title: Effect of caspofungin and micafungin in combination with farnesol against Candida parapsilosis biofilms.
abstract: The in vitro activities of caspofungin and micafungin were determined with and without farnesol against Candida parapsilosis biofilms. Drug interactions were examined using the XTT colorimetric assay-based broth microdilution chequerboard method. Drug-drug interactions were assessed utilising the FICI, Bliss independence models and time-kill experiments. Median sessile MICs of five C. parapsilosis clinical isolates ranged between 32-256 mg/L, 16-512 mg/L and >300 μM for caspofungin, micafungin and farnesol, respectively. Median MICs for caspofungin and micafungin in combination with farnesol showed 8-64- and 4-64-fold decreases, respectively. Paradoxical growth noticed with both echinocandins was eliminated by farnesol. Based on FICIs for sessile clinical isolates, synergism was observed for caspofungin (range of median FICIs, 0.155-0.5) and micafungin (range of median FICIs, 0.093-0.5). Concordantly, MacSynergy analysis and global fitting of non-linear regression based on a Bliss independence models also showed synergism for caspofungin and micafungin. In line with FICI findings and the Bliss independence model, synergistic interactions were confirmed by time-kill experiments. The metabolic activity of fungal cells was significantly inhibited by caspofungin+farnesol at all three tested combinations (4 mg/L+75 μM, 8 mg/L+75 μM and 16 mg/L+75 μM) between 3 and 24 h compared with the control (P<0.05-0.001). Significant inhibition was observed for micafungin+farnesol between 3 and 12h (P<0.001) but not at 24 h. Despite the favourable effect of farnesol in combination with echinocandins, further in vivo studies are needed to confirm its therapeutic advantage in catheter-associated infections caused by C. parapsilosis.
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary. Electronic address: kovacs.renato@med.unideb.hu.
authors.forename: Renátó
authors.initials: R
authors.lastname: Kovács
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: Aliz
authors.initials: A
authors.lastname: Bozó
authors.affiliation: Department of Pharmacology and Pharmacodynamics, University of Debrecen, Debrecen, Hungary.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gesztelyi
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: Marianna
authors.initials: M
authors.lastname: Domán
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Kardos
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: Fruzsina
authors.initials: F
authors.lastname: Nagy
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Tóth
authors.affiliation: Department of Medical Microbiology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Majoros
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D058387:Candidemia / Q000382:microbiology; D000077336:Caspofungin; D003124:Colorimetry; D004347:Drug Interactions; D054714:Echinocandins / Q000494:pharmacology*; D005204:Farnesol / Q000494:pharmacology*; D005562:Formazans / Q000032:analysis; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D000077551:Micafungin; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005562:Formazans; D055666:Lipopeptides; D005204:Farnesol; C059088:1,5-bis(2-methoxy-4-nitro-5-sulfophenyl)-3-((phenylamino)carbonyl)formazan; D000077336:Caspofungin; D000077551:Micafungin
keywords: Drug interaction; Echinocandin; FICI; Fractional inhibitory concentration index; Non-linear regression; Time–kill experiment