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

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 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.

Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection

“…To address some of the concerns with regards to the microbiological data from the MERINO trial, the authors then performed a post hoc analysis of MIC values and resistance genes detected comparative to the 30 day mortality of patients treated with both piperacillin/tazobactam and meropenem. 218 MICs of both test drugs for all organisms isolated from BSI in the MERINO trial were retested using the reference method of broth microdilution and all of the β-lactamase genes present were determined. In retesting, they found that a significant number of isolates that had previously been reported as susceptible to piperacillin/tazobactam were non-susceptible (i.e.…”

“…The authors revised their conclusion to the recommendation of allowing susceptibility testing (reference method) to guide therapy with piperacillin/tazobactam for ESBL-producing strains. 218 Despite these findings and the revised mortality assessment, the authors of the MERINO trial continue to be proponents of the notion that all infections caused by ceftriaxone-resistant organisms (and by association ESBL-positive) should be treated with a carbapenem. 219 Other experts have concluded that there has been an overinterpretation of the MERINO trial results, which has caused an overuse of carbapenems and potentially contributed to the dramatic increase of carbapenem-resistant organisms.…”

Variation in Target Attainment of Beta‐Lactam Antibiotic Dosing Between International Pediatric Formularies

“…Coverage for the resistant Enterobacterales breakpoint of 16 mg/L only accounts for 70% (79−46%). A re‐analysis of the microbiology data from the MERINO trial showed that infection with extended‐spectrum beta‐lactamase organisms, while “sensitive” (with MICs below 16 mg/L), were still associated with increased mortality, 53 with insufficient target attainment a possible cause.…”

Navigating treatment approaches for presumed ESBL-producing infections

“…with piperacillin/tazobactam MICs of ≤16 mg/L according to the results of reference broth microdilution. 6 The increase in mortality was more modest when re-analysing results—the absolute difference in increased risk of 30 day mortality with piperacillin/tazobactam was 5% (95% CI −1% to 10%). While technically no longer significant, the results likely will still give many clinicians pause in confidently prescribing piperacillin/tazobactam for ESBL-producing infections, particularly because, in the real world, inaccuracies in obtaining piperacillin/tazobactam MICs exist in most hospital systems.…”