Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for......

Roberts, J.A., Sime, F.B., Lipman, J. et al. Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units—the SAFE-ICU study. Intensive Care Med (2025). https://doi.org/10.1007/s00134-025-07793-5

Summary of "Are Contemporary Antifungal Doses Sufficient for Critically Ill Patients? Outcomes from an International, Multicenter Pharmacokinetics Study for Screening Antifungal Exposure in Intensive Care Units—The SAFE-ICU Study"

Abstract

This study evaluates the adequacy of current antifungal dosing regimens in critically ill patients by analyzing pharmacokinetic/pharmacodynamic (PK/PD) target attainment across multiple antifungal agents. Conducted in 30 ICUs across 12 countries, the study found that while prophylactic antifungal use often met PK/PD targets, significant variability and subtherapeutic exposures were observed in treatment settings, particularly with voriconazole, posaconazole, micafungin, and amphotericin B. The findings highlight the need for individualized dosing strategies and therapeutic drug monitoring (TDM) to optimize antifungal therapy in critically ill patients.

Key Points

1. 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%).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.

Conclusion

The SAFE-ICU study highlights significant variability in antifungal PK/PD target attainment in critically ill patients, demonstrating that contemporary dosing regimens are often inadequate. Improved strategies incorporating TDM, individualized dosing, and pathogen-specific MIC assessment are necessary to optimize antifungal efficacy and reduce mortality in ICU settings.

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Discussion Questions

1. How can therapeutic drug monitoring be better integrated into ICU protocols to optimize antifungal dosing?
2. What modifications to current antifungal dosing strategies would improve target attainment in critically ill patients?
3. How can future research address the variability in antifungal pharmacokinetics to refine dosing recommendations?

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