Drug Efficacy in Animal Models of Zygomycosis

Animal models of zygomycosis are useful for the study of the pathophysiology of the disease or to develop new diagnostic tools, but could also be used for the in vivo evaluation of antifungal activity (Dannaoui, 2006). Many different models have been developed in different animal species, both in immunocompetent and immucompro-mized animals (Kamei, 2001). Testing antifugal treatments in animal models that take into account host factors and the pharmacokinetic properties of the drugs remains a critical bridge between the in vitro evaluation of a drug and its potential use in patients. Indeed, for zygomycetes, the correlation between in vitro activity of an antifungal and its in vivo efficacy has not been always very good (Dannaoui et al., 2002c; Odds et al., 1998; Sun et al., 2002b; Ibrahim et al., 2005a).

Evaluation of antifungal efficacy in animal models of zygomycosis in recent years has addressed several issues. First, the good activity of amphotericin B has been confirmed in most of the studies. In nonimmunosupressed mice infected intravenously by R. oryzae, amphotericin B at doses of 0.63 to 2.5 mg/kg/day prolonged survival, although it did not sterilize target organs (Odds et al., 1998). Similarly, in a model of R. oryzae disseminated infection in immunocompetent mice, treatment of animals with amphotericin B at 1 mg/kg/day resulted in 100% survival (Dannaoui et al., 2002c). Even in more severe models of R. oryzae infection such as pulmonary infection in cortisone-treated mice, amphotericin B at 1 mg/kg/day led to a 90100% survival rate compared to 0% in untreated animals (Sugar & Liu, 2000). Amphotericin B at 0.5 to 1 mg/kg/day has also shown a good in vivo efficacy against A. corymbifera (Dannaoui et al., 2002c; Mosquera et al., 2001), R. microsporus (Dannaoui et al., 2002c), Apophysomyces elegans (Dannaoui et al., 2002c), and Mucor circinelloides (Sun et al., 2002b). Few studies have compared the efficacy of conventional deoxycholate-amphotericin B to the newer lipid formulations of the drug. In one study, liposomal amphotericin B has been shown to be more effective than deoxycholate amphotericin B in a model of R. oryzae infection in diabetic mice (Ibrahim et al., 2003). While only 40% of untreated animal survived, survival rates for mice treated with amphotericin B at 1 mg/kg/day or liposomal amphoter-icin B at 15 mg/kg/day were 67%, and 90%, respectively.

In vitro studies have documented low MICs for terbinafine against several species of zygomycetes. For this reason, the in vivo efficacy of the drug has been evaluated in vivo against one strain of R. microsporus (terfinafine MIC of 0.25 |g/mL) and one strain of A. corymbifera (MIC of 0.12 |g/mL). Despite documented absorption of terbinafine with tissues concentration of 25 and 10 |g/g in kidney and brain, respectively, treatment was ineffective either in mice infected with R. micro sporus or A. corymbifera (Dannaoui et al., 2002c). Reasons for these discrepancies between the in vitro activity of terbinafine and its in vivo efficacy remain unknown, but similar findings have been observed for other filamentous fungi.

Among the azoles, itraconazole, and posaconazole have been tested in animal models of zygomycosis. Itraconazole showed a certain degree of efficacy against A. corymbifera (Mosquera et al., 2001; Dannaoui et al., 2002c, 2003a) but was less effective than amphotericin B. Similarly, itraconazole treatment reduced mortality in mice infected with A. elegans (Dannaoui et al., 2002c) but was ineffective against R. oryzae (Dannaoui et al., 2003a; Odds et al., 1998), R. microsporus (Dannaoui et al., 2002c, 2003a) and two species of Mucor (Sun et al., 2002b). Posaconazole has been tested in animal model of zygomycosis in three recent studies. Against M. ramosissimus and M. circinelloides, posaconazole at 30 and 60 mg/kg/ day significantly prolonged survival in neutropenic mice and reduced fungal burden in kidneys compared to untreated controls but was less effective than amphotericin Batl mg/kg/day (Sun et al., 2002b). In nonimmunocompromised mice with disseminated infection, posaconazole tested at 5, 25, and 40 mg/kg/day was not effective against R. oryzae, showed a clear dose-response effect against R. microsporus, and was partially active against A. corymbifera (Dannaoui et al., 2003a). In the third study, the prophylactic efficacy of posaconazole, given three consecutive days before infection with either R. oryzae or A. corymbifera, was assessed and compared with prophylaxis with amphotericin B (Barchiesi et al., 2007). Overall, it was shown that posaconazole was more effective against A. corymbifera than against R. oryzae and that amphotericin B was more effective than posaconazole in prolonging survival of mice infected with R. oryzae.

Although caspofungin MICs against zygomycetes are consistently high, this drug has been tested in a model of R. oryzae infection in diabetic mice. Overall, the efficacy of caspofungin treatment was limited (Ibrahim et al., 2005a). Interestingly, low dose (1 mg/kg/day) caspofungin improved survival but high doses (5 or 10 mg/ kg/day) did not. Moreover, this effect was observed in animal infected with a low inoculum but not a large inoculum.

Beside antifungal drugs, other therapeutic strategies have been evaluated in animal. In particular, in one study, the efficacy of hyperbaric oxygen as an adjunct of amphotericin B treatment has been tested in mice infected with R. oryzae (Barratt et al., 2001). In this model the addition of hyperbaric oxygen to amphoter-icin B but did not improve survival compared to amphotericin B alone.

Another study evaluated the effect of deferiprone, an iron chelator, in a mouse model of R. oryzae infection (Ibrahim et al., 2006). Treatment with deferiprone increased survival rate and reduced fungal burden in brain compared to untreated controls with an efficacy similar to that of liposomal amphotericin B given at 15 mg/kg/day. Administration of free iron was shown to suppress the effect of deferiprone therapy demonstrating that the mechanism of protection was chelation of iron (Ibrahim et al., 2006).

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Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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