Treatment of murine cryptococcal meningitis with an SCH 39304-amphotericin B combination

Abstract

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...

Interaction between Posaconazole and Amphotericin B in Concomitant Treatment against Candida albicans In Vivo

“…The absence of FLC-AMB antagonism was observed in murine candidiasis studies (17,21) and by George et al (8) in an immunosuppressed rabbit model of aspergillosis, by Anaissie et al (2) against Trichosporon beigelii infection in mice, and by Barchiesi et al (5) against murine systemic cryptococcosis. Other triazole-AMB combinations were also not antagonistic, including saperconazole against murine systemic candidiasis (20) and SCH 39304 against murine systemic candidiasis (19) and cryptococcal meningitis (1).…”

Combination Antifungal Therapy

“…Investigations that have not confirmed synergy (78,80,161) VOL. 48,2004 MINIREVIEW 697 (14) Improved (3,50,61,157), similar (14,50,60,212), or worse (89) survival Reduced tissue burden (50,78,101,212) Combination associated with better survival than monotherapy and was consistent over a range of doses (3); effects more pronounced at lower doses (101), and single agents were very effective at higher doses alone; 5FC ϩ KTC rarely cleared tissues better than either agent alone (150); hamsters with combination did worse than with ITC alone (89); ITC ϩ 5FC performed similarly to ITC ϩ AmB and better than ITC or 5FC monotherapy in guinea pigs (212); with 10 days of treatment of mice, combination prolonged survival more than either agent alone but not when treatment was limited to 5 days (157); PSC combination not better than monotherapy in terms of survival but better than monotherapy in reducing fungal counts in brain tissue (14) Humans FLC (48,102,124,193,223) Good clinical success (48,102,193 FLC: addition of AmB to FLC had dramatic impact on yeast burden in brain tissue b , but survival with AmB was 100%; effects on survival were greatest at highest dosages of azole-AMB (2,158); improved survival at lower doses of ITC ϩ AmB, but survival was worse when higher doses were used (157); FLU preexposure did not reduce subsequent AmB activity (13) Humans-case report (47) Case report of a woman with meningitis who responded to this combination after failing AmB used lower concentrations of flucytosine and amphotericin B only or used strains with reduced susceptibility to flucytosine, which may have influenced or biased their ability to characterize the full spe...…”

Interactions between Triazoles and Amphotericin B against Cryptococcus neoformans

“…The interaction of amphotericin B (AmB) and azole antifungal drugs in the treatment of fungal infections is still a controversial issue (1,9,11,(16)(17)(18)(19)(20)(21)(23)(24)(25)(26)(27). AmB is believed to act primarily by damaging the fungal cell membrane after binding to fungal sterols, mainly to ergosterol.…”