Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen)

BMJ Open. 2021 Feb 8;11(2):e040210. doi: 10.1136/bmjopen-2020-040210.


Introduction: The optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice.

Methods and analysis: PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant Escherichia coli and Klebsiella bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome.

Ethics and dissemination: The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.

Trial registration numbers: ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).

Keywords: epidemiology; infection control; microbiology.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / therapeutic use
  • Canada
  • Cephalosporins
  • Enterobacteriaceae*
  • Humans
  • Israel
  • Italy
  • Meropenem / therapeutic use
  • Multicenter Studies as Topic
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Sepsis* / drug therapy
  • beta-Lactamases


  • Anti-Bacterial Agents
  • Cephalosporins
  • beta-Lactamases
  • Meropenem

Associated data

  • ClinicalTrials.gov/NCT03671967