A combination of two antifungal drugs, amphotericin B and flucytosine, has been found to result in the most rapid reduction in cryptococcus levels in the cerebrospinal fluid of people diagnosed with cryptococcal meningitis. However, the study was unable to demonstrate whether treatment with this antifungal combination resulted in superior survival when compared with standard treatment in Thailand.
Cryptococcal meningitis is the second most common AIDS-defining illness in north eastern Thailand and survival is poor despite the availability of intravenous antibiotic treatment. 43% of Thai patients diagnosed with cryptococcal meningitis died within a mean of 14 days despite standard treatment with amphotericin B, suggesting that the activity of antifungal medication during the first 14 days of treatment is critical to the long-term success of treatment.
The authors of the new study, an international collaboration of Thai, British, Dutch and US researchers, wanted to know whether combination antifungal treatment resulted in a quicker reduction in cryptococcus levels, and which two- or three-drug combination produced the quickest decline.
A previous multicentre study found no significant difference in the likelihood of culturing cryptococcus from the cerebrospinal fluid after two weeks of treatment with amphotericin B or amphotericin B and flucytosine. Another study found that cryptococcal antigen levels at week 2 predicted survival at week 10.
The newly reported study used a different, more intensive technique for measuring cryptococcus levels, sampling cerebrospinal fluid by lumbar puncture at days 3, 7 and 14 in 64 patients diagnosed with laboratory-confirmed cryptococcal meningitis. They measured levels of cryptococcus colony-forming units in the CSF.
Patients were randomised to receive either amphotericin B alone (0.7mg/kg daily), amphotericin B plus fluconazole (400mg daily), amphotericin B plus flucytosine (100mg/kg daily) or all three drugs together for 14 days, followed by maintenance treatment with fluconazole (400mg) for a further eight weeks, then 200mg a day thereafter. All patients received one litre of saline daily to reduce the risk of kidney toxicity caused by amphotericin B.
Patients treated with amphotericin B plus flucytosine showed significantly faster clearance of cryptococcus (-0.5 log at day 14) (p=0.001) than those treated with amphotericin B alone (-0.31 log) or amphotericin B plus fluconazole (-0.39 log) (p=0.001) or triple therapy (-0.38 log)(P=0.001).
However, there was no significant difference in survival at week 10, despite the fact that patients in the amphotericin B plus fluconazole group showed a trend towards more severe meningitis at diagnosis (defined as seizures or loss of consciousness at presentation). Nevertheless a trend was evident, with only one death in the amphotericin B plus flucytosine group compared to seven deaths in the fluconazole group.
Deaths tended to follow two patterns. Patients with high cryptococcus cell counts and/or cerebral dysfunction tended to die early. Nine out of the 14 patients who died did so during the two weeks of combination treatment.
The other five died after oral fluconazole therapy was substituted at the end of the two-week induction period; in general these were patients who still had significant cell counts after two weeks.
This study is a particularly important one for AIDS treatment in Africa and Asia, where cryptococcal meningitis is second only to tuberculosis as the main cause of death in people with AIDS.
Nonetheless, the fact that the average CD4 count in the 64 patients was 9, and no one had a CD4 count over 23, stands as a reminder that until antiretroviral therapy is available to these populations, diseases such as cryptococcal meningitis will continue to be a frequent cause of death.
Reference
Brouwer AE et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. The Lancet 363: 1764-67, 2004.