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).


Bitterman R(1)(2), Koppel F(1), Mussini C(3), Geffen Y(4), Chowers M(5)(6), Rahav G(7)(8), Nesher L(9)(10), Ben-Ami R(6)(11), Turjeman A(6)(12), Huberman Samuel M(12), Cheng MP(13), Lee TC(13), Leibovici L(6)(12), Yahav D(6)(14), Paul M(15)(2).
Author information:
(1)Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
(2)Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Haifa, Israel.
(3)Infectious Diseases Clinics, University Hospital Modena, Modena, Emilia-Romagna, Italy.
(4)Microbiology Laboratory, Rambam Health Care Campus, Haifa, Israel.
(5)Infectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel.
(6)Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel.
(7)Infectious Diseases Unit, Sheba Medical Center, Tel Hashomer, Israel.
(8)Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
(9)Infectious Diseases Unit, Soroka Medical Center, Beer Sheva, Israel.
(10)Ben-Gurion University of the Negev Faculty of Health Sciences, Beer Sheva, Israel.
(11)Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
(12)Internal Medicine E, Rabin Medical Center, Petah Tikva, Israel.
(13)Division of Infectious Diseases, Department of Medicine, McGill University, Montreal, Quebec, Canada.
(14)Infectious Diseases Unit, Rabin Medical Center, Petah Tikva, Israel.
(15)Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel [Email]


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).

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