In Vitro Antimicrobial Activity of a New Cephalosporin, Ceftaroline, and Determination of Quality Control Ranges for MIC Testing

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 , 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 drugresistant 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 (Ͻ3 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. 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 a...

In Vitro Activity of Ceftaroline-Avibactam against Gram-Negative and Gram-Positive Pathogens Isolated from Patients in Canadian Hospitals from 2010 to 2012: Results from the CANWARD Surveillance Study

“…Ceftaroline also retains its potency against coagulase-negative staphylococci with reduced susceptibility to linezolid, daptomycin, and vancomycin (32). The current study found Ͼ99% of isolates of MRSA, including both health care-associated and communityassociated isolates of MRSA, to be susceptible to ceftarolineavibactam and ceftaroline, similar to results reported by other investigators (5,(27)(28)(29). Isolates of MRSA collected by the CANWARD surveillance study in 2009 (2) demonstrated an MIC 90 (1 g/ml) identical to the one reported by the current study for isolates tested from 2010 to 2012.…”

“…If the ceftaroline FDA susceptibility breakpoint for Enterobacteriaceae (susceptible, Յ0.5 g/ml) was used for ceftarolineavibactam, the susceptibility rate was Ͼ99% (3,846/3,879 isolates) for all Enterobacteriaceae tested. Ceftaroline is known to be hydrolyzed by ESBL, AmpC, KPC, and metallo-␤-lactamases, and its in vitro activity is reflected by the prevalence of these enzymes in isolate collections (9,27,28,29). Isolates of Enterobacteriaceae collected by the CANWARD surveillance study in 2009 (2) demonstrated levels of susceptibility to ceftaroline similar to those reported in the current study from 2010 to 2012 (Table 1).…”

In Vitro Activity of Ceftaroline against Community-Associated Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, and Daptomycin-Nonsusceptible Staphylococcus aureus Isolates

“…Ceftaroline demonstrated in vitro activity against all CA-MRSA isolates, regardless of their SCCmec type, with MICs ranging from 0.25 to 1 g/ml and with the MIC 90 being 1 g/ml. These findings are supported by those of earlier studies, in which the ceftaroline MICs ranged from 0.25 to 1 g/ml for CA-MRSA and from 0.12 to 2 g/ml for MRSA (1,6,10,14,15,20,21). Daptomycin nonsusceptibility among VISA isolates has been reported (11,17), potentially limiting the treatment options for patients infected with these pathogens.…”

Multistep Resistance Development Studies of Ceftaroline in Gram-Positive and -Negative Bacteria

“…After 50 serial subcultures, ceftaroline did not yield resistant clones and demonstrated MICs consistent with previously published reports against all strains of S. aureus, S. pneumoniae, S. pyogenes, M. catarrhalis, and K. pneumoniae tested (8,20,22,31,46,49,50,53,57). One of four H. influenzae strains tested (a quinolone-resistant isolate) produced a ceftaroline clone with increased MIC of 0.06 to 1 g/ml after 20 days of passaging.…”