Is it ever safe to stop azole therapy for Coccidioides immitis meningitis?

OBJECTIVE: To determine 1) whether patients with coccidioidal meningitis who had achieved remission with oral azole therapy were cured and 2) when oral azole therapy could be discontinued in these patients. DESIGN: Data were gathered on patients with coccidioidal meningitis who had successfully responded to azole therapy in previous clinical trials. SETTING: Referral centers, including university, county, and veterans' hospitals and clinics. PATIENTS: 18 patients in whom azole therapy for meningitis had been discontinued, usually because of a presumption of cure. MAIN OUTCOME MEASURES: Clinical and cerebrospinal fluid relapse. RESULTS: 14 of 18 patients (78% [95% CI, 52% to 94%]) had relapse with disseminated disease after discontinuation of therapy, for a total of 1 nonmeningeal and 15 meningeal relapses to date. Relapse occurred both soon and late (range, 0.5 to 30 months) after therapy was discontinued. The characteristics of patients who did not have relapse, including the particular azole used, the duration of therapy, the reason therapy was discontinued, and the cerebrospinal fluid indices before discontinuation, were similar to the characteristics of patients who had relapse. Relapse had serious consequences in some patients; 3 patients died. CONCLUSION: Our data suggest 1) that disease is only suppressed in patients with meningitis who achieve remission while receiving azole therapy and 2) that discontinuing azole therapy is unsafe. The alternative is lifelong treatment with azoles; this appears to be acceptable, because toxicity is uncommon with triazole therapy, even long-term triazole therapy.

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Efficacy of oral amphotericin B in AIDS patients with thrush clinically resistant to fluconazole.

Reports of thrush clinically refractory to azoles in AIDS patients are increasing with the more widespread use of these agents. We studied our own oral preparation of amphotericin B in the treatment of two AIDS patients who developed oral thrush due to Candida glabrata after prolonged fluconazole use. Improvement occurred in both in less than 1 week, with eventual clearing and absence of side effects. Oral amphotericin B may have advantages over alternatives for this increasing problem.

In vitro susceptibility of Nocardia asteroides to 25 antimicrobial agents.

Fifty-two clinical isolates of Nocardia asteroides were tested by agar dilution for their susceptibility to 25 antimicrobial agents. In general, susceptibility could not be predicted based on the antibiotic class tested. However, the beta-lactams, including third-generation cephalosporins, were generally ineffective (MIC for 90% of the organisms [MIC90], between 64 and greater than 256 micrograms/ml), whereas minocycline and doxycycline were generally effective (MIC90, 4 and 8 micrograms/ml, respectively). Cycloserine was not effective below 60 micrograms/ml. The MIC50 and MIC90 of sulfamethoxazole was 16 and 32 micrograms/ml, respectively, and that of trimethoprim varied widely (16 and greater than 256 micrograms/ml, respectively). Based on MIC90 data, only doxycycline, minocycline, sulfamethoxazole, and imipenem could be applied empirically.