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Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone ResistanceA Randomized Clinical Trial

Educational Objective
To understand the challenges of treating patients who have bloodstream infections with ceftriaxone-resistant gram-negative bacteria.
1 Credit CME
Key Points

Question  Can piperacillin-tazobactam be used as carbapenem-sparing therapy in patients with bloodstream infections caused by ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae?

Findings  In this noninferiority randomized clinical trial that included 391 patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, the 30-day mortality rate for patients treated with piperacillin-tazobactam compared with meropenem was 12.3% vs 3.7%, respectively. The difference did not meet the noninferiority margin of 5%.

Meaning  These findings do not support piperacillin-tazobactam compared with meropenem for these infections.

Abstract

Importance  Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers.

Objectives  To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.

Design, Setting, and Participants  Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study.

Interventions  Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.

Main Outcomes and Measures  The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.

Results  Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.

Conclusions and relevance  Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.

Trial Registration  anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122

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Article Information

Corresponding Author: David L. Paterson, MBBS, PhD, University of Queensland Centre for Clinical Research, Faculty of Medicine, Bldg 71/918 Royal Brisbane & Women's Hospital Campus, Herston, QLD 4029, Australia (d.paterson1@uq.edu.au).

Accepted for Publication: July 27, 2018.

Correction: This article was corrected on June 18, 2019, to include information on sample size calculation in the Methods section.

Author Contributions: Drs Harris and Paterson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have approved the final version of the manuscript.

Concept and design: Harris, Rogers, Iredell, Miyakis, Ingram, Athan, Lorenc, Peleg, Paterson.

Acquisition, analysis, or interpretation of data: Harris, Tambyah, Lye, Mo, Lee, Yilmaz, Alenazi, Arabi, Falcone, Bassetti, Righi, Rogers, Kanj, Bhally, Iredell, Mendelson, Boyles, Looke, Miyakis, Walls, Al Khamis, Zikri, Crowe, Ingram, Daneman, Griffin, Athan, Lorenc, Baker, Roberts, Beatson, Peleg, Harris-Brown, Paterson.

Drafting of the manuscript: Harris, Lorenc, Roberts, Harris-Brown, Paterson.

Critical revision of the manuscript for important intellectual content: Harris, Tambyah, Lye, Mo, Lee, Yilmaz, Alenazi, Arabi, Falcone, Bassetti, Righi, Rogers, Kanj, Bhally, Iredell, Mendelson, Boyles, Looke, Miyakis, Walls, Al Khamis, Zikri, Crowe, Ingram, Daneman, Griffin, Athan, Baker, Beatson, Peleg, Harris-Brown, Paterson.

Statistical analysis: Harris, Baker.

Obtained funding: Harris, Mo, Ingram, Harris-Brown, Paterson.

Administrative, technical, or material support: Harris, Tambyah, Lye, Mo, Yilmaz, Arabi, Righi, Rogers, Iredell, Boyles, Walls, Crowe, Daneman, Lorenc, Harris-Brown, Paterson.

Supervision: Harris, Lye, Alenazi, Arabi, Kanj, Bhally, Miyakis, Walls, Al Khamis, Zikri, Athan, Beatson, Peleg, Harris-Brown, Paterson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Harris reported receiving grants from the Australian Society for Antimicrobials; the International Society for Chemotherapy; the National University Hospital Singapore; the Study, Education, and Research Committee of Pathology; and the Royal College of Pathologists of Australasia Foundation. Dr Harris also reported receiving support to speak at an educational event sponsored by Pfizer. Dr Tambyah reported receiving grants from the National University Health System, GlaxoSmithKline, Janssen, Shionogi, Sanofi-Pasteur, Visterra, Baxter, ADAMAS, Merlion Pharmaceuticals, Fabentech, and Inviragen. He has also received honoraria from Novartis and AstraZeneca. Dr Falcone reported receiving personal fees from MSD, Angelini, and Astellas and grants from Gilead. Dr Bassetti reported receiving grants and/or personal fees from Pfizer, MSD, Astellas, Menarini, Roche, Tetraphase, Achaogen, Angelini, AstraZeneca, Bayer, Basilea, Cidara, Gilead, MSD, Paratek, Pfizer, The Medicines Company, and Vifor. Dr Rogers reported receiving grants and personal fees from MSD Australia for attending advisory boards and research and personal fees from Mayne Pharma for consulting. Dr Kanj reported receiving honoraria for speaking and serving on advisory boards for Pfizer, Merck, Bayer, Gilead, Hikma, and Aventis. Ms Lorenc reported receiving grants from the Australian Society for Antimicrobials, the International Society for Chemotherapy, and the National University Hospital Singapore. Dr Beatson reported receiving support for speaking at an educational event sponsored by Pfizer. Dr Peleg reported receiving grants from MSD. Dr Paterson reported receiving grants and/or personal fees from Merck, Pfizer, Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GlaxoSmithKline, and Cubist. No other disclosures were reported.

Funding/Support: The study was sponsored by the University of Queensland. This study was funded by grants from the Australian Society for Antimicrobials (ASA), International Society for Chemotherapy (ISC), National University Hospital Singapore Clinician Researcher Grant NUHSRO/2014/121/CRG/07. Whole-genome sequencing was funded by grants from the Australian Infectious Disease Centre and Australian Genome Research Facility; the Royal College of Pathologists of Australasia (RCPA) Foundation; and the Study, Education, and Research Committee (SERC) of Pathology Queensland. Dr Beatson was supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship during the course of the trial. Dr Harris was supported by an Australian Postgraduate Award from the University of Queensland. Dr Peleg was supported by a NHMRC Career Development and Practitioner Fellowship during the course of the trial. Dr Paterson was supported by a NHMRC Practitioner Fellowship during the course of the trial.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN) members include the following: Royal Brisbane & Women’s Hospital: John McNamara and Rachel Sieler. The Alfred Hospital, Melbourne: Jill Garlick, Jess Costa, Janine Roney, and Nigel Pratt. American University of Beirut Medical Center, Lebanon: Houssam Tabaja, Joumana Kmeid, Ralph Tayyar, and Saeed El Zein. Dandeong Hospital, Australia: Stephanie Jones. Geelong Hospital, Australia: Raquel Cowan, Alex Tai, Belinda Lin, Babak Rad, Eleanor MacMorran, and James Pollard. Istanbul Medipol Mega Hospital Complex, Turkey: Rumeysa Dinleyici, Ayse Istanbullu, Bahadir Ceylan, and Ali Mert. King Fahad Specialist Hospital, Dammam, Saudi Arabia: Mai Hashhoush and Taleb Dalwi. Monash Medical Centre, Australia: Tony Korman, Rula Azzam, Michael Birrell, Carly Hughes, Sadid Khan, Jillian Lau, Layyang Lee, Karen Lim, Yi Dani Lin, David Lister, David New, Nastaran Rafiei, James Stewart, Alex Tai, Mohamad Ali Trad, and Victor Aye Yeung. Middlemore Hospital, Auckland, New Zealand: Stephen McBride, David Holland, Christopher Hopkins, Christopher Luey, Susan Taylor, and Susan Morpeth. Mater Hospital, Brisbane, Australia: Melissa Finney and Megan Martin. North Shore Hospital, Auckland, New Zealand: Umit Holland. National University Hospital, Singapore: Jaminah Ali and Roland Jureen. Princess Alexandria Hospital, Brisbane, Australia: Neil Underwood, Andrew Henderson, and Naomi Runnegar. Peter McCallum Cancer Centre, Melbourne, Australia: Monica Slavin. Royal Perth Hospital and Fiona Stanley Hospital: Owen Robinson. Sunnybrook Hospital, Toronto, Canada: Asgar Rishu. Wollongong Hospital, Australia: Samia Shawkat, Janaye Fish, Kwee Chin Liew, and Peter Newton. Santa Maria Misericordia Hospital, Udine, Italy: Maria Merelli, Alessia Carnelutti, Silvia Ussai, and Davide Pecori. Tan Tock Seng Hospital, Singapore: Ezlyn Izharuddin, Barnaby Young, and Ying Ding. Westmead Hospital, Sydney, Australia: Ristila Ram, June Kelly, and Neela Joshi. Charlotte Maxeke Johannesburg Academic Hospital, South Africa: Guy Richards, Oliver Smith, and Ahmad Alli. Groote Schuur Hospital, Cape Town, South Africa: Inge Vermeulen, Brenda Wright, Chedwin Grey, Annemie Stewart, Denasha Reddy, and Sean Wasserman. King Abdulaziz Medical City, Riyadh, Saudi Arabia: Hanie Richi, Khizra Sultana, Nouf Alanazi, and Eman Bin Awad. Ospedale Luigi Sacco, Milan, Italy: Fabio Franzetti. Pretoria Academic Hospital, South Africa: Anton Stolz, Elsabe De Kock, Tebogo Magongoa, Marizane Dutoit. “Sapienza” University, Rome, Italy: Alessandro Russo. San Remo Hospital: Chiara Dentone. Townsville Hospital, Australia: Damon Eisen, Liz Heyer.

Additional Contributions: We thank the data and safety monitoring board for its assistance with the study: Jesus Rodriguez-Baño (Infectious Diseases Division at Hospital Universitario Virgen Macarena, Seville, Spain) and Yohei Doi (Division of Infectious Diseases University of Pittsburgh, Pittsburgh, Pennsylvania), with independent statistical advice from Aaron Dane. Simon Forsyth, PhD (University of Queensland), helped manage the REDCap database. We also thank Henry Chambers MD, PhD (University of California, San Francisco), and Scott Evans, PhD (Harvard University), for their thoughtful review of the manuscript. Amy Jennison, PhD, and Rikki Graham, PhD (Forensic and Scientific Services Laboratory, Queensland), and the Australian Genome Research Facility helped facilitate bacterial whole-genome sequencing. Nouri Ben-Zakour, PhD (University of Sydney), and Mark Schembri, PhD (University of Queensland), also supported the genomic data analysis. Andrew Henderson, MBBS (University of Queensland), Ernest Tan (University of Queensland), and Kyra Cottrell, BAppSc (University of Queensland), assisted with phenotypic testing of the bacterial strains. Mark Chatfield, MSc (University of Queensland), helped attend to reviewers’ statistical comments. None of these individuals received compensation for their role in the study. The protocol was developed and endorsed by the ASID-CRN, with input from Jeffrey Lipman, MBBCh (University of Queensland), Jason Roberts, PhD (University of Queensland), Andrew Stewardson, MBBS, PhD (Monash University), Sanjoy Paul, PhD (University of Melbourne), and Emma McBryde, MBBS, PhD (James Cook University). They did not receive compensation. We thank the site investigators, collaborators, and research assistants for their help with the study, as well as the participating microbiology laboratories for their assistance with storing and shipping organisms.

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