In vitro antifungal susceptibility testing results of a new antifungal triazole, posaconazole (POS), were compared to results with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), and fluconazole (FLC) against clinical agents of zygomycosis. The MICs of POS at which 50% and 90% of the isolates were inhibited were 0.25 and 4 g/ml, respectively. POS was significantly more active than VRC and FLC and slightly more active than ITC. The results suggest that POS has significant potential for clinical development against the zygomycetes.Invasive mycoses have increased dramatically over the past several years, largely as a result of increasing numbers of immunosuppressed patients. The zygomycetes are less common causes of invasive human infection compared to Aspergillus spp. and Candida spp. In several large studies of the occurrence of fungal infection in high-risk populations, infections with zygomycetes represented 5 to 12% of all fungal infections (1, 14), while in another study, zygomycosis represented up to 25 to 44% of all invasive fungal diseases (6, 9). The manifestations of zygomycosis include primary rhinocerebral, pulmonary, gastrointestinal, cutaneous or subcutaneous, or allergic disease and disseminated disease (11). Amphotericin B (AMB) is the first-line therapy of choice for most cases of zygomycosis, but its use is limited by its potentially severe side effects.In the study described here, we compared the in vitro activities of four triazoles and AMB against 37 clinical isolates of zygomycetes. The isolates included 7 isolates of Mucor spp., 10 isolates of Rhizopus spp., 5 isolates of Absidia coryambifera, 5 isolates of Cunninghamella spp., 4 isolates of Apophysomyces elegans, 2 isolates of Cokeromyces recurvatus, and 4 isolates of Saksenaea vasiformis. All isolates came from the Fungus Testing Laboratory at The University of Texas Health Science Center (UTHSC) at San Antonio. Isolates were retrieved from storage at Ϫ70°C or from water stocks and were subcultured onto slants of potato flake agar with incubation at room temperature until adequate growth was obtained. Paecilomyces variotii strain UTHSC 90-459 was used as a control. MIC endpoints were read visually after 24 and 48 h of incubation. Standard antifungal powders of posaconazole (POS; ScheringPlough), voriconazole (VRC; Pfizer), fluconazole (FLC; Pfizer), itraconazole (ITC; Janssen), and AMB (Bristol-Myers Squibb) were obtained from their respective manufacturers. Stock solutions of POS, VRC, and ITC were prepared in polyethylene glycol 400, while AMB and FLC were dissolved in water. Final dilutions of POS, VRC, FLC, and ITC were made in RPMI 1640 medium with L-glutamine and morpholinepropanesulfonic acid buffer (Angus Chemical Co., Niagara Falls, N.Y.). AMB was made with Antibiotic Medium 3 (Difco). Serial twofold dilutions of each antifungal agent were prepared to the following final drug concentrations: AMB, 0.03 to 16 g/ml; POS and ITC, 0.015 to 8 g/ml; FLC and VRC, 0.125 to 64 g/ml. Stock solutions of these drugs were stored a...

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...