Dataset Information

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.

SUBMITTER: Monti G

PROVIDER: S-EPMC10276329 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Monti Giacomo G Bradic Nikola N Marzaroli Matteo M Konkayev Aidos A Fominskiy Evgeny E Kotani Yuki Y Likhvantsev Valery V VV Momesso Elena E Nogtev Pavel P Lobreglio Rosetta R Redkin Ivan I Toffoletto Fabio F Bruni Andrea A Baiardo Redaelli Martina M D'Andrea Natascia N Paternoster Gianluca G Scandroglio Anna Mara AM Gallicchio Francesca F Ballestra Mariano M Calabrò Maria Grazia MG Cotoia Antonella A Perone Romina R Cuffaro Raffaele R Montrucchio Giorgia G Pota Vincenzo V Ananiadou Sofia S Lembo Rosalba R Musu Mario M Rauch Simon S Galbiati Carola C Pinelli Fulvio F Pasin Laura L Guarracino Fabio F Santarpino Giuseppe G Agrò Felice Eugenio FE Bove Tiziana T Corradi Francesco F Forfori Francesco F Longhini Federico F Cecconi Maurizio M Landoni Giovanni G Bellomo Rinaldo R Zangrillo Alberto A

JAMA 20230701 2

<h4>Importance</h4>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.<h4>Objective</h4>To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or exte ...[more]

PMID: 37326473

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Project description:ImportanceWhether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain.ObjectiveTo evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis.Design, setting, and participantsAn international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis.InterventionEligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first.Main outcomes and measuresThe primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality.ResultsAmong 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different.Conclusions and relevanceThe observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients.Trial registrationClinicalTrials.gov Identifier: NCT03213990.

Project description:IntroductionMeropenem bactericidal activity depends on the time when the free drug concentrations remain above the minimum inhibitory concentration of pathogens. The goal of this study was to compare clinical and bacteriological efficacy of continuous meropenem infusion versus bolus administration in critically ill patients with severe infection, and to evaluate the safety of both dosing regimens.MethodsPatients admitted to the interdisciplinary Intensive Care Unit (ICU) who suffered from severe infections and received meropenem were randomized either in the Infusion group (n = 120) or in the Bolus group (n = 120). Patients in the Infusion group received a loading dose of 2 g of meropenem followed by a continuous infusion of 4 g of meropenem over 24 hours. Patients in the Bolus group were given 2 g of meropenem over 30 minutes every 8 hours. Clinical and microbiological outcome, safety, meropenem-related length of ICU and hospital stay, meropenem-related length of mechanical ventilation, duration of meropenem treatment, total dose of meropenem, and ICU and in-hospital mortality were assessed.ResultsClinical cure at the end of meropenem therapy was comparable between both groups (83.0% patients in the Infusion vs. 75.0% patients in the Bolus group; P = 0.180). Microbiological success rate was higher in the Infusion group as opposed to the Bolus group (90.6% vs. 78.4%; P = 0.020). Multivariate logistic regression identified continuous administration of meropenem as an independent predictor of microbiological success (OR = 2.977; 95% CI = 1.050 to 8.443; P = 0.040). Meropenem-related ICU stay was shorter in the Infusion group compared to the Bolus group (10 (7 to 14) days vs. 12 (7 to 19) days; P = 0.044) as well as shorter duration of meropenem therapy (7 (6 to 8) days vs. 8 (7 to 10) days; P = 0.035) and lower total dose of meropenem (24 (21 to 32) grams vs. 48 (42 to 60) grams; P < 0.0001). No severe adverse events related to meropenem administration in either group were observed.ConclusionsContinuous infusion of meropenem is safe and, in comparison with higher intermittent dosage, provides equal clinical outcome, generates superior bacteriological efficacy and offers encouraging alternative of antimicrobial therapy in critically ill patients.

Project description:BackgroundProviding data on the superior efficacy of vancomycin administered based on the area under the curve over 24 hours to the minimum inhibitory concentration of vancomycin (AUC24/MIC) is crucial. However, data on dosing and monitoring of vancomycin pharmacokinetics in the pediatric population are limited. Previous findings have showed that intermittent infusion of vancomycin (IIV) may not achieve the desired levels, continous infusions of vancomycin (CIV) reach the desired serum concentration faster than IIV and are associated with reduced nephrotoxicity.ObjectivesThis study aimed to compare the serum concentrations, AUC24, clinical variables, and adverse effects of two vancomycin administration methods in the pediatric population.MethodsThis study was a double-blind, randomized, controlled clinical trial conducted at a tertiary children's teaching hospital. Inclusion criteria were age between 2 months and 15 years and weight less than 67 kilograms, with exclusion criteria including renal impairment. Participants were divided into CIV and IIV groups following distinct administration protocols. Demographic, clinical, and laboratory data, including vancomycin serum concentrations, were compiled. Assessments included pediatric mortality risk, pediatric sequential organ failure assessment, and regular temperature monitoring. Pharmacokinetic analysis was conducted using Monolix software 2023R1. Primary endpoints were vancomycin serum levels and AUC24 between cohorts on day three, with nephrotoxicity and additional adverse drug responses evaluated.ResultsSixty-eight patients in the pediatric intensive care unit (PICU) were allocated to either CIV (33) or IIV (35) for vancomycin treatment. In the CIV group, 82% of patients achieved an AUC24 ≥ 400 mg.h/L, compared to 23% in the IIV group. Continuous infusions of vancomycin demonstrated a greater AUC24 (587.7 ± 184.4 mg.h/L vs. 361.9 ± 113.2 mg.h/L, P < 0.05) compared to IIV. Two cases of nephrotoxicity were reported, one in each group, with mortality and adverse events being comparable between the two groups.ConclusionsThis study demonstrated that continuous vancomycin infusion has a higher success rate in safely achieving therapeutic vancomycin levels in PICU patients compared to intermittent vancomycin infusion.

Project description:BACKGROUND:Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS:Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS:The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS:An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION:The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Project description:Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.

Project description:BackgroundAppropriate antimicrobial dosing is challenging because of changes in pharmacokinetics (PK) parameters and an increase in multidrug-resistant (MDR) organisms in critically ill patients. This study aimed to evaluate the effects of an empirical therapy of high-dose versus standard-dose meropenem in sepsis and septic shock patients.MethodsWe performed a prospective randomized open-label study to compare the changes of modified sequential organ failure assessment (mSOFA) score and other clinical outcomes of the high-dose meropenem (2-g infusion over 3 h every 8 h) versus the standard-dose meropenem (1-g infusion over 3 h every 8 h) in sepsis and septic shock patients. Patients' characteristics, clinical and microbiological outcomes, 14 and 28-day mortality, vasopressor- and ventilator-free days, intensive care unit (ICU) and hospital-free days, percent of the time of antibiotic concentrations above the minimum inhibitory concentration (%T>MIC), and safety were assessed.ResultsSeventy-eight patients were enrolled. Median delta mSOFA was comparable between two groups (- 1 in the high-dose group vs. - 1 in the standard-dose group; P value = 0.75). There was no difference between the two groups regarding clinical and microbiological cure, 14- and 28-day mortality, vasopressor- and ventilator-free days, and ICU- and hospital-free days. In patients admitted from the emergency department (ED) with a mSOFA score ≥ 7, the high-dose group demonstrated significantly better microbiological cure compared with the standard-dose group (75% (9/12 patients) vs. 20% (2/10 patients); P value = 0.03). Likewise, the high-dose group presented higher microbiological cure rate in patients admitted from ED who had either APACHE II score > 20 (83.3% (10/12) vs. 28.6% (2/7); P value = 0.045) or on mechanical ventilator (87.5% (7/8) vs. 23.1% (3/13); P value = 0.008) than the standard-dose group. Adverse events were comparable between the two groups.ConclusionsEmpirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients. Besides, subgroup analysis manifested superior microbiological cure rate in sepsis or septic shock patients admitted from ED.Trial registrationClinicalTrials.gov, NCT03344627, registered on November 17, 2017.

Dataset Information

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

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

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

Similar Datasets

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