Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

Wheat, Joseph; Hafner, Richard; Wulfsohn, Michael; Spencer, Patricia; Squires, Kathleen; Powderly, William G.; Wong, Brian J. F.; Rinaldi, Michael G.; Saag, Michael S.; Hamill, Richard J.; Murphy, Robert L.; Connolly‐Stringfield, Patricia; Briggs, Necia; Owens, Susan

doi:10.7326/0003-4819-118-8-199304150-00006

Cited by 192 publications

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“…The level of CD4 and CD8 depletion used in this model may have been greater than that experienced in some AIDS patients with disseminated histoplasmosis, however, since CD4 counts may be above 200/l in up to 15% of patients and CD8 counts are not uniformly or greatly suppressed (13,(20)(21)(22). In our model, CD4 depletion alone increased mortality and fungal burden but not to the extent observed with both CD4 and CD8 depletion (Schnizlein-Bick et al, Abstr.…”

Section: Discussionmentioning

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

Schnizlein-Bick³

et al. 2000

Antimicrob Agents Chemother

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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...

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Section: Discussionmentioning

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

Schnizlein-Bick³

et al. 2000

Antimicrob Agents Chemother

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“…Because of the high rate of relapse, it has been standard practice for AIDS patients who have histoplasmosis to be placed on maintenance azole therapy for life after their initial response to antifungal therapy (129). However, this has changed with the use of highly active antiretroviral therapy that restores CD4 cell numbers to normal or at least higher levels.…”

Section: Disseminated Histoplasmosismentioning

confidence: 99%

Histoplasmosis: a Clinical and Laboratory Update

2007

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SUMMARY Infection with Histoplasma capsulatum occurs commonly in areas in the Midwestern United States and Central America, but symptomatic disease requiring medical care is manifest in very few patients. The extent of disease depends on the number of conidia inhaled and the function of the host's cellular immune system. Pulmonary infection is the primary manifestation of histoplasmosis, varying from mild pneumonitis to severe acute respiratory distress syndrome. In those with emphysema, a chronic progressive form of histoplasmosis can ensue. Dissemination of H. capsulatum within macrophages is common and becomes symptomatic primarily in patients with defects in cellular immunity. The spectrum of disseminated infection includes acute, severe, life-threatening sepsis and chronic, slowly progressive infection. Diagnostic accuracy has improved greatly with the use of an assay for Histoplasma antigen in the urine; serology remains useful for certain forms of histoplasmosis, and culture is the ultimate confirming diagnostic test. Classically, histoplasmosis has been treated with long courses of amphotericin B. Today, amphotericin B is rarely used except for severe infection and then only for a few weeks, followed by azole therapy. Itraconazole is the azole of choice following initial amphotericin B treatment and for primary treatment of mild to moderate histoplasmosis.

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“…However, they may be irregularly absorbed when given orally, and coadministration of several other drugs may accelerate their hepatic degradation (13,15). Furthermore, ketoconazole is not very effective when administered to AIDS patients with histoplasmosis (17). Fluconazole is better absorbed, but it may be less effective than itraconazole in the treatment of histoplasmosis, particularly for patients with AIDS (10).…”

mentioning

confidence: 99%

Liposomal amphotericin B therapy of murine histoplasmosis

Graybill

Bocanegra

1995

Antimicrob Agents Chemother

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Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

Abstract: Itraconazole, 200 mg twice daily, is safe and effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. Antigen clearance from blood and urine correlates with clinical efficacy.

Cited by 192 publications

References 0 publications

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

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

Histoplasmosis: a Clinical and Laboratory Update

Liposomal amphotericin B therapy of murine histoplasmosis

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