Issues with Piperacillin-Tazobactam (PIP-TAZ) Breakpoints

by Robert Rennie

In CMPT Challenge M221-5 (July, 2022), a simulated blood culture with Acinetobacter baumanii, antimicrobial susceptibilities for piperacillin-tazobactam (Pip-Taz) were ungraded due to lack of consensus by the participants. It was unknown what breakpoints were being used for reporting this agent. This short article will attempt to provide some direction going forward regarding changes in breakpoints so that laboratories can provide an accurate and clinically relevant test result for this agent.

For a long time – back as far as the early 1990’s, Pip-Taz breakpoints were established at ≤ 16 mg/L (Susceptible), 32 – 64 mg/L (Intermediate), and ≥ 128mg/L (Resistant).

Times have changed both in our knowledge of antimicrobial agents, the testing methodologies, and methods used to better define the efficacy not only of this beta-lactamase- beta-lactamase inhibitor combination agent, but of many other antimicrobials.

Update studies on the appropriateness of Pip-Taz have been undertaken by a number of organizations (e.g. EUCAST, CLSI, and USCAST). These studies can be viewed on their websites and on their discussion pages. This brief article will provide a summary of those discussions with analysis on the re-setting of breakpoints for Pip-Taz.

Clinical

More recent comparative studies of Pip-Taz with other agents in the treatment of gram negative infections showed increased mortality with Pip-Taz in isolates at  ≥ 16 mg/L compared to those at lower MICs1. These studies also showed that the MICs to Pip-Taz were greater in strains with both ESBL and OXA enzymes, and that these isolates were found in patients with high rates of morbidity and mortality. In one study, the authors showed modal MIC Increases from 2 mg/L to 8 – 16 mg/L in strains with OXA-like enzymes, suggesting that the affinity of tazobactam for OXA enzymes is diminished.2

Antimicrobial Testing

Earlier studies with both Pip-Taz E test strips and some automated methods revealed issues in the interpretation of susceptibility results. The studies showed that there were high percentages (in some cases up to 40%) of Very Major errors (reported falsely as susceptible when they were resistant) compared to standard broth micro-dilution testing. These systems have now been re-formulated so that the Essential and Categorical agreements better reflect the true MICs of isolates tested against Pip-Taz. In addition, long-term MIC data from EUCAST has shown that the Epidemiological Cut-Off (ECOFF or ECV) value for Pip-Taz is 8 mg/L, which supports clinical data on increasing failures at higher MICs.  Most laboratories will not or cannot routinely test for the presence of specific beta-lactamases, and rely mostly on MIC results only to report apparent susceptibility or resistance.

Measurement of Clinical Activity of Pip-Taz

More recent advances in understanding of antimicrobial activity in patients, using pharmacokinetic and pharmacodynamic principles (Monte Carlo simulations) and other criteria now clearly indicate that the original breakpoints were too high.

There are many variables that have led to this understanding. With differences in dosing, prolonged or extended infusion, and studies in patients with normal or impaired renal function, obesity, and other co-morbidities, it has now been shown that the most critical measurement – target attainment (at > 90%) – can be achieved with doses of Pip-Taz of 4.5 g every 6 hr. This dose can cover MICs up to 8 mg/L. The same dose with infusion over 3 hr can cover MIC values of up to 16 mg/L/.

With these parameters in mind EUCAST has now indicated breakpoints of ≤ 8mg/L (Susceptible) and > 8mg/L (Resistant). USCAST suggests breakpoints of ≤ 8mg/L (susceptible) with 16 mg/L (Susceptible-Dose Dependent(S-DD)), and ≥ 32 mg/L (Resistant).

These are considerably more conservative than the original breakpoints and will likely provide better outcomes for patients treated with Pip-Taz so long as these lower breakpoints are provided by testing laboratories and parameters for dosing in a variety of clinical conditions are utilized.

We will provide further updates as these data are utilized more widely. Readers should review and update their reporting for Pip-Taz and consult the appropriate breakpoint development organizations  for updated information.

References

  1. Harris PNA, et al. JAMA. 2018;320:984-994.
  2. Livermore DM, et al. J Antimicrob Chemother 2019; 74:326-333.
  3. EUCAST – Piperacillin-tazobactam Rationale for the EUCAST clinical breakpoints. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Piperacillin-tazobactam_rationale_Nov2010_v_1.0.pdf

 

Note. This brief summary lists only three important critical clinical and laboratory references to provide context. Many additional references are available through the breakpoint organizations (EUCAST, CLSI, USCAST).

 

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