Voriconazole is preferred over fluconazole for invasive aspergillosis. The structural feature of Aspergillus that makes it intrinsically resistant to fluconazole but susceptible to voriconazole is:
- A Aspergillus CYP51 (lanosterol 14-alpha demethylase) has different amino acid composition with lower fluconazole binding affinity ✓
- B Aspergillus lacks the ergosterol biosynthetic pathway targeted by azoles
- C Aspergillus has high expression of CDR efflux pumps that expel fluconazole but not voriconazole
- D Aspergillus hyphae have a thicker cell wall preventing fluconazole penetration
Correct answer: A. Aspergillus CYP51 (lanosterol 14-alpha demethylase) has different amino acid composition with lower fluconazole binding affinity
Explanation
Aspergillus species possess a CYP51A (14-alpha-sterol demethylase) enzyme with structural differences in the binding pocket compared to Candida CYP51. Fluconazole's binding affinity to Aspergillus CYP51 is very low due to these differences, resulting in intrinsic resistance. Voriconazole has a wider spectrum with a bulkier triazole ring and side chain modifications (methyltetrazole) that allow it to fit the Aspergillus CYP51 active site effectively. This is why voriconazole is first-line for invasive aspergillosis.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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