Aims: The objective of the current study was to evaluate paediatric dosing regimens for meropenem plus fosfomycin that generate sufficient coverage against multidrug-resistant bacteria.
Methods: The physiologically based pharmacokinetic (PBPK) models of meropenem and fosfomycin were developed from previously published pharmacokinetic studies in five populations: healthy subjects of Japanese origin, and healthy adults, geriatric, paediatric and renally impaired of primarily Caucasian origins. Pharmacodynamic (PD) analyses were carried out by evaluating dosing regimens that achieved a ≥90% joint probability of target attainment (PTA), which was defined as the minimum of the marginal probabilities to achieve the target PD index of each antibiotic. For meropenem, the percentage of time over a 24-hour period wherein the free drug concentration was above the minimum inhibitory concentration (fT > MIC) of at least 40% was its PD target. The fosfomycin PD index was described by fAUC/MIC of at least 40.8.
Results: For coadministration consisting of 20 mg/kg meropenem q8h as a 3-hour infusion and 35 mg/kg fosfomycin q8h also as a 3-hour infusion in a virtual paediatric population between 1 month and 12 years of age with normal renal function and a corresponding body weight between 3 and 50 kg, a joint PTA ≥ 90% is achieved at MICs of 16 and 64 mg/L for meropenem and fosfomycin coadministration, respectively, against Klebsiella pneumoniae and Pseudomonas aeruginosa.
Conclusion: The current study identified potentially effective paediatric dosing regimens for meropenem plus fosfomycin coadministration against multidrug-resistant bacteria.
Keywords: PBPK; antimicrobial coadministration; pharmacodynamic; probability.
© 2020 The British Pharmacological Society.