Objectives: To compare the antibacterial effects (ABEs) of the free (f) drugs daptomycin, vancomycin and teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), using high and low inocula in a pharmacokinetic in vitro model. To determine the daptomycin fAUC/MIC ratio for a static effect and 3 log reduction in viable count and relate this target to the clinical breakpoint.
Methods: Five clinical MRSA isolates held at Southmead Hospital were used (SMH 15841, SMH 40289, SMH 40275, SMH 33922 and SMH 33024) together with a VRSA isolate (SMH 19898); inocula of 10(6) and 10(8) cfu/mL were used. Daptomycin (6 mg/kg once daily), vancomycin (1 g twice daily) and teicoplanin (400 mg once daily) regimens were simulated. ABEs were measured using the 24 h area-under-the-bacterial kill curve (AUBKC) and log change in viable count at 24 h (Delta24). For daptomycin, dose escalation was used to determine the relationship between ABE and AUC/MIC.
Results: Daptomycin was bactericidal against the MRSA strains. Daptomycin and vancomycin were active against the VRSA strain; teicoplanin had a static effect. The higher inoculum reduced the ABEs. Analysis of variance (ANOVA) indicated that daptomycin had a superior ABE to teicoplanin and vancomycin. Daptomycin fAUC/MIC was related to AUBKC and Delta24; the fAUC/MIC ratios for a static effect and 1 log and 3 log drop were 37.2 +/- 16.5, 40.6 +/- 17.8 and 49.8 +/- 19.2, respectively.
Conclusions: These data define the fAUC/MIC sizes for daptomycin for bacteriostatic and bactericidal ABEs and indicate that a 6 mg/kg dose of daptomycin is superior to vancomycin and teicoplanin against MRSA and VRSA strains.