Breaking Down the Breakpoints: Rationale for the 2022 Clinical and Laboratory Standards Institute Revised Piperacillin-Tazobactam Breakpoints Against Enterobacterales.

Piperacillin-tazobactam (PTZ) is one of the most common antibiotics administered to hospitalized patients. Its broad activity against gram-negative, gram-positive, and anaerobic pathogens; efficacy in clinical trials across diverse infection types and patient populations; and generally favorable toxicity profile make it a particularly appealing antibiotic agent. PTZ susceptibility interpretive criteria (ie, breakpoints) for the Enterobacterales were initially established in 1992, as the drug was undergoing approval by the US Food and Drug Administration. In the ensuing 30 years, changes in the molecular epidemiology of the Enterobacterales and its impact on PTZ susceptibility testing, mounting pharmacokinetic/pharmacodynamic data generated from sophisticated techniques such as population pharmacokinetic modeling and Monte Carlo simulation, and disturbing safety signals in a large clinical trial prompted the Clinical Laboratory and Standards Institute (CLSI) to review available evidence to determine the need for revision of the PTZ breakpoints for Enterobacterales. After an extensive literature review and formal voting process, the susceptibility criteria were revised in the 2022 CLSI M100 document to the following: ≤8/4 µg/mL (susceptible), 16/4 µg/mL (susceptible dose-dependent), and ≥32/4 µg/mL (resistant). Herein, we provide a brief overview of the CLSI process of antibiotic breakpoint revisions and elaborate on the available data that ultimately led to the decision to revise the PTZ breakpoints.
Competing Interests: Potential conflicts of interest. P. N. A. H. has received research grants from Merck & Co, Inc., Sandoz Pharmaceuticals, and Shionogi, Inc.; speaker's fees from Phizer, Inc., Sumitomo Corporation, and Sandoz Pharmaceuticals; and has served on advisory boards for Merck & Co, Inc. and Sandoz Pharmaceuticals. A. J. M. serves on the Advisory Board for Merck & Co, Inc. and Qpex Biopharma, and reports consulting fees from Merck & Co, Inc., Qpex Biopharma, and Melinta Therapeutics. E. W. serves on the speaker's bureau for AbbVie, Inc, Astellas Pharma, Melinta Therapeutics, and Shionogi, Inc., and on the advisory board for Shionogi, Inc., and Merck & Co, Inc.; and reports consulting fees from bioMerieux, Inc.. R. M. H. is a consultant for Roche, Pattern Bioscience, bioMerieux, Inc., Torus Biosystems, Merck & Co, Inc., Qpex Biopharma, and Melinta Therapeutics and reports grants or contracts from bioMerieux, Inc., Momentum Bioscience, International Health Management Associates (IHMA), Qiagen, Pattern Bioscience, and Specific Diagnostics; and stock or stock options include Accelerate Diagnostics, Specific Diagnostics, and NGD Diagnostics. All authors serve as unpaid volunteers for the CLSI. There was no external support for this work. P. D. T. reports no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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