In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program

Abstract

b Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC 90 for all S. aureus isolates was 2 g/ml (interpretive criteria: susceptible, <1 g/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 g/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 g/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu 239 Lys substitution, and 12 of these also carried an additional Glu 447 Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

Impact of EUCAST ceftaroline breakpoint change on the susceptibility of methicillin-resistant Staphylococcus aureus isolates collected from patients with complicated skin and soft-tissue infections

“…The revised ceftaroline resistance rate against MRSA reported by this study in Asia (1.8%), using version 8.0 of the EUCAST breakpoints, was higher than in other participating regions. Previous studies have identified a set of MRSA isolates collected in Thailand with ceftaroline MIC values of 2 mg/L [12,13,15]. Among the isolates selected for molecular characterization, the majority with ceftaroline MIC values of 2 mg/L had a single amino acid substitution in the non-penicillin-binding domain of penicillin-binding protein 2a (PBP2a), and isolates with ceftaroline MICs of 4 mg/L [13] or 8 mg/L [12,15] all had an additional single amino acid substitution in the penicillin-binding domain of PBP2a.…”

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

“…Significantly, it is perhaps the drug's most important and distinguishing feature within the class of beta-lactams, its activity against MRSA, that has been met with the most skepticism. In particular, concerns over the appropriateness of the currently recommended dosage of 600 mg twice daily for the treatment of infections caused by S. aureus isolates with MIC values above the current EUCAST breakpoint of 1 mg/liter (14) have been raised, given that CPT MIC 90 values of 2 mg/liter for MRSA have been reported in certain countries within Europe, in Latin America, and in Asia (15)(16)(17)(18)(19)(20). These concerns have driven the initiation of additional clinical trials evaluating an increased frequency of administration (every 8 h) and an extension of the duration of the intravenous infusion of the drug from 1 to 2 h as a potential future mode of administration for infections caused by less susceptible organisms.…”

High-Level Resistance of Staphylococcus aureus to β-Lactam Antibiotics Mediated by Penicillin-Binding Protein 4 (PBP4)

“…Although it is not approved in the United States, the drug has received the qualified infectious disease product designation from the U.S. FDA. Resistance to both of these drugs has been generated in vitro and has been reported clinically and in surveillance studies worldwide, often in association with mutations in mecA (4,(12)(13)(14)(15)(16)(17). We previously reported that passage of a mecA-negative strain of S. aureus, COLnex, passaged in ceftobiprole selected for a highly resistant mutant strain, CRB (4,12,18).…”