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Fluconazole tolerance in clinical isolates of Cryptococcus neoformans
K Venkateswarlu1, M Taylor, N J Manning
1Department of Molecular Biology and Biotechnology, The University of Sheffield, United Kingdom.
Antimicrobial Agents and Chemotherapy
|April 1, 1997
Summary
Cryptococcus neoformans isolates show varying fluconazole resistance. Mechanisms include altered target enzyme affinity and reduced drug accumulation, impacting treatment strategies.
Area of Science:
- Medical Mycology
- Antifungal Drug Resistance
- Biochemistry
Background:
- Cryptococcus neoformans is an opportunistic fungal pathogen.
- Fluconazole is a key antifungal medication.
- Understanding drug resistance is crucial for effective treatment.
Purpose of the Study:
- To investigate the biochemical mechanisms of fluconazole tolerance in Cryptococcus neoformans isolates.
- To differentiate between low-level and high-level fluconazole resistance.
Main Methods:
- Determining Minimum Inhibitory Concentrations (MICs) for fluconazole.
- Quantifying ergosterol levels in fungal isolates.
- Assessing sterol 14alpha-demethylase enzyme affinity and cellular fluconazole content.
Main Results:
- Isolates exhibited a range of fluconazole resistance (3- to 200-fold higher MICs).
- Low ergosterol levels correlated with amphotericin B resistance.
- Low-level resistance linked to altered sterol 14alpha-demethylase affinity.
- High-level resistance associated with decreased intracellular fluconazole accumulation.
Conclusions:
- Fluconazole resistance in Cryptococcus neoformans is multifactorial.
- Altered enzyme affinity and reduced drug uptake are key resistance mechanisms.
- These findings inform the development of improved antifungal therapies.