CRYPTOCOCCAL MENINGITIS - THE PLACE OF ITRACONAZOLE

Itraconazole, an orally active broad-spectrum triazole antimycotic, ha s demonstrated anti-Cryptococcus activity in vitro and in animal model s of cryptococcal meningitis. The drug has been used by a number of cl inical groups for the treatment of cryptococcal meningitis, predominan tly in AIDS patients. A problem that has been found with ketoconazole is the relatively low absorption of the drug in AIDS patients. This ha s resulted in ketoconazole plasma levels below the MIC90 (1-5 mug ml-1 ) needed to eliminate Cryptococcus neoformans. In addition, tissue lev els of ketoconazole are lower than plasma levels. For itraconazole, th e required MIC90 for Cr. neoformans is 0.1 mug ml-1, and the plasma le vels in AIDS patients receiving 200-400 mg daily, even in the case of reduced absorption, are well above this MIC90. The itraconazole levels in the brain and in the meninges are higher than the plasma levels. C onsequently, itraconazole has been considered a valid candidate for st udies in patients with cryptococcal meningitis. Various treatment moda lities have been used: primary oral therapy alone or in combination wi th amphotericin B or 5-fluorocytosine (5-FC); maintenance oral therapy after initial treatment with amphotericin B (with or without 5-FC); a nd first-line intravenous treatment in.severely ill patients. The resu lts were evaluated in four different groups. When the drug was given a s primary oral therapy without combination with amphotericin B or 5-FC , the results depended greatly on the dose administered and on the lif e expectancy of the patient at inclusion. In general, daily doses of 4 00 mg were better than 200-mg doses. Patients moribund to begin with h ad very little chance of survival. When patients had a life expectancy of a few weeks to a month at the point of inclusion, survival increas ed substantially and the response rate was usually above 70%. In these patients clinical response was fast but mycological cure was slow. It raconazole in combination with amphotericin B or 5-FC seemed to give a t least an equally good clinical response. The CSF was completely clea r of infection faster. The time of initial combination with amphoteric in B or 5-FC varied from 2 to 6 weeks. As is the case with most opport unistic infections in AIDS, relapse is frequent in cryptococcal mening itis. Consequently, maintenance therapy has to be considered after the initial therapy. With itraconazole as maintenance treatment few patie nts developed relapses, and those that did occur were often related to inconsistent intake of the medication by the patients. Even when pati ents' CSF was not free from infection at the end of the primary therap y, maintenance therapy with itraconazole 200 mg daily resulted in yeas t-free CSF. Several AIDS patients with advanced cryptococcal meningiti s were treated with an i.v. formulation of itraconazole in a randomize d comparison with amphotericin B. Clinically both drugs were equivalen t, with a faster mycological cure with amphotericin B and a better tol erance of the i.v. itraconazole. Tolerance of itraconazole was good in this patient population. No severe side-effects were observed and bio chemical parameters showed no consistent drug-induced effects. These r esults suggest that itraconazole is active as primary and maintenance therapy for cryptococcal meningitis. Absorption in the AIDS patients w as not a problem, probably because, even in case of malabsorption, lev els of itraconazole were still above the MIC90. For primary therapy, r esults can be optimized in combination with amphotericin B or 5-FC. Th e results with an experimental i.v. formulation of itraconazole demons trate that an effort should be made to make this drug also available i n an intravenous formulation. Finally, drug tolerance and toxicity in this patient population appear to be good.