title: Analysis of Candida glabrata strains with reduced sensitivity to micafungin in vitro isolated from a patient with persistent Candidemia.
abstract: We report the appearance of Candida glabrata strains with reduced sensitivity during treatment with the echinocandin drug micafungin (MCF). Four C. glabrata strains were isolated from sputum, gastric juice, and blood taken from a patient during hospitalization. Two of these strains, one of which was obtained after treatment with MCF for suspected Candida pneumonia and the other of which was obtained during MCF treatment for candidemia, were isolated from blood and found to have a reduced susceptibility to MCF. These two clinical isolates showed a high minimum inhibitory concentration (MIC) for MCF, with this change in MIC being unique for MCF among established antifungal drugs. To further investigate the mechanism underlying this reduced sensitivity, an in vivo mouse infection model and in vitro enzymatic analysis were performed. MCF had little effect in the mouse disseminated infection model and enzymatic analysis showed the low affinity of MCF to the 1,3-Beta-D-glucan synthase of the clinical isolates, although the enzymes of both clinical isolates and control strain were noncompetitively inhibited by MCF. Taken together, this low affinity of MCF for the enzymes is likely to cause the reduced sensitivities. These data further indicate that MCF could induce acquired MCF-resistant strains during clinical use.
authors.affiliation: Department of Medicine, School of Medicine, Fukuoka University, Fukuoka 814-0181, Japan. takahiko.ishikawa@molbiol.umu.se
authors.forename: Takahiko
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Takata
authors.forename: Souichirou
authors.initials: S
authors.lastname: Akamatsu
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Hatakenaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Maki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeda
authors.forename: Rukako
authors.initials: R
authors.lastname: Tamai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
mesh_terms: D000368:Aged; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001831:Body Temperature; D041221:Candida glabrata / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D058387:Candidemia / Q000188:drug therapy / Q000382:microbiology*; D004195:Disease Models, Animal; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use; D017809:Fatal Outcome; D005260:Female; D005964:Glucosyltransferases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D055666:Lipopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D000077551:Micafungin; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077551:Micafungin