No abstract

An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5-to 4.0-log 10 -unit reductions in viable counts by 24 h with all strains and a 0.5-to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 g/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT MIC ) of 24.5% ؎ 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ؎ 9.5% was associated with a ؊1-log-unit drop, and one of 32.1% ؎ 8.1% was associated with a ؊2-log-unit drop. The MSSA and MRSA strains had similar fT MIC values. fT MIC values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT MIC . fT MIC s of <50% were associated with growth on 4؋ MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of <2 g/ml. An fT MIC of 25 to 30% would make a suitable pharmacodynamic index target, but fT MIC values of >50% are needed to suppress the emergence of resistance and require clinical evaluation. C eftaroline fosamil (CPT) has been approved by the U.S. FDA for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia: market authorization in the European Union (EU) for complicated skin and soft tissue infections and community-acquired pneumonia is pending.Ceftaroline fosamil (previously PP1-0903, T-91825, and TAK-599) is the prodrug of ceftaroline and is the first ␤-lactam with activity against methicillin-resistant Staphylococcus aureus (MRSA) marketed for clinical use in the United States. International surveillance studies conducted on MRSA strains in North America and the EU indicate that in the United States, the ceftaroline MIC 50 and MIC 90 are 1 and 1 g/ml, respectively, with 5.2% of strains having MICs of Ͼ1 g/ml. In contrast, in Europe the MIC 50 and MIC 90 are 1 and 2 g/ml, respectively, with 17.3% of strains having MICs of Ͼ1 g/ml. The FDA clinical breakpoint for susceptibility among S. aureus isolates is Յ1 g/ml (1, 2). The proposed European (EUCAST) clinical breakpoint has not yet been published, but a breakpoint similar to that used in the United States will present significant problems in laboratory testing of ceftaroline, as it will cut through the MRSA MIC distribution.Ceftar...

No abstract