LAUSR

INTRODUCTION The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. OBJECTIVES This study aimed to evaluate dosing regimens for co-administration of daptomycin and ceftaroline in special populations including pediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA. METHODS PBPK models were developed from pharmacokinetic studies of healthy adults, geriatrics, pediatrics, obese, and RI patients. The predicted profiles were used to evaluate joint probability of target attainment (PTA), as well as tissue-to-plasma ratios. RESULTS The adult dosing regimens of 6 mg/kg q24h or q48h daptomycin and 300-600 mg q12h ceftaroline fosamil by RI categories achieved ≥90% joint PTA when the minimum inhibitory concentrations (MICs) in the combination are at or below 1 and 4 μg/mL against MRSA. In pediatrics, wherein there is no recommended daptomycin dosing regimen for S. aureus bacteremia, ≥90% joint PTA is achieved when the MICs in the combination are up to 0.5 and 2 μg/mL for standard pediatric dosing regimens of 7 mg/kg q24h daptomycin and 12 mg/kg q8h ceftaroline fosamil. Model predicted tissue-to-plasma ratios of 0.3 and 0.7 in the skin and lung, respectively, for ceftaroline and 0.8 in the skin for daptomycin. CONCLUSION Our work illustrates how PBPK modeling can inform appropriate dosing of adult and pediatric patients and thereby enable prediction of target attainment in the patients during multi-therapies.