Piperacillin/Tazobactam Dose Optimization in the Setting of Piperacillin/Tazobactam-susceptible, Carbapenem-resistant Pseudomonas aeruginosa: Time to Reconsider Susceptible Dose Dependent

Purpose: This study evaluates the in vitro potency of piperacillin/tazobactam among a global collection of carbapenem-resistant Pseudomonas aeruginosa (CR -PA) and assesses the adequacy of the Clinical and Laboratory Standards Institute (CLSI) P aeruginosa breakpoint dose in the setting of CR-PA using Monte Carlo simulation. Methods: Isolates were collected during the En-hancing Rational Antimicrobials Against Carbapenem-Resistant P aeruginosa (ERACE-PA) Global Surveil-lance Program. Piperacillin/tazobactam MICs were determined using broth microdilution per CLSI stan-dards. A 5000-patient Monte Carlo simulation was performed using various piperacillin/tazobactam dos-ing regimens to determine the probability of target attainment (PTA) for 50% free time above the MIC. The MIC distribution of piperacillin/tazobactam-susceptible CR-PA was used to calculate cumulative fraction of response (CFR). Optimal PTA and CFR were defined as 90% target achievement. Findings: A total of 28% of tested CR-PA were piperacillin/tazobactam susceptible. Of these, 71% had MICs of 8 to 16/4 mg/L. Doses of 3.375 g q6h as 0.5 -hour infusion (current breakpoint dose) had adequate PTA at MIC of 8/4 mg/L (CFR, 81%); however, extended infusion of 3 or 4 hours improved PTA at 16/4 mg/L (CFR, > 90%). Doses of 4.5 g q8h as a 4 -hour infusion and 4.5 g q6h as a 3-hour infusion both provide > 90% PTA at an MIC of 16 mg/L (CFRs, 97 and 100%, respectively), favoring susceptible dose dependent interpretive criteria with these regimens. Implications: Although susceptible, piperacillin/ tazobactam has reduced potency in CR-PA. If piperacillin/tazobactam is used for susceptible CR -PA, high-doses (4.5 g q6h) and extended infusion (3 hours or continuous infusion) are needed to optimize exposure. (Clin Ther. 2023;45:72-77.) (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)