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Pathogen:
Caused by Cryptococcus neoformans, a yeast-like fungus found worldwide,
particularly in soil contaminated with bird excrement.
Sites of Infection:
Most commonly the brain; also the
lungs. Advanced disease can involve almost any organ system.
Symptoms:
Fatigue, fever, headache, nausea, seizure, and
neurological changes; of pulmonary infection: lobar or interstitial pneumonitis
and pleural effusion; or may be asymptomatic.
Diagnosis:
By CSF smear, antigen detection or culture.
For patients with cryptococcal meningitis the most significant pre-treatment
factor predicting early death is abnormal mental status (coma, lethargy,
confusion). Other pre-treatment factors that predict treatment failure in AIDS
patients with cryptococcus include a positive India ink stain, visual
abnormalities, age less than 35 years and absence of antiretroviral therapy.
Treatment Results:
The preferred treatment for cryptococcal meningitis includes two weeks induction
treatment with amphotericin B (0.7 mg/kg/d IV) followed by fluconazole
(200-400 mg PO qd). Both drugs are approved for the treatment of cryptococcal
meningitis. This treatment strategy is based on the results of a study by Saag et
al. that compared oral fluconazole (200 mg PO daily) to intravenous amphotericin
B in 194 patients with cryptococcal meningitis enrolled in an ACTG/MSG study
(ACTG 059, MSG 8A). Saag et al. reported that a complete response (as measured by
two consecutive CSF cultures negative for C. neoformans)was observed in 44/131
(34%) fluconazole recipients and 25/63 (40%) amphotericin B recipients
(difference not significant). Mortality rates were equivalent in both groups (18%
for fluconazole, 14% for amphotericin B). However, mortality during the first two
weeks was higher in the fluconazole group (15% vs. 8%). Disease progression
occurred in more patients receiving fluconazole (20% vs 11%) whereas drug
toxicity leading to treatment failure occurred in more patients receiving
amphotericin B (8% versus 2%).
Van Der Horst et al. recently reported that there is no significant benefit from combining flucytosine (5-FC) with amphotericin B as induction therapy for cryptococcal meningitis. The study (ACTG 159, MSG 017) compared amphotericin B (0.7 mg/kg IV daily) for 14 days) with or without flucytosine (5-FC) (25 mg/kg PO qid for 14 days) followed by a comparison of fluconazole to itraconazole as consolidation therapy in 408 patients with first-time cryptococcal meningitis. Van Der Horst et al. reported data in 381/408 eligible patients. After 14 days of induction therapy, 60% of those receiving amphotericin B and flucytosine remained CSF culture positive, compared to 51% in those receiving amphotericin B alone. CSF culture negative responses at 14 days were negative in 23% and 30% of patients, respectively. These data were not statistically significant. In patients with greater than 250 mL and 350 mL of intracranial pressure (ICP), pressure reduction was administered through lumbar puncture drainage (25-30 ccs daily) and concurrent use with acetazolamide. There was no significant differences in clinical benefit or death between the two groups.
Consolidation therapy results from the continuation of this clinical trial (ACTG 159/MSG 017) have been reported. Saag et al. reported data in 306/381 patients who completed maintenance therapy with either fluconazole (400 mg/daily) or itraconazole (200 mg bid). At ten weeks, 72% of those in the fluconazole group remained culture negative compared to 60% in the itraconazole group. However, symptom reduction was similar in the two groups (68% versus 70%). There was no significant difference in death between the two groups.
Complete responses in patients receiving initial or salvage treatment with high-dose fluconazole (800 mg/day) have been reported (Berry et al. and Haubrich et al.).
The combination of fluconazole/flucytosine may be more effective than fluconazole alone (Milefchik et al.). Thirty-six patients with cryptococcal meningitis were randomized to receive fluconazole (800,1,200 or 1,600 mg/day) alone or in combination with flucytosine (150 mg/kg daily for 4 weeks). Of the patients receiving only fluconazole, 7/24 (29%) survived and became CSF culture negative, compared with 9/12 (75%) receiving the combination.
A phase II safety and efficacy trial of fluconazole (800 mg qd) in combination with flucytosine (5FC) (100 mg/kg qd) is currently underway.
de Gans et al. randomized 28 HIV-1 men with presumptive diagnoses of cryptococcal meningitis to receive itraconazole (200 mg PO twice daily) or amphotericin B/flucytosine (0.3 mg/kg and 150 mg/kg/day). Six patients were excluded from the analysis (3 had negative CSF cultures, and 3 died before completion of the protocol). A complete response was seen in 5/12 (41%) evaluable itraconazole recipients and (10/10) (100%) evaluable amphotericin B/flucytosine recipients.
Twenty-three patients with cryptococcosis were treated with liposomal amphotericin B in an open-label study (Coker et al.). All patients received 1 mg/kg on the first day, 2 mg/kg on the second day and 3 mg/kg IV every day thereafter until cultures were negative for 2 successive weeks. Of the 23 evaluable subjects, 14/23 had complete and 4/23 had partial responses. Sterilization of CSF was achieved in 12/18 responders, with cultures becoming negative after a median of 11 days. Adverse effects included elevated LFT, creatinine, fever, rigor and chills. Similar results using liposomal amphotericin B in similar study populations have been reported by other investigators (Lazar et al. and Schurmann et al.).
Thirty patients with cryptococcal meningitis were randomized to receive either amphotericin B lipid complex (ABLC) or amphotericin B (Graybill et al.). Patients received total ABLC doses of either 46.8, 95, or 120 mg/kg IV; or amphotericin B 24.2 mg/kg IV. Of the 20 evaluable subjects receiving ABLC, 11/20 responded to therapy and 9/20 had quiescent disease evaluable patients receiving amphotericin B responded. No hematologic or nephrotoxicity was noted with ABLC.
Treatment Trials in Progress:
A phase III randomized trial comparing amphotericin B lipid complex (ABLC) and
amphotericin B, followed by fluconazole, is currently underway.
Maintenance:
Long-term maintenance therapy is required to delay relapse. Fluconazole is
superior to amphotericin B and to itraconazole for preventing relapse of
cryptococcal meningitis.
Saag et al. recently reported the results from a clinical trial comparing fluconazole (200 mg PO daily) to itraconazole (200 mg PO daily) in 107 patients who had been successfully treated for cryptoccocal meningitis (MSG 025). Patients were randomized to receive fluconazole (n = 52) or itraconazole (n = 55) and followed for documented CSF-culture positive relapses. Median follow up time was nine months. Recurrence of cryptococcal meningitis was reported in 2/52 (3.8%) patients receiving fluconazole and 13/55 (23.6%) patients receiving itraconazole (P = 0.003), prompting premature closure of the study. No death were attributed to cryptoccocal meningitis in either of the two groups.
Powderly et al. (1992) randomized 189 patients who had recovered from cryptococcal meningitis to receive fluconazole (200 mg PO daily for12 months) or amphotericin B (1 mg/kg weekly for12 months)(ACTG 206). After a median follow-up of 286 days, 2/111 (2%) receiving fluconazole and 14/78 (18%) receiving amphotericin B had relapses of symptomatic cryptococcal disease (P <0.001) (14 patients had meningitis, one had lymphadenitis, and one had hepatic disease). The probability of death, relapse, or drug toxicity one year after the start of the study was 39% in the fluconazole group and 56% in the amphotericin B group. The probability of remaining relapse-free at one year was 97% for the fluconazole group and 78% for the amphotericin B group (P <0.001). Toxicity requiring withdrawal of treatment was more frequent in the amphotericin B group.
Prophylaxis:
The United States Public Health Service has published guidelines for the
prevention of crytococcal meningitis (CDC, 1995). The guidelines state that
physicians may wish to consider chemoprophylaxis with fluconazole for adult and
adolescent patients with CD4+ counts less than 50 cells/mm3. However,
such prophylaxis should not be offered routinely because of the relative
infrequency of crytococcal disease, the possibility of drug interactions, the
potential development of resistance, and the cost of prophylaxis.
Fluconazole is more effective than clotrimazole oral suspension in the prevention
of invasive with serious systemic fungal infections (Powederly et al., 1995). 428
patients with CD4 counts <200 cells/mm3 with no history of systemic
fungal infections were randomized to receive fluconazole 200 mg/day or
clotrimazole 10 mg five times daily (ACTG 981). After a mean follow-up of 35
months, 11 fluconazole recipients and 38 clotrimazole recipients developed
serious fungal infections (including cryptococcosis, histoplasmosis,
coccidioidomycosis, and aspergillosis)(P <.0001). Cryptococcal
meningitis represented 2/11 infections in fluconazole recipients vs. 15/38 in the
clotrimazole recipients (P = 0.0009). No survival benefit to
fluconazole was observed: 98 subjects on fluconazole died vs. 89 on clotrimazole
(P = 0.26).
REFERENCES:
CDC. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in
Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24,1995.
Coker R et al. Treatment of cryptococcosis with liposomal amphotericin B
(Ambisome) in 23 patients with AIDS. AIDS 7: 829-835,1993.
de Gans J et al. Itraconazole compared with amphotericin B plus flucytosine in
AIDS patients with cryptococcal meningitis. AIDS 6: 185-190, 1992.
Graybill JR et al. Amphotericin B lipid complex in treatment of cryptococcal
meningitis in patients with AIDS. 31st ICAAC, Abstract 289: 147, 1991.
Jones BE et al. A phase II trial of fluconazole plus flucytosine for cryptococcal
meningitis. VII Intl Conf AIDS, Florence. Vol 2: 266(W.B.2337),1991.
Haubrich RH et al. High-dose fluconazole for treatment of cryptoccocal disease in
patients with human immunodeficiency virus infection. J Infect Dis 170: 238-242,
1994.
Lazar JT et al. Efficacy and safety of Ambisome (Liposomal Amphotericin B) in
primary episodes of cryptococcosis in patients with HIV infection. VII Intl Conf
AIDS, Florence. VOL 2: 226(W.B.2177), 1991.
Milefchik E et al. High dose fluconazole with and without flucytosine for AIDS
associated Cryptococcal meningitis. Abstract WS-B12-5, IX Intl Conf AIDS, Berlin,
1993.
Pettoello-Mantovani M et al. Enhancement HIV-1 infection by the capsular
polysaccharide of Cryptococcus neoformans. Lancet 339: 21-23, 1992.
Powderly M et al. A randomized trial comparing fluconazole with clotrimazole
troches for the preventionof fungal infections in patients with advanced human
immunodeficiency virus infection. NEJM 332:700-5, 1995.
Powderly M et al. A controlled trial of fluconazole or amphotericin B to prevent
relapse cryptococcal meningitis in patients with the acquired immune deficiency
syndrome. NEJM 326(12): 793-798,1992.
Schurmann D et al. Safety and efficacy of liposomal amphotericin B in treating
AIDS-associated disseminated cryptococcosis. JID 164: 620-622,1991.
Saag M et al. Comparison of fluconazole virus itraconazole as maintenance therapy
of AIDS-associated cryptococcal meningitis. 35th ICAAC, Abstract I218, San
Francisco, 1995.
Saag M et al. Part II: Amphotericin B alone or with Flucytosine (5FC) for the
treatment of, AIDS-related acute crytococcal meningitis, 35th ICAAC, Abstract
l2l6, San Francisco, 1995.
Saag M et al. Comparison of amphotericin B with fluconazole in the treatment of
acute AIDS-associated cryptococcal meningitis. NEJM 326(2): 83-89,1992.
Van Der Horn et al. Part 1: Amphotericin B alone or with Flucytosine (5FC) for
the treatment of acute AIDS-related cryotococcocal meningitis. 35th ICAAC,
Abstract 1216, San Francisco, 1995.
OTHER REPORTS:
Cameron ML et al. Human immunodeficiency virus (HIV)-infected human blood
monocytes and peritoneal macrophages have reduced anticryptococcal activity where
HIV-infected alveolar macrophages retain normal activity. J Infect Dis 170:
60-67, 1994,
Nightingale S et al. Primary prophylaxis with fluconazole against systemic fungal
infections in HIV-positive patients. AIDS 6: 191-194, 1992.
Quagliarello VJ et al. Primary prevention of crytococcal meningitis by
fluconazole in HIV-infected patients. Lancet 345:548-552, 1995.
Viviani MA et al. Experience with itraconazole in cryptococcosis and
aspergillosis.
J Infect Dis 18(2): 151-65,1989.
Berry AJ et al. Use of high fluconazole as salvage therapy for cryptomeningitis
in patients with AIDS. Antimicrob Agts Chemo 36(3): 690-692,1992.
Cameron ML et al. Manifestations of pulmonary cryptococcosis in patients with
acquired immunodeficiency syndrome. Rev Inf Dis 13:64-67, 1991.
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