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

Abstract

In a murine model of disseminated zygomycosis, low doses of amphotericin B (0.3 mg/kg body weight/day) combined with posaconazole (40 mg/kg/day) prolonged survival and reduced tissue burden with respect to that of controls and that of both drugs administered alone. Results were similar to those obtained with amphotericin B given alone at 0.8 mg/kg/day.Zygomycosis is an opportunistic fungal infection that causes a high degree of morbidity and mortality in immunocompromised patients, particularly those with hematologic malignancy or diabetes mellitus. Rhyzopus oryzae infection is the most common cause of zygomycosis in humans (10). Optimal management of zygomycosis has not been defined. Rapid diagnosis, mitigation or reduction of risk factors, administration of antifungal therapy, surgical debridement where possible, and the use of adjunctive therapies all contribute to the successful management of zygomycosis (11). Amphotericin B (AMB) deoxycholate and lipid formulations of AMB are the drugs of choice for treating zygomycoses (10,11,12). Posaconazole (PSC) is safer than AMB and shows good in vitro activity against some zygomycetes (1,14). Clinical data seem to confirm that in two compassionate use trials, outcomes obtained with PSC therapy were similar to those obtained with AMB, supporting the use of this azole in the management of refractory zygomycosis or in cases of patient intolerance to AMB therapy (6, 15). Because animal studies showed limited activity of PSC against R. oryzae infection (2, 4), we hypothesized that the combined use of two drugs with different targets and with proven activities against zygomycetes may act synergistically against R. oryzae infection or, at least, would allow the use of reduced therapeutic doses. Therefore, we evaluated the efficacy of PSC alone and of PSC combined with AMB in a model of disseminated R. oryzae infection in neutropenic mice.Two clinical isolates of R. oryzae, FMR 6485 and FMR 8542, were used. The in vitro antifungal susceptibility of each strain was tested using a reference microdilution method (8), and the in vitro interactions were assessed using a checkerboard method (5, 7). For both of the drugs and their combinations, we used a MIC of 0 as the endpoint criterion.Male OF1 mice weighing 30 g were used. All animal care procedures were supervised and approved by the Universitat Rovira i Virgili animal welfare committee. Animals were immunosuppressed by intraperitoneal administration of a single dose of cyclophosphamide, 200 mg/kg of body weight, plus a single intravenous administration of 5-fluorouracil, 150 mg/kg, 1 day before the infection (3). Mice were injected with 1 ϫ 10 5 CFU in 0.2 ml in the lateral tail vein. Preliminary experiments with both strains (data not shown) showed that this concentration was the optimal dose for killing 100% of the animals within 6 days of infection.AMB (Fungizona) and PSC (Noxafil) were tested. AMB was administered intravenously at 0.3 mg/kg/day or 0.8 mg/kg/day, once daily; PSC was administered orally at 20 mg/kg/day, 40 ...

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.…”

Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries

“…Livio Pagano, 1 Oliver A. Cornely, 2,3 Alessandro Busca, 4 Morena Caira, 1 Simone Cesaro, 5 Cristiana Gasbarrino, 6 Corrado Girmenia, 7 Werner J. Heinz, 8 Raoul Herbrecht, 9 Cornelia Lass-Flörl, 10 Annamaria Nosari, 11 Leonardo Potenza, 12 Zdenek Racil, 13 1-2011-2012).…”

“…6,7 However, pre-clinical studies in neutropenic and diabetic ketoacidotic mice with IM reported no improvement in survival under a combination of posaconazole and liposomal amphotericin B (LAmB), compared to L-AmB monotherapy. 8,9 Given the rarity of IM, these results have not been evaluated systematically in a clinical setting. Therefore, the value of combining a lipid formulation of AmB (Lip-AmB) with posaconazole for the treatment of IM remains a subject of controversy and discussion.…”

Mucormycosis, Pseudallescheriasis, and Other Uncommon Mold Infections

“…Both studies found that addition of posaconazole to polyenes resulted in no additive benefit compared with polyene therapy alone (42,43). No clinical studies have evaluated combination posaconazole-polyene therapy for mucormycosis.…”