Further Insights, Treatment Considerations Around the PETERPEN Study

Antibiotics Deconstructed is a series where we examine newly approved, existing, and novel therapeutics.

At this year’s European Society of Clinical Microbiology and Infectious Diseases (ESCMID) meeting, an interim analysis of the PETERPEN trial was presented which revisited whether piperacillin-tazobactam can safely treat bloodstream infections caused by ESBL-producing organisms. PETERPEN was designed as a replication of the MERINO trial. The findings from MERINO linked piperacillin-tazobactam to higher 30-day mortality than meropenem among patients with ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae bloodstream infections, which prompted many centers to shift toward carbapenem-first therapy for ESBL-producing organisms.¹

In our last issue of Contagion, Ryan Shields, PharmD, MS, and Jason Pogue, PharmD, BCPS, BCIDP, reviewed PETERPEN and discussed the interim analysis as well as touched upon 2 other randomized controlled trials, CEFMEC and ASTARTÉ.

“The CEFMEC trial compared meropenem treatment with cefmetazole (a cephamycin), whereas the ASTARTÉ trial compared carbapenem treatment with temocillin (a penicillin),” Shields and Pogue wrote.

New data from PETERPEN suggest that piperacillin-tazobactam may be noninferior to meropenem for early clinical outcomes in select patients with ESBL bloodstream infections. An interim analysis of the study found extended-infusion piperacillin-tazobactam was noninferior to extended-infusion meropenem for treatment failure on day 7.²

“One of the big things when you're talking about piperacillin-tazobactam for the treatment of ESBL, you need to optimize 2 drugs,” Pogue said. “It's not just the piperacillin component; you have to give enough tazobactam that restores the activity. And honestly, while we have a lot of meropenem PK/PD data, and we have a lot of piperacillin PK/PD data, we don't really have that for tazobactam, so we have very little evidence of what the right tazobactam exposure is. And I will tell you that what we do have is very concerning. And so, even if this result shows noninferiority, there's still going to be concern on my end that the dose optimization strategy.”

Pogue says he would be hesitant to prescribe piperacillin-tazobactam until the preclinical work for dosing is completed for tazobactam.

MERINO and PETERPEN Differences

The MERINO and PETERPEN trials differ in some important ways. PETERPEN excluded septic shock patients, used extended infusions, and had a higher Charlson comorbidity burden. With these differences the final PETERPEN mortality results could end up diverging from MERINO, and this could present some treatment guidance challenges for clinicians.
“I think that's going to be the key piece of the story if it fails in one study and does well in another study…Why are we seeing these two different results? There can be a lot of reasons for that.”

Follow-up Primary PETERPEN Findings

In terms of additional findings for the trial, the last patient's primary-outcome data (30-day mortality and day-7 treatment failure) is supposed to be collected by January 2027, with the study completion estimated to be in April. The final primary results probably won't appear before mid-to-late 2027, so in approximately a year follow-up results may be available.

Is it Time to Switch?

In terms of thinking about treatments around ESBL bacteremia, Pogue points out it is still too early to make a change.

“I think that the drug of choice is still a carbapenem,” he said. “Let's see how PETERPEN falls…Let's assess the things that we've talked about today after the fact, and come to a place with that,” Pogue said. “But I think the other thing that we need to keep in mind when we're trying to figure out how do I use these data to optimally manage an ESBL bloodstream infection is to remember that in these trials, you are talking about once I know the patient has an ESBL that is susceptible to these 2 drugs, then I'm putting patients on one of these 2 treatments. So, even if they're equivalent in that setting, that does not necessarily mean that at time zero they would be equivalent to give those 2 drugs.”

References

1.Harris PNA, Tambyah PA, Lye DC, et al; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163

2. Paul M, Rodríguez-Baño J. The trial run: treatment of ESBL bacteraemia (off to never-never land). Presented at: ESCMID Global 2026; April 20, 2026; Munich, Germany.