Work

Inadequate imipenem dosing in patients with decreased kidney function: a global clinical pharmacokinetic study

Year: 2025

Type: article

Abstract: Objectives A number of population pharmacokinetic (popPK) models of imipenem in critically ill patients are available for dosing optimisation, but they represent only a narrow range of kidney functions. This study evaluates the target attainment of on-label regimens through popPK modelling and simulation in patients across different kidney functions. Methods A popPK model was built based on two datasets from Switzerland (model development population, 151 patients, 322 concentrations) and externally validated on two datasets from the Czech Republic (19 patients, 111 concentrations) and Vietnam (43 patients, 85 concentrations). Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) from a minimum inhibitory concentration (MIC) of 0.125 to 32 mg/L. We estimated the cumulative fraction of response (CFR) against Pseudomonas aeruginosa (the epidemiological cut-off value was 4 mg/L) across a broad range of Cockcroft-Gault creatinine clearance values (CL CRCG 15-130 mL/min). Targets of 40% and 100%ƒT>MIC (percentage of dosing interval estimated free concentrations above MIC) were investigated. Results Decreased kidney function (eGFR CKD-EPI <90mL/min) was observed in 70/151 patients (46.4%) within the model development population, and in 11/19 (57.9%) and 24/43 (55.8%) patients in the Czech Republic and Vietnam, respectively. CL CRCG significantly influenced the imipenem clearance described by a two-compartment model. For PTA, all regimens achieved 40% ƒT>MIC 2mg/L . With a 100%ƒT>MIC target, 500 mg q6h (CL CRCG 30-60 mL/min) could only cover a MIC of up to 1 mg/L, irrespective of infusion time. For CFR, no dosing regimen could cover susceptible P. aeruginosa for 100%ƒT>MIC. Conclusions The highest on-label imipenem dosing regimens failed to attain 100% ƒT>MIC 4mg/L in patients with decreased kidney function. Higher dosing may be necessary to cover MIC of 4mg/L. Future trials should explore their efficacy, toxicity, and the utility of model-informed precision dosing in this population.

Source: Clinical Microbiology and Infection

DOI: 10.1016/j.cmi.2025.05.005