MERINO

Published

Harris PNA, et al. "Effect of piperacillin-tazobactam vs. meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae Bloodstream Infection and ceftriaxone resistance: A randomized clinical trial". JAMA. 2018. 320(10):984-994.
PubMed • Full text • ClinicalTrials.gov

Clinical Question

Among patients with extended-spectrum beta-lactamase E. Coli or Klebsiella pneumoniae bacteremia, is piperacillin-tazobactam non-inferior to meropenem?

Bottom Line

Piperacillin-tazobactam was not shown to be non-inferior to meropenem for the treatment of E. Coli or Klebsiella pneumoniae bacteremia resistant to ceftriaxone (i.e., ESBL).

Major Points

Extended spectrum beta-lactamases (ESBLs) enable bacteria to inactivate many common antibiotics including third-generation cephalosporins such as ceftriaxone or ceftazidime. Carbapenem agents have been the preferred antibiotic for infections with ESBL-producing bacteria as resistance is uncommon. Piperacillin-tazobactam is a beta-lactam/beta-lactamase inhibitor (BLBLI) with in-vitro activity against ESBL pathogens and may be an alternative to carbapenems. Carbapenem-sparing regimens may reduce selection for resistance amongst pathogens.

Published in 2018, the MERINO trial randomized 378 patients with Escherichia coli or Klebsiella pneumoniae bacteremia susceptible to piperacillin-tazobactam and meropenem but not ceftriaxone to treatment with either piperacillin-tazobactam or meropenem. The study was stopped early after the 340 patient interim analysis due to a 3-fold higher 30-day mortality in the piperacillin-tazobactam group, which obviously led to the determination that piperacillin-tazobactam not non-inferior to meropenem. (It's reasonable to say that piperacillin-tazobactam is inferior to meropenem in treatment of this condition, but this was not a superiority trial.)

MERINO provides strong evidence that BLBLI agents, such as piperacillin-tazobactam, are not effective alternatives to carbapenems in the treatment of ESBLs, even when microbiological data suggest a sensitivity to BLBLIs. ESBL genes for OXA beta-lactamases were found in 68% of strains, and may have been an underlying driver for worse outcomes in the piperacillin-tazobactam group as some studies have shown they inhibit tazobactam. Additionally 10% of isolates carried ampC genes, which also are not inhibited by tazobactam. Overall, the results suggest that piperacillin-tazobactam should not be used to treat ESBL bacteremia even if isolates are found to be susceptible to the BLBI combination. It is unknown if this applies to newer BLBLIs that use a beta-lactamase inhibitor other than tazobactam, such as ceftazidime-avibactam.

Guidelines

IDSA (2021, adapted)

• Carbapenem is preferred for extended-spectrum β-lactamase–producing Enterobacterale (ESBL-E) infections outside of the urinary tract
• Even if susceptibility to pip/tazo has been shown, use of pip/tazo should be avoided for ESBL-E infections

Design

• Multicenter, open-label, parallel group, randomized, controlled trial
• N=378
  • Piperacillin-tazobactam (n=187)
  • Meropenem (n=191)
• Setting: 26 centers in Australia, New Zealand, Singapore, Italy, Turkey, Lebanon, South Africa, Saudi Arabia, and Canada.
• Enrollment: 2014-2017
• Mean follow-up: 30 days
• Analysis: per-protocol for at least first dose
• Primary outcome: 30-day mortality

Population

Inclusion Criteria

• Adults
• At least one blood culture positive for E coli or Klebsiella susceptible to piperacillin-tazobactam and meropenem but not ceftriaxone
• Randomized within 72 hours of initial positive blood culture

Exclusion Criteria

• Allergy to trial drugs or similar antibiotics
• Polymicrobial bacteremia
• Not expected to survive more than 96 hours or cure not possible
• Treatment with other antibiotics with gram-negative activity

Baseline Characteristics

Piperacillin-tazobactam vs. meropenem

• Median age: 70 years
• Urinary source: 55% vs 67%
• Diabetes: 31% vs 41%
• Appropriate empirical antibiotic: 67% vs 67%
• Time to receipt of appropriate antibiotics: 5.5 hours vs 9.6 hours
• Neutropenia: 8.5% vs 4.7%

Interventions

• Randomized to piperacillin-tazobactam 4.5 g IV every 6 hours vs meropenem 1g IV every 8 hours.
  • Study drug given for a minimum of 4 days after randomization, up to 14 days.
• Blood cultures collected on day 3 after randomization or if febrile up to day 5
• Follow-up performed by telephone call 30 days after randomization if discharged from hospital

Outcomes

Comparisons are piperacillin-tazobactam vs. meropenem.

Primary Outcomes

All-cause mortality at 30 days

12.3% vs 3.7% (risk difference 8.6%; 97.5% CI negative infinity to 14.5%)

Secondary Outcomes

Clinical and microbiologic resolution by day 4

68.4% vs 74.6% (risk difference -6.2%; 95% CI -15.5 to 3.1%)

Median day of resolution of signs of infection after randomization

3 [IQR 1-5] vs 2 [IQR 1-5]

Subgroup Analysis

There was no interaction with the primary analysis across subgroups by infecting species, Pitt score, hospital-acquired infection, source of infection, and presence of immunocompromise.

Adverse Events

Nonfatal serious adverse events

2.7% vs 1.6%

Criticisms

• Not blinded, although primary outcome was mortality which is likely less subjective to bias.
• Of 1646 screened, only 391 randomized. 123 excluded because declined treating arm, potentially leading to selection bias.

Funding

• Sponsored by University of Queensland
• Grants from: Australian Society for Antimicrobials, International Society for Chemotherapy, National University Hospital Singapore Clinician Researcher Grant