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Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia

Alexander Rosenberg1, Iuliana V Ene2, Maayan Bibi1

  • 1School of Molecular Cell Biology and Biotechnology, Tel Aviv University, 6997801, Ramat Aviv, Israel.

Nature Communications
|June 27, 2018
PubMed

Insights

Antifungal tolerance, a measure of fungal growth above the minimal inhibitory concentration (MIC), is a distinct trait from resistance. This study shows tolerance predicts patient response to fluconazole therapy.

Area of Science:

  • Mycology
  • Pharmacology
  • Infectious Diseases

Background:

  • Antifungal tolerance, defined as fungal growth at drug concentrations above the minimal inhibitory concentration (MIC), is often overlooked in clinical practice.
  • Current understanding and quantification of antifungal tolerance, particularly in Candida albicans, remain limited.
  • Tolerance is mechanistically distinct from antifungal resistance and may influence treatment outcomes.

Purpose of the Study:

  • To quantify antifungal tolerance in Candida albicans isolates.
  • To investigate the relationship between tolerance, drug accumulation, and resistance.
  • To evaluate the clinical relevance of antifungal tolerance in predicting patient response to fluconazole therapy.

Main Methods:

  • Quantification of Candida albicans growth above the MIC to define and measure antifungal tolerance.
  • Assessment of intracellular drug accumulation in relation to tolerance levels.
  • Evaluation of adjuvant drug combinations with fluconazole in an invertebrate infection model.
  • Analysis of patient isolates from persistent candidemia to correlate tolerance with clinical outcomes.

Main Results:

  • Antifungal tolerance in Candida albicans is a distinct phenotype characterized by slow-growing subpopulations that are more stress-tolerant.
  • Tolerance inversely correlates with intracellular antifungal drug accumulation.
  • Adjuvant drugs reduce tolerance without impacting resistance, improving treatment efficacy in an infection model.
  • Isolates from patients with persistent candidemia exhibit higher tolerance than those easily cleared by fluconazole.

Conclusions:

  • Antifungal tolerance is a critical factor in Candida albicans infections, independent of resistance.
  • Tolerance influences the efficacy of fluconazole therapy and can be modulated by adjuvant drugs.
  • Quantifying antifungal tolerance may aid in predicting patient responses to antifungal treatments, particularly fluconazole.

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