Antibacterial effect of ceftaroline against MRSA and VISA strains studied in an in vitro pharmacokinetic model of infection
Abstract number: P795
Noel A.R., Tomaselli S., Elliott H., Bowker K.E., MacGowan A.
Objectives: Ceftaroline (CPT) is a broad spectrum, cephalosporin with bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC50/MIC90/maximum MIC of 0.51/12/2mg/L. MICs for vancomycin intermediate (VISA) strains are 2mg/L. In healthy volunteers, CPT fosamil (the prodrug of the active compound CPT) dosed at 600mg 12 hrly produces a Cmax of about 20mg/L, half life of 2.5h and an AUC12 of 56mg/L·h. We used an in vitro pharmacokinetic (IVPK) model to study the antibacterial effect of simulated CPT serum concentrations on a range of MRSA and VISA strains.
Methods: A dilutional single compartment IVPK model was used to simulate serum concentrations of CPT associated with CPT fosamil dosing of 600mg 12 hrly for 48h (Cmax 23mg/L, half life 2.5h, 4 doses). Three strains of vancomycin susceptible MRSA (CPT MICs 0.25, 0.5 and 1.5mg/L) and three VISA strains (CPT MICs 0.5 or 1.0mg/L) were used at an initial inoculum of 106 CFU/mL. Antibacterial effect was measured by change in viable count and the area under the bacterial kill curve to 24h (AUBKC24, log CFU/mL·h) or 48h (AUBKC48). Risk of emergence of resistance was assessed by changes in population analysis profiles (PAP) measured at 24h and 48h post exposure.
Results: CPT produced a >2 log reduction in viable count after 6hr with all strains and a >3.5 log reduction at 12h with 5 of the 6 strains. The maximum kill was >4 logs. Bacterial growth suppression was maintained over the 48h simulations. There was no relationship between strain CPT MIC and antibacterial effect as measured by AUBKC24 or 48 (ANOVA, p > 0.05). CPT was more bactericidal against VISA strains than MRSA in terms of AUBKC48 (p < 0.05) but not AUBKC24. There was no emergence of resistance measured by PAP with any strain.
Conclusion: At simulated serum concentrations associated with doses of 600mg 12hrly, CPT has a marked bactericidal effect on MRSA strains with MICs in the range 0.251.5mg/L. CPT was more active against VISA strains than MRSA strains as assessed by some effect measures.
|Session name:||Abstracts of 21st ECCMID / 27th ICC|
|Location:||Milan, Italy, 7 - 10 May 2011|
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