International Multicenter Study Reveals Insufficient Antifungal Dosing in Critically Ill Patients

Academic Background

Invasive fungal infections are common and serious nosocomial infections, particularly among patients in the intensive care unit (ICU), where they are associated with high morbidity and mortality rates. Timely and appropriate antifungal therapy is a key factor in improving patient outcomes. However, pharmacokinetics (PK) in critically ill patients often undergo significant changes due to factors such as organ dysfunction, fluid shifts, and concomitant medications, leading to standard doses failing to achieve optimal therapeutic effects. This issue is especially prominent with antifungal drugs, many of which carry significant toxicity risks, such as hepatotoxicity and nephrotoxicity. Therefore, determining the optimal dosing of antifungal drugs in critically ill patients to ensure both effective infection treatment and minimized adverse reactions has become an important topic in clinical practice.

Although there have been some studies on the pharmacokinetics of antifungal drugs in critically ill patients, most of these studies are small, single-center investigations, limiting the generalizability of their results and their guidance for clinical dosing recommendations. To address this issue, an international research team conducted a multicenter pharmacokinetic study named “SAFE-ICU” to evaluate the effectiveness of contemporary antifungal dosing in critically ill patients.

Source of the Paper

The study was jointly completed by scholars from multiple countries, with primary authors including Jason A. Roberts (University of Queensland Centre for Clinical Research), Fekade B. Sime, Jeffrey Lipman, and others. The research team encompassed 30 ICU centers across various countries and regions, including Australia, the Netherlands, Belgium, Greece, Malaysia, Spain, the United States, Italy, Hong Kong, China, and Austria. The study was published in Intensive Care Medicine in 2025, with data sourced from a prospective, open-label, multicenter pharmacokinetic study conducted between 2017 and 2018.

Research Process and Results

1. Study Design and Patient Enrollment

The SAFE-ICU study was a prospective, multicenter pharmacokinetic study aimed at evaluating the effectiveness of triazole (azoles), echinocandin (echinocandins), and polyene (polyenes) antifungal drugs in critically ill patients. The study included 339 ICU patients who were prescribed antifungal drugs for the treatment or prevention of invasive fungal infections. The median age of the patients was 62 years, the median APACHE II score was 22, and 61% were male. Antifungal therapy was primarily for treatment (80.8%), with fluconazole being the most commonly used drug (40.7%).

2. Pharmacokinetic Sampling and Analysis

Blood samples were collected at two time points during the antifungal treatment (days 1-3 and days 4-7). Three samples were taken at each time point: the first sample was collected 30 minutes after the completion of intravenous infusion, the second sample was taken 3-6 hours after the start of infusion, and the third sample was drawn within 30 minutes before the next scheduled dose. Plasma samples were analyzed for total concentration using chromatographic methods, and pharmacokinetic parameters were estimated using noncompartmental methods. The adequacy of antifungal dosing was assessed based on predefined pharmacokinetic/pharmacodynamic (PK/PD) targets.

3. Main Results

The results showed that among the 339 patients, there were a total of 349 antifungal courses. Overall, more than 80% of patients receiving prophylactic treatment achieved target exposure for most drugs. However, among patients receiving treatment, the target exposure rates for voriconazole, posaconazole, micafungin, and amphotericin B were relatively low, at 57.1%, 63.2%, 64.1%, and 41.7%, respectively. This indicates that contemporary dosing regimens failed to effectively achieve the exposure levels necessary for treatment with these drugs.

Additionally, the study found that infection sites (e.g., vascular access, lungs, skin, and central nervous system abscesses) were associated with lower target exposure rates and higher clinical failure rates. Patients using vasopressors or inotropes had higher target exposure rates, but the specific mechanisms behind this phenomenon require further investigation. The study also found that higher Sequential Organ Failure Assessment (SOFA) scores were significantly associated with clinical failure rates and 30-day mortality.

4. Conclusions and Implications

This study was the first to systematically assess the pharmacokinetic characteristics and target exposure rates of antifungal drugs in critically ill patients on an international scale. The results indicate that contemporary antifungal dosing is generally insufficient in critically ill patients, especially for voriconazole, posaconazole, micafungin, and amphotericin B. This finding underscores the necessity of optimizing antifungal drug dosing in critically ill patients, particularly for individualized dose adjustments and therapeutic drug monitoring (TDM) in high-risk patients.

Moreover, the study pointed out that future research should focus more on the initial loading doses of antifungal drugs to ensure early achievement of effective exposure levels. Additionally, collecting minimum inhibitory concentration (MIC) data for pathogens will help more accurately evaluate the target exposure rates of antifungal drugs and patient outcomes.

Highlights of the Study

1. Multicenter Large-Sample Design: This study was the first to include 30 ICU centers from 12 countries internationally, with a large sample size, providing high generalizability of the results.
2. Pharmacokinetic Evaluation: Through rigorous pharmacokinetic sampling and analysis, the study revealed significant variability and insufficiency in antifungal drug exposure in critically ill patients.
3. Individualized Dosing Recommendations: The study results provide important evidence for individualized dose adjustments of antifungal drugs in critically ill patients, especially for optimizing treatment in high-risk patients.
4. Promotion of Therapeutic Drug Monitoring: The study emphasizes the importance of therapeutic drug monitoring in antifungal treatment in critically ill patients, offering new guidance for clinical practice.

Other Valuable Information

The study also mentioned that certain antifungal drugs (e.g., voriconazole) have a narrow therapeutic window, and excessive exposure may lead to toxic reactions. Therefore, while increasing the dose, careful monitoring of drug concentrations is necessary to ensure the safety and effectiveness of the treatment. Additionally, the research team called for future studies to further explore the pharmacokinetic characteristics of antifungal drugs in specific patient populations (e.g., patients receiving continuous renal replacement therapy) to optimize dosing regimens.

The SAFE-ICU study provides important scientific evidence for optimizing antifungal dosing in critically ill patients, promoting individualized treatment strategies in clinical practice.