AAC Accepts, published online ahead of print on 19 October 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00860-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Patients with Long-term Oral Carriage Harbor High-persister Mutants of C. albicans

Michael D. LaFleur, Qingguo Qi, and Kim Lewis^*

Antimicrobial Discovery Center and Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115; and School of Stomatology, Shandong University, 44-1# Wenhuaxi Road, Jinan, China 250012

^* To whom correspondence should be addressed. Email: k.lewis{at}neu.edu.

Fungal biofilms produce a small number of persister cells which can tolerate high concentrations of fungicidal agents. Persisters form upon attachment to surface, an important step in Candida pathogenesis. Periodic application of antimicrobial agents may select for strains with increased levels of persister cells. In order to test this possibility, 150 isolates of C. albicans and C. glabrata were obtained from cancer patients at high risk for developing oral candidiasis, who had been treated with topical chlorhexidine once a day. Persister levels were measured by exposing biofilms growing in wells of microtiter plates to high concentrations of amphotericin B and plating for survivors. Persister levels of the isolates varied from 0.2 to 9% and strains isolated from patients with long-term carriage had high levels of persisters. High persister strains were isolated from every patient with Candida carriage of more than 8 consecutive weeks and no patients with transient carriage. All of the high persister isolates had a wild type MIC to amphotericin B, indicating that these strains were drug tolerant mutants, rather than resistant. Biofilms of the majority of high persister strains also showed an increased tolerance to chlorhexidine, and had the same MIC to this antimicrobial as the wild type. This study suggests persister cells are clinically relevant, and antimicrobial therapy selects for high persister strains in vivo. Drug tolerance of persisters may be a critical, but overlooked component responsible for antimicrobial drug failure and relapsing infections.