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1.
J Antimicrob Chemother ; 74(10): 2950-2958, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31361006

RESUMEN

OBJECTIVES: The growing emergence of azole-resistant Aspergillus fumigatus strains worldwide is a major concern for current systemic antifungal treatment. Here we report antifungal activities of a novel inhaled triazole, PC1244, against a collection of multi-azole-resistant A. fumigatus strains. METHODS: MICs of PC1244 were determined for A. fumigatus carrying TR34/L98H (n = 81), TR46/Y121F/T289A (n = 24), M220 (n = 6), G54 (n = 11), TR53 (n = 1), TR463/Y121F/T289A (n = 2), G448S (n = 1), G432C (n = 1) and P216S (n = 1) resistance alleles originating from either India, the Netherlands or France. The effects of PC1244 were confirmed in an in vitro model of the human alveolus and in vivo in temporarily neutropenic, immunocompromised mice. RESULTS: PC1244 exhibited potent inhibition [geometric mean MIC (range), 1.0 mg/L (0.125 to >8 mg/L)] of growth of A. fumigatus strains carrying cyp51A gene mutations, showing much greater potency than voriconazole [15 mg/L (0.5 to >16 mg/L)], and an effect similar to those on other azole-susceptible Aspergillus spp. (Aspergillus flavus, Aspergillus terreus, Aspergillus tubingensis, Aspergillus nidulans, Aspergillus niger, Aspergillus nomius, Aspergillus tamarii) (0.18-1 mg/L). In TR34/L98H and TR46/Y121F/T289A A. fumigatus-infected in vitro human alveolus models, PC1244 achieved superior inhibition (IC50, 0.25 and 0.34 mg/L, respectively) compared with that of voriconazole (IC90, >3 mg/L and >10 mg/L, respectively). In vivo, once-daily intranasal administration of PC1244 (0.56-70 µg/mouse) to the A. fumigatus (AF91 with M220V)-infected mice reduced pulmonary fungal load and serum galactomannan more than intranasal posaconazole. CONCLUSIONS: PC1244 has the potential to become a novel topical treatment of azole-resistant pulmonary aspergillosis.


Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Triazoles/farmacología , Animales , Aspergillus/clasificación , Aspergillus/aislamiento & purificación , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Francia , Galactosa/análogos & derivados , Humanos , India , Pulmón/microbiología , Mananos/sangre , Ratones , Pruebas de Sensibilidad Microbiana , Países Bajos , Aspergilosis Pulmonar/microbiología , Resultado del Tratamiento , Triazoles/administración & dosificación
2.
Sci Rep ; 9(1): 9482, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31263150

RESUMEN

Invasive pulmonary Aspergillosis is a leading cause of morbidity and mortality in immunosuppressed patients and treatment outcomes using oral antifungal triazoles remain suboptimal. Here we show that combining topical treatment using PC945, a novel inhaled triazole, with systemic treatment using known triazoles demonstrated synergistic antifungal effects against Aspergillus fumigatus (AF) in an in vitro human alveolus bilayer model and in the lungs of neutropenic immunocompromised mice. Combination treatment with apical PC945 and either basolateral posaconazole or voriconazole resulted in a synergistic interaction with potency improved over either compound as a monotherapy against both azole-susceptible and resistant AF invasion in vitro. Surprisingly there was little, or no synergistic interaction observed when apical and basolateral posaconazole or voriconazole were combined. In addition, repeated prophylactic treatment with PC945, but not posaconazole or voriconazole, showed superior effects to single prophylactic dose, suggesting tissue retention and/or accumulation of PC945. Furthermore, in mice infected with AF intranasally, 83% of animals treated with a combination of intranasal PC945 and oral posaconazole survived until day 7, while little protective effects were observed by either compound alone. Thus, the combination of a highly optimised topical triazole with oral triazoles potentially induces synergistic effects against AF infection.


Asunto(s)
Antifúngicos/farmacología , Aspergillus fumigatus/crecimiento & desarrollo , Benzamidas/farmacología , Alveolos Pulmonares , Aspergilosis Pulmonar/tratamiento farmacológico , Triazoles/farmacología , Voriconazol/farmacología , Administración Tópica , Benzamidas/agonistas , Línea Celular , Sinergismo Farmacológico , Humanos , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/microbiología , Alveolos Pulmonares/patología , Aspergilosis Pulmonar/metabolismo , Aspergilosis Pulmonar/patología , Triazoles/agonistas , Voriconazol/agonistas
3.
Mycoses ; 60(11): 728-735, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28699245

RESUMEN

Although anti-fungal triazoles are dosed orally or systemically for Aspergillus fumigatus infection, systemic adverse events and limited exposure of the lung cavity would make a topical treatment for the lung an attractive option. In this study, we examined the effects of intranasally dosed posaconazole on survival rates and biomarkers in A. fumigatus (itraconazole susceptible: ATCC13073 [Af]; or resistant: NCPF7100 [AfR]) infected, temporarily neutropenic A/J mice. Once daily treatment produced a dose-dependent improvement of survival of Af-infected mice (ED50 : 0.019 mg/mouse [approx. 0.755 mg/kg, in]), similar to its potency (ED50 : 0.775 mg/kg, po) after once daily oral dosing. For AfR infection, either intranasal or oral posaconazole was largely ineffective on survival, although the highest dose of intranasal treatment (0.35 mg/mouse) achieved 75% survival rate. Early intervention (treated on days 0, 1, 2 and 3 postinfection) and late intervention (treated on days 1, 2 and 3) with intranasal posaconazole (0.014-0.35 mg/mouse) demonstrated potent inhibition of lung fungal load and galactomannan levels in both bronchoalveolar lavage fluid (BALF) and serum as well as inflammatory cells, IFN-γ, IL-17 and malondialdehyde (MDA) in BALF. Thus, posaconazole when dosed intranasally once daily showed an improvement of survival equivalent to or better than oral treatment, and produced potent inhibition of fungal load and biomarkers.


Asunto(s)
Antifúngicos/farmacología , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Mananos/análisis , Triazoles/farmacología , Administración Intranasal , Administración Oral , Animales , Aspergilosis/microbiología , Aspergilosis/patología , Biomarcadores/análisis , Citocinas/análisis , Modelos Animales de Enfermedad , Farmacorresistencia Fúngica , Galactosa/análogos & derivados , Humanos , Huésped Inmunocomprometido , Itraconazol/farmacología , Pulmón/microbiología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Organismos Libres de Patógenos Específicos
4.
Artículo en Inglés | MEDLINE | ID: mdl-28630185

RESUMEN

PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days -7 to +3 or days -7 to 0) were also compared with those of the shorter treatment regimens (days -1 to +3 or days -1 and 0). Early and late interventions with PC945 (2.8 to 350 µg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 µg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans.


Asunto(s)
Antifúngicos/farmacología , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Biomarcadores/metabolismo , Huésped Inmunocomprometido/efectos de los fármacos , Triazoles/farmacología , Administración Intranasal/métodos , Animales , Aspergilosis/metabolismo , Aspergilosis/microbiología , Líquido del Lavado Bronquioalveolar/microbiología , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/microbiología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Voriconazol/farmacología
5.
Artículo en Inglés | MEDLINE | ID: mdl-28223388

RESUMEN

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 µM and 0.22 µM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 µg/ml, while those of voriconazole ranged from 0.064 to 4 µg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 µg/ml, whereas voriconazole (0.019 to >1 µg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 µg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 µg/mouse, while posaconazole showed similar effects (44%) at 14 µg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.


Asunto(s)
Antifúngicos/farmacología , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Benzamidas/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Triazoles/farmacología , Animales , Aspergilosis/microbiología , Aspergillus fumigatus/aislamiento & purificación , Células Cultivadas , Sistema Enzimático del Citocromo P-450 , Humanos , Itraconazol/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Voriconazol/farmacología
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