MERINO

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Harris PNA, et al. "Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E coli or Klebsiella pneumoniae Bloodstreatm Infection and Ceftriaxone Resistance: A Randomized Clinical Trial". JAMA. 2018. 320(10):984-994.
PubMedFull textPDFClinicalTrials.gov


Clinical Question

In 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.

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.

The MERINO trial randomized 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 statistically significant difference in the primary outcome. Piperacillin-tazobactam was not able to be shown to be non-inferior to meropenem in terms of 30-day mortality, suggesting that the BLBLI is not an effective alternative to spare carbapenems. ESBL genes for OXA beta-lactamases were found in 68% and ampC in 10% 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

As of May 2021, IDSA guidelines recommend avoiding piperacillin-tazobactam for ESBL enterobacterales infections even if isolate is susceptible.

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: February 2014 to July 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.% CI -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

Further Reading