Cryptococcal meningitis is associated with significant acute mortality and current drug regimens frequently take more than 2 weeks to sterilise the CSF. In vitro and animal studies support the use of antifungal combinations, including amphotericin B (AmB) plus fluconazole, for the treatment of cryptococcosis. Therefore, we examined whether initial drug combinations that include fluconazole lead to more rapid CSF sterilisation. CSF sterilisation rate was evaluated using a new endpoint, the initial rate of reduction in CSF colony forming units (CFU) as defined by quantitative CSF cultures. Sixty four patients with a first episode of cryptococcal meningitis were randomised to one of four arms: AmB (0.7 mg/kg/d) alone; AmB plus flucytosine (100 mg/kg/d); AmB plus fluconazole (400mg/d); and triple therapy with AmB, flucytosine and fluconazole. After 2 weeks, all 4 arms were followed by standard consolidation phase fluconazole (400 mg/d) for 8 weeks and maintenance fluconazole (200 mg/d) thereafter. Follow up lumbar punctures were done on days 3, 7, and 14. The reduction in log CFU was linear and monoexponential. For each patient, the decrease in log CFU per ml CSF per day was calculated using the slope of the linear regression of log CFU against time. The mean rate of fall in CSF log CFU counts, or early fungicidal activity (EFA), was significantly greater for AmB plus flucytosine compared with AmB alone (P = 0.004), AmB plus fluconazole (P = 0.04), or triple therapy with AmB, flucytosine and fluconazole (P = 0.02). Quantitation of CSF cultures provides a means by which the fungicidal activity of treatment regimes can be accurately assessed, and significantly increases the power to detect differences in the activity of alternative regimens. While further work is required to demonstrate correlation of EFA with clinical outcomes, the technique enables fungicidal activity to be compared in few patients with only the most active new combinations moving forward to clinical endpoint trials.
Full conference title:
The 15 th Congress of the International Society for Human and Animal Mycology
- ISHAM 15th (2003)