title: Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia.
abstract: To give an indication of a fitness cost conferred by FKS mutation-associated echinocandin resistance in Candida glabrata during human infection. Six C. glabrata clinical strains sequentially isolated from blood and a hepatic abscess in a solid organ transplant recipient were analysed. The patient had received long-term azole and echinocandin therapy for invasive aspergillosis and persistent candidaemia. Minimal inhibitory concentrations were determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Molecular mechanisms of antifungal resistance were determined by sequencing hot spots of the FKS. Strain relatedness was determined using a microsatellite-based typing method. Typing analysis revealed an identical microsatellite pattern for all isolates, supporting a close relation. The first C. glabrata isolate showed wild-type phenotype (i.e. susceptibility to echinocandins and low level of azole resistance). After voriconazole therapy, the C. glabrata quickly acquired pan-azole resistance. Later, echinocandin treatment led to the emergence of a FKS2 S663P alteration and echinocandin resistance. After disruption of both azole and echinocandin therapy in favour of liposomal amphotericin B, C. glabrata isolates regained full susceptibility to echinocandin and lost the FKS2 S663P alteration while nonetheless maintaining their pan-azole resistance. Our clinical report supports the potential existence of a fitness cost conferred by FKS mutation in C. glabrata, as disruption of treatment led to a rapid disappearance of the resistant clone. This suggests that a more restricted use and/or a discontinuous administration of echinocandins may limit the spread of clinical resistance to this class.
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Imbert
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Castain
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Réanimation Chirurgicale Polyvalente, Département d'Anesthésie Réanimation, F-75013, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Pons
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Jacob
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Meyer
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Palous
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Réanimation Chirurgicale Polyvalente, Département d'Anesthésie Réanimation, F-75013, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Vezinet
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Réanimation Chirurgicale Polyvalente, Département d'Anesthésie Réanimation, F-75013, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Langeron
authors.affiliation: AP-HP, Groupe Hospitalier Saint-Antoine, Service de Parasitologie Mycologie, F-75012, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Hennequin
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Réanimation Chirurgicale Polyvalente, Département d'Anesthésie Réanimation, F-75013, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Monsel
authors.affiliation: AP-HP, Groupe Hospitalier La Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France. Electronic address: arnaud.fekkar@aphp.fr.
authors.forename: A
authors.initials: A
authors.lastname: Fekkar
mesh_terms: D001393:Azoles / Q000494:pharmacology / Q000627:therapeutic use*; D041221:Candida glabrata / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D058387:Candidemia / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use*; D056084:Genetic Fitness; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D016533:Mycological Typing Techniques; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D001393:Azoles; D054714:Echinocandins
keywords: Amphotericin B; Anidulafungin; Antifungal resistance; Azoles; Candidaemia; Caspofungin; Echinocandin; Micafungin