FDA Rationale for Piperacillin Tazobactam Breakpoints for Pseudomonas aeruginosa

FDA has completed their review of the rationale document titled, “Piperacillin-Tazobactam Breakpoints for Pseudomonas aeruginosa” (MR15, January 2024), submitted by the Clinical and Laboratory Standards Institute (CLSI) to the public docket, FDA-2017-N-5925-0012, in January 2024.

Piperacillin-tazobactam is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a β-lactamase inhibitor, indicated for the treatment of:

• Intra-abdominal infections in adult and pediatric patients 2 months of age and older
• Nosocomial pneumonia in adult and pediatric patients 2 months of age and older
• Skin and skin structure infections in adults
• Female pelvic infections in adults
• Community-acquired pneumonia in adults

In adults with creatinine clearance greater than 40 mL/min, piperacillin-tazobactam is approved at 4.5 g every 6 hours administered by intravenous infusion over 30 minutes for nosocomial pneumonia, and at 3.375 g every 6 hours as a 30-minute infusion for all other indications.

CLSI notes that since the revision of piperacillin-tazobactam breakpoints in 2012, multiple studies using modern PK/PD methods highlighted a low probability of target attainment (PTA) at minimal inhibitory concentrations (MIC) > 16 mcg/mL necessitating updating the piperacillin-tazobactam breakpoints against P. aeruginosa. The updated breakpoints were published in the 33rd ed. of CLSI M100 in 2023. The current FDA breakpoints and the historical and current CLSI breakpoints are presented in Table 1.

Table 1. Current FDA and Current and Historical CLSI Piperacillin-Tazobactam MIC and Zone Diameter Breakpoints for P. aeruginosa

	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion (zone diameter in mm)
	S	I	R	S	I	R
FDA	≤16/4	32/4-64/4	≥128/4	≥21	15-20	≤14
CLSI 2012	≤16/4	32/4-64/4	≥128/4	≥21	15-20	≤14
CLSI 2023	≤16/4	32/4	≥ 64/4	≥ 22	18-21	≤17

Breakpoints as of the time of the submission of the CLSI rationale document.
MIC: minimal inhibitory concentration; R: resistant; S: susceptible; I: intermediate.

The current CLSI susceptible breakpoint is based on a piperacillin-tazobactam dosage regimen of 4.5 g administered every 6 hours as a 30-minutes or 3-hour infusion. FDA does not specify a dosage regimen for the piperacillin-tazobactam breakpoint on its susceptibility test interpretative criteria (STIC) website.

CLSI provided the following rationale to support their revised breakpoints:

1. Piperacillin-tazobactam epidemiologic cutoff value (ECV) for P. aeruginosa of 16 mcg/mL. CLSI notes that breakpoints set below the ECV reduce the ability of antimicrobial susceptibility testing methods to reliably distinguish between interpretive categories, potentially leading to unacceptably high error rates. CLSI notes that the P. aeruginosa ECV was one log² dilution higher than the Enterobacterales ECV and corresponding susceptibility breakpoint of ≤ 8/4 mcg/mL, thereby preventing breakpoint harmonization across these organism groups.
2. PK-PD data: The CLSI analyzed several studies investigating piperacillin-tazobactam achievable MIC targets for ≥ 90% probability of target attainment (PTA) at ≥ 50% fT_>MIC. The studies used various dosage regimens and infusion durations. Extended-infusion dosing over 3 to 4 hours of the 4.5 g dose every 6 to 8 hours more reliably achieved ≥ 90% PTA at MICs ≤ 16/4 mcg/mL. The CLSI notes that no dosage regimen demonstrated acceptable PTA at MICs ≥ 32/4 mcg/mL in patients with normal renal function regardless of study methodology or infusion duration.
3. Clinical data indicating a clinical failure signal for P. aeruginosa isolates with MICs ≥ 32 mcg/mL treated with piperacillin-tazobactam. ^1,2,3,4 The CLSI acknowledged limitations of the four analyzed studies related to their retrospective design, likely selection bias, generally small sample size and variable piperacillin-tazobactam dosing.

The CLSI concludes that MICs ≥32/4 mcg/mL are associated with unacceptably low PTA and increased mortality, and that the intermediate breakpoint of 32/4 mcg/mL for piperacillin-tazobactam against P. aeruginosa is meant only to account for technical variability inherent to susceptibility testing, does not imply dose-dependent susceptibility, and administration of piperacillin-tazobactam against P. aeruginosa isolates with MIC 32/4 mcg/mL is not advised. ⁵

FDA reviewed the submitted information and agrees that provided data support lowering the breakpoints for piperacillin-tazobactam against P. aeruginosa. However, FDA declines to recognizes the CLSI breakpoints for the reasons described below.

FDA has concluded that an MIC of ≤ 16/4 mcg/mL is appropriate as a susceptible-dose dependent (SDD) breakpoint contingent on the dosage regimen of 4.5 g every 6 hours as a 3-hour infusion with a susceptible breakpoint at 8/4 mcg/mL. This conclusion is based on two lines of evidence. First, a clinical failure signal for P. aeruginosa isolates with MICs of ≥32/4 mcg/mL treated with piperacillin-tazobactam. Second, PTA data demonstrating that the standard 0.5-hour infusion of PTZ does not achieve ≥90% PTA at an MIC of 16/4 mcg/mL even when the highest approved dose of 4.5 g every 6 hours is used. Considering the limitations of the provided PTA analyses, which are described below, FDA recommends using the maximum approved dose of 4.5 g (rather than 3.375 g) every 6 hours with an extended infusion over 3 hours to improve PTA at MIC of 16/4 mcg/mL by maximizing the fT_{C> piperacillin-tazobactam MIC}/τ in support of the SDD breakpoint. FDA acknowledges that the piperacillin-tazobactam ECV for P. aeruginosa is 16/4 mcg/mL, but because the MIC of 16/4 mcg/mL still falls within the susceptible range, the introduction of the SDD breakpoint does not result in splitting of the wild-type population.

As for the MIC of 32/4 mcg/mL, FDA concludes that the available data indicate that this MIC is more consistent with a resistant rather than an intermediate breakpoint. FDA notes that an intermediate breakpoint defines isolates with MICs or zone diameters that approach usually attainable blood and tissue levels, and while clinical response rates for intermediate isolates may be lower than for susceptible ones, an intermediate breakpoint implies a reasonable expectation of clinical success. However, the provided data demonstrate that the MIC of 32/4 mcg/mL for PTZ against P. aeruginosa is associated with unreliable and unacceptably low drug exposures, and increased mortality in clinical studies.

Specifically, a 67% PTA at MICs ≥32/4 mg/L with 4.5 g every 6 hours as a 3-hour infusion versus <40% PTA at MICs of ≥ 32/4 mg/L with 4.5 g every 6 hours as a 0.5 hour infusion is predicted in patients with CrCl 41-120 mL/min by Thabet et al.⁶ We note that this simulation study excluded patients with CrCl > 120 mL/min and used a virtual population generation method that has limitations. This is significant as patients with sepsis may have augmented renal clearance and predicted piperacillin exposures would be even less favorable in achieving the PK-PD target in such patients at an MIC of 32/4 mcg/mL. Similarly, the above reported probabilities cannot be universally applied to all patients within the 41-120 mL/min CrCl range as patients with normal CrCl (90-120 mL/min) will have lower predicted piperacillin exposures resulting in lower probabilities of achieving the PK-PD target in such patients at an MIC of 32/4 mcg/mL versus those with some degree of renal impairment (41-89 mL/min). FDA also notes that available clinical data do not allow evaluating the differences in clinical outcomes associated with MIC of 32/4 mcg/mL vs MICs > 32/4 mcg/mL. Thus, isolates at an MIC of ≥ 32/4 mcg/mL would not likely be inhibited by the usually achievable drug concentrations with the 4.5 g every 6 hours as a 3-hour infusion dosage regimen and clinical efficacy against isolates at an MIC of ≥ 32/4 mcg/mL has not been reliably shown.

FDA acknowledges that the intermediate category includes a buffer zone for inherent variability in test methods to mitigate major discrepancies in interpretations. However, in the case of PTZ for P. aeruginosa, the intermediate breakpoint of 32/4 may not provide an intended buffer given that isolates with an MIC of 32/4 mcg/mL should be considered resistant and their reporting as susceptible would represent a major misclassification.

FDA notes several limitations of the provided PK/PD data. The relied upon PK-PD target of piperacillin 50% fTC>MIC/τ is not sufficiently justified. While FDA acknowledges that this target has been used in several published PTA analyses for piperacillin-tazobactam, the target has not been adequately evaluated for P. aeruginosa. The commonly cited publication supporting this target evaluated the relationship between the time above the MIC and bacteriologic cure for beta-lactams against S. pneumoniae and H. influenzae rather than P. aeruginosa.⁷ Only one study referenced in the CLSI rationale document described a range of piperacillin-tazobactam MIC-based PK-PD exposures achieved in a murine P. aeruginosa infection model commonly accepted for PK/PD target characterization.⁸ The study, however, used an immunocompetent rather than neutropenic mouse model, which would be expected to result in greater bacterial killing than a neutropenic mouse model, but achieved less than 1 log10 decrease in P. aeruginosa bacterial burden, which would not be considered adequate for serious infections. The other referenced studies either tested pathogens other than P. aeruginosa or did not characterize the PK-PD target. FDA also notes that a target of 60% fT_C>MIC was reported to be associated with improved survival in patients with P. aeruginosa bacteremia.⁹

Given the limitations of the PTA analyses and an increase in mortality associated with the MIC of 32/4 mcg/mL, FDA has concluded that a more cautious approach to establishing the piperacillin-tazobactam breakpoints for P. aeruginosa is warranted and updates the breakpoints as shown below. In its calculations of zone diameter breakpoints, FDA used an MIC of 16/4 as an intermediate category to arrive at acceptable error rates.

Piperacillin-Tazobactam MIC and Zone Diameter Breakpoints for P. aeruginosa

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

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.

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⁵https://www.regulations.gov/comment/FDA-2017-N-5925-0032
⁶ Thabit AK et al. Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function. J Pharm Pract. 2017 Dec;30(6):593-599.
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⁹ Tannous E et al. Time above the MIC of Piperacillin-Tazobactam as a Predictor of Outcome in Pseudomonas aeruginosa Bacteremia. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e02571-19.