Activity of Posaconazole against Pseudallescheria boydii : In Vitro and In Vivo Assays

Abstract

Thirty isolates of Pseudallescheria boydii were tested to compare the in vitro activity of posaconazole with those of fluconazole and itraconazole, using NCCLS methods. Posaconazole was evaluated in an immunosuppressed mouse model of disseminated pseudallescheriasis. Posaconazole was more effective than itraconazole and as effective as fluconazole in preventing death and significantly reducing the CFU of P. boydii from tissues.In the last few decades, Pseudallescheria boydii has emerged as an important human pathogen, particularly in the immunocompromised host (1,13,14). The diagnosis of invasive pseudallescheriasis is difficult to make histologically, since the tissue specimens show only septate, branching hyphae that resemble Aspergillus. This is a major problem frequently leading to unsuitable therapy, since amphotericin B (AMB) is the treatment of choice for aspergillosis but P. boydii is resistant to AMB.It has been reported that P. boydii exhibits resistance to AMB in vitro and resistance to flucytosine and that many isolates are only moderately susceptible to miconazole, ketoconazole, and itraconazole (ITRA) (3, 7, 10). There have been some reports of successful treatment of fungal infections with miconazole, ketoconazole, ITRA, and the newer triazole voriconazole (2,4,8). Posaconazole (POS) (SCH 56592) is a new antifungal agent currently undergoing clinical development by Schering-Plough Research Institute (Kenilworth, N.J.). POS is a broad-spectrum triazole and has been shown to have potent in vitro and in vivo activity against Candida spp., Cryptococcus neoformans, Aspergillus spp., and numerous other opportunistic fungi that are likely to be encountered clinically (6,11,12).The purpose of this study was to evaluate the in vitro and in vivo activities of POS against P. boydii. We compared the activity of POS with the activities of the triazoles ITRA and fluconazole (FLU) against a series of P. boydii strains using National Committee for Clinical Laboratory Standards (NCCLS) methods. An animal model of disseminated pseudallescheriasis was used to determine the in vivo efficacies of POS and other drugs.Thirty clinical isolates of P. boydii were used in this study. All isolates were obtained from the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio.Each isolate of P. boydii was grown for 10 days at 35°C on potato flake agar slants. Isolates were evaluated using the NCCLS broth macrodilution proposed standard reference method M38-P for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi (9). The conidial suspensions were vortexed and adjusted for a transmittance of 68 to 70% at 530 nm in a spectrophotometer (Spectronic 21; Milton Roy Company); this was verified by plating 10 l of each inoculum onto potato dextrose agar plates, incubating the plates at 35°C, and measuring the resulting growth. POS (Schering-Plough Research Institute) and ITRA (Janssen Pharmaceutica, Beerse, Belgium) were dissolved in polyethylene glycol 400 (Sigma, St. Lo...

Infections Caused byScedosporiumspp

“…In an immunocompromised murine model, posaconazole prolonged survival by 70 to 75% at dosages of Ͼ30 mg/kg/day. Surprisingly, in the same model, 40 mg/kg/day of fluconazole resulted in 55% survival and a reduced fungal burden (163). The posaconazole and fluconazole MICs in the latter study were 0.125 to 1 g/ml and 32 to Ͼ64 g/ml, respectively.…”

“…21,2008 INFECTIONS CAUSED BY SCEDOSPORIUM SPP. 163 the graphium type of conidial state and has not been found to produce a teleomorph (237,349,427). Microscopic features.…”

“…Experimental S. apiospermum infections. Multiple studies have shown the lack of efficacy of conventional and liposomal amphotericin B and itraconazole (63,65,163,322). However, in an immunocompromised murine model of scedosporiosis using a low inoculum (2 ϫ 10 6 CFU/kg) of S. apiospermum, a small effect, with a prolongation of mouse survival of 10 to 40%, was found with amphotericin B and itraconazole (322).…”

Antifungal Activities of Posaconazole and Granulocyte-Macrophage Colony-Stimulating Factor Ex Vivo and in Mice with Disseminated Infection Due to Scedosporium prolificans

“…This discordance may be related to the animal model used as well as to pharmacodynamic and pharmacokinetic factors related to the two agents in mice. Even though the therapeutic regimen used in this study was chosen on the basis of pharmacokinetic studies of POS in mice (1,16,17,21,30,31), the resilient nature of the isolate that we used resulted in deep infections that progressively damaged the tissues studied.…”

“…It possesses potent antifungal activity against a broad spectrum of fungal pathogens (5,9,11,12,21,22,(31)(32)(33)(34)42). A recent report (16) has demonstrated that POS is active in a murine model of infection due to Scedosporium apiospermum, the second medically important species of the genus Scedosporium.…”