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A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive
Jason A Roberts1,2,3, Fekade Sime1, Jeffrey Lipman1,3,4
1University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Objective:
To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity.
Design Setting And Participants:
This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected.
Main Outcome Measures:
The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured.
Results And Conclusions:
This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.
Insights
This study evaluates if current antifungal drug doses provide effective levels in critically ill patients. Optimized dosing is crucial for improving survival and outcomes in patients with fungal infections.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Critical Care Medicine
- Infectious Diseases
Background:
- Adequate antifungal therapy is vital for survival in critically ill patients with fungal infections.
- Critical illness can significantly alter drug pharmacokinetics, potentially leading to suboptimal drug exposure.
- Suboptimal antifungal exposure risks treatment failure and increased toxicity in vulnerable patient populations.
Purpose of the Study:
- To determine if current antifungal drug dosing regimens achieve therapeutic exposures in critically ill patients.
- To assess the relationship between drug exposures and optimal clinical outcomes in this patient group.
- To inform the development of optimized antifungal dosing strategies for intensive care unit (ICU) patients.
Main Methods:
- An international, multicenter, observational pharmacokinetic study involving adult critically ill patients.
- Enrolled patients received various antifungal agents (fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, amphotericin B).
- Pharmacokinetic sampling occurred during two dosing intervals (days 1-3 and days 4-7), with three samples per occasion.
Main Results:
- The study describes contemporary antifungal drug dosing and achieved drug exposures in critically ill patients.
- Pharmacokinetic/pharmacodynamic (PK/PD) target exposures associated with optimal efficacy were evaluated.
- Thirty-day mortality was measured as a key clinical outcome.
Conclusions:
- Contemporary antifungal dosing may not consistently achieve exposures linked to optimal outcomes in critically ill patients.
- Findings support the need for optimized antifungal dosing algorithms tailored for critically ill populations.
- Prioritizing optimized drug dosing is essential for enhancing clinical outcomes in severe fungal infections.
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