A patient undergoing hematopoietic stem cell transplantation develops breakthrough invasive fungal infection on micafungin prophylaxis. The mould cultured shows hyphae with 45° branching and parallel walls on lactophenol cotton blue. Galactomannan index is 2.5. Voriconazole is started, but the patient deteriorates. Susceptibility testing reveals elevated MIC for voriconazole. The MOST likely mechanism of resistance is:

• A Hotspot mutations in Cyp51A gene (tandem repeats TR34/L98H) conferring pan-azole resistance ✓
• B Upregulation of efflux pumps encoded by CDR1 and MDR1 genes
• C Acquisition of FKS1 hot-spot mutation reducing echinocandin sensitivity
• D Loss of ERG11 gene encoding lanosterol 14-alpha demethylase

Explanation

Cyp51A gene mutations — particularly the tandem repeat promoter mutations (TR34/L98H, TR46/Y121F/T289A) — are the predominant mechanisms of acquired pan-azole resistance in Aspergillus fumigatus. These mutations arise from environmental azole exposure (agricultural fungicides) and are detected by Cyp51A sequencing. CDR1/MDR1 efflux pumps mediate azole resistance in Candida, not Aspergillus. FKS1 hot-spot mutations cause echinocandin resistance. ERG11 mutations are relevant to Candida azole resistance. Detecting Cyp51A mutations guides therapeutic switch to liposomal amphotericin B or combination therapy.

Reference: Ananthanarayan & Paniker's Textbook of Microbiology, 11th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.