Personalized Optimization of Antibiotic Therapy in Pulmonary Sepsis Critically Ill Patients Through Application of Rapid Microbiological Diagnostic Technologies and Pharmacokinetic/Pharmacodynamic Modelling
- Conditions
- Pulmonary Sepsis
- Registration Number
- NCT06956053
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 658
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Rate of treatment failure Up to 10 days after inclusion It includes treatment failure that occurred early (≤72 hours) or late (\>72 hours), or at both times.
- Secondary Outcome Measures
Name Time Method Time to availability of pathogen Up to 180 days ID/AST, MICs and conventional results
Ventilator free days At day 28 Vasopressor free days At day 90 ICU length of stay up to day 180 Hospital length of stay up to day 180 Number of serious adverse events up to day 180 As per MEDDRA classification
Time to achieve targeted optimized therapy Up to 180 days It includes both pathogen-appropriate drug selection and appropriate dosing with plasma ABX concentration achieving PK/PD targets.
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 Up to 180 days At hospital discharge
All Cause Mortality At day 180 SOFA score assessment Up to 28 days Evolution of organ failures by daily SOFA score assessment
Organ-failure free days (SOFA<6) Up to day 28 Proportion of patients requiring invasive mechanical ventilation At day 90 Duration of invasive mechanical ventilation