Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase-Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2)

Abstract

Background: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative.

Methods: We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days.

Results: Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, -12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were bla _CMY-2, bla _DHA-17, bla _CMH-3, and bla _ACT-17. No ESBL, OXA, or other carbapenemase genes were identified.

Conclusions: Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen.

Clinical trials registration: NCT02437045.

Keywords: Enterobacterales; ampC β-lactamase; carbapenem; clinical trial; piperacillin-tazobactam.

Figure 1.

MERINO-2 patient recruitment, randomization, and flow through study. ^aPatients could meet >1 exclusion criteria. A total of 235 were excluded because >72 hours had elapsed since initial blood culture; 337, based on microbiology criteria; 48, allergy to trial drug; 205, polymicrobial infection; 46, not expected to survive >96 hours; 3, pregnant or breastfeeding; 12, no intent to cure; 16, <18 years old (<21 years in Singapore); and 4, previously enrolled. For 337 patients, microbiological exclusions based on susceptibility testing were as follows: 105 were nonsusceptible to third-generation cephalosporins, 120 were nonsusceptible to either meropenem or piperacillin-tazobactam and 205 were polymicrobial infections. Other exclusions included patient requiring ongoing antibiotic therapy (other than study drug) with activity against gram-negative bacilli (n = 21), Pitt bacteremia score >4 (n = 67), central nervous system source of infection (n = 25).

Figure 2.

Piperacillin-tazobactam and meropenem minimum inhibitory concentration by intervention arm. Abbreviations: EUCAST, European Committee on Antimicrobial Susceptibility Testing; MIC, minimum inhibitory concentration.

Figure 3.

Scatterplot comparison of piperacillin-tazobactam and meropenem susceptibility testing by disk diffusion testing (x-axis; zone diameter) and broth microdilution (y-axis; minimum inhibitory concentration). The red dashed line represents the European Committee on Antimicrobial Susceptibility Testing susceptible breakpoint and the blue dashed line represents the Clinical and Laboratory Standards Institute susceptible breakpoint. Abbreviation: BMD, broth microdilution.