FDA has reevaluated the rationale document entitled, “Piperacillin-Tazobactam Breakpoints for Pseudomonas aeruginosa” (MR15, January 2024), submitted by the Clinical and Laboratory Standards Institute (CLSI) to susceptibility test interpretive criteria docket #FDA-2017-N-5925-0012. The initial review was completed by FDA in March 2024.1

At that time, due to limitations of provided PK-PD data and an increase in mortality in P. aeruginosa infections caused by isolates with a piperacillin-tazobactam minimum inhibitory concentration (MIC) of ≥ 32/4 mcg/mL, FDA did not recognize the CLSI piperacillin-tazobactam breakpoints for P. aeruginosa but identified alternative breakpoints shown in the table below:

Current FDA and CLSI Piperacillin-Tazobactam Breakpoints for P. aeruginosa

	Minimum Inhibitory Concentrations (mcg/mL)	Disk Diffusion (zone diameter in mm)
S	SDDa	I	R	S	SDDa	I	R
FDA	≤8/4	16/4	–	≥32/4	≥23	19-22	–	≤18
CLSI	≤16/4	–	32/4	≥64/4	≥22	–	18-21	≤17

Abbreviations: S, susceptible; SDD, susceptible-dose dependent; I, intermediate; R, resistant;

a Susceptible-dose dependent breakpoints are based on a dosage regimen of 4.5 grams every 6 hours as a 3-hour infusion in patients with creatinine clearance 41-120 mL/min.

FDA understands that its current piperacillin-tazobactam breakpoints do not include an intermediate category that would provide a buffer zone for inherent variability in antimicrobial susceptibility test methods. FDA also acknowledges that accurate categorization of the piperacillin-tazobactam SDD breakpoint for P. aeruginosa may be challenging because the piperacillin-tazobactam epidemiological cutoff value for P. aeruginosa is 16/4 mcg/mL and the current testing methodology may not reliably identify MIC values within the wild-type population.

Based on this re-evaluation, FDA recognizes the CLSI piperacillin-tazobactam breakpoints for P. aeruginosa but recommends the breakpoints be based on the maximum approved piperacillin-tazobactam dose of 4.5 g every 6 hours administered over 3 hours.

1 Available at: https://www.fda.gov/drugs/development-resources/notice-updates