Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group.

BACKGROUND: In previous open-label noncomparative clinical trials, both fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis. OBJECTIVE: To determine whether fluconazole or itraconazole is superior for treatment of nonmeningeal progressive coccidioidal infections. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 7 treatment centers in California, Arizona, and Texas. PATIENTS: 198 patients with chronic pulmonary, soft tissue, or skeletal coccidioidal infections. INTERVENTION: Oral fluconazole, 400 mg/d, or itraconazole, 200 mg twice daily. MEASUREMENTS: After 4, 8, and 12 months, a predefined scoring system was used to assess severity of infection. Findings were compared with those at baseline. RESULTS: Overall, 50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively (difference, 13 percentage points [95% CI, -2 to 28 percentage points]; P = 0.08). Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole. By 12 months, 57% of patients had responded to fluconazole and 72% had responded to itraconazole (difference, 15 percentage points [CI, 0.003 to 30 percentage points]; P = 0.05). Soft tissue disease was associated with increased likelihood of response, as in previous studies. Azole drug was detected in serum specimens from all but 3 patients; however, drug concentrations were not helpful in predicting outcome. Relapse rates after discontinuation of therapy did not differ significantly between groups (28% after fluconazole treatment and 18% after itraconazole treatment). Both drugs were well tolerated. CONCLUSIONS: Neither fluconazole nor itraconazole showed statistically superior efficacy in nonmeningeal coccidioidomycosis, although there is a trend toward slightly greater efficacy with itraconazole at the doses studied.

Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group.

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.

Fluconazole therapy for histoplasmosis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.

We assessed the efficacy of oral fluconazole (200-800 mg daily) in the treatment of non-life-threatening acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, or disseminated histoplasmosis in patients without human immunodeficiency virus infection. Of 27 evaluable patients, two had progressive acute pulmonary histoplasmosis, 11 had chronic pulmonary histoplasmosis, and 14 had disseminated histoplasmosis. Median durations of treatment in each of the three groups were 6 months, 7 months, and 11 months, respectively. Nineteen patients were treated with 400 mg of fluconazole daily (two of these patients received 800 mg daily for a portion of their treatment courses), seven were treated with 200 mg daily, and one was treated with 800 mg daily. Treatment was successful in 17 (63%) of 27 cases. Both of the patients with acute pulmonary infection responded to therapy, as did five (46%) of 11 patients with chronic pulmonary infection and 10 (71%) of 14 patients with disseminated infection. No substantial toxicity was observed. We conclude that fluconazole therapy for histoplasmosis is only moderately effective and should be reserved for patients who cannot take itraconazole.

Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS.

The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B (AmB) lipid complex (ABLC) in the treatment of AIDS-associated cryptococcal meningitis. Of 55 patients randomly assigned to 6 weeks of therapy with ABLC (1.2-5.0 mg/[kg.d], with ascending doses for three sequential cohorts) or AmB (0.7-1.2 mg/[kg.d]), 46 received > or = 12 doses. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with AmB than with ABLC. The total number of adverse events, infusion-related events, and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar. Among 21 recipients of ABLC at a dosage of 5 mg/kg (daily for 2 weeks and then thrice weekly for 4 weeks), symptoms and signs resolved for 18 (86%). Of those receiving > or = 12 doses of ABLC, cultures converted to negative for 8 (42%), were undeterminable for 3 (16%), and remained positive for 8 (42%) despite resolution of symptoms. Although preliminary, these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis. Because this formulation has less hematologic and renal toxicity than does AmB, further evaluation of ABLC is warranted.

Alopecia associated with fluconazole therapy.

OBJECTIVE: To describe the association between fluconazole and reversible alopecia. DESIGN: A retrospective survey of 1) patients enrolled in NIAID Mycoses Study Group (MSG) protocols involving the long-term use of fluconazole for treatment of endemic mycoses and 2) patients treated with fluconazole outside of a protocol setting but by the MSG investigators who were MSG members. SETTING: 26 MSG sites in the United States. PATIENTS: 33 patients with various deep and superficial mycoses who developed alopecia while receiving fluconazole. RESULTS: 11 of 26 investigators reported a total of 33 patients with substantial alopecia related to fluconazole therapy. Underlying mycoses included blastomycosis, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and mucosal candidiasis. In separate MSG studies, 17 of 136 (12.5%) and 8 of 40 (20%) patients had substantial reversible alopecia associated with fluconazole therapy. Eight patients who were not in the protocol had similar adverse effects. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily for a mean of 7.1 months. Alopecia developed a median of 3 months after initiation of fluconazole therapy and involved the scalp in all patients. Other sites were involved in about one third of patients. Three patients required wigs because of extensive hair loss. Alopecia resolved within 6 months of discontinuation of fluconazole therapy or reduction of the daily dose by at least 50%. CONCLUSIONS: Alopecia appears to be a common adverse event associated with higher-dose (400 mg/d) fluconazole given for 2 months or longer. This effect may be severe but is reversed by discontinuing fluconazole therapy or substantially reducing the daily dose.

Treatment of coccidioidomycosis with SCH 39304.

A new oral triazole antifungal, SCH 39304, was administered to 54 patients with progressive infections due to Coccidioides immitis from six collaborating centers. Patients were grouped according to site of infection including chronic pulmonary (25), bone/joint (17) and skin/soft tissue (12). The median age was 40 years; 83% were male, 52% white, 13% HIV-infected and 35% had failed previous therapy. The majority of patients were treated with either 100 mg or 200 mg day-1. One patient on renal dialysis received 300 mg day-1. Baseline abnormalities were reassessed for evidence of efficacy every 4 months and expressed in a standardized scoring system. Cumulative overall response rates at 4, 8 and 12 months were 7%, 36% and 66% respectively. Twelve month response rates by disease were 77% (pulmonary), 62% (skin/soft tissue) and 31% (bone/joint). Fifteen patients failed therapy although seven of these were still on treatment when the study was discontinued. Two failed due to toxicity. Possible symptoms or signs of toxicity occurred in 24 (44%) patients and were generally mild. SCH 39304 is an effective and well tolerated therapy for progressive forms of coccidioidomycosis.

Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing.

The pharmacokinetics of SCH-39304, an investigational, orally active, broad-spectrum antifungal agent, were evaluated in 17 adult, human immunodeficiency virus-positive males. Patients were studied on days 1 and 16 and were divided into the following three treatment groups: (i) patients with culture-proven oropharyngeal candidiasis who were not receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 6); (ii) patients with culture-proven oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 5); and (iii) patients with or without oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 200 mg of SCH-39304 daily (n = 6). All patients received a single daily dose of the study medication for 16 days. Plasma samples for SCH-39304 concentration measurement were collected for 6 h following the initial dose and for 504 h following the day 16 dose. Urine was collected for 24 h following SCH-39304 administration on days 1 and 16. All samples were assayed for SCH-39304 by gas chromatography. Wide intersubject variations in SCH-39304 plasma concentration-versus-time profiles were observed on each study day. Absorption appeared to be slow, with mean day 1 peak plasma SCH-39304 concentrations of 1.2 micrograms/ml at 2.1 h (50 mg) and 3.9 micrograms/ml at 4.0 h (200 mg) after drug administration. Mean peak plasma SCH-39304 concentrations on day 16 were 7.6 micrograms/ml at 4.3 h (50 mg) and 17.2 micrograms/ml at 3.2 h (200 mg) after drug administration. Mean elimination half-lives on day 16 for the 50- and 200-mg daily dosages were 100 and 89 h, respectively. SCH-39304 was cleared primarily unchanged in the urine. Mean areas under the plasma concentration-versus-time curve (from 0 to 24 h) on day 16 reflect a lower than expected increase with the 200-mg/day regimen (314.5 microgram.h/ml) compared with that for the 50-mg/day regimen (139.9 microgram.h/ml), suggesting the potential for reduced bioavailability at higher dosages. No significant effect of concurrent zidovudine therapy on the kinetics of SCH-39304 was observed.

Mycotic pulmonary infections.

Mycotic infections involve the lungs in the majority of cases. Some of the infections are limited in geographic location, while others are worldwide. Often the patients may present with minimal symptoms, unlike bacterial infections, and these symptoms may persist for a longer duration. In this article the authors describe the clinical and radiographic findings of mycotic infections in humans with emphasis on common features.

Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.

Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.

Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

BACKGROUND: Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS: In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS: Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS: Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.

High-dose itraconazole in the treatment of severe mycoses.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Itraconazole treatment of phaeohyphomycosis.

Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these, 17 were assessable for clinical outcome. Of these, two had received no prior therapy, five had failed amphotericin B therapy, four had failed ketoconazole or miconazole therapy, and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients, soft tissue in nine, sinuses in eight, bone in five, joints in two, and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment, one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis, including patients refractory to other antifungal agents.

Fungal infections and their management.

The first oral agents for treatment of mycoses included potassium iodide, griseofulvin and flucytosine. While each is still used in specific indications, the advent of ketoconazole in the late 1980s radically expanded the spectrum and efficacy of oral antifungals. Ketoconazole was the first drug sufficiently potent and benign to permit use for both superficial and deep fungal infections. Ketoconazole quickly proved highly effective in many systemic and cutaneous infections, but it was soon appreciated that high doses caused impairment of testosterone and ultimately cortisol synthesis. Dose-dependent nausea and vomiting also became apparent, as did the necessity for very high doses for treatment of fungal meningitis. Hepatic cellular toxicity was also noticed, particularly after prolonged treatment at high doses. Just as these limitations became apparent, Janssen, Pfizer and, most recently, Schering brought forth the triazole antifungals. These differ markedly in pharmacokinetics and fungal spectrum, requiring careful consideration of the appropriate drug. In addition to the above, terbinafine has been recently developed for dermatophytes, particularly refractory onychomycoses.

Bipolaris hawaiiensis-caused phaeohyphomycotic orbitopathy. A devastating fungal sinusitis in an apparently immunocompetent host.

The authors present a case report of a devastating bilateral optic neuropathy and orbitopathy initiated by a contiguous fungal sinusitis, in an apparently immunocompetent young man. The causative organism, Bipolaris hawaiiensis, and other species classified in the genus Bipolaris, are being recognized with increased frequency as causes of several ophthalmic and systemic disorders in both immunocompromised and normal hosts. A literature review demonstrates the variety of clinical presentations with emphasis on those cases which may present to the ophthalmologist.