Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy.

OBJECTIVE: To study the efficacy of fluconazole against chronic disseminated candidiasis (hepatosplenic candidiasis) in patients with leukemia in whom amphotericin B treatment had failed. DESIGN: Retrospective analysis of patients with chronic disseminated candidiasis treated with fluconazole on a compassionate investigational new drug protocol. SETTING: Multi-institutional. PATIENTS AND METHODS: Twenty consecutive patients received 100 to 400 mg of fluconazole per day for a median of 30 weeks. All had either failed to respond to treatment with more than 2 g of amphotericin B or had serious amphotericin B-related toxicities. RESULTS: Fourteen of 16 evaluable patients (88%) responded. Responses were observed in seven of nine patients in whom adequate doses of amphotericin B had failed and in all seven patients who had amphotericin B-related toxicities. In 12 patients, cytotoxic chemotherapy was continued without flare of the infection. Fluconazole was well tolerated with rare side effects. Aspergillus superinfection developed in three patients and contributed to the death of two of them. CONCLUSION: Fluconazole is a safe and effective agent with significant activity against chronic disseminated candidiasis.

Ketoconazole treatment of nonprimary coccidioidomycosis. Evaluation of 60 patients during three years of study.

Sixty patients with coccidioidomycosis were treated with ketoconazole rather than with another antifungal agent, and their responses were evaluated in relation to the predominant site of involvement. For the three main groups, improvement occurred in 12 of 19 patients with chronic pulmonary infections, in 20 of 23 with soft tissue lesions and in six of 11 with skeletal involvement. Infections in soft tissues improved most rapidly (average of 34 days) and often with 200 mg per day, whereas pulmonary and skeletal infections improved more slowly (63 and 165 days, respectively), usually requiring 400 mg per day. Of 12 patients with response in whom therapy has been discontinued, seven have had relapses. Recurrence was apparent usually within the first month and after six months or less of treatment. Patients in remission had received ketoconazole for six to 17 months. Untoward drug effects included abdominal complaints (23 percent) and gynecomastia (8 percent). Therapy was discontinued in only three patients for side effects. Our findings support the use of ketoconazole in the treatment of certain forms of chronic coccidioidal infections.

The incidence and implications of coccidioidouria.

To estimate the frequency and significance of isolating Coccidioides immitis from urine specimens, we reviewed the records of 75 patients with various forms of coccidioidomycosis of whom 29 had urine cultures for fungi. The 7 patients (24%) who had coccidioidouria appeared similar as a group to those whose cultured urine did not yield C. immitis. Over half of the patients had no other evidence of extrathoracic spread, and in 2 patients with coccidioidouria, illness resolved without treatment. Usually only a few colonies of the fungus were isolated from 200-ml specimens. Thus, our use of a concentrating technique and repeated sampling may account for the high incidence of coccidioidouria in this study. Isolating C. immitis from the urine may be helpful for diagnosis and should lead to further evaluation of the urinary tract for destructive parenchymal lesions. However, as an isolated finding, coccidioidouria does not always indicate the need for therapy.

Disposition of ketoconazole, an oral antifungal, in humans.

The pharmacology of ketoconazole was studied in patients with fungal infections. After administration of 50-, 100-, and 200-mg doses of ketoconazole, there was a linear increase in the area under the curve of serum concentrations; this was not apparent when higher doses of ketoconazole were given. An increase in the area under the curve occurred in patients receiving 200 mg daily who were restudied after 1 to 12 months of therapy. However, normalized area under the curve appeared to decrease after higher doses were administered chronically. The half life ranged from 2.0 to 3.3 h. Peak serum concentrations up to 50 micrograms/ml were detected in this study, and potentially therapeutic concentrations were detectable up to 26 h after high doses. Ketoconazole penetrated the saliva and inflamed joint fluid and meninges, although variably, and could be demonstrated in some other tissue compartments. In the presence of renal failure, ketoconazole disposition was not altered, whereas in the presence of hepatic insufficiency, an alteration in disposition was suggested. The interactions of ketoconazole and other drugs were studied. Of note, antacids did not significantly affect ketoconazole pharmacokinetics (nor did meals), and ketoconazole and warfarin did not appear to affect the pharmacokinetics of the other.

Gynecomastia with ketoconazole.

Three of forty men developed bilateral gynecomastia upon ketoconazole treatment. Symptoms abated despite continued therapy. This appears to be a direct drug effect on breast tissue.