Abstract
The spectrum of activity of ceftaroline was evaluated against 1,247 bacterial isolates representing 44 different species or phenotypic groups. For the majority of species, the activity of ceftaroline was comparable or superior to that of ceftriaxone. MIC and/or disk diffusion quality control ranges of ceftaroline were determined for five standard ATCC reference strains.
Ceftaroline fosamil (formerly PPI-0903 [TAK-599]), an N-phosphono prodrug cephalosporin, is a novel, parenteral, bactericidal, anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin which displays a broad spectrum of activity against important community- and hospital-acquired gram-positive and gram-negative pathogens. In plasma, the prodrug is rapidly converted into active ceftaroline (formerly PPI-0903 M). Ceftaroline has potent activity against MRSA owing to high-affinity binding to penicillin binding protein 2a (10, 17) and is also very active against drug-resistant Streptococcus pneumoniae and bacteria with multiple resistance phenotypes (9, 13, 14, 15). The in vivo efficacy of ceftaroline has been demonstrated using animal models (1, 9, 11, 12) and in a phase 2 clinical trial of patients with complicated skin or skin structure infections (cSSSI) (16). Phase 3 clinical trials for ceftaroline for treatment of cSSSI were recently completed, and trials are in progress for community-associated pneumonia. Results from the CANVAS-1 trial for cSSSI demonstrated a good safety profile for ceftaroline and noninferiority in clinical cure rates to the combination of vancomycin and aztreonam (6).
The present study was designed to compare the in vitro antibacterial activity of ceftaroline with those of ceftriaxone, levofloxacin, and imipenem against a broad range of bacterial pathogens for which ceftaroline might be considered for therapy and to propose MIC and/or disk diffusion quality control ranges for five aerobic quality control strains.
A total of 1,247 recent clinical bacterial isolates were tested, which included 203 streptococci, 105 enterococci, 111 S. aureus isolates, 103 coagulase-negative staphylococci, 368 members of the Enterobacteriaceae, 108 nonfermentative gram-negative rods, 105 Haemophilus influenzae isolates, and 144 representatives of miscellaneous species. The majority (i.e., 78.7%) of these strains were recent (<3 years) clinical isolates from within the United States. The remaining strains were specifically selected in order to provide a challenge set of phenotypic resistance patterns.
Ceftaroline powder was provided by Takeda Pharmaceuticals, Inc. (lot no. M599-R1001). Ceftriaxone (lot no. 105K0522) was purchased from Sigma. Levofloxacin (lot no. AABCC63) was obtained from R. W. Johnson. Imipenem (lot no. SEH4050) was obtained from Merck & Co. Commercially prepared 30-μg ceftaroline disks (lot no. 191110) were obtained from Hardy Diagnostics.
All organisms were tested by the broth microdilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) (3) using cation-adjusted Mueller-Hinton broth. The medium was supplemented with 3% lysed horse blood for testing of the streptococci or made up as Haemophilus test medium for testing of H. influenzae. All organisms were tested simultaneously by the disk diffusion method outlined by the CLSI (4) using Mueller-Hinton agar plus 5% sheep blood (streptococci), Haemophilus test medium agar (for H. influenzae), or plain Muller-Hinton agar (for all other genera).
For the quality control portion of the study, bacteria were tested by both the broth microdilution method and the disk diffusion method as described by the CLSI (2). An eight-laboratory study was undertaken in order to propose quality control ranges for MIC and disk diffusion methodologies. The testing laboratories included both hospital and commercial microbiology laboratories in the United States. The eight participants included D. Bade, Microbial Research, Inc., Fort Collins, CO; S. Brown, Clinical Microbiology Institute, Wilsonville, OR; J. Daly, Primary Children's Medical Center, Salt Lake City, UT; D. Hardy, University of Rochester Medical Center, Rochester, NY; J. Hindler, University of California Los Angeles, Los Angeles, CA; C. Knapp, TREK Diagnostic Systems, Cleveland, OH; G. Procop, Cleveland Clinic Foundation, Cleveland, OH; and R. Rennie, University of Alberta Hospital, Alberta, Canada. The quality control organisms were those recommended by the CLSI (3, 4, 5) and included S. aureus ATCC 29213 and ATCC 25923, S. pneumoniae ATCC 49619, Escherichia coli ATCC 25922, and H. influenzae ATCC 49247. Internal quality control results for the control drug, cefotaxime, were within published ranges (5) for the majority of tests. When any control value was out of the established range, all of the ceftaroline data associated with that day's testing were discarded. This study involved replicate tests on three lots of Mueller-Hinton broth or agar and two lots of 30-μg ceftaroline disks (Remel lot no. 441796 and Hardy lot no. 191110). This exercise generated 240 MICs and 480 disk diffusion zone diameters with each appropriate quality control strain. Zone diameters were evaluated using the statistics of Gavan et al. (7).
The antibacterial activity of ceftaroline against 1,247 isolates is summarized in Table 1. Ceftaroline was very active in vitro against the majority of gram-positive strains, including methicillin-susceptible and -resistant S. aureus (MIC at which 90% of bacteria were inhibited [MIC90] = 1 μg/ml) and coagulase-negative staphylococci (MIC90 = 0.5 μg/ml). The highest MIC observed against all staphylococci, including MRSA and vancomycin-intermediate S. aureus, was 2 μg/ml. Ceftaroline also exhibited potent activity against Moraxella catarrhalis, Enterobacter cloacae, extended-spectrum beta-lactamase (ESBL)-negative E. coli and ESBL-negative Klebsiella pneumoniae, Shigella species, all streptococci, and H. influenzae, with MIC90s of ≤1 μg/ml (Table 1). None of the isolates of E. cloacae were found to exhibit a derepressed AmpC phenotype. Although the ceftaroline MIC90s were modestly higher for the methicillin-resistant strains of staphylococci, penicillin-resistant strains of S. pneumoniae, and ß-lactamase-positive strains of H. influenzae than for susceptible isolates, the MIC90s remained low (≤1 μg/ml). Ceftaroline was generally more active than ceftriaxone, levofloxacin, and imipenem against S. aureus, coagulase-negative staphylococci, and S. pneumoniae. Levofloxacin was more active than ceftaroline against most of the Enterobacteriaceae, and imipenem was more active than ceftaroline against many of the Enterobacteriaceae and nonfermentative gram-negative bacilli.
TABLE 1.
Susceptibilities of aerobic bacteria to ceftaroline and comparator drugs
| Species or group and phenotype (na)b | MIC (μg/ml) of indicated drug
|
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ceftaroline
|
Ceftriaxone
|
Levofloxacin
|
Imipenem
|
|||||||||
| Range | 50% | 90% | Range | 50% | 90% | Range | 50% | 90% | Range | 50% | 90% | |
| Gram-positive species | ||||||||||||
| All S. aureus strains combined (111) | 0.25-2 | 0.5 | 1 | 2->32 | 16 | >32 | 0.12->32 | 4 | >32 | 0.015->32 | 0.25 | 32 |
| S. aureus, methicillin R (55) | 0.5-1 | 0.5 | 1 | 8->32 | 32 | >32 | 0.12->32 | 8 | >32 | 0.03->32 | 0.25 | 32 |
| S. aureus, methicillin S (29) | 0.25-0.5 | 0.25 | 0.25 | 2-8 | 4 | 4 | 0.12->32 | 0.25 | 8 | 0.015-0.03 | 0.015 | 0.03 |
| S. aureus, vancomycin I (24) | 0.25-2 | 1 | 1 | 4->32 | >32 | >32 | 0.25->32 | 16 | 32 | 0.015->32 | 0.25 | >32 |
| S. aureus, vancomycin R (3) | 0.5-1 | NAc | NA | >32->32 | NA | NA | 16-16 | NA | NA | 1->32 | NA | NA |
| All CNS (103) | 0.03-1 | 0.25 | 0.5 | 0.5->32 | 16 | >32 | 0.06->32 | 4 | >32 | 0.015->32 | 0.03 | 32 |
| All methicillin-R CNS (68) | 0.12-1 | 0.25 | 0.5 | 4->32 | 16 | >32 | 0.12->32 | 8 | >32 | 0.015->32 | 0.25 | 32 |
| All methicillin-S CNS (35) | 0.03-0.25 | 0.06 | 0.25 | 0.5-16 | 2 | 8 | 0.06-32 | 0.25 | 16 | 0.015-0.03 | 0.015 | 0.03 |
| All enterococcal strains combined (105) | 0.015->32 | 2 | 32 | 0.5->32 | >32 | >32 | 0.5->32 | 32 | >32 | 0.03->32 | 1 | >32 |
| E. faecalis, vancomycin I or R (26) | 0.12-8 | 2 | 4 | 1->32 | >32 | >32 | 0.5->32 | 1 | 32 | 0.25-2 | 1 | 2 |
| E. faecalis, vancomycin S (27) | 1-4 | 1 | 4 | >32->32 | >32 | >32 | 1->32 | 1 | >32 | 0.5-2 | 1 | 2 |
| E. faecium, vancomycin I or R (27) | 2->32 | 32 | >32 | >32->32 | >32 | >32 | 1->32 | >32 | >32 | 1->32 | >32 | >32 |
| E. faecium, vancomycin S (25) | 0.015-16 | 1 | 16 | 0.5->32 | >32 | >32 | 0.5->32 | 2 | >32 | 0.03->32 | 4 | >32 |
| C. jeikeium (22) | 0.12->32 | >32 | >32 | 4->32 | >32 | >32 | 0.5->32 | >32 | >32 | 0.06->32 | >32 | >32 |
| L. monocytogenes (21) | 2-4 | 4 | 4 | 8->32 | >32 | >32 | 1-2 | 1 | 1 | 0.03-0.12 | 0.06 | 0.06 |
| Streptococcus agalactiae (27) | 0.015-0.03 | 0.015 | 0.015 | 0.06-0.12 | 0.06 | 0.12 | 0.5-1 | 1 | 1 | 0.015-0.015 | 0.015 | 0.015 |
| S. pneumoniae, all strains combined (125) | 0.015-0.5 | 0.06 | 0.25 | 0.015-8 | 0.5 | 2 | 0.5->32 | 1 | 16 | 0.015-2 | 0.12 | 1 |
| S. pneumoniae, levofloxacin R (23) | 0.015-0.25 | 0.03 | 0.25 | 0.015-4 | 0.25 | 2 | 4->32 | 16 | >32 | 0.015-0.5 | 0.03 | 0.25 |
| S. pneumoniae, penicillin R (29) | 0.015-0.5 | 0.25 | 0.5 | 0.06-8 | 2 | 8 | 0.5-32 | 1 | 1 | 0.015-2 | 0.5 | 1 |
| S. pneumoniae, penicillin I (26) | 0.015-0.12 | 0.03 | 0.06 | 0.03-0.5 | 0.25 | 0.5 | 0.5-2 | 1 | 1 | 0.015-0.12 | 0.03 | 0.06 |
| S. pneumoniae, penicillin S (22) | 0.015-0.12 | 0.015 | 0.015 | 0.015-0.5 | 0.03 | 0.06 | 0.5->32 | 1 | 2 | 0.015-0.12 | 0.015 | 0.015 |
| Streptococcus pyogenes, all strains combined (25) | 0.015-0.015 | 0.015 | 0.015 | 0.015-0.03 | 0.015 | 0.03 | 0.25-2 | 0.5 | 1 | 0.015-0.015 | 0.015 | 0.015 |
| S. pyogenes, macrolide R (8) | 0.015-0.015 | 0.015 | 0.015 | 0.015-0.03 | 0.015 | 0.03 | 0.5-0.5 | 0.5 | 0.5 | 0.015-0.015 | 0.015 | 0.015 |
| S. pyogenes, macrolide S (17) | 0.015-0.015 | 0.015 | 0.015 | 0.015-0.03 | 0.015 | 0.03 | 0.25-2 | 0.5 | 2 | 0.015-0.015 | 0.015 | 0.015 |
| Viridans group streptococci (26) | 0.015-4 | 0.015 | 0.12 | 0.015->32 | 0.12 | 1 | 0.12-2 | 1 | 2 | 0.015-2 | 0.015 | 0.12 |
| Gram-negative species | ||||||||||||
| All Enterobacteriaceae (368) | 0.015->32 | 0.25 | >32 | 0.015->32 | 0.12 | >32 | 0.015->32 | 0.06 | 2 | 0.06-8 | 0.25 | 2 |
| Enterobacter aerogenes, ESBL− (42) | 0.03->32 | 0.12 | >32 | 0.03->32 | 0.12 | >32 | 0.03-8 | 0.06 | 0.5 | 0.06-4 | 1 | 1 |
| E. cloacae, ESBL− (41) | 0.06-2 | 0.12 | 0.5 | 0.06-8 | 0.25 | 0.5 | 0.015-0.5 | 0.03 | 0.06 | 0.12-1 | 0.25 | 0.5 |
| E. coli, ESBL− (51) | 0.015-16 | 0.06 | 1 | 0.015-32 | 0.06 | 0.25 | 0.015-32 | 0.03 | 0.25 | 0.06-2 | 0.12 | 0.25 |
| E. coli, ESBL+ (26) | 0.06->32 | >32 | >32 | 0.015->32 | >32 | >32 | 0.015-32 | 0.25 | 32 | 0.06-4 | 0.12 | 0.25 |
| K. pneumoniae, ESBL− (50) | 0.03-1 | 0.06 | 0.25 | 0.015-0.5 | 0.06 | 0.12 | 0.015-1 | 0.06 | 0.5 | 0.06-1 | 0.25 | 0.5 |
| K. pneumoniae, ESBL+ (43) | 0.5->32 | 32 | >32 | 0.03->32 | 32 | >32 | 0.03->32 | 0.5 | 8 | 0.06-0.5 | 0.12 | 0.25 |
| Morganella morganii (21) | 0.06->32 | >32 | >32 | 0.015-32 | 0.5 | 32 | 0.015-32 | 0.06 | 8 | 2-4 | 4 | 4 |
| P. mirabilis (16) | 0.03-32 | 0.06 | 4 | 0.015->32 | 0.015 | 0.015 | 0.03-2 | 0.03 | 0.25 | 0.25-8 | 2 | 4 |
| P. rettgeri (6), P. stuartii (9) | 0.06->32 | 1 | 4 | 0.015-1 | 0.06 | 0.25 | 0.06->32 | 0.12 | >32 | 0.5-8 | 2 | 4 |
| Proteus vulgaris (16) | 0.03->32 | 16 | >32 | 0.015->32 | 1 | >32 | 0.015-0.06 | 0.03 | 0.06 | 1-4 | 2 | 4 |
| S. marcescens (16) | 0.5-16 | 0.5 | 8 | 0.06-4 | 0.25 | 2 | 0.06-1 | 0.12 | 0.25 | 0.25-2 | 0.5 | 1 |
| Shigella spp. (15) | 0.015-0.25 | 0.03 | 0.12 | 0.03-0.06 | 0.03 | 0.06 | 0.015-0.06 | 0.03 | 0.06 | 0.12-0.25 | 0.12 | 0.25 |
| Salmonella spp. (16) | 0.06->32 | 0.12 | >32 | 0.03->32 | 0.06 | >32 | 0.03-0.25 | 0.03 | 0.06 | 0.12-0.25 | 0.25 | 0.25 |
| Non-Enterobacteriaceae (108) | 0.03->32 | 16 | >32 | 0.03->32 | >32 | >32 | 0.015->32 | 1 | 32 | 0.12->32 | 4 | >32 |
| Burkholderia cepacia (28) | 0.03->32 | >32 | >32 | 0.03->32 | >32 | >32 | 0.015-32 | 1 | 32 | 0.12->32 | 8 | 32 |
| Pseudomonas aeruginosa (25) | 0.5->32 | 16 | >32 | 1->32 | >32 | >32 | 0.25->32 | 2 | >32 | 1-32 | 1 | 16 |
| P. aeruginosa, multidrug R (10) | 4->32 | 16 | >32 | 16->32 | >32 | >32 | 0.5->32 | 32 | >32 | 1-32 | 8 | 16 |
| Stenotrophomonas maltophilia (27) | 0.12->32 | >32 | >32 | 0.5->32 | >32 | >32 | 0.06-32 | 1 | 16 | 8->32 | >32 | >32 |
| M. catarrhalis (101) | 0.015-1 | 0.12 | 0.25 | 0.015-2 | 0.5 | 1 | 0.015-0.06 | 0.03 | 0.03 | 0.015-0.12 | 0.06 | 0.06 |
| H. influenzae, all strains combined (105) | 0.015-0.25 | 0.015 | 0.12 | 0.015-0.25 | 0.015 | 0.12 | 0.015-0.12 | 0.03 | 0.03 | 0.015-1 | 0.5 | 0.5 |
| H. influenzae, β-lactamase negative (27) | 0.015-0.15 | 0.015 | 0.015 | 0.015-0.015 | 0.015 | 0.015 | 0.015-0.03 | 0.03 | 0.03 | 0.03-0.5 | 0.5 | 0.5 |
| H. influenzae, β-lactamase positive (52) | 0.015-0.06 | 0.015 | 0.06 | 0.015-0.015 | 0.015 | 0.015 | 0.015-0.12 | 0.03 | 0.03 | 0.015-1 | 0.25 | 0.5 |
| H. influenzae, β-lactamase negative, ampicillin R (26) | 0.015-0.25 | 0.12 | 0.25 | 0.015-0.25 | 0.12 | 0.12 | 0.015-0.06 | 0.03 | 0.06 | 0.03-1 | 0.5 | 1 |
n, no. of strains.
S, susceptible; R, resistant; I, intermediate; CNS, coagulase-negative staphylococcal strains; ESBL−, ESBL negative; ESBL+, ESBL positive.
NA, not applicable.
Activities of ceftaroline against Enterococcus faecalis, Proteus mirabilis, Providencia rettgeri, and Providencia stuartii were similar to those of imipenem, with MIC90s in the range of 4 to 8 μg/ml. Ceftaroline was less active than imipenem against Serratia marcescens and Listeria monocytogenes. In similarity to other cephalosporins, poor activity (i.e., MIC90 of ≥32 μg/ml) was noted for the ESBL-positive strains of E. coli and K. pneumoniae, as well as miscellaneous species of the Enterobacteriaceae, Enterococcus faecium, Corynebacterium jeikeium, and nearly all nonfermentative strains of gram-negative bacilli. Ceftriaxone was slightly more active than ceftaroline against ESBL-negative E. coli, P. mirabilis, P. rettgeri, S. marcescens, and beta-lactamase-positive H. influenzae. For the majority of species, the gram-for-gram activity of ceftaroline was either comparable or substantially superior to that of ceftriaxone.
Quality control ranges for MIC testing were proposed on the basis of the modal MICs observed ± 1 log2 dilution (Table 2). Disk diffusion zone diameter ranges were proposed using the method of Gavan et al. (7) with adjustments as needed in order to encompass at least 95% of observed values (Table 3). The proposed MIC and zone diameter ranges are presented in Tables 2 and 3, respectively. These quality control ranges were accepted by the Antimicrobial Susceptibility Testing Subcommittee of the CLSI at their June 2006 meeting.
TABLE 2.
Ceftaroline MIC quality control
| Quality control strain | No. of occurrences at MIC (μg/ml) ofa:
|
% in rangeb | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.004 | 0.008 | 0.016 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | ||
| E. coli ATCC 25922 | 0 | 0 | 0 | 12 | 179 | 49 | 0 | 0 | 0 | 0 | 0 | 0 | 100 |
| S. aureus ATCC 29213 | 0 | 0 | 0 | 0 | 0 | 16 | 215 | 9 | 0 | 0 | 0 | 0 | 100 |
| S. pneumoniae ATCC 49619 | 0 | 9 | 224 | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 100 |
| H. influenzae ATCC 49247 | 0 | 0 | 0 | 8 | 216 | 16 | 0 | 0 | 0 | 0 | 0 | 0 | 100 |
CLSI-recommended quality control ranges are represented in bold.
Percentage of results which fall within the recommended range; acceptable limit of >95%.
TABLE 3.
Ceftaroline disk diffusion quality control
| Quality control strain | No. of occurrences at zone diameter (mm) ofa:
|
% in rangeb | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 40 | 41 | ≥42 | ||
| E. coli ATCC 25922 | 3 | 5 | 31 | 63 | 87 | 100 | 97 | 47 | 29 | 14 | 5 | 97 | ||||||||||
| S. aureus ATCC 25923 | 1 | 1 | 6 | 10 | 22 | 38 | 65 | 93 | 70 | 48 | 30 | 33 | 31 | 17 | 11 | 4 | 95 | |||||
| S. pneumoniae ATCC 49619 | 1 | 4 | 6 | 26 | 27 | 52 | 75 | 84 | 76 | 50 | 36 | 29 | 7 | 7 | 98 | |||||||
| H. influenzae ATCC 49247 | 5 | 13 | 7 | 22 | 12 | 22 | 60 | 74 | 108 | 61 | 52 | 34 | 12 | 5 | 1 | 95 | ||||||
CLSI-recommended quality control ranges are represented in bold.
Percentage of results which fall within the recommended range.
In vivo pharmacokinetic/pharmacodynamic studies of ceftaroline using mouse models of infection determined that the percentages of time that serum concentrations of free drug were above the MIC (%T>MIC) for a 1-log kill were 43%, 33%, and 41% of the dosing interval against S. pneumoniae, S. aureus, and members of the Enterobacteriaceae, respectively (1). A population pharmacokinetic analysis of data from phase 1 and phase 2 trials for ceftaroline found that the probability of target attainment for %T>MIC of 50% for a 1-μg/ml target was 96%, and 50% for a 2-μg/ml target, for subjects with normal renal function when administered 600 mg ceftaroline over a 1-h infusion every 12 h (8).
Ceftaroline demonstrated potent activity in vitro against the majority of gram-positive strains tested, with particularly notable activity against methicillin-susceptible and -resistant staphylococci and all streptococci. The inclusion of MRSA in ceftaroline's spectrum of activity sets this drug apart from the majority of cephalosporin and carbapenem antimicrobials and places it with another anti-MRSA cephalosporin currently under FDA regulatory review, ceftobiprole. Ceftaroline also exhibited potent activity against M. catarrhalis, E. cloacae, ESBL-negative E. coli and K. pneumoniae, Shigella species, and H. influenzae, including ß-lactamase-positive and ß-lactamase-negative ampicillin-resistant (BLNAR) strains. Moderate activity was noted for E. faecalis (but not E. faecium), P. mirabilis, P. rettgeri, P. stuartii, S. marcescens, and L. monocytogenes. Similar to the case with other cephalosporins, low activity was noted for the ESBL-positive strains of E. coli and K. pneumoniae, as well as miscellaneous species of the Enterobacteriaceae, E. faecium, C. jeikeium, and nearly all nonfermentative strains of gram-negative bacilli. Ceftaroline quality control ranges for both MIC and disk diffusion methodologies have been accepted by the CLSI (5).
Acknowledgments
Financial support for this project was provided by Forest Laboratories, Inc.
Footnotes
Published ahead of print on 29 December 2008.
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