Cryptococcal meningitis was induced in BALB/c mice by intracerebral infection with Cryptococcus neoformans. Drug therapy was initiated 1 day later, with mice receiving amphotericin B (AMB), SCH 39304, combination therapy, or no drug therapy (controls). Most, but not all, combinations showed additive benefits, significantly prolonging survival and reducing organism counts in tissues compared with those in controls and groups which received the drugs independently. Optimum protection was obtained when a single dose of 10 mg of AMB per kg of body weight was combined with a fairly narrow SCH 39304 dose range. AMB antagonism did not occur with any regimen tested. AMB-azole combinations may be reasonable alternatives for patients who fail standard cryptococcosis therapeutic regimens.One of the most common life-threatening infections in patients with AIDS is cryptococcal meningitis (8,14). Thirty percent of these patients fail to respond to the traditional drug combination of amphotericin B (AMB) and flucytosine (25), and therapy must be stopped in many patients because of the toxicity and severe side effects of the drugs (8, 24). Additionally, 50 to 65% of patients have relapses after an apparent initial therapeutic success. This has convinced many investigators that long-term and even lifelong suppressive antifungal therapy is necessary (1, 14). With no current way of predicting which patients will have relapses, maintenance therapy is recommended for all patients (2). With the marked increase in systemic mycoses, there has been a corresponding increase in the number and kinds of antifungal agents used to treat them.In this study, we evaluated combination therapy with AMB and the new triazole SCH 39304 in murine cryptococcal meningitis. We sought to determine whether the efficacy of the combination is superior to the efficacy of each drug administered alone. Additionally, we compared the efficacy of one large dose of AMB followed by SCH 39304 therapy with that of multiple, smaller doses of AMB combined with SCH 39304 to determine whether the efficacy of AMB could be maintained but the duration of therapy could be shortened. Finally, we wished to determine whether pretreatment of mice with SCH 39304 would antagonize the effects of AMB.MATERIALS AND METHODS Animals. Six-week-old BALB/c, heterozygous (nul+) mice were obtained from the colony at our institution. Mice were maintained at five mice per bonneted cage and had access to food and water ad libitum.Pathogen. Clinical isolate 89-98 of Cryptococcus neoformans was used to challenge the mice. Three days prior to each trial, C. neoformans was subcultured onto Sabouraud dextrose agar plates and incubated at 370C.Challenge. Organisms were washed three times in sterile 0.9% saline, counted on a hemacytometer, and diluted to the * Corresponding author. desired count. Anesthetized mice (methoxyflurane; Metophane; Pitman-Moore, Washington Crossing, N.J.) were inoculated intracranially (direct, midline, 6 mm posterior to the orbit) with 0.06 ml per mouse. The total CFU per m...