Managing HIV-Related Cryptococcal Meningitis? -- HIV/AIDS INFO AND UPDATES

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Date Posted: 11:49:14 05/16/02 Thu
Author: Anonymous
Subject: Managing HIV-Related Cryptococcal Meningitis?

Neurologic Complications in HIV Disease Ask The Expert
Managing HIV-Related Cryptococcal Meningitis?

from Medscape HIV/AIDS

Question
A 40-year-old HIV-infected woman with cryptococcal meningitis was given amphotericin (0.7 mg/kg/day) along with 2 weeks of standard doses of flucytosine. At the end of 8 weeks of therapy, her CSF culture still grows Cryptococcus neoformans. How does one treat such resistant cases?

Response
from William G. Powderly, MD, 04/25/2002

As a result of a large randomized, controlled trial (and experience during the first 15 years of the AIDS epidemic), standard guidelines for treatment of cryptococcal meningitis recommend 2 weeks of amphotericin B at a dose of 0.7 mg/kg/day (with flucytosine) followed by fluconazole at a dose of 400 mg/day for another 8 weeks.[1,2] This approach is associated with a response rate at 10 weeks of approximately 70%. In other words, at 10 weeks patients will have a clinical response and will have sterile CSF cultures. Of the 30% of patients who fail, about one third will have died and the remainder are usually clinically improved but not mycologically cleared.

The patient in question is clearly failing mycologically with the current regimen, but it is not clear whether there has been clinical improvement. If there has, I would be less concerned. Although a positive culture in the CSF at the end of therapy portends a greater risk of relapse, it is still likely that with continued treatment the patient will respond.

The question suggests that amphotericin B has been given for 8 weeks. If that is the case, at this point I would consider switching to fluconazole. There are several reasons for this advice. First, the patient will avoid further amphotericin toxicity and the problems associated with an intravenous line. Furthermore, it is quite possible that the patient will have a mycologic response to the new treatment.

If the patient has indeed been receiving fluconazole, then I would investigate adherence. It has been shown in several studies that relapsing cryptococcal infection is usually due to the same strain, strongly suggesting that failure to adhere to fluconazole is an important issue.[3]

If the patient is clinically deteriorating or still symptomatic, then I would have greater concerns. I would repeat the lumbar puncture with an opening pressure measurement to determine if cerebral edema is a concern. If the opening pressure is elevated, I would consider measures to reduce it by repeated lumbar punctures or neurosurgical intervention.[2,4] I would also perform imaging of the brain (by CT or MRI) to evaluate the patient for an intracranial focus. With a symptomatic patient I would also consider changing therapy. Options include liposomal amphotericin B, higher doses of fluconazole (800 mg/day or more), and the combination of fluconazole and flucytosine.[5-7] Unfortunately, there have been no controlled studies to indicate which of these options is best.

Another important consideration at this point is to try to improve immune function with optimal antiretroviral therapy. There is some risk of an immune reconstitution illness which in cryptococcal infections is manifest by a sterile aseptic meningitis or lymphadenitis.[8] However, in this situation the risk is outweighed by the antifungal benefit of an improved immune response.

Finally, it is usually not necessary to postulate resistant infection. Indeed, resistance is rare with C neoformans even in patients with AIDS. Only isolated case reports of amphotericin B-resistant infection have been described.[9] Fluconazole resistance is also unusual, but has been described in the context of patients on chronic secondary suppressive therapy.[10]

References

1. van der Horst C, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med. 1997;337:15-21.
2. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:710-718.
3. Brandt ME, Pfaller MA, Hajjeh RA, et al. Molecular subtypes and antifungal susceptibilities of serial Cryptococcus neoformans isolates in human immunodeficiency virus-associated cryptococcosis. Cryptococcal Disease Active Surveillance Group. J Infect Dis. 1996;174:812-820.
4. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis. 2000;30:47-54.
5. Coker RJ, Viviani M, Gazzard BG, et al. Treatment of cryptococcosis with liposomal amphotericin B (AmBiSome) in 23 patients with AIDS. AIDS. 1993;7:829-834.
6. Berry AJ, Rinaldi MG, Graybill JR. Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS. Antimicrob Agents Chemother. 1992;36:690-692.
7. Larsen RA, Bozzette SA, Jones B, et al. Fluconazole combined with flucytosine for cryptococcal meningitis in persons with AIDS. Clin Infect Dis. 1994;19:741-745.
8. Haddad NE, Powderly WG. The changing face of mycoses in patients with HIV/AIDS. AIDS Read. 2001;11:365-368, 375-378.
9. Kelly SL, Lamb DC, Taylor M, Corran AJ, Baldwin BC, Powderly WG. Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient. FEMS Microbiol Lett. 1994;122:39-42.
10. Berg J, Clancy CJ, Nguyen MH. The hidden danger of primary fluconazole prophylaxis for patients with AIDS. Clin Infect Dis. 1998; 26:186-187.

About the Panel Members
Associate Professor at the Washington University School of Medicine, Principal Investigator at the Washington University AIDS Clinical Trials Unit, and Co-Director of the Division of Infectious Diseases at Barnes-Jewish Hospital in St. Louis, Missouri.

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