Clearance of <i>Histoplasma capsulatum</i> variety <i>capsulatum</i> antigen is useful for monitoring treatment of experimental histoplasmosi

et al. 2000

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A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F 1 mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F 1 mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 10 4 Histoplasma capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts and Histoplasma antigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.Histoplasmosis is an important cause of progressive infection in immunocompromised individuals, including those with AIDS. In persons with AIDS, the course of disseminated histoplasmosis often is more severe than and the response to treatment is inferior (23,24) to that in nonimmunocompromised individuals or those with other immunosuppressive disorders (19). Eighty-five percent of cases in patients with AIDS have occurred in those with CD4 cell counts below 200/l (13, 20, 22), suggesting that CD4 cells play an important role in defense against Histoplasma capsulatum. Recent studies confirm the association of CD4 cell reduction with increased risk for disseminated histoplasmosis in persons with human immunodeficiency virus infection; case rates were 4.6 times higher in persons with CD4 cell counts below 150/l than in those with higher counts (18). CD8 cell counts were below 200/l in 35% of cases in AIDS patients enrolled in clinical trials evaluating the treatment of histoplasmosis (L. J. Wheat, unpublished data).We have shown that dual depletion of CD4 and CD8 cells markedly alters the course of experimental histoplasmosis following pulmonary challenge (6; C. Schnizlein-Bick, M. Durkin, P. Connolly, S. Kohler, and J. Wheat, Program Abstr. 34th Annu. Meet. Infect. Dis. Soc. Am., abstr. 207, p. 74, 1996). While nonimmunosuppressed mice recovered uneventfully following intratracheal inoculation with 10 3 yeasts, CD4-and CD8-depleted m...

“…A 20-gauge, 1.25-in. Angiocath (Becton Dickinson) was passed through the mouth into the trachea, and 25 l of the H. capsulatum inoculum was administered (7,17).…”

Section: Methodsmentioning

confidence: 99%

Comparison of a New Triazole, Posaconazole, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in Immunocompromised Mice

Connolly¹,

Wheat

et al. 2000

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“…Six-week-old B6C3F 1 mice (Harlan Sprague Dawley) were anesthetized with 4.5% halothane at an oxygen flow rate of 0.9 liter/min. A 20-gauge, 1.25-inch Angiocath (Becton Dickinson) was passed through the mouth into the trachea, and 25 l of the H. capsulatum inoculum was administered by a stylet passed to the bifurcation of the trachea (7,10).…”

Section: Methodsmentioning

confidence: 99%

Comparison of a New Triazole Antifungal Agent, Schering 56592, with Itraconazole and Amphotericin B for Treatment of Histoplasmosis in Immunocompetent Mice

Connolly¹,

Wheat

et al. 1999

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A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 μg/ml for SCH 56592, 0.5 μg/ml for amphotericin B, and ≤0.019 μg/ml for itraconazole. Survival studies were done on groups of 10 B6C3F1 mice with a lethal inoculum of 105. All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29. Only 44% of mice receiving 5 mg of itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 104showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day). Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 μg/ml at 3 h and 0.35 μg/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 μg/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 μg/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 μg/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.

“…A 20-gauge, 1-1/4-in. angiocath (Becton Dickinson) was passed through the mouth into the trachea, and 25 l of the H. capsulatum inoculum was administered by stylet passed to the bifurcation of the trachea (6,11).…”

Section: Methodsmentioning

confidence: 99%

Comparison of Nikkomycin Z with Amphotericin B and Itraconazole for Treatment of Histoplasmosis in a Murine Model

Goldberg¹,

Connolly²,

et al. 2000

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Nikkomycin Z was tested both in vitro and in vivo for efficacy against Histoplasma capsulatum. Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole. The median MIC was 8 g/ml with a range of 4 to 64 g/ml for nikkomycin Z, 0.56 g/ml with a range of 0.5 to 1.0 g/ml for amphotericin B, and <0.019 g/ml for itraconazole. Primary studies were carried out by using a clinical isolate of H. capsulatum for which the MIC of nikkomycin Z was greater than or equal to 64 g/ml.