Pharmacokinetic/pharmacodynamic evaluation of the efficacy and safety of daptomycin against Staphylococcus aureus

Daptomycin is a novel lipopeptide exhibiting concentration-dependent bactericidal activity against multidrug-resistant Gram-positive pathogens, including MRSA. Approval of daptomycin is granted at 4–6 mg/kg once daily, however off-label use of doses up to 12 mg/kg daily has been utilised without evidence of significant toxicity. Our aim was to optimise daptomycin regimens by assessing the probability of bacteriological efficacy (pTA) and toxicity (pTOX) at various MICs using Monte Carlo simulation (MCS) techniques. Population pharmacokinetic, pharmacodynamic and toxicodynamic models were developed based on current literature. MCS was performed for 10 000 patients, who were assigned true weight and creatinine clearances, and were infected with four Staphylococcus aureus strains at each MIC. Bacteriostatic and bactericidal %pTA was calculated following administration of 6, 8, 10 and 12 mg/kg daptomycin; activity was deemed adequate at %pTA ≥ 90%. Considerable pharmacodynamic variability was observed in derived AUC/MIC targets between strains. Bacteriostatic targets were adequately attained against all strains at MIC ≤ 1 mg/L with daptomycin >6 mg/kg. However, bactericidal target attainment was only achieved against all strains at the lowest MIC of 0.5 mg/L with daptomycin >8 mg/kg. At MIC = 2 mg/kg, bactericidal target attainment was extremely poor even at the highest dose of 12 mg/kg. pTOX increased from 3.31% to 17.7% following exposure to 6 mg/kg to 12 mg/kg daily, respectively. Formal benefit:risk analyses favoured doses of 10 mg/kg against infections with MIC < 2 mg/L, whilst modest improvements in activity at 12 mg/kg could not justify the marked increase in pTOX.