.5 | 94.5/— |
| Ceftriaxone | 1 | 2 | 0.25–8 | 52.7/7.4 |
| Cefuroxime | 8 | 16 | 2–>16 | 0.0/99.2 |
| Amoxicillin-clavulanate | 8 | 8 | ≤1–>8 | 21.6/66.3 |
| Penicillind | 4 | 4 | 2–>4 | 31.6/4.7 |
| Tetracycline | >8 | >8 | ≤0.25–>8 | 30.1/69.9 |
| TMP-SMX | 4 | >4 | ≤0.5–>4 | 20.3/77.3 |
| Erythromycin | >8 | >8 | ≤0.06–>8 | 9.0/90.6 |
| Clindamycin | >1 | >1 | ≤0.25–>1 | 34.0/65.6 |
| Levofloxacin | 1 | 1 | ≤0.5–>4 | 98.8/0.8 |
| H. influenzae (770) | ||||
| Ceftarolinec | ≤0.008 | 0.03 | ≤0.008–0.5 | 99.7/— |
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06–1 | 100/— |
| Cefuroxime | 0.5 | 2 | ≤0.12–8 | 99.5/0.0 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–4 | 100/0.0 |
| Azithromycin | 1 | 2 | ≤0.25–>4 | 98.6/— |
| Clarithromycin | 8 | 16 | ≤0.25–>32 | 78.7/3.1 |
| Tetracycline | 0.5 | 1 | ≤0.25–>8 | 98.7/1.2 |
| TMP-SMX | ≤0.5 | >4 | ≤0.5–>4 | 76.2/21.0 |
| Levofloxacin | ≤0.5 | ≤0.5 | ≤0.5–1 | 100/— |
| H. parainfluenzae (68) | ||||
| Ceftaroline | ≤0.008 | 0.03 | ≤0.008–0.5 | —/— |
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06–0.12 | 100/— |
| Cefuroxime | 0.25 | 1 | ≤0.12–4 | 100/0.0 |
| Ampicillin | ≤1 | ≤1 | ≤1–>8 | 91.2/7.4 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1–2 | 100/0.0 |
| Azithromycin | 1 | 2 | ≤0.25–>8 | 98.5/— |
| Clarithromycin | 8 | 16 | ≤0.25–>32 | 76.5/2.9 |
| Tetracycline | 0.5 | 1 | ≤0.25–>8 | 97.1/1.5 |
| TMP-SMX | ≤0.5 | 4 | ≤0.5–>4 | 85.3/14.7 |
| Levofloxacin | ≤0.5 | ≤0.5 | ≤0.5–>4 | 97.1/— |
| Moraxella catarrhalis (200) | ||||
| Ceftaroline | 0.06 | 0.12 | ≤0.008–0.25 | —/— |
| Ceftriaxone | 0.25 | 0.5 | ≤0.06–2 | 100/— |
| Cefuroxime | 1 | 2 | ≤0.12–8 | 99.5/0.0 |
| Amoxicillin-clavulanate | ≤1 | ≤1 | ≤1 | 100/0.0 |
| Erythromycin | 0.12 | 0.25 | ≤0.06–4 | 99.5/— |
| Tetracycline | ≤0.25 | 0.5 | ≤0.25–1 | 100/0.0 |
| TMP-SMX | ≤0.5 | ≤0.5 | ≤0.5–>4 | 96.0/2.0 |
| Levofloxacin | ≤0.5 | ≤0.5 | ≤0.5–1 | 100/— |
Criteria as published by the CLSI (8). S, susceptible; R, resistant.
Criteria as published by the CLSI (8) for “penicillin parenteral (nonmeningitis).”
U.S. FDA Teflaro product insert (11) breakpoints were applied when available: S. pneumoniae, susceptible, ≤0.25 μg/ml; H. influenzae, susceptible, ≤0.12 μg/ml.
Criteria as published by the CLSI (8) for “penicillin (oral penicillin V).”
TMP-SMX, trimethoprim-sulfamethoxazole.
—, no interpretive breakpoint assignment exists for this agent for this category.
Activity of ceftaroline against Gram-positive bacteria: staphylococci, enterococci, and streptococci.
S. aureus was susceptible to ceftaroline (MIC50, 0.5 μg/ml, and MIC90, 1 μg/ml [Tables 1 and 2]). When tested against MSSA, ceftaroline (MIC50 and MIC90, 0.25 μg/ml) was 16-fold more active than ceftriaxone (MIC50 and MIC90, 4 μg/ml) and 4-fold more active than linezolid (MIC50 and MIC90, 1 μg/ml [Table 2]). The highest ceftaroline MIC value among MSSA strains was only 0.5 μg/ml, and 97.5% of strains were inhibited at a ceftaroline MIC of ≤0.25 μg/ml (Table 1). Ceftaroline susceptibility for MSSA was 100.0% by U.S. FDA criteria (Table 2) (11).
Approximately 50% of S. aureus isolates were methicillin resistant. Ceftaroline MIC values ranged from 0.25 to 2 μg/ml (MIC50, 0.5 μg/ml, and MIC90, 1 μg/ml) when tested against MRSA (Tables 1 and 2). At ceftaroline MIC values of ≤1 μg/ml, 98.4% were inhibited (Tables 1 and 2) based upon U.S. FDA interpretive criteria (11). The remaining 1.6% of isolates (MIC, 2 μg/ml) exhibited a MIC value of 1 doubling dilution above the ceftaroline-susceptible breakpoint. No breakpoint interpretive criteria have been established for isolates with MIC values of >1 μg/ml, as they are uncommon, and it is recommended that these be sent to a reference laboratory for further testing (11). As there is no guidance on treatment of patients with isolates with MIC values of >1 μg/ml, one may want to consider a variety of factors, including the pharmacokinetics/pharmacodynamics of ceftaroline. As reported in the work of Biek et al., target attainment based on a 40% T>MIC for isolates with MIC values of 2 μg/ml was 90% (3). Although ceftaroline MIC values were slightly higher (2- to 4-fold) among MRSA strains than among MSSA strains, the activity of ceftaroline was considerably greater than those of other cephalosporins (ceftriaxone and cefuroxime [Table 2]) and carbapenems tested against MRSA (data not shown). Furthermore, ceftaroline is unique among the β-lactam agents in having regulatory approval for the treatment of MRSA in ABSSSI. Ceftaroline (MIC50, 0.5 μg/ml, and MIC90, 1 μg/ml) was slightly more potent than linezolid and vancomycin, each with a MIC50 and MIC90 of 1 μg/ml. In contrast, ceftaroline was less active than tigecycline (MIC50, 0.06 μg/ml, and MIC90, 0.25 μg/ml) when tested against MRSA strains (Table 2). MRSA strains exhibited high rates of resistance to erythromycin (88.5%), clindamycin (28.6%), and levofloxacin (65.5%) (Table 2).
Ceftaroline was active (MIC50, 0.25 μg/ml, and MIC90, 0.5 μg/ml [Table 1]) against CoNS strains, 61.3% of which were methicillin resistant (MRCoNS). Ceftaroline was 2- to 4-fold more active against methicillin-susceptible CoNS (MSCoNS; MIC50, 0.06 μg/ml, and MIC90, 0.12 μg/ml [Table 2]) than against MSSA. Furthermore, ceftaroline activity was 8- to 32-fold greater than that of other cephalosporins tested against MSCoNS, such as ceftriaxone (MIC50, 2 μg/ml [Table 2]) and cefuroxime (MIC50, 0.5 μg/ml [data not shown]). Although all MRCoNS should be considered resistant to all β-lactams, ceftaroline was potent against MRCoNS collected in U.S. medical centers (MIC90, 0.5 μg/ml [Table 2]). Antimicrobial activities of ceftaroline and comparator agents tested against Staphylococcus epidermidis, Staphylococcus haemolyticus, and Staphylococcus hominis were analyzed separately (data not shown). These most prevalent species exhibited high rates of oxacillin resistance, varying from 60.0% among S. hominis isolates to 69.9% for S. epidermidis. Ceftaroline activity was greater against S. epidermidis and S. hominis (MIC50, 0.25 μg/ml, and MIC90, 0.5 μg/ml, for both species) than against S. haemolyticus (MIC50, 0.25 μg/ml, and MIC90, 1 μg/ml).
Ceftaroline exhibited modest in vitro activity against E. faecalis (MIC50, 2 μg/ml, and MIC90, 8 μg/ml [Table 2]). Activity against the subset of seven vancomycin-nonsusceptible E. faecalis isolates was similar to that for vancomycin-susceptible isolates (range from 2 to 8 μg/ml). All other cephalosporins tested showed limited activity against E. faecalis (data not shown). All isolates were susceptible to ampicillin (MIC50, ≤1 μg/ml, and MIC90, 2 μg/ml [Table 2]).
VGS isolates exhibited a MIC50 value of 0.015 μg/ml and a MIC90 value of 0.12 μg/ml (Table 2). Ceftaroline was 4- to 8-fold more active than penicillin (MIC50, 0.06 μg/ml, and MIC90, 1 μg/ml) and ceftriaxone (MIC50, 0.12 μg/ml, and MIC90, 1 μg/ml) against this organism/species group (Table 2). Streptococcus anginosus MIC50 and MIC90 values were 0.03 μg/ml and 0.06 μg/ml, respectively (MIC range, ≤0.008 to 0.25 μg/ml [data not shown]).
Ceftaroline was potent against BHS, with the highest MIC value being only 0.12 μg/ml (MIC90, 0.015 μg/ml [Table 1]). Among BHS, group A isolates (MIC50 and MIC90, ≤0.008 μg/ml) exhibited slightly lower MIC values than did group B isolates (MIC50, 0.015 μg/ml, and MIC90, 0.03 μg/ml), with 99.1% of the group A and 99.7% of group B isolates being susceptible according to the U.S. FDA interpretive criteria.
Activity of ceftaroline against Gram-negative Enterobacteriaceae.
E. coli isolates were generally susceptible to ceftaroline (MIC50, 0.12 μg/ml, and MIC90, 8 μg/ml), with 84.8% of the strains being susceptible at the U.S. FDA breakpoint (Table 3) (11). Among non-ESBL-phenotype strains, 95.5% and 98.1% of strains were inhibited at ceftaroline MICs of ≤0.5 and ≤1 μg/ml, respectively (MIC50, 0.06 μg/ml, and MIC90, 0.25 μg/ml [Tables 1 and 3]), while ESBL-phenotype strains (MICs of ≥2 μg/ml for ceftazidime, ceftriaxone, or aztreonam) were usually resistant to ceftaroline (MIC50 and MIC90, >32 μg/ml) and all other cephalosporins tested (Table 1). Ceftaroline was active against non-ESBL-phenotype Klebsiella strains with a MIC50 of 0.12 μg/ml and a MIC90 of 0.25 μg/ml, and 97.7% of strains were inhibited at ≤0.5 μg/ml (Table 1). In contrast, the majority of ESBL-phenotype strains showed elevated ceftaroline MIC values (MIC50 and MIC90, >32 μg/ml). Resistance rates to expanded-spectrum cephalosporins were high among ESBL-phenotype Klebsiella spp. (89.3 and 58.0% were resistant to ceftriaxone and ceftazidime, respectively [data not shown]). Decreased susceptibility to meropenem (MIC, ≥2 μg/ml) was observed in 33.7% of ESBL-phenotype K. pneumoniae isolates and 6.2% of ESBL-phenotype K. oxytoca isolates (data not shown).
Table 3.
In vitro activity of ceftaroline in comparison to those of selected antimicrobial agents against AWARE 2010 Enterobacteriaceae
| Organism and antimicrobial agent (no. of isolates tested) | MIC (μg/ml) |
CLSI % S/% Ra | ||
|---|---|---|---|---|
| 50% | 90% | Range | ||
| E. coli (657) | ||||
| Ceftarolineb | 0.12 | 8 | ≤0.008–>32 | 84.8/12.6 |
| Ceftazidime | 0.12 | 2 | 0.03–>32 | 92.4/5.5 |
| Ceftriaxone | ≤0.06 | 4 | ≤0.06–>8 | 89.2/10.5 |
| Ampicillin-sulbactam | 4 | 32 | 0.5–>32 | 57.7/23.0 |
| Piperacillin-tazobactam | 2 | 8 | ≤0.5–>64 | 95.3/1.8 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–0.25 | 100/0.0 |
| Gentamicin | ≤1 | >8 | ≤1–>8 | 89.3/10.2 |
| Levofloxacin | ≤0.5 | >4 | ≤0.5–>4 | 70.9/28.8 |
| Non-ESBL phenotype (579) | ||||
| Ceftarolineb | 0.06 | 0.25 | ≤0.008–16 | 95.5/1.9 |
| Ceftazidime | 0.12 | 0.25 | 0.03–1 | 100/0.0 |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06–1 | 100/0.0 |
| Ampicillin-sulbactam | 4 | 32 | 0.5–>32 | 63.2/18.1 |
| Piperacillin-tazobactam | 2 | 4 | ≤0.5–>64 | 98.1/1.0 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–0.25 | 100/0.0 |
| Gentamicin | ≤1 | 2 | ≤1–>8 | 91.5/7.9 |
| Levofloxacin | ≤0.5 | >4 | ≤0.5–>4 | 77.7/22.1 |
| Klebsiella spp. (903) | ||||
| Ceftarolineb | 0.12 | 8 | ≤0.008–>32 | 85.8/12.6 |
| Ceftriaxone | ≤0.06 | 4 | ≤0.06–>8 | 88.7/11.1 |
| Ceftazidime | 0.12 | 2 | 0.03–>32 | 92.0/7.2 |
| Ampicillin-sulbactam | 8 | 32 | 0.5–>32 | 75.6/13.8 |
| Piperacillin-tazobactam | 2 | 16 | ≤0.5–>64 | 91.4/6.9 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–>8 | 96.8/2.8 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 95.1/3.2 |
| Levofloxacin | ≤0.5 | 1 | ≤0.5–>4 | 92.1/6.9 |
| Non-ESBL phenotype (791) | ||||
| Ceftarolineb | 0.12 | 0.25 | ≤0.008–8 | 97.7/0.8 |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06–1 | 100/0.0 |
| Ceftazidime | 0.12 | 0.25 | 0.03–1 | 100/0.0 |
| Ampicillin-sulbactam | 4 | 16 | 0.5–>32 | 85.2/4.3 |
| Piperacillin-tazobactam | 2 | 4 | ≤0.5–>64 | 98.7/0.8 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–0.25 | 100/0.0 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 99.0/0.9 |
| Levofloxacin | ≤0.5 | ≤0.5 | ≤0.5–>4 | 98.6/0.9 |
| Klebsiella pneumoniae (653) | ||||
| Ceftarolineb | 0.12 | 8 | ≤0.008–>32 | 86.1/12.7 |
| Ceftriaxone | ≤0.06 | 4 | ≤0.06–>8 | 88.8/11.0 |
| Ceftazidime | 0.12 | 4 | 0.03–>32 | 90.2/8.9 |
| Ampicillin-sulbactam | 4 | 32 | 0.5–>32 | 77.2/14.5 |
| Piperacillin-tazobactam | 2 | 16 | ≤0.5–>64 | 91.7/6.3 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–>8 | 95.9/3.7 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 94.3/3.8 |
| Levofloxacin | ≤0.5 | 4 | ≤0.5–>4 | 89.7/9.2 |
| Klebsiella oxytoca (250) | ||||
| Ceftarolineb | 0.25 | 8 | 0.015–>32 | 85.2/12.4 |
| Ceftriaxone | ≤0.06 | 4 | ≤0.06–>8 | 88.4/11.2 |
| Ceftazidime | 0.12 | 0.5 | 0.03–>32 | 96.8/2.8 |
| Ampicillin-sulbactam | 8 | 32 | 0.5–>32 | 71.6/12.0 |
| Piperacillin-tazobactam | 2 | 16 | ≤0.5–>64 | 90.4/8.4 |
| Meropenem | ≤0.12 | ≤0.12 | ≤0.12–4 | 99.2/0.4 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 97.2/1.6 |
| Levofloxacin | ≤0.5 | ≤0.5 | ≤0.5–>4 | 98.4/0.8 |
Activity of ceftaroline against the fastidious respiratory tract pathogens.
The in vitro activity of ceftaroline, as with those of other β-lactams, varied according to the susceptibility to penicillin. However, ceftaroline was the most potent of all β-lactams tested against S. pneumoniae strains (MIC50, ≤0.008 μg/ml, and MIC90, 0.12 μg/ml [Table 1]). The highest ceftaroline MIC value observed was only 0.5 μg/ml (14 strains [1.2%] [Table 1]) while the MIC50 varied from ≤0.008 μg/ml for the penicillin-susceptible (MIC, ≤0.06 μg/ml) strains to 0.12 μg/ml for the penicillin-resistant (MIC, ≥2 μg/ml) strains (Table 4). Against penicillin-resistant (MIC, ≥2 μg/ml) pneumococci, ceftaroline (MIC50, 0.12 μg/ml, and MIC90, 0.25 μg/ml) was 8-fold more active than ceftriaxone (MIC50, 1 μg/ml, and MIC90, 2 μg/ml) and 64-fold more potent than amoxicillin-clavulanic acid (MIC50 and MIC90, 8 μg/ml [Table 4]).
Ceftaroline was also active against S. pneumoniae strains with penicillin MIC values of ≥8 μg/ml (12 isolates). Ceftaroline MIC values ranged from 0.06 to 0.5 μg/ml (MIC50, 0.25 μg/ml, and MIC90, 0.5 μg/ml), and 66.7% of strains were inhibited at ceftaroline MIC values of ≤0.25 μg/ml (data not shown). These 12 isolates were categorized as nonsusceptible for other β-lactam agents tested, except for one isolate (8.3%) that was susceptible only to ceftriaxone. Furthermore, ceftaroline (MIC50, 0.25 μg/ml) was 8- and > 32-fold more active than ceftriaxone (MIC50, 2 μg/ml) and amoxicillin-clavulanate (MIC50, >8 μg/ml), respectively, against this group of multidrug-resistant S. pneumoniae (MDR-SPN) isolates (data not shown), each considered refractory to high-dose penicillin therapy.
Ceftaroline was potent against H. influenzae (MIC50, ≤0.008 μg/ml, and MIC90, 0.03 μg/ml [Table 4]), and 99.9% of strains were inhibited at a ceftaroline MIC of ≤0.25 μg/ml (only one isolate had a ceftaroline MIC of 0.5 μg/ml [Table 1]). β-Lactamase-producing strains had ceftaroline MIC values slightly higher (MIC50, 0.015 μg/ml, and MIC90, 0.03 μg/ml) than those of non-β-lactamase-producing ampicillin-susceptible strains (MIC50, ≤0.008 μg/ml, and MIC90, 0.015 μg/ml; highest MIC, 0.06 μg/ml) but were still susceptible to ceftaroline (data not shown). Against H. parainfluenzae (Table 1), 98.5% of strains were inhibited at a ceftaroline MIC of ≤0.12 μg/ml, the MIC50 was ≤0.008 μg/ml, and the MIC90 was 0.03 μg/ml (Tables 1 and 4). Ceftaroline was also active against M. catarrhalis (MIC50, 0.06 μg/ml, and MIC90, 0.12 μg/ml [Table 4]).
DISCUSSION
Ceftaroline demonstrated broad-spectrum potent activity against both Gram-positive and common Gram-negative pathogens. This spectrum includes major bacterial pathogens found in ABSSSI and CABP (9, 10, 21, 29). Staphylococcus spp., including MRSA, in vitro were particularly susceptible to ceftaroline. Ceftaroline also showed potent in vitro activity against streptococci, including S. pneumoniae isolates resistant to penicillin (MIC, ≥8 μg/ml), and Gram-negative pathogens (H. influenzae, H. parainfluenzae, and M. catarrhalis) associated with community-acquired respiratory tract infections. Furthermore, wild-type strains of Enterobacteriaceae (non-ESBL-producing strains and non-AmpC-hyperproducing strains) were often susceptible to ceftaroline. ESBL-phenotype strains were usually resistant to ceftaroline and to expanded-spectrum cephalosporins. The overall susceptibility to ceftaroline of Gram-negative pathogens was similar to that to ceftriaxone.
Ceftaroline MIC values for MRSA were generally 2- to 4-fold higher than those for MSSA. Also, penicillin-resistant S. pneumoniae exhibited higher MIC values than did penicillin-susceptible strains. In spite of the elevation in MIC relative to that of the wild type, the MIC90 values were 1 and 0.25 μg/ml for MRSA and penicillin-resistant S. pneumoniae, respectively. These MIC90 values were within the predicted pharmacokinetic/pharmacodynamic target attainment (3), and the susceptibility rates for MRSA and for penicillin-resistant S. pneumoniae were 98.4% and 94.5%, respectively.
The results of the 2010 U.S. AWARE program indicated that over 99% of S. aureus strains in the United States were susceptible to ceftaroline and that all staphylococcal isolates (S. aureus and CoNS) were inhibited at ceftaroline MIC values of ≤2 μg/ml. A high level of susceptibility, over 99%, was also demonstrated for beta-hemolytic streptococci. As clinical identification of the causative agent in an ABSSSI before beginning treatment is difficult, this degree of susceptibility for S. aureus and beta-hemolytic streptococci coupled with the activity of ceftaroline against common non-ESBL-producing strains of Enterobacteriaceae makes ceftaroline an attractive choice for monotherapy. In fact, in two large randomized phase III clinical trials, ceftaroline fosamil was shown to be efficacious in patients with monomicrobial and polymicrobial infections (9, 29). S. aureus was the most common pathogen isolated from the primary infection site or blood at 73.4 and 76.0% in each treatment arm for the CANVAS 1 study (NCT00424190) and 80.7 and 84.0% in the CANVAS 2 study (NCT00423657). MRSA isolation rates for each treatment arm were 30.4 and 34.3% for the CANVAS 1 study and 27.4 and 32.0% for the CANVAS 2 study.
In the 2010 U.S. AWARE program, ceftaroline was shown to be markedly active in vitro against penicillin-susceptible strains of S. pneumoniae that were susceptible to cephalosporins. Furthermore, ceftaroline was 8- and 64-fold more active than ceftriaxone and amoxicillin-clavulanate, respectively, against penicillin-resistant (MIC, ≥2 μg/ml) strains (Table 4). S. pneumoniae strains with high-level resistance to penicillin (MIC values, ≥8 μg/ml; 12 strains tested) were also susceptible to ceftaroline (MIC50, 0.25 μg/ml, and MIC90, 0.5 μg/ml). S. pneumoniae is the most common bacterial pathogen in CABP, and concerns about emerging resistance in S. pneumoniae make the choice of a treatment agent challenging. With its potent in vitro activity against S. pneumoniae, as well as its activity against S. aureus, H. influenzae, H. parainfluenzae, M. catarrhalis, and non-ESBL-producing strains of Enterobacteriaceae, ceftaroline fosamil could be an attractive treatment choice. In two large randomized phase III clinical studies of CABP (FOCUS 1 [NCT00621504] and FOCUS 2 [NCT00509106]) (10, 21), ceftaroline fosamil achieved high clinical and microbiologic response rates among these organisms.
Given its antimicrobial profile, ceftaroline is a new agent (anti-MRSA β-lactam) that provides in vitro coverage for key pathogens found in ABSSSI and CABP. In contrast to other first-line agents for treating ABSSSI such as vancomycin and linezolid, ceftaroline offers bactericidal activity and a broader spectrum of coverage. In CABP, ceftaroline with its broad spectrum of in vitro activity for both Gram-positive and Gram-negative bacteria, including drug-resistant S. pneumoniae and MRSA, may be an option when considering local susceptibility patterns and recommendations from treatment guidelines.
Surveillance monitoring of this agent in the 2010 U.S. AWARE program has demonstrated the excellent activity of ceftaroline against bacteria from across the United States. The continuation of the AWARE surveillance program will provide both current and longitudinal information on the state of activity of ceftaroline and comparators in the future. This information will provide clinicians with up-to-date information to assist in therapeutic decision making.
ACKNOWLEDGMENTS
This study was funded by educational/research grants from Cerexa, Inc. (Oakland, CA), a wholly owned subsidiary of Forest Laboratories, Inc. (New York, NY). Cerexa was involved in the study design and decision to present these results. Cerexa had no involvement in the collection, analysis, or 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 2009 to 2011 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, bioMérieux, Cempra, Cerexa, Cosmo Technologies, Contrafect, Cubist, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Paratek, Pfizer (Wyeth), PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, Shionogi USA, The Medicines Co., Theravance, ThermoFisher, Trek Diagnostics, Vertex Pharmaceuticals, and some other corporations. Some JMI Laboratories employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest, Johnson & Johnson, and Theravance. In regard to speakers bureaus and stock options, there are none to declare, except for R.K.F., who has stock options with Johnson & Johnson.
We express our appreciation to S. Benning and P. Clark in the preparation of the manuscript and to the following JMI Laboratories staff members for scientific assistance in performing this study: D. J. Biedenbach, P. R. Rhomberg, R. Mendes, M. Castanheira, G. J. Moet, and J. Ross.
Footnotes
Published ahead of print 2 April 2012
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