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FDA Rationale for Piperacillin-Tazobactam Breakpoints for Enterobacterales

FDA has completed their review of the rationale document titled, “Piperacillin-Tazobactam Breakpoints for Enterobacterales” (MR14, February 2022), submitted by the Clinical and Laboratory Standards Institute (CLSI) to the public docket, FDA-2017-N-5925-0012, in March 2022.

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

For nosocomial pneumonia in adults, piperacillin-tazobactam is approved at 4.5 g every 6 hours administered by intravenous infusion over 30 minutes (min). For all other indications in adults, piperacillin-tazobactam is approved at 3.375 g every 6 hours administered by intravenous infusion over 30 min.

CLSI notes that since the approval of piperacillin-tazobactam in 1993, the spectrum of β-lactamases found in Enterobacterales expanded to include those that are poorly inhibited by tazobactam (e.g., OXA-1 and OXA-30). This shift in epidemiology, coupled with new pharmacokinetic-pharmacodynamic (PK-PD) and clinical outcome data, led to the current revision of the breakpoints by CLSI. The FDA breakpoints (CLSI’s previously accepted breakpoints) and the revised CLSI breakpoints are presented in Table 1.

Table 1. Current FDA and CLSI Piperacillin-Tazobactam MIC and Zone Diameter Breakpoints for Enterobacterales

 

Minimum Inhibitory Concentrations
(mcg/mL)

Disk Diffusion
(zone diameter in mm)

S

SDD

I

R

S

SDD

I

R

FDA

≤16/4

-

32/4-64/4

≥128/4

≥21

-

18-20

≤17

CLSI

≤ 8/4

16/4

-

≥ 32/4

≥ 25

21–24

-

≤20

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

Of note, the CLSI breakpoints for the susceptible category are based on a dosage regimen of 3.375-4.5 g administered every 6 hours as a 30 min infusion. Breakpoints for the susceptible-dose dependent (SDD) category are based on a dosage regimen of 4.5 g administered every 6 hours as a 3-hour infusion or 4.5 g administered every 8 hours as a 4-hour infusion. CLSI notes that an SDD category was selected over an intermediate category for piperacillin-tazobactam MICs of 16 mcg/mL based on available PK-PD data demonstrating an improved likelihood of appropriate target attainment for piperacillin-tazobactam MICs of 16 mcg/mL with extended-infusion strategies.

CLSI provided the following data to support their revised breakpoints:

  1. Epidemiologic Cutoff Value (ECV) for E. coli and K. pneumoniae of 8 mcg/mL.
  2. PK-PD data estimating ≥ 90% probability of target attainment using a piperacillin PK-PD target of 50% fTC>MIC (i.e., the percentage of time during a dosing interval that free-drug concentration remains above the MIC) with the following proposed breakpoint specific dosage:
    • Susceptible breakpoint of ≤ 8 mcg/mL: 3.375 g every 6 hours (q6h) or 4.5 g q6h over 30 min infusion [this infusion time is included in the piperacillin-tazobactam U.S. prescribing information].
    • SDD breakpoint of ≤ 16 mcg/mL: 4.5 g q8h over 4-hour infusion or 4.5 g q6h over 3-hour infusion [these infusion times are not included in the piperacillin-tazobactam U.S. prescribing information].
    No reviewed studies demonstrated that ≥ 90% probability of target attainment was achievable at MIC of > 16 mcg/mL with any dose or infusion time.
  3. Clinical data demonstrating a mortality increase associated with Enterobacterales isolates with MIC > 16 mcg/mL.1

FDA reviewed the submitted microbiology, PK-PD, and clinical information and agrees with lowering the piperacillin-tazobactam susceptible and resistant breakpoints for Enterobacterales as proposed by CLSI.

The selection of a susceptible breakpoint of 8 mcg/mL for piperacillin-tazobactam for Enterobacterales is supported by an epidemiological cutoff value (ECV) of 8 mcg/mL for both E. coli and K. pneumoniae. To note, CLSI proposes to grant breakpoints for all Enterobacterales in the absence of data demonstrating that this ECV would apply to other species beyond E. coli and K. pneumoniae. The current FDA susceptibility test interpretive criteria (STIC) webpage for piperacillin-tazobactam also lists STIC for Enterobacterales without specifying species2 whereas the only Enterobacterales pathogens included in the first list of the piperacillin-tazobactam prescribing information are E. coli and K. pneumoniae3. Therefore, a footnote to the breakpoint table on the FDA piperacillin-tazobactam STIC webpage to state, “Clinical efficacy was shown for E. coli and K. pneumoniae,” will be added. Additional support for lowering the susceptible breakpoint is provided given a concern regarding the precision of the piperacillin-tazobactam susceptibility testing at an MIC of 16 mcg/mL. As for a resistant breakpoint, the provided clinical data demonstrate an increase in mortality at piperacillin-tazobactam MICs of > 16 mcg/mL thus indicating that the current FDA resistant breakpoint of 128/4 mcg/mL is likely too high.1

FDA, however, does not accept an SDD breakpoint of 16 mcg/mL because available PK-PD and clinical data are insufficient to support the proposed SDD breakpoint. The PK-PD target of a piperacillin 50% fTC>MIC/τ used in the analyses was derived largely based on in vivo and clinical studies of penicillin (not piperacillin or piperacillin-tazobactam) against Streptococcus pneumoniae rather than against Enterobacterales and the distribution of PK-PD target values (e.g., weighted mean) across Enterobacterales species was not considered. FDA notes that several observational clinical trials in patients with gram-negative infections suggest a piperacillin fTC>MIC greater than 50% is more optimal in clinical efficacy response4,5,6. Other published PK-PD investigations have suggested maximal bacterial killing when drug concentrations were maintained above 4 times the MIC for a prolonged period of time7,8. Also, CLSI’s rationale does not specify tazobactam PK-PD targets nor includes tazobactam PK-PD target attainment analyses to demonstrate that tazobactam exposure will be sufficiently high to drive piperacillin efficacy with the dosing regimens noted for the proposed breakpoints. Although extended infusions (i.e., 3- or 4-hour infusion) may result in increased probability of target attainment compared to the 30-minute infusion, uncertainty with the PK-PD targets does not allow a determination of a specific ‘susceptible dose dependent’ breakpoint based on the probability of target attainment. No clinical studies have directly evaluated the efficacy of piperacillin-tazobactam extended infusions in patients with infections caused by Enterobacterales isolates with an MIC of 16 mcg/mL.

Thus, FDA considers an MIC breakpoint of 16 mcg/ml as ‘intermediate’. In conclusion, FDA will recognize the piperacillin-tazobactam breakpoints for Enterobacterales as follows.

Piperacillin-Tazobactam MIC and Zone Diameter Breakpoints for Enterobacterales

Minimum Inhibitory Concentrations
(mcg/mL)

Disk Diffusion
(zone diameter in mm)

S

I

R

S

I

R

≤ 8/4

16/4

≥ 32/4

≥ 25

21–24

≤20


1 Henderson A, Paterson DL, Chatfield MD, et al. Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the MERINO study. Clin Infect Dis. 2021;73(11):e3842-e3850. doi:10.1093/cid/ciaa1479.
2 https://www.fda.gov/drugs/development-resources/piperacillin-tazobactam-injection-products
3 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050684s100,050750s047lbl.pdf
4 Abdul-Aziz MH, Lipman J, Akova M, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother. 2016;71(1):196-207.
5 Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med. 2016;42(10):1535-1545.
6 Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.
7 Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA. Continuous beta-lactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care. 2012;2(1):37. Published 2012 Aug 16.
8 Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother. 1994;38(5):931-936.

 
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