Combination of oral flucytosine and ketoconazole as therapy for experimental cryptococcal meningitis.

Current therapy for cryptococcal meningitis often is ineffective, toxic, and inconvenient. Ketoconazole has been shown to penetrate into brain tissue of mice and cerebrospinal fluid of humans and to improve the course of human coccidioidal meningitis. Ketoconazole, flucytosine, and amphotericin B, alone and in two-drug combinations, were used to treat cryptococcal meningitis in mice injected intracranially with Cryptococcus neoformans.

Experimental murine aspergillosis. Comparison of amphotericin B and a new polyene antifungal drug, SCH 28191.

In a model of experimental murine aspergillosis, efficacy of amphotericin B (AMB) desoxycholate was compared with SCH 28191, the D-ornithyl methyl ester derivative of amphotericin B (SCH). In vitro studies showed that the Aspergillus isolate was equally susceptible to AMB and SCH. Both drugs were equally effective in prolonging survival after intravenous challenge with conidia of A.

Treatment of experimental murine candidiasis with liposome-associated amphotericin B.

Mice were challenged intravenously with Candida albicans, and then treated either with nothing (controls), amphotericin B-desoxycholate (AMB), or amphotericin B associated with liposomes (AMB-lipo). AMB-lipo permitted larger doses of amphotericin B to be given, and also appeared to have no severe toxicity in the animal model. High doses of AMB-lipo were protective, but at equal doses, AMB-lipo was not as effective as commercial AMB.

R 51211 (itraconazole) therapy of murine cryptococcosis.

A new antifungal triazole, itraconazole (R51211), was compared with ketoconazole in treatment of murine cryptococcosis. Itraconazole is sparingly soluble in water, and must be administered orally in solvents such as polyethylene glycol. Serum concentrations are lower than those achieved with ketoconazole, but sustained for longer periods.

Comparative activities of Bay n7133, ICI 153,066, and ketoconazole in murine cryptococcosis.

Two new antifungal triazoles, BAY n7133 and ICI 153,066, were compared with ketoconazole in treatment of mice challenged intraperitoneally with Cryptococcus neoformans. At high challenge doses, thymus-containing normal mice had prolonged survival after treatment with BAY n7133. Athymic mice, which have severely deficient cell-mediated immunity, were not protected.

Treatment of experimental murine aspergillosis with BAY n7133.

BAY n7133, a recently developed imidazole antifungal drug, was evaluated in experimental murine aspergillosis. BALB/c mice were challenged with conidia of Aspergillus fumigatus by either the intravenous or the intranasal route. One day after challenge, oral treatment with BAY n7133, ketoconazole, or a placebo control was begun BAY n7133 was well absorbed after oral administration and penetrated all tissues evaluated.

Interaction of rifampin with other antifungal agents in experimental murine candidiasis.

A murine model of systemic candidiasis was used for evaluation of the interaction of rifampin with ketoconazole and amphotericin B. In vitro studies with a clinical isolate of Candida albicans showed that rifampin modestly potentiated the antifungal activity of both of these drugs. When mice were challenged iv with C.

Pulmonary cryptococcosis in the rat.

We evaluated a rat model of pulmonary cryptococcosis. Rats immunized subcutaneously with cryptococcal antigen developed peritoneal but not pulmonary macrophage migration inhibition factor (MIF) to cryptococcal cell extract antigens. They did not develop MIF to capsular polysaccharide antigens.

High-dose ketoconazole for treatment of fungal infections of the central nervous system.

Mortality and complication rates remain unacceptably high with conventional intravenous and intrathecal therapy for patients with coccidioidal meningitis and intracerebral fungal lesions. We studied the ventricular and lumbar cerebrospinal fluid penetration of ketoconazole and the responses to therapy in two patients receiving ketoconazole orally, 800 mg daily, and amphotericin B intraventricularly for meningeal and extrameningeal coccidioidomycosis. Five patients received only 1200 mg of ketoconazole: one had uncomplicated coccidioidal meningitis, three had obstructive hydrocephalus due to coccidioidal meningitis, and one had a histoplasmal brain abscess.

Ketoconazole therapy for fungal urinary tract infections.

Ketoconazole was used in 11 patients to treat 12 episodes of fungal urinary infections: 6 in the upper urinary tract and 6 presumed to be in the lower urinary tract. Five patients had catheters in place. Of the 12 infections 8 were caused by Candida species, 1 by mixed Candida tropicalis and Torulopsis glabrata, and 3 by Torulopsis glabrata.

Antifungal agents used in systemic mycoses. Activity and therapeutic use.

The development of the polyene antibiotic, amphotericin B, provided for the first time a drug which was clinically effective in many serious mycotic diseases. Unfortunately, it requires parenteral administration and is often toxic, factors which limit the total cumulative dose which can be given. Efforts to utilise combinations of amphotericin B with other agents were best realised with amphotericin B/flucytosine in cryptococcal meningitis, and to a lesser degree in systemic candidiasis.

Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients. National Institute of Allergy and Infectious Diseases collaborative antifungal study.

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16.

Ketoconazole therapy for systemic fungal infections: inadequacy of standard dosage regimens.

We treated 29 patients with ketoconazole for systemic mycoses. Twenty-two had coccidioidomycosis, 5 had histoplasmosis, and 2 had sporotrichosis. Of the 25 patients who received 200 mg/day, 16% improved on that dose.

Ketoconazole therapy of murine cryptococcal meningitis.

Currently, even optimal therapy of cryptococcal meningitis is associated with appreciable mortality, drug toxicity, and prolonged hospitalization. Ketoconazole, a new oral imidazole, has therefore been evaluated in a murine model of cryptococcosis. Cryptococcal meningitis was induced in BALB/c mice by intracranial injection of Cryptococcus neoformans.

Amphotericin B in liposomes: a novel therapy for histoplasmosis.

Incorporation of amphotericin B into liposomes significantly altered its toxicity, tissue distribution, and efficacy. Compared with intravenously administered amphotericin B-desoxycholate, liposome-amphotericin B showed a reduced acute toxicity and a maximal tolerable dose 9 times greater than amphotericin B-desoxycholate. Liposome-amphotericin B also produced higher tissue and lower serum concentrations than amphotericin B-desoxycholate, and was significantly more effective in prolonging survival of mice infected with Histoplasma capsulatum.

Host defense against experimental paracoccidioidomycosis.

An experimental model for the study of paracoccidioidomycosis was established in BALB/c mice. Both normal and athymic nu/nu animals were challenged intraperitoneally and intratracheally with yeastlike cells of Paracoccidioides brasiliensis. After challenge, all immunologically intact (+/+) mice survived, whereas nu/nu mice gradually succumbed.

Treatment of murine cryptococcosis with liposome-associated amphotericin B.

Liposomes were prepared to incorporate large amounts of amphotericin B. BALB/c mice were challenged with Cryptococcus neoformans and given liposome-associated amphotericin B (AMBL) or amphotericin B-deoxycholate (AMBD) intravenously. Mice that were treated with AMBL survived longer and had lower tissue counts of cryptococci than mice treated with AMBD or untreated control mice.

Immunogenic fractions of Cryptococcus neoformans.

Cryptococcus neoformans cell and culture supernatant extracts were fractionated by ion exchange and gel filtration column chromatography. Various fractions were used to immunize mice, and to assess the release of migration inhibition factor, delayed type hypersensitivity, and protective immunity after challenge with C. neoformans.

Sensitive bioassay for ketoconazole in serum and cerebrospinal fluid.

Ketoconazole is a broad-spectrum antifungal agent which appears promising for treatment of a variety of systemic mycoses. Pharmacokinetic studies are limited due to a lack of readily available methods for quantitation of ketoconazole in serum or cerebrospinal fluid. We developed a rapid, simple bioassay for measurement of ketoconazole alone or in the presence of therapeutic levels of amphotericin B, using an agar diffusion assay incorporating Candida pseudotropicalis.

Adoptive transfer of immunity to Histoplasma capsulatum in athymic nude mice.

Studies of adoptive transfer of resistance to Histoplasma capsulatum were performed with athymic nude (nu/nu) recipients and heterozygous (nu/+) donor mice. This model has the benefit of employing a recipient mouse (nu/nu) which cannot be immunized actively against H. capsulatum.

Ketoconazole treatment of chronic mucocutaneous candidiasis.

Five patients received ketoconazole treatment of chronic mucocutaneous candidiasis. One also had disseminated histoplasmosis and cryptococcosis. Ketoconazole was well absorbed after an oral dose of 200 mg and produced detectable antifungal blood levels for more than eight hours after each dose.