Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

Abstract

Three isolates of zygomycetes belonging to two different genera (Rhizopus oryzae and Absidia corymbifera) were used to produce a systemic infection in neutropenic mice. On days ؊2 and ؊1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day. Antifungal drug efficacy was assessed by determination of the prolongation of survival, determination of the percentage of infected organs (brain, lung, spleen, and kidney), and histological examination for the number of infection foci and their sizes in brain and kidney tissues. AMB significantly prolonged the survival of mice infected with all isolates. POS significantly prolonged the survival of mice infected with zygomycetes. Cultured organs from mice infected with R. oryzae were all positive, while treated mice challenged with A. corymbifera generally showed lower percentages of infected organs compared with the percentages for the controls. Zygomycete isolates established an active infection (the presence of hyphae) in the brains and the kidneys of all controls. In mice challenged with R. oryzae, both antifungal drugs were effective at reducing the number and the size of infection foci in the kidneys. Only AMB reduced the numbers, but not the sizes, of infection foci in the brain. Finally, both drugs significantly reduced the numbers and the sizes of infection foci in both tissues of mice infected with A. corymbifera. Our data suggest that prophylaxis with POS has some potential to prevent zygomycosis. Zygomycosis is a rare but highly aggressive filamentous fungal infection (4). The clinical manifestations of zygomycosis include primary rhinocerebral, pulmonary, gastrointestinal, cutaneous or subcutaneous, and allergic disease and disseminated disease (4, 6, 7, 13). The zygomycetes most commonly identified as etiologic agents of human diseases are Rhizopus species, Rhizomucor species, Mucor species, and Absidia species (13). The invasive forms of zygomycosis cause angioinvasion, followed by progressive, necrotic, and generally fatal infections in immunocompromised hosts, such as diabetic patients with ketoacidosis, neutropenic patients, patients taking corticosteroids, and subjects with burns or iron overload (4,6,7,12,13). The standard therapy for these life-threatening infections consists of removal of the predisposing factors, widespread surgical debridement, and high doses of intravenous amphotericin B (AMB) (13). Nevertheless, even with aggressive therapy, the rate of mortality is often above 50% (4, 6). It is clear that new strategies for the treatment of zygomycosis are urgently needed.Posaconazole (POS) is a new broad-spectrum triazole with activity against many filamentous fungal pathogens, including zygomycetes (3,8,11,13,14). Experimental infection models and clinical data showed that POS might be useful for the treatment of zygomycosis (3,11,14). No data on the effects of POS prophylaxis against these infections are available. Therefore, in th...

Posaconazole Combined with Amphotericin B, an Effective Therapy for a Murine Disseminated Infection Caused by Rhizopus oryzae

“…In an animal infection model, PSC showed poor efficacy against a strain of R. oryzae (4). Similarly, prophylactic administration of PSC to neutropenic mice prolonged survival but did not reduce the tissue burden in a disseminated infection caused by R. oryzae (2). The current study partly confirmed these results.…”

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

“…68 A few animal studies have been conducted to explore the in vivo efficacy of posaconazole in screening models of disseminated mucormycosis that used survival and/or fungal tissue burden as end points. [69][70][71][72][73] Posaconazole prolonged the survival and reduced tissue burden in neutropenic mice with disseminated Mucor infection and was as effective as standard AmB at the highest dose level. 69 In non-immunocompromised mice, no beneficial effects were observed against R. oryzae, while partial activity was shown against Lichtheimia corymbifera and dose-dependent activity against Rhizopus microsporus.…”

“…In both of these last two studies, AmB significantly prolonged the survival of mice infected with all isolates. 70,72 In a further neutropenic murine model of disseminated R.oryzae mucormycosis, posaconazole had modest, but significant effects on survival that were statistically inferior to AmB at 0.8 mg/kg/day. 73 Finally, in diabetic ketoacidotic or neutropenic mice with disseminated mucormycosis caused by R. oryzae, posaconazole monotherapy did not improve survival or reduce fungal burden as compared to placebo while L-AmB was effective.…”

Correlation between In Vitro Activity of Posaconazole and In Vivo Efficacy against Rhizopus oryzae Infection in Mice

“…Considering the low frequency of infection with this organism and the difficulty in obtaining statistically significant data regarding the efficacies of antifungal agents, animal models have proved very useful for this purpose. Previous animal studies evaluating the efficacy of PSC against zygomycetes have included only one or two strains of R. oryzae (3,4,9,19). In the study described here, we have tested a panel of 50 clinical isolates of R. oryzae and, after determining their in vitro susceptibilities to PSC by different methods, have selected a subset of strains with various degrees of susceptibility to evaluate the efficacy of PSC in a murine model of infection.…”