Population Pharmacokinetics of High Dose Continuous Infusion Meropenem and Considerations for the Use in the Treatment of Infections due to KPC-Producing Klebsiella pneumoniae [PublishAheadOfPrint]

We assessed the population pharmacokinetics of high-dose continuous infusion (HDCI) meropenem in a cohort of patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with ≤10-15% likelihood of meropenem steady-state concentrations (C_ss) >100 mg/L. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100%T_>1xMIC, 100%T_>2xMIC, 100%T_>3xMIC, 100%T_>4xMIC) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n=169). Ninety-seven meropenem C_ss were included in the analysis. The final model included creatinine clearance (CrCL) as covariate, and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages up to 6g/day predicted acceptable PTA (>80%) of 100%T_>1xMIC against KPC-Kp with an MIC for meropenem ≤32 mg/L in patients with CrCL <130 mL/min. Dosages of 8g/day were needed for achieving the same target in patients with CrCL 130-200 mL/min. When dealing with pathogens with an MIC for meropenem of 64mg/L, higher than licensed HDCI meropenem regimens should be considered. In these cases, real time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

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