BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.)

Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1 , VCAM-1 , E-selectin , and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0 -90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0 -36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria. (Am J Pathol 1999, 155:395-410)Severe falciparum malaria remains one of the most important causes of death in the tropics. Cerebral malaria is the major lethal manifestation of this infection. The sequestration of red blood cells containing mature forms of Plasmodium falciparum in the cerebral microvasculature is considered to be the essential underlying pathological process, although how this leads to coma and death remains unresolved.

Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.

Artemether is a satisfactory alternative to quinine for the treatment of severe malaria in adults.

Hemofiltration is superior to peritoneal dialysis in the treatment of infection-associated acute renal failure.