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

Обзор

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.

Вмешательства

• Диагностический тест Rapid ID/AST method
  1. BioFire® Film Array® Blood Culture Identification 2 BCID2 panel, bioMérieux/BioFire Diagnostics, CE marked (FDA cleared) 2. BioFire® FilmArray® Pneumonia Panels, CE marked (FDA cleared) 3. SPECIFIC REVEAL® Rapid Antimicrobial Susceptibility test (AST) System, bioMérieux/Specific Diagnostics, CE-IVD and -IVDR marked
• Диагностический тест Conventional biological methods
  Usual care

Первичные конечные точки

• Rate of treatment failure [Срок оценки: Up to 10 days after inclusion]

Вторичные конечные точки (12)

• Time to availability of pathogen [Срок оценки: Up to 180 days]
• Time to achieve targeted optimized therapy [Срок оценки: Up to 180 days]
• Time to antibiotic switches [Срок оценки: Up to 180 days]
• Number of started, stopped, added or adjusted (escalation or de-escalation) antibiotics [Срок оценки: Up to 180 days]
• Time to Aantibiotic dose adjustments to achieve PK/PD targets [Срок оценки: Up to 180 days]
• All-Cause mortality [Срок оценки: Up to 180 days]
• All-Cause mortality [Срок оценки: Up to 180 days]
• All Cause Mortality [Срок оценки: At day 90]
• All Cause Mortality [Срок оценки: At day 180]
• SOFA score assessment [Срок оценки: Up to 28 days]
• Organ-failure free days (SOFA<6) [Срок оценки: Up to day 28]
• Proportion of patients requiring invasive mechanical ventilation [Срок оценки: At day 7]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT06956053 · APHP180673

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗