Changing strategies for treatment of systemic mycoses

There have been a number of changes in strategies in antifungal therapy in the past few years. AIDS related mycoses hade decreased, and the increse of fluconazole resistant Candida albicans may be slowing because fewer severely immune depressed patients require constant fluconazole suppression. Candida species continue to be relatively commun blood culture isolates. About half of these are C.albicans and half non-albicans species. In recent years, we have moved from the use of amphotericin B to fluconazole for initial treatment of candidemia. We have seen fluconazole resistent isolates emerge, primarily C.glabrata and a few C.krusei, but also C.albicans. It is unclear whether the increasing use of fluconazole in intensive care units will worsen this problem. There appears to be no advantage for the lipid formulations of amphotericin B, though they are useful to reduce or prevent renal toxicity. In the United States and Europe, prevention and treatment of aspergillosis have become increasingly important. There are increasing data suggesting that lipid formulations are more effective for both treatment and prevention of invasive disease in the most vulnerable patients with this infection. Renal toxicity is reduced but not avoided by use of the lipid formulations of amphotericin B. For those patients with less acutely progressing disease, the triazoles may be effective options. It is unclear at present whether itraconazole, voriconazole, or posaconazole will be the most favored drug. One promising new class, now in clinical trials, is the echinocandin group. Other agents, such as the sordarins, the chitin synthase inhibitors, and topoisomerase inhibitors, have promise but are much earlier in development. Unfortunately, we still have >50 (percent) treatment failure with acute invasive aspergillosis, and 20 (percent)-30 (percent) failures with candidemia. Now that we have multiple classes of antifungal drugs available, and others in preclinical trials, it would be advantageous to begin more active exploration of conbination therapy with antifungals and with combined immune modulators and antifungals.

Cryptococcal meningitis

Meningitis is the most common manifestation of dissiminated cryptococcosis. Cryptococcal meningitis is the most common systemic mycotic infecction in AIDS, which is the most frequent predisposing condition. The most severe complication is acute cerebral hypertension. Medical options for therapy have broadened considerably, but generally include initial intensive treatment follwed, in patients with AIDS, by chronic supression. With agressive management of cryptococcal meningitis, mortality may be reduced to 10 percent or less.

Experimental murine chromomycosis mimicking chronic progressive human disease

Congenitally athymic (nu/nu) mice, mice defective in NK cell and macrophage function (bg/bg) and normal BALB/c mice were inoculated sc with 10 5-6 conidia of Fonsecae pedrosoi (FP). In immunologically intact and immunodeficient mice, a local infection developed approximately 2 weeks post-inoculation and enlarged over 1-2 weeks. In bg/bg and normal nu/+ mice, lesions resolved within 5-6 weeks. However, nu/nu mice continued to have enlarging cs lesions during >4-6 months od observation. These eventually metastasized. Lesions contained, few hyphal elements and massive numbers of sclerotic bodies. Five weeks after inoculation. 10 4-6 conidia froming units/gm of tissue were recovered from lesions. Delayed type hypersensitivity and serum antibody to FP antigens were demonstrated. Adoptive transfer of lymphocytes from nu/+ mice was followed in months bu the resolution of the lesions