Susceptibilities of Madurella mycetomatis against amphotericin B and itraconazole in vitro were determined by protocols based on NCCLS guidelines (visual reading) and a 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) assay for fungal viability. The XTT assay was reproducible and sensitive for both antifungals. Itraconazole (MIC at which 50% of the isolates tested are inhibited [MIC50]) of 0.06 to 0.13 mg/liter) was superior to amphotericin B (MIC50 of 0.5 to 1.0 mg/liter)
The biodistribution of liposomal amphotericin B (L-AmB; AmBisome) and amphotericin B-desoxycholate were compared after a single injection of drug in uninfected immunocompetent mice and in leucopenic mice 6 h after inoculation with Candida albicans. Amphotericin B-desoxycholate was administered at the maximum tolerated dose (MTD) of 0.3 mg/kg whereas L-AmB was given at either 0.3 mg/kg or the MTD of 7 mg/kg. Amphotericin B (AmB) concentrations in the blood, liver, spleen, lungs and kidneys were determined by HPLC analysis at various intervals during the 48 h after administration. The biodistribution of both preparations of AmB followed similar patterns in both uninfected immunocompetent mice as well as those that were leucopenic and infected with C. albicans. Administration of L-AmB resulted in increased concentrations of drug in the blood, liver, and spleen but decreased concentrations in the kidney and lung. Hepatosplenic uptake of L-AmB was highly dose dependent with 7 mg/kg resulting in a relatively prolonged blood circulation. Blood and tissues retained high AmB concentrations after administration of L-AmB at the MTD. By using radiolabelled L-AmB, it was found that the high AmB concentrations in blood represented liposome-associated AmB and that during circulation in blood slow release of AmB occurred.
Eumycetoma due to Madurella mycetomatis is a major mycological health problem in endemic areas. We infected BALB/c mice (male or female) with various amounts of M. mycetomatis mycelium, containing sterilized soil as a natural adjuvant or Freund's incomplete adjuvant. Mice differed with respect to age and immune status. Intraperitoneal, subcutaneous and intravenous inoculation was explored and survival was monitored. Mice were killed at various intervals after inoculation, checked for the presence of the characteristic black grains, and organs were cultured for M. mycetomatis. Infected organs were subjected to histopathological examination. Immunocompetent male mice were as susceptible as immunocompromised female mice, but showed higher mortality rates. In conclusion, a reproducible mouse model of intraperitoneal M. mycetomatis infection with characteristic black grains in immunocompetent adult or young female mice was developed. Although this experimental model does not simulate macroscopic features of the subcutaneous M. mycetomatis infection in humans, the histopathological characteristics of the lesions and the development of black grains are clearly representative for the human infection. This model will enable further studies on the pathogenesis as well as prevention and treatment of the fungal infection.
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