Therapeutic and prophylactic efficacy of aminocandin (IP960) against disseminated candidiasis in mice

ABSTRACTExtended interval dosing of the echinocandins has been suggested as a potential strategy to overcome the need for daily intravenous administration. This study evaluated the therapeutic and prophylactic efficacy of single doses of aminocandin, a new echinocandin in preclinical development, in a murine model of invasive candidiasis. For therapy, groups of mice were infected with Candida albicans, followed by a single dose of aminocandin (1–15 mg/kg) or placebo (mannitol 5% w/v) administered 1 day after inoculation. As prophylaxis, mice were given a single dose (5 or 30 mg/kg) of aminocandin, caspofungin, or placebo at increasing intervals between dose and inoculation. In both treatment and prophylaxis studies, survival was assessed at 21 days post-inoculation. The reduction in fungal burden was assessed in kidney tissue on day 8 post-inoculation. For treatment, single doses of aminocandin of ≥2.5 mg/kg prolonged survival significantly. In addition, the two doses evaluated for reductions in fungal burden (5 and 15 mg/kg) revealed fungicidal activity. As prophylaxis, both aminocandin and caspofungin 5 and 30 mg/kg prolonged survival when given 7 days before inoculation. Aminocandin and caspofungin 30 mg/kg were both able to prolong survival when the interval between dose and inoculation was increased to 10 days. When this interval was extended to 14 days, only aminocandin 30 mg/kg prolonged survival and reduced fungal burden. These results demonstrate that single doses of aminocandin are effective as treatment and prophylaxis, and suggest that extended interval dosing may be a useful strategy for treating invasive candidiasis

Interactions of Posaconazole and Flucytosine against Cryptococcus neoformans

A checkerboard methodology, based on standardized methods proposed by the National Committee for Clinical Laboratory Standards for broth microdilution antifungal susceptibility testing, was applied to study the in vitro interactions of flucytosine (FC) and posaconazole (SCH 56592) (FC-SCH) against 15 isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of <0.50, was observed for 33% of the isolates tested. When synergy was not achieved, there was still a decrease in the MIC of one or both drugs when they were used in combination. Antagonism, defined as a FIC of >4.0, was not observed. The in vitro efficacy of combined therapy was confirmed by quantitative determination of the CFU of C. neoformans 486, an isolate against which the FC-SCH association yielded a synergistic interaction. To investigate the potential beneficial effects of this combination therapy in vivo, we established two experimental murine models of cryptococcosis by intracranial or intravenous injection of cells of C. neoformans 486. At 1 day postinfection, the mice were randomized into different treatment groups. One group each received each drug alone, and one group received the drugs in combination. While combination therapy was not found to be significantly more effective than each single drug in terms of survival, tissue burden experiments confirmed the potentiation of antifungal activity with the combination. Our study demonstrates that SCH and FC combined are significantly more active than either drug alone against C. neoformans in vitro as well in vivo. These findings suggest that this therapeutic approach could be useful in the treatment of cryptococcal infections

Activity of two different triazoles in a murine model of paracoccidioidomycosis Actividad de dos triazoles diferentes en un modelo murino de paracoccidioidomicosis

A new orally absorbable triazole (Schering 39304) with a long serum half-life in man (60 hours), was tried in a murine model of progressive paracoccidioidomycosis and compared with itraconazole, another triazole which has proven effective in this mycosis. Only 15% of the infected, untreated mice survived while 53 to 75% of the animals receiving itraconazole survived. Mice treated with Schering 39304 exhibited higher (86 - 100%) survival rates. Statistically, the 5 mg/kg Sch 39304 was superior to the 50 mg/kg itraconazole dose. Lung cultures showed that 20 mg/kg/day of Sch achieved sterilization of the infectious foci. These results indicate that the new triazole will have a place in the treatment of paracoccidioidomycosis<br>Un nuevo derivado triazólico Schering 39304 que tiene una vida promedio prolongada (60 horas), asi como otro triazol (itraconazole) de eficacia comprobada en la paracoccidioidomicosis, fueron ensayados en un modelo murino. Se encontró que solo sobrevivían el 15% de los animales infectados no tratados; del grupo tratado con Itrazonazol sobrevivieron el 53% de los que recibieron 20 mg/kg/dia y el 86% de aquellos con 50 mg/kg/dia. De los ratones que recibieron Sch 39304 sobrevivieron el 86% de los tratados con la dosis baja (5 mg/kg) y el 100% con la dosis mayor (20 mg/kg). Se encontraron diferencias estadísticamente significativas entre esta última droga y el itraconazol. Además, los cultivos de pulmón mostraron que solo Sch 39304 a la dosis alta, era capaz de erradicar el hongo de los tejidos. Estos resultados indican que tal triazol tendrá importancia en el tratamiento de la paracoccidioidomicosis human