Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

Abstract

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300 mg I.V. q12h, q8h, and q6h, and 600 mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5 h) and an EI (1 h, 2 h, 3 h, and 4 h).For a target of 40%fT>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug–resistant P. aeruginosa (MDR-PA) and even non–MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600 mg q12h over 2–4 h EI regimens could achieve CFR>90% with 20%fT>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.