Blog Written by Dr Jose Chacko

Background

The efficacy of beta-lactam antibiotics is related to the duration for which drug levels remain above the minimum inhibitory concentration (MIC) (1). However, they are generally administered as intermittent doses. Intermittent dosing leads to peaks and troughs in drug levels that may potentially lead to the development of resistant organisms (2). Administration over a longer duration as a continuous infusion sustains levels above the MIC and may improve efficacy besides reducing the emergence of resistant organisms. Pharmacokinetic data suggest that administration over a longer duration provides sustained serum levels above the MIC and may enhance the efficacy of beta-lactams (3). The Surviving Sepsis Guidelines recommend continuous administration of beta-lactams, supported by a moderate quality of evidence (4). Based on pharmacokinetic studies, continuous administration of meropenem can potentially maintain serum levels above the MIC for a longer duration, improve bacterial clearance, and reduce the growth of resistant organisms (5). Meta-analyses have revealed improved survival with continuous infusion of beta-lactams compared with intermittent dosing (5,6). A previous randomized controlled trial (RCT) had demonstrated a higher microbiological success rate, reduced ICU length of stay, and reduced duration of therapy with continuous infusion compared with intermittent dosing of meropenem (7). However, no adequately powered RCT had evaluated the efficacy of continuous compared with intermittent administration of meropenem. The investigators of the MERCY (The Continuous Infusion vs. Intermittent Administration of Meropenem in Critically Ill Patients) RCT hypothesized that continuous administration of meropenem may lead to an improvement in the composite outcome of mortality and the emergence of resistant organisms compared with intermittent administration (8).

Setting and design

The MERCY randomized controlled trial (RCT) was conducted across 31 ICUs in four countries, including Croatia, Italy, Kazakhstan, and Russia. The study included ICU patients 18 years or older, admitted to the ICU, had sepsis or septic shock, and required treatment with meropenem based on clinician judgment. Sepsis was defined as documented or suspected infection, with systemic inflammatory response syndrome and a SOFA score ≥2. Septic shock was defined as persistent hypotension after fluid resuscitation, requiring vasopressors to maintain a MAP >65 mm Hg and elevated serum lactate level of >2 mmol/L. The diagnosis was based on clinician assessment. The study was double-blinded; randomization was performed in a 1:1 ratio and stratified by the study center.

Excluded

Patients who had previously been treated with carbapenems, those with a poor likelihood of survival with a SAPS II score of ≥65 points, and patients who had evidence of severe immunosuppression were excluded.

Continuous administration

After collection of culture samples, meropenem, 1 g intravenously, was administered as a loading dose. This was followed by 3 g as a continuous intravenous infusion over 24 hours.

Intermittent administration

Following the loading dose, meropenem was administered intermittently, in three divided doses of 1 g every 8 hours. Each dose was administered over a period of 30–60 minutes.

Both groups

If renal dysfunction was present (creatinine clearance <50 mL/min/m²), the dose of meropenem was reduced to 2 g/day. A double dose could be administered if deemed appropriate, based on clinician judgment. Treatment of sepsis was according to local protocols based on the Surviving Sepsis Guidelines.

Sample size calculation

The primary outcome was a composite of mortality and the emergence of pan-resistant or extensively resistant bacteria at 28 days. The authors assumed that the primary outcome would occur in 52% of patients in the intermittent administration group. A strategy of continuous infusion was expected to result in an absolute risk reduction of 12%. A sample size of 300 patients was calculated which would provide the study with 80% power at an alpha level of 0.05.

Results

Baseline characteristics

Among 896 patients who were screened, 607 were included in the study – 303 were randomized to the continuous infusion group and 304 to the intermittent administration group. Patients were well-matched at baseline. Sepsis (without shock) was diagnosed in 38% of patients in the continuous infusion group and 40% in the intermittent administration group; septic shock was present in 62 and 60%, respectively. Respiratory tract infections were most common (33% in both groups) followed by gastrointestinal tract and catheter-related bloodstream infections. The median duration from hospitalization to randomization was 9 days in the continuous infusion group and 8 days in the intermittent administration group. The median time from ICU admission to randomization was 5 days in both groups. The severity of illness was similar in both groups, based on the SAPS and the SOFA scores. The overall median duration of treatment with meropenem was 11 days in both groups; among survivors at 28 days, the median duration of treatment was 13 days.

The causative organism was not identified in 28% of patients in the continuous infusion group and 30% of patients in the intermittent administration group. Gram-negative infections were more common. Among the gram-negative organisms isolated, Klebsiella was most common, followed by Pseudomonas, Escherichia Coli, and Acinetobacter species.

The primary outcome

The composite primary outcome of 28-day mortality and the emergence of pan-resistant or extensively resistant bacteria was similar in both groups (continuous (infusion vs. intermittent administration: 47% vs. 49%, relative risk, 0.96 [95% CI, 0.81 to 1.13], P = 0.60). The individual components of the composite outcome were also similar (28-day mortality: 30% vs. 33%; emergence of resistant bacteria: 24% vs. 25%).

Secondary outcomes

Among the secondary outcomes, the 90-day mortality was 42% in both groups. The number of days alive and antibiotic-free, and the number of days alive and ICU-free at 28 days were also not significantly different between groups.

Post-hoc exploratory outcomes

Among the post-hoc exploratory outcomes, there was no significant difference between groups in the ICU length of stay, the hospital length of stay, or readmission to the ICU.

Sensitivity analysis of the primary outcome

No significant difference was observed when analysis was performed with stratification by trial center and modified intention-to-treat or per-protocol analysis for the primary outcome. Univariate and multivariate analysis for association with baseline characteristics did not reveal any significant impact of continuous infusion.

The main findings of the study are summarized in Table 1.

Table 1. Main findings of the study

Strengths

• The largest randomized controlled trial so far that has evaluated the effect of a continuous infusion of meropenem
• Double-blinded, multicenter trial; provides external validity
• The study followed strict inclusion criteria based on standard definitions, and the management was protocolized
• The study population included patients with sepsis or septic shock in whom the question is most relevant

Limitations

• A composite primary outcome may not be the most optimal. The study was underpowered to evaluate the 28-day mortality.
• The investigators could have included clinical cure and microbiological cure among the outcomes
• A large number of patients in both groups received antibiotic therapy within 3 months of before the study (67% in the continuous and 65% in the intermittent group) – would this have contributed to the emergence of resistant organisms?
• Information is not available regarding details of concomitant antibiotic therapy
• The median time from hospital admission to randomization was 9 vs. 8 days and from ICU admission to randomization was 5 days. During this period, other antibiotics may have been administered. Could this have biased the results, particularly with emergence of resistant organisms?
• The median duration of treatment may be considered long (11 days overall; 13 days among 28-day survivors), particularly considering that if source control is achieved, the duration of therapy may be curtailed. No preset criteria were followed for cessation of therapy
• No information is available on medical vs. surgical patients
• Although guidelines were provided for dosing, adjustments were allowed based on clinician judgment
• Would the study apply to high-dose (6 g/day) therapy?
• Patients who were severely immunosuppressed were excluded – would they be a patient population that might benefit from continuous infusion?
• The results of the study may not apply to other beta-lactam antibiotics
• Details of concurrent antibiotic therapy were not available