In Vivo Activity of Posaconazole againstMucorspp. in an Immunosuppressed-Mouse Model

Abstract

The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared. The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp. used in this study ranged from 0.125 to 8 g/ml and 0.25 to 8 g/ml, respectively. The in vitro MIC range for amphotericin B is 0.125 to 0.25 g/ml. At twice-daily doses of >15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.Zygomycosis is a relatively uncommon but highly aggressive fungal infection that affects diabetics, neutropenic patients, and subjects with burns or iron overload but that only rarely affects healthy people (15,19). Illness may rapidly progress with angioinvasion and tissue infarction. The existing methods for treatment are often ineffective (4, 9, 17). Presently, therapy utilizes aggressive surgical measures and high doses of amphotericin B. There are scattered reports of lipid-associated amphotericin B in salvage, but there is no evidence that these forms are more efficacious than amphotericin B (2, 3, 5). Even with aggressive therapy, mortality is often above 50% (6). Of the alternative antifungals, itraconazole has been effective in vitro, particularly against Absidia spp. One mouse study has also shown some activity against Absidia, but the clinical evidence of efficacy is less clear (2, 6, 10, 16; E. Dannaoui, J. Meletiadis, J. Meis, J. W. Moulton, and P. E. Verweij, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 939, 2000). Posaconazole is a new broad-spectrum triazole with activity against many filamentous fungal pathogens (1,8,12,18). This study describes the in vivo activity of posaconazole against three Mucor spp. isolates in a neutropenic-mouse model.Three clinical Mucor isolates were tested in vitro by the NCCLS microdilution method for triazoles adapted to filamentous fungi (11). The endpoint was a visual MIC at which azoles were seen to reduce growth by 80% compared to that in the drug-free control tube. The MIC of amphotericin B was taken as the least drug producing a visually clear tube. MICs of posaconazole and itraconazole at 48 h were 0.125 and 0.25 g/ml for Mucor ramosissimus strain 98-1763, 0.25 and 0.25 g/ml for Mucor ramosissimus 95-2650, and 8 and 8 g/ml for Mucor circinelloides 00-1194, respectively. The 48-h MIC of amphotericin B was 0.25 g/ml for all three isolates. The isolates were grown on potato flake agar plates at room temperature for 1 week. They were harvested by scraping the plates with sterile isotonic saline and filtering the suspension through glass wool. The inoculum was calculated by determining hemacytometer counts.For the mouse model, we used 18-week-old BALB/c males. One day before infection, mice were rendered neutropenic with single doses of 5-fluorouracil administered intravenously at 150 mg/kg of body weight and with cyclophosphamide administered intraperitoneally at 200 mg/kg. In groups of five uninfected mice, this treatment reduced the neutrophil count from a median pretreatm...

A rare presentation of zygomycosis (mucormycosis) and review of the literature: Figure 1

“…16 This drug could have potential for clinical development in the treatment of zygomycosis. 16 Surgical resection of the involved tissue along with amphotericin improves survival. 1 3 17 However, the surgical option may not be feasible because of involvement at multiple sites, low platelet and neutrophil counts, and poor performance status.…”

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.…”

“…[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. 70 In neutropenic mice, posaconazole started two days prior to inoculation was used against L. corymbifera and against one of the two isolates of R. oryzae in an inoculum-dependent manner.…”

Rhinocerebral Mucormycosis Treated with Posaconazole: A Case Report

“…İtrakonazolün ise Absidia türlerine karşı etkinliği vardır (19). Posakonazol yeni, geniş spektrumlu, oral yoldan kullanılabilen, zigomisetlere etkili olduğu in vitro çalışmalarda ve immünosüprese hayvan modellerinde gösterilmiş, azol grubundan bir antifungal ajandır (9,10,21). Retrospektif bir çalışmada önceki antifungal tedaviye dirençli ya da intoleran 91 mukormikoz olgusunda kurtarma tedavisinde posakonazol kullanıldığı ve hastaların %60'ında tedavi başarısı (tam ya da kısmi yanıt), %21'inde ise hastalığın stabilizasyonunun sağlandığı bildirilmiştir (13).…”