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)

Adam G Stewart; David L Paterson; Barnaby Young; David C Lye; Joshua S Davis; Kellie Schneider; Mesut Yilmaz; Rumeysa Dinleyici; Naomi Runnegar; Andrew Henderson; Sophia Archuleta; Shirin Kalimuddin; Brian M Forde; Mark D Chatfield; Michelle J Bauer; Jeffrey Lipman; Tiffany Harris-Brown; Patrick N A Harris; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

doi:10.1093/ofid/ofab387

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)

Open Forum Infect Dis. 2021 Aug 2;8(8):ofab387. doi: 10.1093/ofid/ofab387. eCollection 2021 Aug.

Authors

Adam G Stewart^{1

2}, David L Paterson^{1

2}, Barnaby Young^{3

4

5}, David C Lye^{3

4

5

6}, Joshua S Davis^{7

8}, Kellie Schneider⁷, Mesut Yilmaz⁹, Rumeysa Dinleyici⁹, Naomi Runnegar¹⁰, Andrew Henderson^{1

10}, Sophia Archuleta^{6

11}, Shirin Kalimuddin^{12

13}, Brian M Forde^{1

14

15}, Mark D Chatfield¹, Michelle J Bauer¹, Jeffrey Lipman^{1

16

17}, Tiffany Harris-Brown¹, Patrick N A Harris^{1

18}; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

Collaborators

MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN):
Po Ying Chia, Gail Cross, Jyoti Somani, Gabriel Yan

Affiliations

¹ University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.
² Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, Australia.
³ National Centre for Infectious Disease, Singapore.
⁴ Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore.
⁵ Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore.
⁶ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁷ Infectious Disease Department, John Hunter Hospital, Newcastle, Australia.
⁸ Menzies School of Health Research, Darwin, Australia.
⁹ Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol, Turkey.
¹⁰ Infection Management Services, Princess Alexandra Hospital, Brisbane, Australia.
¹¹ Division of Infectious Diseases, Department of Medicine, National University Hospital, National University Health System, Singapore.
¹² Department of Infectious Diseases, Singapore General Hospital, Singapore.
¹³ Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore.
¹⁴ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
¹⁵ Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia.
¹⁶ Intensive Care Services, Royal Brisbane and Women's Hospital, Brisbane, Australia.
¹⁷ Scientific Consultant, Nimes University Hospital, University of Montpellier, Nimes, France.
¹⁸ Central Microbiology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.

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.

Associated data

ClinicalTrials.gov/NCT02437045