Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis

Abstract

ImportanceMeropenem 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.ObjectiveTo 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 ParticipantsA 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.InterventionsPatients 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 MeasuresThe 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.ResultsAll 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT03452839

Meropenem Administration in Critically Ill Patients With Sepsis—Reply

“…Augmented kidney clearance occurs in approximately 20% of patients with critical illness, especially in younger patients, in those with burns, and during the first week of hospital admission . None of these circumstances were frequent in the MERCY trial; patients were older (mean age, 64 years) and mainly had respiratory infections (33% of patients). Meropenem therapy was usually initiated later than 1 week after hospital admission, following failure of other antibiotics (66% were already receiving treatment at randomization).…”

“…In the MERCY trial, continuous administration of meropenem, compared with intermittent boluses, did not significantly decrease the composite primary outcome of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28 (47% vs 49%, respectively; relative risk [RR], 0.96 [95% CI, 0.81-1.13]; P = .60) . The GFR estimated with the Cockroft-Gault equation was available for 586 of 607 patients randomized in the MERCY trial, and only 94 patients (16%) had a GFR of 130 mL/min/1.73 m 2 or greater.…”

“…Furthermore, creatinine clearance often fails to correlate with the concentration of β-lactam antibiotics; the most appropriate approach would be use of therapeutic drug monitoring. The MERCY trial did not perform routine therapeutic drug monitoring for meropenem because no clear recommendation was available at the time of development of the trial protocol. However, data from a study of therapeutic drug monitoring found that the target meropenem concentration was achieved with standard dosing regimens in patients with a creatinine clearance of less than 70 mL/min/1.73 m 2 .…”

“…The hypothesis that the primary outcome of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28 can be affected by continuous infusion of meropenem in patients with augmented kidney clearance is not supported by the MERCY trial data. The relatively small number of patients with augmented kidney clearance requiring meropenem will make it difficult to conduct an adequately powered randomized clinical trial examining this question.…”

Meropenem Administration in Critically Ill Patients With Sepsis

“…To the Editor The MERCY randomized clinical trial in critically ill patients with sepsis found that the meropenem dosing strategy (continuous infusion vs intermittent bolus) did not improve the composite outcome of mortality and emergence of drug-resistant bacteria. However, we are concerned that the population for whom the administration of meropenem as a continuous infusion is expected to be most beneficial was not well represented in the trial.…”