title: Combination of voriconazole and anidulafungin for treatment of triazole-resistant aspergillus fumigatus in an in vitro model of invasive pulmonary aspergillosis.
abstract: Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.
authors: School of Translational Medicine, University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, and Foundation Trust, Manchester, United Kingdom.
authors: Adam R
authors: AR
authors: Jeans
authors: Susan J
authors: SJ
authors: Howard
authors: Zaid
authors: Z
authors: Al-Nakeeb
authors: Joanne
authors: J
authors: Goodwin
authors: Lea
authors: L
authors: Gregson
authors: Peter A
authors: PA
authors: Warn
authors: William W
authors: WW
authors: Hope
mesh_terms: D000077612:Anidulafungin; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D054714:Echinocandins / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000382:microbiology*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D011650:Pulmonary Alveoli; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D011743:Pyrimidines; D014230:Triazoles; D000077612:Anidulafungin; D065819:Voriconazole