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

Autor(es)

Rosenberg, Alexander ^[1] ; Ene, V, Iuliana ; Bibi, Maayan ^[1] ; Zakin, Shiri ^[1] ; Segal, Ella Shtifman ^[1] ; Ziv, Naomi ^[2] ; Dahan, Alon M. ^[1] ; Colombo, Arnaldo Lopes ^[3] ; Bennett, Richard J. ^[4] ; Berman, Judith ^[1]

Afiliação do(s) autor(es)

^[1] Tel Aviv Univ, Sch Mol Cell Biol & Biotechnol, IL-6997801 Ramat Aviv - Israel

^[2] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 - USA

^[3] Univ Fed Sao Paulo, Dept Med, BR-04021001 Sao Paulo - Brazil

^[4] Ene, Iuliana, V, Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 - USA

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 9, JUN 25 2018.
• Citações Web of Science: 20

Resumo

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. (AU)

• Processo FAPESP: 17/02203-7 - Rede multidisciplinar internacional para caracterização de aspectos microbiológicos e da história natural de Infecções Fúngicas Invasivas (IFI) por espécies do gênero Candida
• Beneficiário: Arnaldo Lopes Colombo
• Modalidade de apoio: Auxílio à Pesquisa - Temático