Patterns of Antifungal Resistance in Adult Patients with Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials

Importance: Antifungal resistance has been shown to impact treatment success, but research analyzing antifungal resistance is scarce. Objective: To evaluate changes in antifungal resistance over time. Design, Setting, and Participants: Ad hoc analysis of 3 randomized clinical trials including consecutive patients 18 years and older presenting with smear-positive fungal ulcers to Aravind Eye Hospitals in Madurai, Coimbatore, Pondicherry, and Tirunelveli in South India who participated in 1 of 3 clinical trials: the Mycotic Ulcer Treatment Trials (MUTT) I (2010 to 2011) or II (2010 to 2015) or the Cross-Linking Assisted Infection Reduction (CLAIR) trial (2016 to 2018). This post hoc analysis was designed in March 2021 and data were analyzed in May and November 2021. Interventions: Minimum inhibitory concentration (MIC) of natamycin and voriconazole was determined from corneal cultures obtained using standardized methods outlined in the Clinical and Laboratory Standards Institute. Main Outcomes and Measures: The primary outcome of this post hoc analysis was MIC of natamycin and voriconazole. Results: A total of 890 fungal isolates were obtained from 651 patients (mean [SD] age, 49.6 [13.0]; 191 [43.3%] female) from 2010 to 2018. MICs were available for 522 samples in 446 patients. Fungal isolates overall demonstrated a 1.02-fold increase per year in voriconazole resistance as measured by MICs (95% CI, 1.00-1.04; P =.06). In subgroup analyses, Fusarium species demonstrated a 1.04-fold increase in voriconazole resistance per year (95% CI, 1.00-1.06; P =.01). Fungal isolates showed a 1.06-fold increase in natamycin resistance per year overall (95% CI, 1.03-1.09; P <.001). Fusarium species had a 1.06-fold increase in natamycin resistance (95% CI, 1.05-1.08; P <.001), Aspergillus had a 1.09-fold increase in resistance (95% CI, 1.05-1.15; P <.001), and other filamentous fungi had a 1.07-fold increase in resistance to natamycin per year (95% CI, 1.04-1.10; P <.001). Conclusions and Relevance: This post hoc analysis suggests that susceptibility to both natamycin and voriconazole may be decreasing over the last decade in South India. While a trend of increasing resistance could impact treatment of mycoses in general and infectious fungal keratitis in particular, further study is needed to confirm these findings and determine their generalizability to other regions of the world. Trial Registration: ClinicalTrials.gov Identifiers: NCT00996736 and NCT02570321.