Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study

Andrew Henderson(The University of Queensland), David L. Paterson(The University of Queensland), Mark D. Chatfield(The University of Queensland), Paul Anantharajah Tambyah(National University Hospital), David Chien Lye(National University of Singapore), Partha Pratim De(Tan Tock Seng Hospital), R.T.P. Lin(Tan Tock Seng Hospital), Ka Lip Chew(National University Hospital), Yin Mo(National University Hospital), T H Lee(National University of Singapore), Mesut Yılmaz(Istanbul Medipol University), Rümeysa Çakmak(Istanbul Medipol University), Thamer H. Alenazi(King Saud bin Abdulaziz University for Health Sciences), Yaseen M. Arabi(King Saud bin Abdulaziz University for Health Sciences), Marco Falcone(University of Pisa), Matteo Bassetti(Ospedale Policlinico San Martino), Elda Righi(University of Verona), Benjamin A. Rogers(Monash Health), Souha S. Kanj(American University of Beirut Medical Center), Hasan Bhally(North Shore Hospital), Jonathan R. Iredell(The University of Sydney), Marc Mendelson(University of Cape Town), Tom Boyles(University of Cape Town), David Looke(The University of Queensland), N J Runnegar(The University of Queensland), Spiros Miyakis(University of Wollongong), Genevieve Walls(Middlemore Hospital), Mwinyi Khamis(King Fahad Specialist Hospital), Ahmed Zikri(King Fahad Specialist Hospital), Amy Crowe(St Vincent's Hospital Melbourne), Paul R. Ingram(The University of Western Australia), Nick Daneman(Sunnybrook Health Science Centre), Paul Griffin(The University of Queensland), Eugene Athan(Barwon Health), Leah W. Roberts(The University of Queensland), Scott A. Beatson(The University of Queensland), Anton Y. Peleg(Australian Regenerative Medicine Institute), Kyra Cottrell(The University of Queensland), Michelle J. Bauer(The University of Queensland), Elizabeth N. Tan(The University of Queensland), Khin Chaw(Mater Health Services), Graeme R. Nimmo(Royal Brisbane and Women's Hospital), Tiffany Harris‐Brown(The University of Queensland), Patrick N. A. Harris(The University of Queensland), Peter O. Newton, H Wren, Maryza Graham, Tony M. Korman, Sameera Aljohani, Bassam Alalwan, Khizra Sultana, Assunta Sartor, Darren Welch, Gunnar Kahlmeter
Clinical Infectious Diseases
October 3, 2020
10.1093/cid/ciaa1479
Cited by 154Open Access
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Abstract

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

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