Targeting Pseudomonas aeruginosa resistance at the exposure frontier: a population PK/PD blueprint for ceftolozane/tazobactam continuous infusion.

Abstract

Ceftolozane/tazobactam is a key antibiotic for Pseudomonas aeruginosa infections. Our objective was to determine whether continuous infusion (CI) of ceftolozane/tazobactam can achieve aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets that suppress resistance and improve outcomes in severe Pseudomonas aeruginosa infections. A retrospective analysis of adult patients receiving CI ceftolozane/tazobactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modeling identified the most accurate method for estimating ceftolozane/tazobactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive PK/PD target attainment of ceftolozane/tazobactam. The 2021 non-race-based Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation with body surface area indexation provided the most reliable clearance estimates. Simulations showed that CI regimens of 4-6 g/2-3 g daily achieved optimal target attainment (≥90%) across all kidney function strata for MICs up to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint. Cumulative fraction of responses remained robust against key resistance phenotypes: MDR (12.6%; 83.8%), pan-beta-lactam-nonsusceptible (8.2%; 78.2%), and difficult-to-treat resistant (6.7%; 71.7%). Even among isolates with MIC >4 mg/L, aggressive target attainment was reached in 15%-40% of cases. This study suggests that CI ceftolozane/tazobactam, informed by TDM and optimized for aggressive PK/PD targets, offers a promising strategy to maximize efficacy and suppress resistance in severe Pseudomonas aeruginosa infections. These findings warrant prospective clinical trials of CI-based, exposure-guided therapy.