PK/PD of Extended-infusion Meropenem, Piperacillin-tazobactam and Cefepime in the Early Phase of Septic Shock (PAACS)

Pharmacokinetics and Pharmacodynamic (PK/PD) of Extended-infusion Meropenem, Piperacillin-tazobactam and Cefepime in the Early Phase of Septic Shock

This study evaluates PK/PD of an extended-infusion protocol of meropenem, piperacillin-tazobactam and cefepime, in the early phase of septic shock.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: MEROPENEM; Drug: PIPERACILLIN-TAZOBACTAM; Drug: CEFEPIME

Detailed Description

Beta Lactams are the keystones of shock septic treatment. Early phase of septic shock is a period of disturbed pharmacokinetics, with augmented renal clearance and distribution volume of hydrophilic drugs as Beta Lactams. Consequently, early phase of septic shock is a period at risk of underdosing Beta Lactam, which could increase the risk of clinical failure an mortality.

Data are available concerning underdosing of MEROPENEM, PIPERACILLIN-TAZOBACTAM and CEFEPIME, when administered in bolus.

No data exist concerning the achievement of a target of 100% of the whole interval above 4 time the superior breakpoint of Pseudomonas Aeruginosa according to EUCAST (European Committee on Antimicrobial Susceptibility Testing), during the 48 first hours of treatment of septic shock, when Beta Lactam are administered in extended infusion.

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Besançon, France, 25000
    • CHU Besançon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Septic shock
• Meropenem, piperacillin-tazobactam or cefepime started after enrollment

Exclusion Criteria:

• Pregnancy
• Central nervous system infection
• Burns

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MEROPENEM; After enrollment, patients of MEROPENEM arm will receive an initial 2g bolus of MEROPENEM and 2g infusion over 3 hours every eight hours, during 48 hours, without modification of rhythm and dose according to renal function.	Drug: MEROPENEM; Administration of MEROPENEM according to a protocol of extended infusion defining dose and duration of infusion.
Active Comparator: PIPERACILLIN-TAZOBACTAM; After enrollment, patients of PIPERACILLIN - TAZOBACTAM arm will receive an initial 4g bolus of PIPERACILLIN - TAZOBACTAM and a 16g continuous infusion per day, during 48 hours, without modification of rhythm and dose according to renal function.	Drug: PIPERACILLIN-TAZOBACTAM; Administration of PIPERACILLIN-TAZOBACTAM according to a protocol of continuous infusion defining dose and duration of infusion.
Active Comparator: CEFEPIME; After enrollment, patients of CEFEPIME arm will receive an initial 2g bolus of CEFEPIME and a 6g continuous infusion per day, during 48 hours, without modification of rhythm and dose according to renal function.	Drug: CEFEPIME; Administration of CEFEPIME according to a protocol of continuous infusion defining dose and duration of infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving the PK/PD target	Proportion of patients achieving the target of 100% of 48 first hours of treatment above 4 time the upper critical breakpoint for Pseudomonas Aeruginosa	First 48 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
All cause mortality	28th day

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Besançon

Publications and helpful links

General Publications

• Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126. doi: 10.1186/cc9091. Epub 2010 Jul 1.
• Winiszewski H, Despres C, Puyraveau M, Lagoutte-Renosi J, Montange D, Besch G, Floury SP, Chaignat C, Labro G, Vettoretti L, Clairet AL, Capellier G, Vivet B, Piton G. beta-lactam dosing at the early phase of sepsis: Performance of a pragmatic protocol for target concentration achievement in a prospective cohort study. J Crit Care. 2022 Feb;67:141-146. doi: 10.1016/j.jcrc.2021.10.023. Epub 2021 Nov 9.

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2016
• Primary Completion (Actual): October 4, 2018
• Study Completion (Actual): October 4, 2018

Study Registration Dates

• First Submitted: June 29, 2016
• First Submitted That Met QC Criteria: June 29, 2016
• First Posted (Estimated): July 1, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 15, 2025
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Septic shock, Beta Lactams, Extended infusion, PK/PD
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; beta-Lactamase Inhibitors; Meropenem; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefepime; Piperacillin
• Other Study ID Numbers: 15/493

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED