1. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial
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Peter Baker, Tau H. Lee, Yin Mo, David L. Paterson, Elda Righi, Paul R. Ingram, Nick Daneman, Tom H. Boyles, Leah W. Roberts, Matteo Bassetti, Penelope Lorenc, Marc Mendelson, Amy Crowe, Thamer H. Alenazi, Anton Y. Peleg, Yaseen M. Arabi, Marco Falcone, Benjamin A. Rogers, Patrick N A Harris, Paul M. Griffin, David C. Lye, Mohammed Al Khamis, Mesut Yilmaz, Spiros Miyakis, Souha S. Kanj, Scott A. Beatson, Eugene Athan, Tiffany Harris-Brown, David Looke, Hasan Bhally, Genevieve Walls, Paul A. Tambyah, Jon Iredell, Ahmed Zikri, Harris, Patrick N. A., Lorenc, Penelope, Harris-Brown, Tiffany Univ Queensland, UQ Ctr Clin Res, Brisbane, Qld, Australia, Harris, Patrick N. A. Royal Brisbane & Womens Hosp, Pathol Queensland, Dept Microbiol, Brisbane, Qld, Australia, Looke, David Princess Alexandra Hosp, Infect Management Serv, Brisbane, Qld, Australia, Tambyah, Paul A., Mo, Yin Natl Univ Singapore Hosp, Dept Infect Dis, Singapore, Singapore, Lye, David C., Lee, Tau H. Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore, Singapore, Lee, Tau H. Tan Tock Seng Hosp, Inst Infect Dis & Epidemiol, Dept Infect Dis, Singapore, Singapore, Lee, Tau H. Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore, Yilmaz, Mesut Istanbul Medipol Univ, Sch Med, Dept Infect Dis & Clin Microbiol, Istanbul, Turkey, Alenazi, Tamer H., Arabi, Yaseen King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia, Arabi, Yaseen King Abdullah Int Med Res Ctr, Riyadh, Saudi Arabia, Falcone, Marco Sapienza Univ Rome, Dept Publ Hlth & Infect Dis, Rome, Italy, Bassetti, Matteo, Righi, Elda Univ Udine, Dept Med, Infect Dis Clin, Udine, Italy, Righi, Elda Santa Maria Misericordia Hosp, Udine, Italy, Rogers, Benjamin A. Monash Univ, Ctr Inflammatory Dis, Melbourne, Vic, Australia, Rogers, Benjamin A. Monash Hlth, Monash Infect Dis, Melbourne, Vic, Australia, Kanj, Souha Amer Univ Beirut, Med Ctr, Dept Internal Med, Div Infect Dis, Beirut, Lebanon, Bhally, Hasan North Shore Hosp, Dept Med & Infect Dis, Auckland, New Zealand, Iredell, Jon Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia, Iredell, Jon Westmead Hosp, Ctr Infect Dis & Microbiol, Westmead, NSW, Australia, Mendelson, Marc, Boyles, Tom H. Univ Cape Town, Groote Schuur Hosp, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa, Looke, David, Griffin, Paul Univ Queensland, Brisbane, Qld, Australia, Miyakis, Spiros Univ Wollongong, Sch Med, Wollongong, NSW, Australia, Miyakis, Spiros Illawarra Hlth & Med Res Inst, Wollongong, NSW, Australia, Miyakis, Spiros Wollongong Hosp, Dept Infect Dis, Wollongong, NSW, Australia, Walls, Genevieve Middlemore Hosp, Dept Infect Dis, Auckland, New Zealand, Al Khamis, Mohammed, Zikri, Ahmed King Fahad Specialist Hosp, Dammam, Saudi Arabia, Crowe, Amy St Vincents Hosp, Dept Infect Dis, Melbourne, Vic, Australia, Crowe, Amy St Vincents Hosp, Dept Microbiol, Melbourne, Vic, Australia, Ingram, Paul Univ Western Australia, Sch Pathol & Lab Med, Crawley, Australia, Ingram, Paul Fiona Stanley Hosp, Dept Infect Dis, Murdoch, WA, Australia, Ingram, Paul PathWest Lab Med, Dept Microbiol, Perth, WA, Australia, Daneman, Nick Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada, Griffin, Paul Mater Hosp, Dept Med & Infect Dis, Brisbane, Qld, Australia, Griffin, Paul Mater Med Res Inst, Brisbane, Qld, Australia, Griffin, Paul QIMR Berghofer, Brisbane, Qld, Australia, Athan, Eugene Barwon Hlth, Dept Infect Dis, Geelong, Vic, Australia, Athan, Eugene Deakin Univ, Geelong, Vic, Australia, Baker, Peter Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia, Roberts, Leah, Beatson, Scott A. Univ Queensland, Sch Chem & Mol Biosci, Australian Ctr Ecogen, Brisbane, Qld, Australia, Peleg, Anton Y. Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic, Australia, Peleg, Anton Y. Monash Univ, Dept Microbiol, Clayton, Vic, Australia, Peleg, Anton Y. Monash Univ, Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia, Peleg, Anton Y. Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia, Paterson, David L. Royal Brisbane & Womens Hosp, Dept Infect Dis, Brisbane, Qld, Australia, Beatson, Scott -- 0000-0002-1806-3283, Harris, Patrick -- 0000-0002-2895-0345, Runnegar, Naomi J -- 0000-0003-1196-4131, Paterson, David -- 0000-0003-2079-4437, YILMAZ, Mesut -- 0000-0001-8022-7325, and Griffin, Paul -- 0000-0002-1656-421X
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0301 basic medicine ,Male ,Carbapenem ,Drug Resistance ,Penicillanic Acid ,Bacteremia ,Drug resistance ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Cause of Death ,polycyclic compounds ,Medicine ,030212 general & internal medicine ,Piperacillin-Tazobactam ,Piperacillin-Tazobactam, Meropenem, Mortality, E coli, Klebsiella pneumoniae ,Escherichia coli Infections ,Original Investigation ,Tazobactam Drug Combination ,education.field_of_study ,Ceftriaxone ,Bacterial ,General Medicine ,E coli ,Middle Aged ,Anti-Bacterial Agents ,Klebsiella pneumoniae ,Piperacillin/tazobactam ,Female ,Adult ,Aged ,Drug Resistance, Bacterial ,Escherichia coli ,Humans ,Klebsiella Infections ,Meropenem ,Piperacillin ,Piperacillin, Tazobactam Drug Combination ,Thienamycins ,Beta-Lactamases ,medicine.drug ,medicine.medical_specialty ,030106 microbiology ,Population ,education ,03 medical and health sciences ,Internal medicine ,Mortality ,business.industry ,Piperacillin Plus Tazobactam ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,ESBL Genes ,business - Abstract
WOS: 000444341400012 PubMed ID: 30208454 IMPORTANCE Extended-spectrum beta-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 beta-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, -infinity 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. University of Queensland; Australian Society for Antimicrobials (ASA); International Society for Chemotherapy (ISC); National University Hospital Singapore Clinician Researcher Grant [NUHSRO/2014/121/CRG/07]; Australian Infectious Disease Centre; Australian Genome Research Facility; Royal College of Pathologists of Australasia (RCPA) Foundation; Study, Education, and Research Committee (SERC) of Pathology Queensland; National Health and Medical Research Council (NHMRC) Career Development Fellowship; Australian Postgraduate Award from the University of Queensland; NHMRC Career Development and Practitioner Fellowship; NHMRC Practitioner Fellowship 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.
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- 2018