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    Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the MERINO study
    (Oxford University Press, 2021) Henderson, A.; Paterson, D. L.; Chatfield, M. D.; Tambyah, P. A.; Lye, D. C.; De, P. P.; Lin, R. T. P.; Chew, K. L.; Yin, M.; Lee, T. H.; Yılmaz, Mesut; Çakmak, Rümeysa; Alenazi, T. H.; Arabi, Y. M; Falcone, M.; Bassetti, M.; Righi, E.; Ba, Rogers; Kanj, S. S.; Bhally, H.; Iredell, J.; Mendelson, M.; Boyles, T. H.; Looke, D. F. M.; Runnegar, N. J.; Miyakis, S.; Walls, G.; Ai Khamis, M.; Zikri, A.; Crowe, A.; Ingram, P. R.; Daneman, N. N.; Griffin, P.; Athan, E.; Roberts, L.; Beatson, S. A.; Peleg, A. Y.; Cottrell, K. K.; Bauer, M. J.; Tan, E.; Chaw, K.; Nimmo, G. R.; Harris-Brown, T.; Harris, P. N. A.
    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: 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam non-susceptible breakpoint (MIC > 16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% 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% - 10%) after excluding strains with piperacillin/tazobactam MIC values > 16 mg/L. Isolates co-harboring ESBL and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-mortality of 14% (95% CI 2% - 28%).Conclusion: After excluding non-susceptible strains, the 30-day mortality difference was 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 co-harboring ESBLs suggests meropenem remains the preferred choice for definitive treatment of ceftriaxone non-susceptible E. coli and Klebsiella.