TY - JOUR

T1 - In vivo efficacy and pharmacokinetics of voriconazole in an animal model of dermatophytosis

AU - Saunte, D M

AU - Simmel, F

AU - Frimodt-Moller, N

AU - Stolle, L B

AU - Lyngsøe Svejgaard, Else

AU - Haedersdal, M

AU - Kloft, Charlotte

AU - Arendrup, M C

PY - 2007/9

Y1 - 2007/9

N2 - The standard treatment for tinea capitis caused by Microsporum species for many years has been oral griseofulvin, which is no longer universally marketed. Voriconazole has been demonstrated to inhibit growth of Microsporum canis in vitro. We evaluated the efficacy and tissue pharmacokinetics of oral voriconazole in a guinea pig model of dermatophytosis. Guinea pigs (n = 16) were inoculated with M. canis conidia on razed skin. Voriconazole was dosed orally at 20 mg/kg/day for 12 days (days 3 to 14). The guinea pigs were scored clinically (redness and lesion severity) and mycologically (microscopy and culture) until day 17. Voriconazole concentrations were measured day 14 in blood, skin biopsy specimens, and interstitial fluid obtained by microdialysis in selected animals. Clinically, the voriconazole-treated animals had significantly less redness and lower lesion scores than untreated animals from days 7 and 10, respectively (P < 0.05). Skin scrapings from seven of eight animals in the voriconazole-treated group were microscopy and culture negative in contrast to zero of eight animals from the untreated group at day 14. The colony counts per specimen were significantly higher in samples from untreated animals (mean colony count of 28) than in the voriconazole-treated animals (<1 in the voriconazole group [P < 0.0001]). The voriconazole concentration in microdialysate (unbound) ranged from 0.9 to 2.0 microg/ml and in the skin biopsy specimens total from 9.1 to 35.9 microg/g. In conclusion, orally administered voriconazole leads to skin concentrations greater than the necessary MICs for Microsporum and was shown to be highly efficacious in an animal model of dermatophytosis. Voriconazole may be a future alternative for treatment of tinea capitis in humans.

AB - The standard treatment for tinea capitis caused by Microsporum species for many years has been oral griseofulvin, which is no longer universally marketed. Voriconazole has been demonstrated to inhibit growth of Microsporum canis in vitro. We evaluated the efficacy and tissue pharmacokinetics of oral voriconazole in a guinea pig model of dermatophytosis. Guinea pigs (n = 16) were inoculated with M. canis conidia on razed skin. Voriconazole was dosed orally at 20 mg/kg/day for 12 days (days 3 to 14). The guinea pigs were scored clinically (redness and lesion severity) and mycologically (microscopy and culture) until day 17. Voriconazole concentrations were measured day 14 in blood, skin biopsy specimens, and interstitial fluid obtained by microdialysis in selected animals. Clinically, the voriconazole-treated animals had significantly less redness and lower lesion scores than untreated animals from days 7 and 10, respectively (P < 0.05). Skin scrapings from seven of eight animals in the voriconazole-treated group were microscopy and culture negative in contrast to zero of eight animals from the untreated group at day 14. The colony counts per specimen were significantly higher in samples from untreated animals (mean colony count of 28) than in the voriconazole-treated animals (<1 in the voriconazole group [P < 0.0001]). The voriconazole concentration in microdialysate (unbound) ranged from 0.9 to 2.0 microg/ml and in the skin biopsy specimens total from 9.1 to 35.9 microg/g. In conclusion, orally administered voriconazole leads to skin concentrations greater than the necessary MICs for Microsporum and was shown to be highly efficacious in an animal model of dermatophytosis. Voriconazole may be a future alternative for treatment of tinea capitis in humans.

KW - Animals

KW - Antifungal Agents/pharmacokinetics

KW - Chromatography, High Pressure Liquid

KW - Colony Count, Microbial

KW - Dermatomycoses/drug therapy

KW - Extracellular Fluid/chemistry

KW - Female

KW - Guinea Pigs

KW - Microbial Sensitivity Tests

KW - Microdialysis

KW - Microsporum/drug effects

KW - Pyrimidines/pharmacokinetics

KW - Skin/metabolism

KW - Triazoles/pharmacokinetics

KW - Voriconazole

U2 - 10.1128/AAC.01185-06

DO - 10.1128/AAC.01185-06

M3 - Journal article

C2 - 17576826

VL - 51

SP - 3317

EP - 3321

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

ER -