Bernard E. Levine

The Role of Long-term Continuous Oxygen Administration in Patients with Chronic Airway Obstruction with Hypoxemia

Excerpt Oxygen is a valuable therapeutic tool for patients with chronic airway obstruction with hypoxemia. The applications of oxygen in acute respiratory decompensation (1-3) and as an adjunct to ...

Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis.

The pharmacokinetics of fluconazole, a new oral azole, were evaluated in cerebrospinal fluid and sera of eight patients with coccidioidal meningitis. At a dose of 50 mg/day, peak concentrations of 2.5 to 3.5 and 2.0 to 2.3 micrograms/ml occurred at 2 to 6 and 4 to 8 h in serum and cerebrospinal fluid, respectively. At 100 mg/day, peak concentrations of 4.5 to 8.0 and 3.4 to 6.2 micrograms/ml occurred at 2 to 4 and 4 to 12 h, respectively. The mean ratios of the concentration in cerebrospinal fluid to that in serum were 73.8% at 50 mg/day and 88.7% at 100 mg/day. Results suggested that there was a prolonged half-life in both cerebrospinal fluid and serum and that it was slightly longer in the former. Minimal toxicity was noted in 34 patient months of therapy (12 months on 50 mg daily; 22 months on 100 mg daily). After a mean of 4.5 months of therapy, five patients responded to therapy and three were unevaluable. The penetration of fluconazole into cerebrospinal fluid was substantial, toxicity was minimal, and early clinical experience was encouraging. Fluconazole holds promise as the sole or adjunctive therapy for fungal meningitis.

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis

PURPOSE To determine the efficacy and safety of fluconazole as treatment for coccidioidomycosis. PATIENTS AND METHODS This was a multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft-tissue, 42 had chronic pulmonary, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, 7 of whom had HIV infection. Patients were given oral fluconazole 200 mg/d. Nonresponders were increased to 400 mg/d. Treatment courses were long: a mean of 323 +/- 230 days at 200 mg and 433 +/- 178 days at 400 mg. Predefined assessment of disease-related abnormalities was performed at the time of enrollment and repeated at least every 4 months. A satisfactory response was defined as any reduction of baseline abnormality by month 4 and at least 51% reduction by month 8. RESULTS Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease. Five patients (7%) required modification of treatment due to toxicity. Forty-one patients who responded were followed off drug. Fifteen (37%) of them experienced reactivation of infection. CONCLUSION Fluconazole 200 or 400 mg/d is well tolerated and a moderately effective treatment for chronic pulmonary or nonmeningeal disseminated coccidioidomycosis. The relapse rate following therapy is high. Treatment trials with higher doses appear warranted. The relative efficacy of fluconazole versus other azoles or amphotericin B remains unknown.

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 concentrations in ventricular and lumbar fluid ranged from 0.05 to 1.65 micrograms/mL 4 and 8 hours after the dose. The mean penetration of ketoconazole (+/- SD) was 1.9% +/- 0.8% for ventricular fluid and 5.4% +/- 2.6% for lumbar fluid. Ketoconazole concentrations in cerebrospinal fluid varied directly with those in serum and with cerebrospinal fluid protein content. The encouraging clinical responses, convenience, safety, and the consistent penetration of ketoconazole into obstructed and nonobstructed cerebrospinal fluid support the use of these regimens as alternatives to conventional therapy.

Safety, Tolerance, and Efficacy of Posaconazole Therapy in Patients with Nonmeningeal Disseminated or Chronic Pulmonary Coccidioidomycosis

BACKGROUND Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis. METHODS Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point. Patients received posaconazole (400 mg/day) in capsule formulation for up to 6 months. Safety was evaluated on the basis of the occurrence of adverse events. A satisfactory efficacy response was defined as a >or=50% reduction in the Mycoses Study Group score from baseline. RESULTS Seventeen (85%) of 20 patients had a satisfactory response to treatment. The median duration of treatment was 173 days. Paired baseline and end-of-treatment culture results for Coccidioides species were available for 4 patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by 3 of 9 patients who did not receive antifungal therapy during the follow-up period. In general, posaconazole therapy was well tolerated, with 12 of 20 patients reporting adverse events that were possibly or probably related to treatment. The most common adverse events were dry mouth (in 5 patients [25%]) and headache (in 3 patients [15%]). CONCLUSIONS Courses of posaconazole therapy that were up to 6 months in duration were well tolerated in patients with coccidioidomycosis. Although this study was limited by the number of patients enrolled, it clearly demonstrates that posaconazole shows promise in the treatment of patients with coccidioidomycosis and warrants additional investigation in a full-scale clinical trial.

Ketoconazole for treatment of disseminated coccidioidomycosis.

Of 29 selected patients with disseminated coccidioidomycosis, 27 were treated for at least 6 months with ketoconazole, 200 to 600 mg/d. Two patients had progression of coccidioidal disease shortly after starting ketoconazole, and one developed meningitis. Seven of eight patients with synovitis had prompt improvement in symptoms, but four either had recurrent synovial thickening without recoverable Coccidioides immitis or could not remain free of symptoms off the drug. The response of osteomyelitis to ketoconazole was hard to assess; three of eight cases clearly improved and none progressed. Abscess or sinus formation clearly improved in eight of patients; five remained free of disease after the drug was discontinued. Skin lesions improved in six of nine; three lesions remain healed off the drug. Ketoconazole is absorbed readily after oral ingestion and has little toxicity. In the dosages used, it seems to suppress but not eradicate C. immitis. The drug may be able to stabilize the infection while cell-mediated immunity is restored.

Ketoconazole for Treatment of Chronic Pulmonary Coccidioidomycosis

Twenty-one patients with chronic pulmonary coccidioidomycosis were treated with ketoconazole. In 16 patients with chronic cavitary disease, nine improved, four showed no change, and the condition of three deteriorated; three of nine patients had culture conversion. Roentgenograms showed improvement in two patients, no change in 12, and deterioration in two. Serologic improvement was not noted. In five patients with persistent infiltrative disease, the response was more favorable. Radiographic improvement, culture conversion, and serologic improvement were seen in most patients. Ketoconazole-induced side effects were mild and of short duration, ending in the first days of therapy. Ketoconazole seems to be of significant value in infiltrative pulmonary disease, but seems unable, at the doses used, to change finding in the sputum or to change radiographic findings in chronic cavitary disease. Further long-term observation is necessary to evaluate fully the role of this drug in chronic pulmonary coccidioidomycosis.