Effectiveness and Safety of Empirical Antifungal Strategies in Critically Ill, Non-Neutropenic Patients: A Multi-Center Observational Study

Shahad A Albakri,1 Ahmad K Aljabri,2 Emad A Alharbi,2 Buthainah B Alammash,1 Salman A Alabdali,2 Maha F Alahmadi,1 Nawaf T Almutairi,1 Hindi S Alharbi,2 Fahad Alzahrani,3 Faris S Alnezary3 1Pharmaceutical Care Department, King Fahad Hospital, Ministry of Health, Madinah, Saudi Arabia; 2Pharmaceutical Care Department, King Salman bin Abdulaziz Medical City, Madinah Health Cluster, Madinah, Saudi Arabia; 3Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, 41477, Saudi ArabiaCorrespondence: Faris S Alnezary, Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, 41477, Saudi Arabia, Email [email protected]: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in critically ill patients. While early empirical antifungal therapy (EAFT) is a common strategy to combat diagnostic delays, the choice of agent and its overall benefit remain debated. This study evaluates the clinical outcomes and safety profiles associated with different empirical antifungal strategies in non-neutropenic ICU patients with suspected IFIs.Methods: A retrospective observational study was conducted on 324 non-neutropenic patients who received EAFT in eight ICUs from 2015 to 2023. Data on demographics, comorbidities, treatments, and outcomes were collected from medical records. The primary endpoints were survival, clinical improvement, and incidence of confirmed fungal infection. Mortality predictors were identified using multivariate logistic regression.Results: Among the 324 patients, the overall in-hospital mortality rate was 78.70%. Mortality was significantly lower in the group receiving fluconazole (63.16%) compared to those receiving caspofungin (76.80%), liposomal amphotericin B (75%), and anidulafungin (84.83%) (p = 0.028). Regarding safety, fluconazole demonstrated the lowest incidence of hepatotoxicity (13.16%) and nephrotoxicity (7.89%). In contrast, anidulafungin was associated with the highest rate of hepatotoxicity (33.79%, p=0.035), and caspofungin was associated with the highest rate of nephrotoxicity (39.52%, p=0.003). Only 17.28% of patients achieved clinical improvement. After the initiation of EAFT, a fungal infection was confirmed in only 7.41% of patients.Conclusion: Fluconazole-based EAFT was associated with lower mortality rates compared to other antifungal agents. However, with a confirmed fungal infection rate of only 7.41%, these findings suggest that current patient selection for EAFT is suboptimal. The high overall mortality, coupled with the low infection confirmation rate, underscores the need for improved risk stratification tools to ensure the judicious use of antifungals in this critically ill population.Keywords: empirical antifungal therapy, invasive fungal infections, intensive care unit, mortality, fluconazole