[Source: JAMA, full page: (LINK). Abstract, edited.]
Original Investigation / September 11, 2018
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
Patrick N. A. Harris, MBBS1,2,3; Paul A. Tambyah, MD4; David C. Lye, MBBS5,6,7; et al Yin Mo, MBBS4; Tau H. Lee, MBBS5,6,7; Mesut Yilmaz, MD8; Thamer H. Alenazi, MD9; Yaseen Arabi, MD9; Marco Falcone, MD10; Matteo Bassetti, MD, PhD11; Elda Righi, MD, PhD11; Benjamin A. Rogers, MBBS, PhD12,13; Souha Kanj, MD14; Hasan Bhally, MBBS15; Jon Iredell, MBBS, PhD16,17; Marc Mendelson, MBBS, PhD18; Tom H. Boyles, MD18; David Looke, MBBS3,19; Spiros Miyakis, MD, PhD20,21,22; Genevieve Walls, MB, ChB23; Mohammed Al Khamis, MD24; Ahmed Zikri, PharmD24; Amy Crowe, MBBS25,26; Paul Ingram, MBBS27,28,29; Nick Daneman, MD30; Paul Griffin, MBBS19,31,32; Eugene Athan, MBBS, MPH, PhD33; Penelope Lorenc, RN1; Peter Baker, PhD34; Leah Roberts, BSc35; Scott A. Beatson, PhD35; Anton Y. Peleg, MBBS, PhD36,37,38; Tiffany Harris-Brown, RN, MPH1; David L. Paterson, MBBS, PhD1,39; for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)
Author Affiliations: 1 University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia; 2 Department of Microbiology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia; 3 Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia; 4 Department of Infectious Diseases, National University Hospital, Singapore; 5 Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 6 Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore; 7 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 8 Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey; 9 King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 10 Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Italy; 11 Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy; 12 Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia; 13 Monash Infectious Diseases, Monash Health, Melbourne, Victoria, Australia; 14 Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 15 Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand; 16 Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, New South Wales, Australia; 17 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia; 18 Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; 19 University of Queensland, Brisbane, Queensland, Australia; 20 School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia; 21 Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia; 22 Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia; 23 Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand; 24 King Fahad Specialist Hospital, Dammam, Saudi Arabia; 25 Department of Infectious Diseases, St Vincent’s Hospital, Melbourne, Victoria, Australia; 26 Department of Microbiology, St Vincent’s Hospital, Melbourne, Victoria, Australia; 27 School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia; 28 Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia; 29 Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia; 30 Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; 31 Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Queensland, Australia; 32 QIMR Berghofer, Brisbane, Queensland, Australia; 33 Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia; 34 School of Public Health, University of Queensland, Brisbane, Queensland, Australia; 35 Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Australia; 36 Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia; 37 Department of Microbiology, Monash University, Clayton, Australia; 38 Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia; 39 Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163
- 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.
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.
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.
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.
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
Keywords: Antibiotics; Drugs Resistance; Beta-lactams; Ceftriaxone; Piperacillin; Tazobactam; E. Coli; K. Pneumoniae; Bacteremia.