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Dosing Amphotericin B in Cryptococcal Meningitis William G. Powderly
University College Dublin School of Medicine and Medical Science, Dublin, Ireland (See the article by Bicanic et al. on pages 123–30)
It is salutary to note that, although for the 0.3 mg/kg per day was effective when given advent of effective antiretroviral therapy past 50 years of therapeutics, amphoteri- led to a substantial reduction in the num- cin B has been the mainstay of antifungal rospect, the methodology of these trials, ber of new cases of cryptococcal infection treatment for cryptococcal meningitis, in an era of evidence-based medicine, we re- who died early in the course of treatment, dose of this drug to use when giving treat- praisal of low dosages of amphotericin B.
ment to patients. The article by Bicanic et Certainly, initial results in the treatment al. [1] provides some useful insight into this question, but before considering the tion in resource-poor settings, particularly new data, it is worth reviewing the history in Southeast Asia and Africa. Fluconazole America’s current guidelines [4] for the is widely available in generic form; how- treatment of cryptococcal meningitis rec- ever, there are concerns that fluconazole may not be as effective as amphotericin B for treatment of cryptococcal meningitis.
years before large, randomized trials in- rived largely from a large randomized trial In a small trial, Brouwer et al. [8] dem- vestigating its use for systemic fungal in- of 381 patients who received the agent at onstrated that amphotericin B (0.7 mg per rather arbitrarily. An earlier trial of the B alone and with amphotericin B plus flu- dosage 0.4 mg/kg per day produced results that were generally regarded as unsatisfac- ined the rate of decrease of cryptococcal tory [6]. Several investigators favored dos- ages as high as 1.0 mg/kg per day, but there days of treatment. In the current trial, this were considerable concerns about toxicity study design is used to compare 2 dosages at that dosage. A dosage of 0.7 mg/kg per studies [2, 3] led to the conclusion that a day was therefore selected, especially be- ence with this dosage [7]. The overall suc- Received 21 March 2008; accepted 21 March 2008; flucytosine, lead to a more rapid fungicidal electronically published 27 May 2008.
Reprints or correspondence: Dr. William G. Powderly, UCD School of Medicine and Medical Science, University College Dublin, Health Sciences Centre, Belfield, Dublin 4, Ireland nance therapy was believed to be sufficient spread use of the drug at this dosage (1.0 Clinical Infectious Diseases
2008; 47:131–2
ᮊ 2008 by the Infectious Diseases Society of America. All well be correct; however, dosing of a toxic cially nephrotoxicity—amphotericin B is drug is always a balance between clinical 1058-4838/2008/4701-0022$15.00DOI: 10.1086/588818 generally well tolerated for 2 weeks. The benefit and adverse effects, and this study is too small to adequately answer this cost- late, 0.7 mg/kg per day, revealed equivalent nation amphotericin B and flucytosine for fouras compared with six weeks. N Engl J Med outcomes [9]. Scandalously, this trial has 1987; 317:334–41.
4. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal
disease. Clin Infect Dis 2000; 30:710–8.
outcomes, and the sample size is too small photericin B is expensive, and flucytosine 5. van der Horst CM, Saag MS, Cloud GA, et al.
to conclude that a clinically relevant dif- availability is limited. As is true for so Treatment of cryptococcal meningitis associ- ference was not missed. The authors’ sug- ated with the acquired immunodeficiency syn-
drome. N Engl J Med 1997; 337:15–21.
6. Saag MS, Powderly WG, Cloud GA, et al. Com- by an earlier switch to fluconazole is rea- earlier antiretroviral therapy to prevent the parison of amphotericin B with fluconazole in occurrence of cryptococcal infections.
the treatment of acute AIDS-associated cryp-
tococcal meningitis. N Engl J Med 1992; 326:
larger trial, lead to differences in efficacy.
Acknowledgments
7. Larsen RA, Leal MAE, Chan LS. Fluconazole Potential conflicts of interest.
compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a ran-
domized trial. Ann Intern Med 1990; 113:
gitis, especially in the context of AIDS.
References
There is little prospect of new antifungal 8. Brouwer AE, Rajanuwong A, Chierakul W, et 1. Bicanic T, Wood R, Meintjes G, et al. High- al. Combination antifungal therapies for HIV- dose amphotericin B with flucytosine for the associated cryptococcal meningitis: a random- use the available drugs. In the developed treatment of cryptococcal meningitis in HIV- ised trial. Lancet 2004; 363:1764–7.
world, there are several (expensive) alter- infected patients: a randomized trial. Clin Infect 9. Hamill RJ, Sobel J, El-Sadr W, et al. Random- native formulations of amphotericin B.
Dis 2008; 47:123–30 (in this issue).
ized double-blind trial of AmBisome (liposo- 2. Bennett JE, Dismukes WE, Duma RJ, et al. A mal amphotericin B) and amphotericin B in There is no evidence that they are better comparison of amphotericin B alone and com- acute cryptococcal meningitis in AIDS patients bined with flucytosine in the treatment of cryp- [abstract 1161]. In: Program and abstracts of ycholate. A large trial comparing liposo- tococcal meningitis. N Engl J Med 1979; 301:
the 39th Interscience Conference on Antimi- crobial Agents and Chemotherapy (San Fran- 3. Dismukes WE, Cloud G, Gallis HA, et al. Treat- cisco). Washington, DC: American Society for ment of cryptococcal meningitis with combi- Microbiology, 1999.

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