Fluconazole shown to be more effective against cryptococcal meningitis at higher dose

A small Ugandan study has shown that 1200mg of fluconazole per day appears to be a better treatment for cryptococcal meningitis than 400 to 800mg per day, which is the dosage typically administered to patients in many African health facilities. The study was reported in the December 15^th edition of Clinical Infectious Diseases.

Thirty HIV-positive individuals with cryptococcal meningitis were treated in two study arms. Patients in the first arm received 800mg of fluconazole per day for two weeks, and patients in the second arm received 1200mg of fluconazole per day for two weeks. The dosage for all patients was then reduced to a maintenance level of 400mg per day for eight more weeks. Patients taking the higher initial dose of fluconazole had a more rapid rate of clearance of infection.

Cryptococcal meningitis is a dangerous inflammation of the membranes covering the brain and spinal cord. It is caused by the fungus Cryptococcus neoformans, and can be treated effectively with an antifungal medication known as amphotericin B. However, amphotericin B must be administered intravenously and causes severe side-effects. Another obstacle to its use in resource-limited settings is its relatively high cost. Fluconazole, another antifungal medication, is often used in lieu of amphotericin B in resource-limited settings, although it is widely recognised to be an inferior treatment.

The Ugandan study enrolled HIV-positive adults who had been hospitalised with their first diagnosis of cryptococcal meningitis and who were not yet taking antitretroviral therapy. Lumbar punctures were performed to obtain cerebrospinal fluid samples for analysis at baseline and on days three, seven and 14. In accordance with medical guidelines for the treatment of cryptococcal meningitis, additional lumbar punctures were performed on some study participants during the two-week period to reduce intracranial pressure.

Researchers assessed the impact of the two fluconazole regimens by comparing rates of clearance of infection, reflected in decreases in log cryptococcal colony-forming unit counts in the cerebrospinal fluid. More rapid clearance occurred in the group receiving the higher-dose regimen, with a difference of 0.11 log₁₀ cryptococcal colony-forming unit /m per day (95% CI, 0.03-0.18 log₁₀ cryptococcal colony-forming unit /mL per day, p = 0.006).

Importantly, both doses of fluconazole were equally well tolerated. There were no adverse reactions requiring study participants to withdraw from either group, and changes in levels of alanine aminotransferase, a marker of how well the liver is working, were comparable.

At two weeks and at ten weeks, the groups showed no significant differences in mortality, although such differences were unlikely to be found in such a small study population. At six months, 30% of patients from the lower-dose group and 43% of patients from the higher-dose group were known to be alive.

The researchers express concern about the advanced state of illness in many study participants, writing, “efforts are needed to promote awareness of the clinical significance of headache in patients with possible late-stage HIV infection, and studies are needed to test strategies to facilitate rapid referral, diagnosis, and initiation of therapy for patients with cryptococcal disease or to screen for early, subclinical disease.”

They also suggest that it may be beneficial to continue high-dose fluconazole in patients with cryptococcal meningitis until they begin taking antiretroviral therapy. (All participants in the study began taking antiretroviral therapy after they were discharged from the hospital.)

Severe liver inflammation is a rare but potentially fatal side-effect of fluconazole. Research presented at the 2004 International AIDS Conference suggested that the risk of liver toxicity may be higher in people who are also taking nevirapine because fluconazole increases blood levels of nevirapine, an antiretroviral drug that is also associated with liver toxicity. However, two studies published subsequently have shown that fluconazole and nevirapine can be taken together safely.

The authors of the Uganda study note that amphotericin B remains the superior treatment because it clears cryptococcal infection more rapidly. Therefore they advocate testing two strategies in settings where standard two-week amphotericin B regimens are not available: adding flucytosine to optimised fluconazole treatment, and adding a short course of amphotericin B to optimised fluconazole treatment. Flucytosine is sometimes added to amphotericin B because it is thought to accelerate the clearance of infection, and it may also have a beneficial effect when added to fluconazole.

“In the meantime,” they conclude, “at African health care centres where fluconazole is currently used, these data would support the use of 1200mg per day as the initial dosage, with continued vigilance for the possibility of rare drug-related adverse events.”