Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial

Abstract

Importance: Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.

Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.

Design, setting, and participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.

Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).

Main outcomes and measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.

Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).

Conclusions and relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.

Trial registration: ClinicalTrials.gov Identifier: NCT03452839.

Figure 1.. Assessment, Exclusions, and Randomization for the MERCY Randomized Clinical Trial

MERCY indicates Continuous Infusion vs Intermittent Administration of Meropenem in Critically Ill Patients. Randomization was stratified according to study center. ^aCalculated based on the patient characteristics, reason for intensive care admission, and physiological abnormalities. The score range is from 0 to 163; a higher score indicates higher severity of disease and higher risk of death. ^bAfter randomization, it was discovered that 12 patients actually met the exclusion criteria (were already receiving carbapenem antibiotics, had previous allergy to carbapenem antibiotics, had high Simplified Acute Physiology Score II [≥65], were taking immunosuppressants or chronic corticosteroid therapy, or had AIDS). A per-protocol analysis was performed excluding these 12 patients.

Figure 2.. Kaplan-Meier Analysis for the Composite Primary Outcome and the Secondary Outcome of Probability of Mortality at Day 28

Emergence of pandrug-resistant bacteria or extensively drug-resistant bacteria is shown as occurring on the day the positive culture was sent to the laboratory. All patients were followed up to death or emergence of resistant bacteria or through day 28.