Combination Antifungal Therapy for Cryptococcal Meningitis

Day, Jeremy N., Chau, Tran T.H., Wolbers, Marcel, Mai, Pham P., Dung, Nguyen T., Mai, Nguyen H., Phu, Nguyen H., Nghia, Ho D., Phong, Nguyen D., Thai, Cao Q., Thai, Le H., Chuong, Ly V., Sinh, Dinh X., Duong, Van A., Hoang, Thu N., Diep, Pham T., Campbell, James I., Sieu, Tran P.M., Baker, Stephen G., Chau, Nguyen V.V., Hien, Tran T., Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200 and Farrar, Jeremy J. (2013) 'Combination Antifungal Therapy for Cryptococcal Meningitis'. New England Journal of Medicine, Vol 368, Issue 14, pp. 1291-1302.

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Abstract

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.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 252 Antifungal agents. Antifungal antibiotics QV Pharmacology > QV 38 Drug action. WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 245 Meningococcal infections WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1056/NEJMoa1110404
Depositing User:	Martin Chapman
Date Deposited:	23 Apr 2013 11:54
Last Modified:	06 Dec 2018 11:20
URI:	https://archive.lstmed.ac.uk/id/eprint/3370

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