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We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients withKlebsiella pneumoniae carbapenemase (KPC)-producingKlebsiella 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 a ≤10% to 15% likelihood of meropenem steady-state concentrations (C ss ) of &gt;100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T&gt;1×MIC , 100% T&gt;2×MIC , 100% T&gt;3×MIC , and 100% T&gt;4×MIC , where “T&gt;MIC ” represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) 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 meropenemC ss were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (&gt;80%) of 100% T&gt;1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of  75% in all of the classes of renal function.

antimicrobial agents and chemotherapy

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