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

Alexander Rosenberg, Iuliana V. Ene, Maayan Bibi, Shiri Zakin, Ella Shtifman Segal, Naomi Ziv, Alon M. Dahan, Arnaldo Lopes Colombo, Richard J. Bennett and Judith Berman ()
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Alexander Rosenberg: Tel Aviv University
Iuliana V. Ene: Brown University
Maayan Bibi: Tel Aviv University
Shiri Zakin: Tel Aviv University
Ella Shtifman Segal: Tel Aviv University
Naomi Ziv: University of California
Alon M. Dahan: Tel Aviv University
Arnaldo Lopes Colombo: Federal University of São Paulo
Richard J. Bennett: Brown University
Judith Berman: Tel Aviv University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy.

Date: 2018
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DOI: 10.1038/s41467-018-04926-x

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