Abstract
Purpose
Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients.
Methods
In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets.
Results
We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51–70) years, median APACHE II score 22 (IQR, 17–28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%).
Conclusion
This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist.
Key Points
- Variability in Antifungal Target Attainment: The study demonstrated significant differences in PK/PD target attainment across antifungal agents, with low target attainment observed in patients receiving voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%), and amphotericin B (41.7%).
- Impact of Pharmacokinetics in Critical Illness: Altered pharmacokinetics in critically ill patients, driven by factors such as organ dysfunction, fluid shifts, and concurrent medications, can lead to unpredictable drug exposures and suboptimal therapeutic outcomes.
- Differences Between Prophylaxis and Treatment: Prophylactic antifungal dosing generally resulted in higher target attainment (>80% in most cases), whereas treatment regimens demonstrated more variability, with some agents achieving subtherapeutic levels.
- Antifungal Dosing Inadequacy: Standard dosing regimens often failed to reach the predefined PK/PD targets in critically ill patients, indicating that current dosing strategies may need revision to ensure effective therapeutic exposure.
- Influence of Site of Infection: Patients with infections outside of the blood, intra-abdominal, and urinary tract sites had lower target attainment and increased rates of clinical failure, suggesting that infection location plays a role in antifungal efficacy.
- Association with Organ Failure and Mortality: Higher Sequential Organ Failure Assessment (SOFA) scores correlated with increased clinical failure and 30-day mortality, emphasizing the need for optimized antifungal management in critically ill patients.
- Significance of Therapeutic Drug Monitoring (TDM): Given the wide interpatient variability in antifungal pharmacokinetics, TDM is crucial in ensuring that drug exposures remain within therapeutic ranges while minimizing toxicity risks.
- Dosing Challenges with Azoles and Echinocandins: Fluconazole demonstrated better target attainment compared to voriconazole and posaconazole, which showed significant treatment failures. Similarly, micafungin and anidulafungin exhibited suboptimal exposures in a subset of patients.
- Need for Individualized Dosing Approaches: The study suggests that weight-based and severity-adjusted dosing strategies may be necessary to improve antifungal efficacy, particularly in ICU settings with altered pharmacokinetics.
- Global Implications for Antifungal Therapy: The findings underscore the importance of reassessing antifungal dosing guidelines for critically ill patients worldwide, with a focus on individualized, PK-guided dosing regimens to improve patient outcomes.
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