Personalized Optimization of Antibiotic Therapy in Pulmonary Sepsis Critically Ill Patients Through Application of Rapid Microbiological Diagnostic Technologies and Pharmacokinetic/Pharmacodynamic Modelling (IDAST)

Severe community-acquired and nosocomial pneumonia are associated with substantial morbidity and mortality. Early and appropriate antimicrobial therapy (AAT) is consistently the most effective intervention for reducing mortality. Cure is most likely when pharmacokinetic (PK) / pharmacodynamics (PD) targets associated with maximum antibiotic (ABX) activity are achieved. However, the process of optimizing antibiotic therapy for critically ill patients remains a complicated challenge.

A key issue is pathogen identification (ID) with subsequent antibiotic susceptibility testing (AST) results which allow for selection of AAT. Standard laboratory procedures typically require 2-3 days to provide ID and AST results. Optimal ABX dosing/dosing intervals depend in large part on PK properties in individual patients, and antibacterial effects on the infecting bacteria (PD). Alterations in the primary PK parameters, namely volume of distribution (Vd) and clearance (CL), are commonly observed, and are the most influential parameters in determining ABX dosing and exposure. ABX dosing/dosing intervals that do not account for these features are likely to lead to suboptimal ABX exposure and therapeutic failures. Because of 48-72-hours delays in ID/AST, initial treatment is frequently inappropriate in coverage, unnecessarily broad in spectrum, and/or suboptimal in dosing.

Methods for rapid bacterial growth, ID, AST and minimum inhibitory concentration (MIC) identification were developed and are capable of quantitative ID in 1-2 hours and major AST in 6-8 hours using clinical specimens. Rapid ID of the infecting pathogen and its individual AST could significantly impact the early selection of AAT and, combined with therapeutic drug monitoring data, could be used to calculate optimized dosing regimens that are personalized for the patient in order to achieve appropriate PK/PD targets.

Hypothesis: Application of these rapid ID/AST systems, together with prospective PK/PD monitoring of antibiotic plasma concentrations, will significantly shorten time from "sample to answer" for pathogen ID/AST, enhance personalized prescribing of antibiotics, optimize the time to targeted effective and AAT, and result in decreased treatment failure.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Sepsis
• Intervention / Treatment: Diagnostic test: Rapid ID/AST method; Diagnostic test: Conventional biological methods

• Study Type: Interventional
• Enrollment (Estimated): 658
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pierre Moine, MD PhD; Phone Number: +33 1 47 10 77 82; Email: pierre.moine@aphp.fr
• Study Contact Backup: Name: Jérôme Lambert, MD PhD; Phone Number: +33 1 42 49 97 42; Email: jerome.lambert@u-paris.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients hospitalized in ICU
• 18 years of age or older
• With a pulmonary sepsis defined a s documented or suspected acute pulmonary infection (nosocomial and community-acquired pneumonia) and a SOFA score >2.
• Written Informed consent from the patient whenever possible or written ascent from next of kin whenever present at inclusion. When a patient would not be capable of consenting prior to randomization, his/her deferred consent will be gotten.

Exclusion Criteria:

• COVID-19 patients
• Severe anaphylactic beta-lactam allergy
• First measurements of prescribed antibiotic concentration (TDM) not possible within 24 hr after randomization
• Pregnancy or lactation
• Any decision of limitation of care
• Pre-existing medical condition with a life expectancy of less than 3 months
• Absence of affiliation to social security
• Patient under guardianship, curatorship and deprived of liberty

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapid ID/AST method	Diagnostic test: Rapid ID/AST method; BioFire® Film Array® Blood Culture Identification 2 BCID2 panel, bioMérieux/BioFire Diagnostics, CE marked (FDA cleared); BioFire® FilmArray® Pneumonia Panels, CE marked (FDA cleared); SPECIFIC REVEAL® Rapid Antimicrobial Susceptibility test (AST) System, bioMérieux/Specific Diagnostics, CE-IVD and -IVDR marked
Active Comparator: Conventional microbiological methods	Diagnostic test: Conventional biological methods; Usual care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of treatment failure	It includes treatment failure that occurred early (≤72 hours) or late (>72 hours), or at both times.	Up to 10 days after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital length of stay		up to day 180
Time to availability of pathogen	ID/AST, MICs and conventional results	Up to 180 days
Time to achieve targeted optimized therapy	It includes both pathogen-appropriate drug selection and appropriate dosing with plasma ABX concentration achieving PK/PD targets.	Up to 180 days
Time to antibiotic switches		Up to 180 days
Number of started, stopped, added or adjusted (escalation or de-escalation) antibiotics		Up to 180 days
Time to Aantibiotic dose adjustments to achieve PK/PD targets		Up to 180 days
All-Cause mortality	At ICU	Up to 180 days
All-Cause mortality	At hospital discharge	Up to 180 days
All Cause Mortality		At day 90
All Cause Mortality		At day 180
SOFA score assessment	Evolution of organ failures by daily SOFA score assessment	Up to 28 days
Organ-failure free days (SOFA<6)		Up to day 28
Proportion of patients requiring invasive mechanical ventilation	Duration of invasive mechanical ventilation	At day 7
Proportion of patients requiring invasive mechanical ventilation	Duration of invasive mechanical ventilation	At day 14
Proportion of patients requiring invasive mechanical ventilation	Duration of invasive mechanical ventilation	At day 28
Proportion of patients requiring invasive mechanical ventilation	Duration of invasive mechanical ventilation	At day 90
Ventilator free days		At day 28
Vasopressor free days		At day 28
Vasopressor free days		At day 90
ICU length of stay		up to day 180
Number of serious adverse events	As per MEDDRA classification	up to day 180

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): May 30, 2025
• Primary Completion (Estimated): May 30, 2028
• Study Completion (Estimated): November 30, 2028

Study Registration Dates

• First Submitted: April 25, 2025
• First Submitted That Met QC Criteria: April 25, 2025
• First Posted (Actual): May 2, 2025

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 25, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: APHP180673

Drug and device information, study documents

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