Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation

Abstract

Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC_0-24:MIC) ≥666 was used to determine the PTA for efficacy (PTA_E). Minimum concentration (C_min) ≥24.3 mg/L determined the PTA for toxicity (PTA_T). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTA_E and ≤5% PTA_T. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTA_E in children 13-24 months, 39.5% PTA_E in children 2-6 years, 30.1% PTA_E in children 7-11 years, and 50.1% PTA_E in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24 mg/kg in children 3-12 months, 20-24 mg/kg in children 13-24 months, 19-24 mg/kg in children 2-6 years, 17-19 mg/kg in children 7-11 years, and 10-14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7-11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.