Editorial response: A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis.

Fluconazole at a dosage of 200 mg daily has again been is effective, while those with persistent urinary cryptococcosis should receive at least 400 mg daily of fluconazole. demonstrated to be highly effective in reducing the risk of relapse after recovery from cryptococcal meningitis [1]. UnforAn interesting note in the clinical study reported by Dr. Saag and colleagues was the possible adjuvant role of flucytosine in tunately, Dr. Saag and his colleagues were not able to demonstrate that itraconazole, at the doses tested, could be used as the initial therapy for cryptococcal meningitis. While not a controlled element of this clinical investigation, those who rean alternative therapy to fluconazole. The measured rate of recurrent meningitis with itraconazole (23%) is similar to that ceived flucytosine in their initial chemotherapy did better. It seems most likely that such an outcome was the result of found with weekly infusions of amphotericin B (18%) and placebo (15%) [2, 3]. Thus, at the present time, fluconazole selection bias, that is, those who can tolerate flucytosine are healthier, or was because subjects who received flucytosine as appears to be the only agent with proven efficacy for preventing relapse of cryptococcal meningitis. Neither itraconazole nor part of their initial therapy had a more rapid conversion of their CSF from positive to negative and a longer interval receiving weekly infusions of amphotericin B appear to be superior to placebo, although neither itraconazole nor weekly infusions of intensive initial chemotherapy with a negative CSF culture before their enrollment in the prevention-of-relapse study. It amphotericin B have been directly compared with placebo. For the patient unable to take fluconazole, albeit a rare event, there seems most prudent and highly desirable to rapidly gain control of the CNS infection by use of combinations of flucytosine appears to be no suitable alternative. with amphotericin B or fluconazole [8] and to obtain CSF to demonstrate that the CSF culture has converted from positive to See article by Saag et al. on pages 291–6. negative before beginning prevention-of-relapse therapy with fluconazole. The caveats associated with prevention of relapse of cryptoNot addressed by any of the prevention-of-relapse studies is coccal meningitis are twofold. First, it is imperative that the the non–AIDS-associated cryptococcal meningitis population. CSF be rendered sterile. All clinical trials conducted have reThe only controlled clinical trial evaluating relapse in this popquired that the CSF be culture-negative at study entry. Persisulation randomized subjects to receive 4 weeks vs. 6 weeks of tence of viable cryptococcal organisms in the completely amphotericin B plus flucytosine and then followed patients asymptomatic patient is well documented, including those with expectantly [9]. The rate of CNS relapse was 15% in those negative serum and CSF cryptococcal antigen titers [3–5]. Secwho received 6 weeks of therapy vs. 27% among those who ond, the failure of fluconazole to prevent relapse of cryptococreceived 4 weeks. While untested, fluconazole should prove to cal meningitis is higher among patients with persistent urinary be as effective in the non-AIDS population as among those cryptococcosis, even when using fluconazole at a dosage of infected with HIV, and I see no reason why patients with 400 mg daily [6]. Thus, it is clinically necessary and desirable AIDS should have a lower risk of relapse, because of receiving to obtain an end-of-therapy sample of CSF and a urine sample fluconazole, than do those without AIDS, who receive no prefollowing prostatic massage before suspending more intensive vention-of-relapse therapy. The duration of such therapy in the initial therapy. These end-of-therapy samples should be neganon-AIDS population is unknown, but it is well established tive after a 2-week incubation period before instituting daily that the risk of relapse remains for several years. For practical fluconazole as lifelong preventive therapy. During that 2-week purposes, I use fluconazole for 2 years or until the risk factor incubation period, initial induction therapy should continue, for disseminated cryptococcal disease abates, for example, for it is difficult for patients to recover lost ground if they stopping immunosuppressive therapy. The cost of such an apshould prove to have positive cultures and receive only flucoproach, while several thousand dollars yearly, is well justified nazole at 200 or 400 mg daily as treatment for active meningitis. given that the majority of non-AIDS patients who have reBe mindful that only one-third of patients with active meningilapse die. tis respond to therapy with fluconazole alone [4, 7]. For those without urinary tract involvement, fluconazole at 200 mg daily Robert A. Larsen Department of Medicine, University of Southern California School of Medicine, Los Angeles, California