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evident
Original paper
2018JAMAInfectious Disease

MERINO

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

RCTBloodstream infection

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Overview

Piperacillin-tazobactam was not noninferior to meropenem for 30-day death in ceftriaxone-resistant E. coli or Klebsiella bacteremia.

Clinical takeaway

Do not use piperacillin-tazobactam as carbapenem-sparing definitive therapy for ceftriaxone-resistant E. coli or Klebsiella bloodstream infection. Noninferiority was not shown.

Key result

30-day death was 12.3% (23 of 187) with piperacillin-tazobactam versus 3.7% (7 of 191) with meropenem (risk difference 8.6 percentage points; 1-sided 97.5% CI -infinity to 14.5%; P=0.90 for noninferiority).

Practice impact

Use meropenem, not piperacillin-tazobactam, for definitive treatment of ceftriaxone-resistant E. coli or Klebsiella bacteremia.

Evidence

Study design

Noninferiority, parallel-group, randomized clinical trial of definitive piperacillin-tazobactam versus meropenem.

Enrollment

379

Follow-up

All-cause mortality at 30 days after randomization.

Geography

26 sites in 9 countries

Clinical question

Is definitive piperacillin-tazobactam noninferior to meropenem for 30-day mortality in bloodstream infection caused by ceftriaxone-nonsusceptible E. coli or K. pneumoniae?

Population

  • Hospitalized adults with at least one positive blood culture with E. coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam.
  • Of 1646 patients screened, 391 were included; 379 who were randomized appropriately and received at least one dose of study drug were in the primary analysis population (mean age 66.5 years; 47.8% women).

Intervention

Intravenous piperacillin-tazobactam 4.5 g every 6 hours (188 participants assigned) for a minimum of 4 days and a maximum of 14 days, with total duration determined by the treating clinician.

Comparator

Intravenous meropenem 1 g every 8 hours (191 participants assigned) for the same duration window.

Primary outcome

All-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.

Noninferiority of piperacillin-tazobactam versus meropenem was not shown. Observed 30-day mortality was 12.3% vs 3.7% (risk difference 8.6 percentage points; 1-sided 97.5% CI -infinity to 14.5%; P=0.90 for noninferiority). This is a failed noninferiority result, not a completed superiority test.

Risk difference (percentage points) / 8.6 / 1-sided 97.5% CI -infinity to 14.5% / p=0.90

Key results

  • Among 379 patients in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome.
  • 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam died by 30 days compared with 7 of 191 (3.7%) randomized to meropenem; risk difference 8.6 percentage points (1-sided 97.5% CI -infinity to 14.5%; P=0.90 for noninferiority). Noninferiority was not shown.
  • Effects were consistent in an analysis of the per-protocol population.

Harms

  • Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.

Clinical Use

Practice impact

  • Do not de-escalate to piperacillin-tazobactam for definitive treatment of ceftriaxone-resistant E. coli or Klebsiella bloodstream infection when meropenem is an option.

Applicability

  • Hospitalized adults with E. coli or Klebsiella bloodstream infection that is ceftriaxone-nonsusceptible and piperacillin-tazobactam-susceptible.
  • This is a definitive-therapy question, not an empiric-therapy trial.

Limitations

  • The P value of 0.90 is for noninferiority, not a superiority test of higher mortality.
  • 391 patients were included and 379 were randomized appropriately and received study drug; the primary mortality counts use 187 and 191 patients.
  • The abstract does not report a superiority p-value for the mortality difference.

Common misinterpretations

  • Failed noninferiority is not proof of inferiority. Observed 30-day death was 12.3% vs 3.7%; the abstract reports no superiority p-value and does not support piperacillin-tazobactam in this setting.
  • Piperacillin-tazobactam susceptibility in vitro did not establish clinical noninferiority for these bloodstream infections.

Citation

Harris PNA, Tambyah PA, Lye DC, 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. doi:10.1001/jama.2018.12163

Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality.