U.S. flag An official website of the United States government

On Oct. 1, 2024, the FDA began implementing a reorganization impacting many parts of the agency. We are in the process of updating FDA.gov content to reflect these changes.

U.S. Food and Drug Administration
  1. Home
  2. Drugs
  3. Development & Approval Process | Drugs
  4. Development Resources
  5. FDA Rationale for Breakpoints Recognition Decision: Piperacillin-Tazobactam and Pseudomonas aeruginosa
  1. Development Resources

FDA Rationale for Breakpoints Recognition Decision: Piperacillin-Tazobactam and Pseudomonas aeruginosa

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.

Back to Top