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Azole resistance in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis

S J Howard1, A C Pasqualotto, D W Denning

  • 1The University of Manchester, The Manchester Academic Health Science Centre, Manchester, UK. susan.j.howard@manchester.ac.uk

Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases
|August 14, 2009
PubMed

Insights

Long-term azole antifungal therapy for aspergillosis can lead to drug resistance. This study reports azole-resistant Aspergillus fumigatus in two patients, highlighting the risk of treatment failure and the need for monitoring.

Area of Science:

  • Mycology
  • Infectious Diseases
  • Pharmacology

Background:

  • Oral azole antifungals are a cornerstone for treating various forms of aspergillosis, including allergic bronchopulmonary aspergillosis (ABPA).
  • Prolonged antifungal administration raises concerns regarding the potential development of azole resistance in Aspergillus species.
  • Innate immune defects can predispose patients to chronic Aspergillus-related conditions like ABPA and Aspergillus bronchitis.

Observation:

  • Two patients with ABPA and Aspergillus bronchitis, linked to immune defects, developed resistance to itraconazole and voriconazole, with decreased susceptibility to posaconazole.
  • Initial azole-susceptible Aspergillus fumigatus strains in one patient were replaced by genetically distinct azole-resistant strains, potentially due to sub-therapeutic itraconazole levels.
  • Azole resistance mechanisms included a Cyp51A L98H mutation and increased cyp51A promoter expression via tandem repeats in one patient, while the other showed no Cyp51A mutation.

Findings:

  • Development of itraconazole and voriconazole resistance in Aspergillus fumigatus isolates from two immunocompromised patients.
  • Identification of a specific Cyp51A mutation (L98H) and promoter alterations contributing to azole resistance.
  • Successful treatment of resistant infections with posaconazole, achieving therapeutic plasma levels and leading to eradication and replacement by susceptible strains.

Implications:

  • Highlights the clinical risk of azole resistance emergence during long-term antifungal therapy for aspergillosis.
  • Underscores the importance of therapeutic drug monitoring and susceptibility testing to guide treatment decisions.
  • Suggests posaconazole as a viable alternative for managing azole-resistant Aspergillus infections, even in complex cases.

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