Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study
Andrew Henderson, David L. Paterson, Mark D. Chatfield, Paul Anantharajah Tambyah, David Chien Lye, Partha Pratim De, R.T.P. Lin, Ka Lip Chew, Yin Mo, T H Lee, Mesut Yılmaz, Rümeysa Çakmak, Thamer H. Alenazi, Yaseen M. Arabi, Marco Falcone, Matteo Bassetti, Elda Righi, Benjamin A. Rogers, Souha S. Kanj, Hasan Bhally, Jonathan R. Iredell, Marc Mendelson, Tom Boyles, David Looke, N J Runnegar, Spiros Miyakis, Genevieve Walls, Mwinyi Khamis, Ahmed Zikri, Amy Crowe, Paul R. Ingram, Nick Daneman, Paul Griffin, Eugene Athan, Leah W. Roberts, Scott A. Beatson, Anton Y. Peleg, Kyra Cottrell, Michelle J. Bauer, Elizabeth N. Tan, Khin Chaw, Graeme R. Nimmo, Tiffany Harris‐Brown, Patrick N. A. Harris, Peter O. Newton, H Wren, Maryza Graham, Tony M. Korman, Sameera Aljohani, Bassam Alalwan, Khizra Sultana, Assunta Sartor, Darren Welch, Gunnar Kahlmeter
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.