ASTRACT & COMMENTARY
Synopsis: Treatment of blastomycosis with 400 mg or 800 mg of fluconazole daily was associated with successful outcomes in 87% of patients.
Source: Pappas PG, et al. Treatment of blastomycosis with higher doses of fluconazole. Clin Infect Dis 1997;25:200-205.
Pappas and colleagues randomized non-hiv- infected patients with blastomycosis to receive therapy with fluconazole in doses of either 400 mg or 800 mg daily. Patients with either life-threatening or acute, self-limited infection were excluded, as were individuals with liver function studies greater than five times the upper limit of normal.
Forty-four percent of patients had disease limited to the lungs, 33% had only extrapulmonary disease, and 23% had both. Seventeen (89%) of 19 patients randomized to receive 400 mg daily and 17 (85%) of 20 patients assigned to 800 mg daily were successfully treated, meaning that they were either "cured" or "improved" (cultures negative during the final month of therapy and, respectively, at least 75% reduction in symptoms and signs, including lesion size). Successfully treated patients received fluconazole for a median of 8.0 months (range, 2-24 months), with no significant difference between groups. However, five patients started on 400 mg daily underwent dose escalation to either 600 mg (1 patient) or 800 mg (4 patients) daily because of an inadequate response; four of the five were treatment successes. One subject had a dose reduction from 800 mg to 400 mg daily because of a skin eruption; the eruption resolved, and the infection was successfully treated.
The successes included six patients who had failed prior antifungal therapy. No patients died of blastomycosis, and none of 25 with follow-up (duration not indicated) relapsed. All five patients who failed fluconazole therapy responded to subsequent therapy with either itraconazole or amphotericin B.
Only one patient was removed from the study because of drug toxicity, and one underwent dose reduction for this reason. The former complained of severe anorexia and nausea while receiving 400 mg fluconazole daily; the latter was the patient with rash mentioned above. Minor toxicity, most commonly upper gastrointestinal complaints or alopecia, was observed in approximately one-half the patients. Gastrointestinal complaints occurred in five patients in each group, while reversible hair loss was reported by two patients in the 400 mg group and seven in the 800 mg group.
COMMENT BY STAN DERESINSKI, MD, FACP
Blastomycosis is an infrequently encountered infection caused by Blastomyces dermatitidis, the imperfect or asexual stage of Ajellomyces dermatitidis, whose endemic area includes the states of the Mississippi and Ohio river basins, as well as states of the Midwest and Canadian provinces along the Great Lakes with extension along the basin of the St. Lawrence River. In addition to these regions of North America, cases are reported from Africa, Central and South America, the Middle East, and India.
The organism has been isolated in soil and decaying vegetable material. Infection ordinarily occurs by inhalation of conidia. Resultant pulmonary disease may be self-limited, progressive, or persistent and may be associated with dissemination. The most common sites at which disseminated infection is detected are skin and bone. Skin lesions are most often verrucous or ulcerative; the latter may be associated with sinus tracts from, for example, sites of osteomyelitis.
Patients who are severely immunocompromised and/or have life-threatening disease should receive initial treatment with amphotericin B. In other situations, patients may be treated with itraconazole, which has been reported to be successful in 38 (95%) of 40 patients with blastomycosis treated for at least two months with doses of 200-400 mg daily (Dismukes WE, at al. Am J Med 1992;93:872-879). A small study of fluconazole therapy published two years ago, using doses of only 200-400 mg daily, found success rates of 62-70% (Pappas PG, et al. Clin Infect Dis 1995;20:267-271). The study reviewed here reports apparently improved response rates when doses of fluconazole as high as 800 mg daily are used. In fact, the response rates are similar to those reported with itraconazole and demonstrate that treatment with such doses of fluconazole represents a reasonable alternative approach in selected patients with blastomycosis.