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Drug resistance and tolerance in fungi

An Author Correction to this article was published on 29 June 2020

Abstract

Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial proportion of patients do not respond to therapy despite being infected with fungi that are susceptible to the drug. The discordance between overall treatment outcome and low levels of clinical resistance may be attributable to antifungal drug tolerance. In this Review, we define and distinguish resistance and tolerance and discuss the current understanding of the molecular, genetic and physiological mechanisms that contribute to those phenomena. Distinguishing tolerance from resistance might provide important insights into the reasons for treatment failure in some settings.

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Fig. 1: Phenotypic characteristics and pathways required for antifungal tolerance.

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Acknowledgements

The authors thank M. Ralser, D. Jarosz and members of the Berman laboratory for helpful comments, and S. Everson, Iuliana Ene, Brown University, Anton Levitan, Tel-Aviv University, Aleeza C. Gerstein, University of Manitoba and M. Hajooj for help with illustrations. Work in the authors’ laboratories was supported by the European Research Council (RAPLODAPT 340087) and the Israel Science Foundation (grant number 997/18) (J.B.), and by the National Institutes of Health (1R01AI125094) (D.J.K.).

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Candida Genome Database: http://www.candidagenome.org/

Supplementary information

Glossary

Candidaemia

Candidaemia is a candidal infection of the blood stream.

Susceptibility

Sensitivity to a drug, arresting growth (static drugs) and/or killing cells (cidal drugs).

Fraction of growth

A measure of tolerance based on assays performed on a solid medium. Measured at 48 h, the growth within the zone of inhibition (and thus above the minimum inhibitory concentration) is estimated as a proportion of total growth possible outside the zone of inhibition.

Supra-MIC growth

(SMG). A measure of tolerance based on assays performed in a liquid medium. Growth at concentrations above the minimum inhibitory concentration is estimated as a proportion of the total growth without a drug. SMG provides a quantitative measure of growth similar to some measures of trailing growth.

Phenotypic heterogeneity

The expression of different phenotypes in different cells within an isogenic population of cells. For example, some fungal cells grow whereas other sister cells do not grow (or grow too slowly to be detected) in the presence of an antifungal drug.

Fungistatic drugs

Drugs that inhibit growth but do not necessarily kill a majority of the cell population at concentrations at or above the minimum inhibitory concentration.

Heteroresistance

A clinical term for isolates that contain small subpopulations of cells (generally <1%) that have the ability to grow at drug concentrations that are at least 8× the minimum inhibitory concentration for the vast majority of susceptible cells in the population.

Trailing growth

Generally defined as reduced but persistent visible growth of Candida spp. at fluconazole concentrations above the minimum inhibitory concentration (MIC). Trailing has also been described as an increase in the MIC during growth beyond 24 h (the standard end point for MIC measurements for Candida spp.) and can be measured as the residual growth in the presence of fluconazole concentrations above the MIC. Trailing was quantified in a recent study as the percentage of residual yeast growth at fluconazole concentrations above the MIC in each well and mean trailing as the geometric mean of trailing observed in all of the wells above the MIC.

Paradoxical growth

Also referred to as the Eagle effect. The ability of a fungal isolate to reconstitute growth in the presence of high drug concentrations, but being fully susceptible at lower concentrations. Paradoxical growth appears with a delay of one to several days, but resembles growth in the absence of the drug. Paradoxical growth has been reported primarily for echinocandins.

Adjuvants

A drug that potentiates the effect of an anti-infective, but is not an anti-infective on its own.

Fungicidal activity

Drugs with fungicidal activity reduce a population of cells by >99.9% or 3 log10 units at a concentration equal to or greater than the minimum inhibitory concentration.

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Berman, J., Krysan, D.J. Drug resistance and tolerance in fungi. Nat Rev Microbiol 18, 319–331 (2020). https://doi.org/10.1038/s41579-019-0322-2

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