title: Evaluation of antifungal combination against Cryptococcus spp.
abstract: The second cause of death among systemic mycoses, cryptococcosis treatment represents a challenge since that 5-flucytosine is not currently available in Brazil. Looking for alternatives, this study evaluated antifungal agents, alone and combined, correlating susceptibility to genotypes. Eighty Cryptococcus clinical isolates were genotyped by URA5 gene restriction fragment length polymorphism. Antifungal susceptibility was assessed following CLSI-M27A3 for amphotericin (AMB), 5-flucytosine (5FC), fluconazole (FCZ), voriconazole (VRZ), itraconazole (ITZ) and terbinafine (TRB). Drug interaction chequerboard assay evaluated: AMB + 5FC, AMB + FCZ, AMB + TRB and FCZ + TRB. Molecular typing divided isolates into 14 C. deuterogattii (VGII) and C. neoformans isolates were found to belong to genotype VNI (n = 62) and VNII (n = 4). C. neoformans VNII was significantly less susceptible than VNI (P = 0.0407) to AMB; C. deuterogattii was significantly less susceptible than VNI and VNII to VRZ (P < 0.0001). C. deuterogattii was less susceptible than C. neoformans VNI for FCZ (P = 0.0170), ITZ (P < 0.0001) and TRB (P = 0.0090). The combination FCZ + TRB showed 95.16% of synergistic effect against C. neoformans genotype VNI isolates and all combinations showed 100% of synergism against genotype VNII isolates, suggesting the relevance of cryptococcal genotyping as it is widely known that the various genotypes (now species) have significant impact in antifungal susceptibilities and clinical outcome. In difficult-to-treat cryptococcosis, terbinafine and different antifungal combinations might be alternatives to 5FC.
authors.affiliation: Clinical Pathology Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Franqueline
authors.initials: F
authors.lastname: Reichert-Lima
authors.affiliation: Internal Medicine Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Ariane F
authors.initials: AF
authors.lastname: Busso-Lopes
authors.affiliation: Clinical Pathology Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Luzia
authors.initials: L
authors.lastname: Lyra
authors.affiliation: Clinical Pathology Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Isabela Haddad
authors.initials: IH
authors.lastname: Peron
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Taguchi
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Mikami
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Katsuiko
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Internal Medicine Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Maria Luiza
authors.initials: ML
authors.lastname: Moretti
authors.affiliation: Clinical Pathology Department, Faculty of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil.
authors.forename: Angelica Z
authors.initials: AZ
authors.lastname: Schreiber
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D001938:Brazil; D003453:Cryptococcosis / Q000382:microbiology*; D003454:Cryptococcus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics; D004338:Drug Combinations; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology; D005437:Flucytosine / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D058889:Molecular Typing; D009281:Naphthalenes / Q000494:pharmacology; D012150:Polymorphism, Restriction Fragment Length; D000077291:Terbinafine; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D009281:Naphthalenes; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine; D000077291:Terbinafine; D065819:Voriconazole
keywords: Cryptococcus deuterogattii; Cryptococcus gattii; Cryptococcus neoformans; RFLP, combined antifungal agents