Predictors for the Development of Invasive Infection of Fluconazole Non-Susceptible or Echinocandin Non-Susceptible Candida Species Across the Veterans Health Administration

Background: Antifungal-resistant Candida species have become increasingly prevalent in recent years, posing significant therapeutic challenges in the inpatient setting. Despite their clinical relevance, comprehensive data evaluating risk factors for the development of invasive infections caused by Candida sp. with antifungal resistance are limited. Objective: This study aims to identify independent predictors for the development of invasive clinical infections caused by fluconazole-resistant or echinocandin-resistant Candida sp. in hospitalized veterans across the United States Veterans Health Administration. Methods: This retrospective, observational, nationwide analysis included adults ≥18 years admitted to any Veterans Affairs Medical Center between January 1, 2009, and September 30, 2024, with culture-positive or rapid diagnostic test-confirmed invasive Candida sp. infection from otherwise-sterile sites. Data were gathered on baseline demographics, baseline laboratory data, comorbid conditions, and exposure to antibacterial agents, antifungal agents, β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, and immunosuppressant drug therapy. Univariate and multivariate logistic regression models were used to assess associations between clinical variables and the development of invasive fluconazole-resistant and echinocandin-resistant Candida sp. infections. Results: Eligible cases were found from 25 Veterans Affairs Medical Center facilities; 1651 episodes had available fluconazole susceptibility data, and 1117 episodes had echinocandin susceptibility data. Fluconazole non-susceptibility was independently associated with at least 7 days of recent exposure to either fluconazole or an echinocandin, among a few other variables. Echinocandin resistance, while less common, was strongly linked to the receipt of dialysis, prolonged Gram-positive antibacterial exposure, and any prior antifungal use. Conclusions and Relevance: These findings can inform antifungal stewardship efforts to curb the rise of resistant Candida sp.