Patrick N A Harris1,2,3, Paul A Tambyah4, David C Lye5,6,7, Yin Mo4, Tau H Lee5,6,7, Mesut Yilmaz8, Thamer H Alenazi9, Yaseen Arabi9, Marco Falcone10, Matteo Bassetti11, Elda Righi11, Benjamin A Rogers12,13, Souha Kanj14, Hasan Bhally15, Jon Iredell16,17, Marc Mendelson18, Tom H Boyles18, David Looke3,19, Spiros Miyakis20,21,22, Genevieve Walls23, Mohammed Al Khamis24, Ahmed Zikri24, Amy Crowe25,26, Paul Ingram27,28,29, Nick Daneman30, Paul Griffin19,31,32, Eugene Athan33, Penelope Lorenc1, Peter Baker34, Leah Roberts35, Scott A Beatson35, Anton Y Peleg36,37,38, Tiffany Harris-Brown1, David L Paterson1,39. 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.
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 toceftriaxone 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 withpiperacillin-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.
RCT Entities:
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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