RESUMEN
Aspergillus spp. infections remain a global concern, with â¼30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg/kg after 5 days of QD administration (155 and 1033 µg*h/ml, respectively), with a further increase with 40 mg/kg BID dosing (1354 µg*h/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 µg/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg/kg, intermediate decreases at QD 20 mg/kg and maximum or near maximum decreases at 40 mg/kg QD and BID. The PK/PD relationships of AUCfree/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/uso terapéutico , Antifúngicos/uso terapéutico , Aspergillus fumigatus/efectos de los fármacos , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Piridinas/uso terapéutico , Tetrazoles/uso terapéutico , Animales , Antifúngicos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Neutropenia , Piridinas/farmacocinética , Tetrazoles/farmacocinéticaRESUMEN
The clinical utility of the echinocandins is potentially compromised by the emergence of drug resistance. We investigated whether Candida albicans with amino acid substitutions at position Ser645 in Fks1 can be treated with either a conventional or an elevated dosage of micafungin. We studied Candida albicans (wild-type SC5314; MIC, 0.06 mg/liter) and four fks1 mutants (one FKS1/fks1 heterozygote mutant [MIC, 0.5 mg/liter] and three fks1/fks1 homozygous mutants [MICs for all, 2 mg/liter]) with a variety of amino acid substitutions at Ser645. The pharmacokinetic and pharmacodynamic relationships were characterized in a persistently neutropenic murine model of disseminated candidiasis. A mathematical model was fitted to all pharmacokinetic and pharmacodynamic data. This mathematical model was then used to "humanize" the murine pharmacokinetics, and the predicted antifungal effect was determined. The estimated maximal rate of growth and ultimate fungal densities in the kidney for each of the strains were similar. The administration of micafungin at 1 mg/kg of body weight to the wild type resulted in moderate antifungal activity, whereas the administration of 5 and 20 mg/kg resulted in rapid fungicidal activity. In contrast, the FKS1/fks heterozygote was killed only with 20 mg/kg, and the homozygous fks1 mutants failed to respond to any dosage. The bridging study revealed that human dosages of 100 and 400 mg/day were active only against the wild type, with no activity against either the heterozygote or the homozygote mutants. Ser645 Fks1 Candida albicans mutants cannot be treated with either conventional or elevated dosages of micafungin and should be deemed resistant.
Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Equinocandinas/metabolismo , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Sustitución de Aminoácidos , Animales , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Candida albicans/genética , Candida albicans/patogenicidad , Candidiasis/microbiología , Farmacorresistencia Fúngica/genética , Equinocandinas/administración & dosificación , Equinocandinas/química , Equinocandinas/genética , Equinocandinas/farmacocinética , Equinocandinas/farmacología , Equinocandinas/uso terapéutico , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genotipo , Humanos , Lipopéptidos/administración & dosificación , Lipopéptidos/farmacocinética , Masculino , Micafungina , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
OBJECTIVES: The aim of this study was to assess the dose-response of isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections. METHODS: Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei. RESULTS: Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P<0.05) in the C. krusei model; fluconazole (all doses) and voriconazole (5 and 20 mg/kg) did not. In the C. krusei kidney burden model, isavuconazole 120 and 150 mg/kg and voriconazole 40 mg/kg were superior to controls and fluconazole. In the C. tropicalis model, PN isavuconazole (all doses), voriconazole (>5 mg/kg) and fluconazole (all doses) reduced kidney burden (P<0.05). Only isavuconazole (all doses) and 40 mg/kg voriconazole were effective against C. krusei in the brain, isavuconazole and voriconazole reduced tissue burden (P<0.05). Fluconazole had no significant effect on brain burden even at 150 mg/kg. CONCLUSIONS: Isavuconazole significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burdens in mice infected with C. krusei. Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden.
Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Fluconazol/uso terapéutico , Nitrilos/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Triazoles/uso terapéutico , Animales , Antifúngicos/administración & dosificación , Encéfalo/microbiología , Candidiasis/complicaciones , Recuento de Colonia Microbiana , Relación Dosis-Respuesta a Droga , Fluconazol/administración & dosificación , Riñón/microbiología , Masculino , Ratones , Neutropenia , Nitrilos/administración & dosificación , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Resultado del Tratamiento , Triazoles/administración & dosificación , VoriconazolRESUMEN
The activities of amphotericin B and itraconazole were studied in a temporarily neutropenic murine model of disseminated Absidia corymbifera infection, caused by two different strains. Amphotericin B MICs were 0.25 mg/L for both strains and itraconazole MICs were 1 and 2 mg/L. Amphotericin B was effective in vivo with both isolates. Itraconazole was less effective.
Asunto(s)
Absidia/efectos de los fármacos , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Itraconazol/uso terapéutico , Mucormicosis/tratamiento farmacológico , Absidia/clasificación , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Mucormicosis/microbiologíaRESUMEN
We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.