Clinical Outcome Study of High-dose Meropenem in Sepsis and Septic Shock Patients

Sepsis and septic shock patients are considered to have a high risk of complications and death. Appropriate antimicrobial therapy plays an important role in determining outcomes in septic patients. However, pathophysiologic changes associated with critical illness have an impact on pharmacokinetics of antimicrobials. In addition, increasing bacterial resistance is also a growing concern, especially in intensive care units., Consequently, standard antimicrobial dose may not be sufficient to achieve pharmacokinetic/pharmacodynamic target in sepsis and septic shock patients. The purpose of this study is to compare a therapy between meropenem standard dose and meropenem high dose in the treatment of sepsis and septic shock

Study Overview

• Status: Completed
• Conditions: Sepsis; Critical Illness; Septic Shock; Morality; Pharmacokinetic; Carbapenem; Pharmacodynamic; Clinical Outcome; Organ Failure, Multiple
• Intervention / Treatment: Drug: Meropenem standard dose; Drug: Meropenem high dose

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Thailand
  • Bangkok
    • Ratchathewi, Bangkok, Thailand, 10400
      • Faculty of Medicine Ramathibodi Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults (18 years and older) with sepsis and/or septic shock according to SEPSIS-3 criteria and receive meropenem within 1 hour after diagnosis
• Informed consent signed by patient or their legally authorized representative

Exclusion Criteria:

• Subjects with infective endocarditis
• Subjects with central nervous system infection
• Subjects who requires surgical condition within 72 hours after randomization
• Subjects on extracorporeal membrane oxygenation (ECMO) within 3 days after randomization
• Subjects with active seizure
• History of receiving meropenem within 1 week prior to randomization
• Pregnancy women and lactation
• Known allergy to meropenem
• Not complete a 72-hour course of empirical meropenem treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Meropenem standard dose; Meropenem 1 g every 8 hours	Drug: Meropenem standard dose; Empirical with 1 g meropenem intravenous infusion in 30 minutes then 1 g intravenous infusion in 3 hours every 8 hours.; Dosage is adjusted in case of renal dysfunction. Duration of therapy is varied regarding source(s) of infection.
Active Comparator: Meropenem high dose; Meropenem 2 g every 8 hours	Drug: Meropenem high dose; Empirical with 2 g meropenem intravenous infusion in 30 minutes then 2 g intravenous infusion in 3 hours every 8 hours.; Dosage is adjusted in case of renal dysfunction. Duration of therapy is varied regarding source(s) of infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOFA score change	The Sequential organ failure assessment (SOFA) score describe the time course of multiple organ dysfunction. The SOFA score is composed of scores for six organ systems (respiratory, cardiovascular, neurological, hepatic, renal and coagulation). The function of six organ systems is scored from 0 (no organ dysfunction) to 4 (severe organ dysfunction), and the individual organ scores are then summed to a total score between 0 and 24. Primary outcome is assessing change between SOFA score at baseline and SOFA score at day 4 after treatment by meropenem	Change from Baseline SOFA score at day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	In hospital mortality	14 and 28 days
Clinical cure	Composite of: Persistent fever and/or; Stable or increased white blood cell count	Day 3, 5, 7, 10 and 14
Microbiological cure	Elimination of the study entry pathogen within 14 days after received meropenem; Bacteremia: no growth in blood cultures; Intra-abdominal infection: no growth in blood cultures; UTI: uropathogen growth of less than 10^4 CFU/mL in women or less than 10^3 CFU/mL in men; HAP/VAP: pathogen in sputum culture growth of less than 10^3 CFU/mL; SSTI: no growth in blood cultures	Day 3, 5, 7, 10 and 14
Duration of vasopressor agents	Time interval (day) from time of vasopressor agents initiation to time to vasopressor agents discontinuation	14 and 28 days
Duration of mechanical ventilator	Time interval (day) of mechanical ventilator	14 and 28 days
Length of ICU stay	Time interval (day) from ICU admission (after randomization) to ICU discharge	14 and 28 days
Length of hospital stay	Time interval (day) from hospital admission (after randomization) to hospital discharge	14 and 28 days
%T > MIC	% time of meropenem concentration above MIC	Day 1

Collaborators and Investigators

• Sponsor: Mahidol University
• Investigators: Principal Investigator: Tospon Lertwattanachai, B.sc.(Pharm), Faculty of Pharmacy, Mahidol University

Publications and helpful links

General Publications

• Jaruratanasirikul S, Thengyai S, Wongpoowarak W, Wattanavijitkul T, Tangkitwanitjaroen K, Sukarnjanaset W, Jullangkoon M, Samaeng M. Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units. Antimicrob Agents Chemother. 2015;59(6):2995-3001. doi: 10.1128/AAC.04166-14. Epub 2015 Mar 9.
• Roberts JA, Kumar A, Lipman J. Right Dose, Right Now: Customized Drug Dosing in the Critically Ill. Crit Care Med. 2017 Feb;45(2):331-336. doi: 10.1097/CCM.0000000000002210.
• Suwantarat N, Carroll KC. Epidemiology and molecular characterization of multidrug-resistant Gram-negative bacteria in Southeast Asia. Antimicrob Resist Infect Control. 2016 May 4;5:15. doi: 10.1186/s13756-016-0115-6. eCollection 2016.
• Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014 Nov 20;77:3-11. doi: 10.1016/j.addr.2014.07.006. Epub 2014 Jul 15.
• Marquet K, Liesenborgs A, Bergs J, Vleugels A, Claes N. Incidence and outcome of inappropriate in-hospital empiric antibiotics for severe infection: a systematic review and meta-analysis. Crit Care. 2015 Feb 16;19(1):63. doi: 10.1186/s13054-015-0795-y.
• Mouton JW, van den Anker JN. Meropenem clinical pharmacokinetics. Clin Pharmacokinet. 1995 Apr;28(4):275-86. doi: 10.2165/00003088-199528040-00002.
• de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017 Feb 24;21(1):38. doi: 10.1186/s13054-017-1609-1.
• Lertwattanachai T, Montakantikul P, Tangsujaritvijit V, Sanguanwit P, Sueajai J, Auparakkitanon S, Dilokpattanamongkol P. Clinical outcomes of empirical high-dose meropenem in critically ill patients with sepsis and septic shock: a randomized controlled trial. J Intensive Care. 2020 Apr 15;8:26. doi: 10.1186/s40560-020-00442-7. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Actual): November 30, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: November 8, 2017
• First Submitted That Met QC Criteria: November 13, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): March 12, 2019
• Last Update Submitted That Met QC Criteria: March 9, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Toxemia; Shock, Septic; Shock; Critical Illness; Multiple Organ Failure; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem
• Other Study ID Numbers: ID07-60-19

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No