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)

Abstract

IntroductionThe 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 analysisPeterPen 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 disseminationThe study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.Trial registration numbersClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).

Extended‐spectrum β‐lactamase‐producing and carbapenem‐resistant Enterobacterales bloodstream infection after solid organ transplantation: Recent trends in epidemiology and therapeutic approaches

“…On the other hand, this conclusion is in line with the results reported for hematological neutropenic patients, including hematopoietic stem cell transplant recipients 67 . The debate on to what extent carbapenems may be safely spared in favor of BLBLIs is far from being settled, 68,69 pending on the results of ongoing RCTs 70 …”

“…67 The debate on to what extent carbapenems may be safely spared in favor of BLB-LIs is far from being settled, 68,69 pending on the results of ongoing RCTs. 70 Another relevant question is whether ertapenem and meropenem are equally effective for ESBL-E BSI from a urinary source. The increasing prevalence of ESBL producers among uropathogens in KT recipients has contributed to the widespread use of carbapenems.…”

Piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections: A systematic review with meta‐analysis

“…6,19,60 Six planned, ongoing, withdrawn, or suspended RCTs were also identified (Table S1). [61][62][63][64][65][66] Authors were contacted for data if trials were completed but unpublished 59,63 or suspended 66 , or if outcome data were presented qualitatively 19,39,40,47,52,60 or as part of a composite outcome. 42,48 One trial provided additional but confidential data and was included in the qualitative synthesis.…”

“… 6,19,32–58,60 Six planned, ongoing, withdrawn, or suspended RCTs were also identified (Table S1). 61–66 …”

Current and Emerging Treatment Options for Multidrug Resistant Escherichia coli Urosepsis: A Review

“…One such additional study is a phase 4 clinical trial aiming to replicate the MERINO trial in lower risk patients. The study is currently recruiting and estimated to be completed in April 2024 [ 73 ].…”