Source: van der Horst CM, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21.
Van Der Horst and colleagues randomized AIDS patients with cryptococcal meningitis to initially receive, for two weeks, either amphotericin B (0.7 mg/kg/d) alone or together with flucytosine (100 mg/kg/d po in 4 divided doses). Patients who were stable or improved after this period of "induction therapy" were randomized to receive, orally, either fluconazole or itraconazole for an eight-week "consolidation" period. A loading dose of fluconazole 800 mg/d for two days was followed by 400 mg daily, while itraconazole was administered in a dose of 600 mg/d for three days followed by 200 mg bid.
After two weeks of induction therapy, CSF culture was negative in 60% of the 202 patients given amphotericin B plus flucytosine and in 51% of the 179 given amphotericin B alone (P = 0.06; no CSF was obtained from 33 patients in each group; these were considered "positive"). Clinical improvement was similar in both groups, as was the change in median titer of CSF cryptococcal antigen, which decreased from a baseline of 1:1024 in each of the groups to 1:200 in those receiving combination therapy and 1:256 in the single drug group (P = 0.56).
At 10 weeks (after completion of the 8-week consolidation phase), CSF cultures were negative in 72% of the fluconazole recipients and in 60% of the itraconazole recipients (not significant; no CSF was obtained from 39 and 54 patients, respectively). Clinical improvement also did not differ between the two treatment groups; median CSF cryptococcal antigen decreased to 1:57 in the fluconazole group and 1:32 in the itraconazole recipients (P = 0.22).
Twenty-one patients (5.5%) died during induction therapy; 11 received amphotericin B alone. During consolidation therapy, two fluconazole and five itraconazole recipients died. Therapy was well tolerated during each phase.
The median baseline CSF opening pressure was 220 mm in the 123 patients with a negative CSF culture at two weeks and 280 mm in the 97 patients with a positive CSF culture at that time (P = 0.01). Thirteen of 14 patients who died had a CSF opening pressure greater than 250 mm at the last measurement.
Multivariate analysis found that an elevated baseline serum creatinine (P = 0.04), treatment with amphotericin B plus flucytosine (P = 0.01), the presence of fever (P = 0.02), and a negative blood culture for Cryptococcus neoformans (P = 0.001) were independently associated with a negative CSF culture at two weeks. The absence of intravenous drug use (P = 0.03), fluconazole therapy (P = 0.02), and a negative CSF culture at two weeks were independently associated with a negative CSF culture at 10 weeks.
COMMENT BY STAN DERESINSKI, MD, FACP
This study found that treatment with amphotericin B at a dose of 0.7 mg/kg/d plus flucytosine at a dose of 100 mg/kg/d in divided doses was associated with improved CSF sterilization when compared to amphotericin B alone. The dose of flucytosine used was lower than has previously been used in some studies of the treatment of cryptococcal meningitis (150 mg/kg/d). Since flucytosine is renally excreted, the association of increased serum creatinine at baseline with improved outcome may potentially be explained by the effect of impaired renal function on clearance of this drug. This, in turn, suggests that using a higher dose of flucytosine may improve the results seen here with combination therapy.
Consolidation therapy with fluconazole was similarly associated with a higher rate of CSF sterilization than was therapy with itraconazole. This is consistent with a previous study demonstrating that chronic suppressive therapy with fluconazole (200 mg daily) was superior to suppression with itraconazole (200 mg daily) (Saag MS, et al. 35th ICAAC, 1995). It is possible that use of the newly available oral suspension of itraconazole may produce better results because of its improved bioavailability. However, the greater potential for drug interactions with itraconazole relative to fluconazole is a potential problem given the polypharmacy practiced with AIDS patients.
The outcomes in this study were superior to those in studies using lower doses (0.4 mg/kg/d) of amphotericin B (Saag MS, et al. N Engl J Med 1992;326:83-89). A study using a dose of 1 mg/kg/d with or without flucytosine reported no mortality and a successful outcome in 29 of 31 subjects (de Lalla F, et al. Clin Infect Dis 1995;20:263-266).
Of particular interest is an investigation by the California Collaborative Treatment Group. The efficacy of varying doses of fluconazole with or without flucytosine was evaluated in 89 AIDS patients with first episode cryptococcal meningitis. A successful outcome (survival with negative CSF culture) after 10 weeks of therapy was observed in 11%, 37%, 62%, and 62% of those who received 800, 1200, 1600, and 2000 mg of fluconazole daily, respectively (P < 0.01). The addition of flucytosine (150 mg/kg/d) for the first four weeks improved the outcome at each dose of fluconazole; 10-week success rates with the addition of flucytosine were 75%, 87%, 69%, and 83% at each of the above doses (P < 0.01). This suggests that the optimal doses for wholly oral treatment of cryptococcal meningitis may be 1200 mg of fluconazole daily plus flucytosine 150 mg/kg/ in divided doses (4th Conference on Retroviruses and Opportunistic Infections, Abstract #5).
Of particular note in the current study is the importance of elevated CSF opening pressure and its association with mortality. The investigators used an algorithmic approach to the management of increased pressure, which included the use of daily lumbar puncture, administration of acetazolamide and ventriculoperitoneal shunting for asymptomatic patients with pressures greater than 320 mm, and for symptomatic patients with pressures greater than 180 mm. We agree that aggressive management of elevated CSF pressure is warranted in these patients.
While this study indicates that, with regard to rapidity of sterilization of CSF, a two-week induction period of amphotericin B plus flucytosine followed by an eight-week consolidation period with fluconazole is superior to the comparator regimens, there were no significant differences with regard to clinical outcome, including death. Thus, in circumstances in which this regimen cannot be used, the alternative regimen can be safely prescribed.
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