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PubMed1999

The prognostic factors of cryptococcal meningitis in HIV-negative patients.

Seventy-one patients with cryptococcal meningitis, 46 males and 25 females, aged 15-83 years, were included in this study. Their initial clinical manifestations, cerebrospinal fluid (CSF) features, and therapeutic results were analysed. Patients were treated with three different regimens: amphotericin B, fluconazole, and combination therapy. Based on the therapeutic results, the 71 patients were also divided into cured, improved, and failed groups. For statistical comparison, the clinical manifestations and CSF features, were compared according to therapeutic outcome. There was no statistical difference in outcome among the three different antifungal regimens. However, patients treated with fluconazole required 36% fewer days of hospitalization compared with those receiving amphotericin B. Significant prognostic factors, included low CSF glucose, high CSF lactate, high CSF cryptococcal antigen titre (> or = 1:1024), initial level of consciousness, the presence of seizure, hydrocephalus, and central nervous system vasculitis. Multiple logistic regression analysis showed that only initial level of consciousness, and CSF antigen titre were strongly associated with therapeutic failure after other potentially confounding factors were adjusted for. Because some of the prognostic factors in cryptococcal meningitis can be corrected, early diagnosis, early use of appropriate antifungal treatment, and the correction of the underlying metabolic derangements are important in management.

Adolescent↗
PubMed1989

[A case of cryptococcal meningitis successfully treated with miconazole and CSF drainage].

Cryptococcal meningitis is the most frequent fungal infection of the central nervous system, known readily to complicate with immuno-compromised patients. There are only a few cases of primary infection in healthy non-immuno-compromised patients. Amphotericin-B (AMPH-B) and 5-Fluorocytosine (5-FC) are effective agents against Cryptococcal meningitis, although, their toxicity and drug resistance are limiting factors. However, in recent years Miconazole has been widely used against fungal infections and it's effectiveness has been reported. This is a 68 y.o. male who was admitted to Toyohashi Municipal Hospital on March 15, 1987 because of headache, vomiting, diplopia and gait disturbance. Continuous lumbar drainage was performed since lumbar puncture revealed surprisingly high cerebrospinal fluid (CSF) pressure and presence of many Cryptococcus neoformans, i.v. AMPH-B and p.o. 5-FC was also administrated. A 7 day course of i.v. AMPH-B and p.o. 5-FC showed no improvement with side effects of macrohematuria and anorexia. Then Miconazole was administrated i.v. and intrathecal (i.t.). The clinical signs and CSF laboratory data improved after a 90 day course of Miconazole therapy and the patient was discharged on August 24. But the patient was readmitted from March 10 to April 30, 1988, because of a slight increase of C. neoformans in CSF (17/mm3) and improved by i.v. and i.t. Miconazole. The total Miconazole dosage was 90.6 g (i.t.: 505 mg) at the first admission and 36 g (i.t.: 50 mg) at the second admission, but no side effect was seen. The reduction of elevated CSF pressure with continuous CSF drainage was also important for the treatment of such cases with increased intracranial pressure.

Aged↗
PubMed1991

Cryptococcal meningitis in pregnancy: a case report.

We report a pregnant woman with cryptococcal meningitis. She experienced symptoms of meningitis before gestation which worsened during pregnancy. Combined treatment of amphotericin B and flucytosine, including ventriculo-peritoneal shunt gave a favorable outcome for both the patient and her child. We suggest that pregnant women with cryptococcal meningitis should continue their pregnancy and prefer to use combination of both drugs in standard doses because of the effectiveness, shorter duration of treatment and less toxicity than amphotericin B alone.

Adult↗
PubMed2005

Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.

A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.

Animals↗
PubMed1992

Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis.

OBJECTIVE: We conducted a comparison of itraconazole versus amphotericin B plus flucytosine in the initial treatment of cryptococcal meningitis in patients with AIDS and established the efficacy of itraconazole as maintenance treatment. DESIGN: The trial was a prospective, randomized, and non-blinded study. SETTING: The study was performed at an academic centre for AIDS, Amsterdam, The Netherlands. PATIENTS, PARTICIPANTS: Twenty-eight HIV-1-seropositive men with a presumptive diagnosis of cryptococcal meningitis, randomized between 5 February 1987 and 1 January 1990, were included for analysis. INTERVENTIONS: Oral itraconazole (200 mg twice daily), versus amphotericin B (0.3 mg/kg daily) intravenously plus oral flucytosine (150 mg/kg daily) was administered for 6 weeks followed by maintenance therapy with oral itraconazole (200 mg daily) to all patients. MAIN OUTCOME MEASURES: Outcome measures were a complete or partial response, recrudescence and relapse. RESULTS: A complete response was observed in five out of the 12 patients who completed 6 weeks of initial treatment with itraconazole versus all 10 patients who completed treatment with amphotericin B plus flucytosine (P = 0.009). A partial response was observed in seven out of the 14 patients assigned to itraconazole. During maintenance therapy, recrudescence (n = 6) or relapse (n = 1) occurred in seven out of the 12 patients initially assigned to itraconazole, whereas two relapses occurred among nine patients initially treated with amphotericin B plus flucytosine (P = 0.22); recurrence of clinical symptoms was significantly related to a positive cerebrospinal fluid culture at 6 weeks (P = 0.003). CONCLUSION: Itraconazole is less effective compared with amphotericin B plus flucytosine in achieving a complete response in initial therapy in AIDS patients with cryptococcal meningitis.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Cryptococcal meningitis in human immunodeficiency virus (HIV)-positive and HIV-negative patients.

This study compared clinical manifestations, blood biochemistry and cerebrospinal fluid (CSF) results of HIV-positive and HIV-negative patients with cryptococcal meningitis. We collected 57 cases of cryptococcal meningitis from cytological specimens submitted to the Department of Tropical Pathology, Faculty of Tropical Medicine. Pertinent clinical data were analyzed retrospectively in 47 cases for clinical manifestations, laboratory features and outcomes of 38 HIV-positive and 9 HIV-negative patients. Headache was the most common symptom seen in all cases, of which 70.2% occurred with fever. CSF examination of both groups revealed elevated opening pressure. Increased CSF protein and depressed CSF glucose levels were seen in HIV-negative cases, which differed from HIV-positive cases, where a slight change was noted. CSF pleocytosis in HIV-positive patients was variable. Forty-eight percent of HIV-positive patients had CSF leukocyte counts below 20 cells/ mm3. None was found in the HIV-negative patients. Specific treatments with amphotericin B and fluconazole were given. Five fatal cases of cryptococcal meningitis were noted, all of which were HIV-positive. There were statistically significant differences in blood neutrophils, blood eosinophils, CSF leukocyte counts, CSF neutrophils, CSF lymphocytes, CSF glucose, and CSF total protein, in HIV-positive and HIV-negative patients (p = 0.050, p = 0.022, p = 0.002, p = 0.016, p = 0.047, p = 0.031, p = 0.009, respectively).

Adolescent↗
PubMed2004

A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency.

OBJECTIVES: To assess the efficacy and survival benefit of low-dose fluconazole (400 mg weekly) for primary prophylaxis for cryptococcal meningitis in patients with advanced HIV infection. METHODS: A prospective multicentre, randomized, double-blind, placebo-controlled study was carried out in HIV-infected patients with CD4 counts <100 cells/microL. RESULTS: Of 90 patients enrolled, 44 received fluconazole and 46 received placebo. The baseline characteristics were similar in the two groups. On an intent-to-treat basis, 10 cases of cryptococcal meningitis developed, three (6.8%) in the fluconazole group and seven (15.2%) in the placebo group. Patients in the placebo group were more likely to develop cryptococcal meningitis than those in the fluconazole group [hazard ratio=2.23; 95% confidence interval (CI): 0.58-8.63; P=0.245]. The survival benefit of fluconazole was greater than that of the placebo. The number of deaths per 10 000 person-days was 2.7 for the fluconazole group (2/7342) and 11.7 for the placebo group (9/7713) (rate difference=9; 95% CI: 0.4-17.5; P=0.046). Based on survival analysis, patients in the placebo group were 4.3 times more likely to die than those in the fluconazole group (95% CI: 0.9-19.8; P=0.065). CONCLUSION: Fluconazole 400 mg once weekly for primary prophylaxis for cryptococcal meningitis in Thailand should be considered in HIV-infected patients, as our study suggested a survival benefit. However, a larger study should be conducted to confirm our findings.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Cryptococcal meningitis in patients with the acquired immunodeficiency syndrome.

The optimum therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS) remains unresolved. Traditional therapy consists of amphotericin B with or without flucytosine. Obstacles exist in administering these agents to patients with AIDS. Mortality rates during initial therapy are relatively high. Given the lack of proved benefit, we do not recommend adding flucytosine to amphotericin B routinely. The search for more efficacious and less toxic agents continues. The oral triazoles, especially fluconazole, have increased the options for treatment of this disease. New strategies and novel approaches in managing cryptococcal meningitis in patients with AIDS continue to be developed.

AIDS-Related Opportunistic Infections↗
PubMed1996

Cryptococcus neoformans var. gattii among patients with cryptococcal meningitis in Mexico. First observations.

A retrospective study of 20 patients with cryptococcal meningitis and their isolated strains was performed. Cryptococcus neoformans var. neoformans was recovered from 14 (70%) cases, and var. gattii was recovered from six (30%) patients. Twelve patients had AIDS (all carrying var. neoformans), two had other diseases (one with var. neoformans and one var. gattii) and there was no identifiable underlying disease in six (one var. neoformans and five var. gattii). Fourteen patients (11 var. neoformans and three var. gattii) resided in the Mexico City area, where a temperate climate is prevalent, and there were six cases (three var. neoformans and three var. gattii) from states with a tropical/subtropical climate. Although there was no significant statistical difference between the two varieties, the fatal outcome was higher in patients with var. neoformans. The disease caused by var. gattii strains was characterized by a higher opening pressure, more inflamatory changes of CSF and a longer clinical course (delayed clinical and mycological cure). Cryptococcus neoformans var. gattii is a significant cause of cryptococcal meningitis in patients without underlying diseases in Mexico.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients.

We retrospectively compared the clinical manifestations, laboratory features, and outcome of cryptococcal meningitis in 44 human immunodeficiency virus (HIV)-positive and 21 HIV-negative patients in Durban, South Africa, and contrasted our findings with those in the developed world. Cryptococcal meningitis was the initial AIDS-defining illness in 84% of patients. Headache, fever, convulsions, neck stiffness, and neurological signs were more common in HIV-positive patients. We detected neurological abnormalities in 50% of the HIV-positive group. Seventeen percent of HIV-positive patients had completely normal CSF indices. HIV-positive patients with cryptococcal meningitis frequently had oral candidiasis and tuberculosis as coexistent illnesses. Prognostic factors identified in the West do not appear to be applicable in Africa. Death during hospitalization was significantly higher in the HIV-positive group. HIV-associated cryptococcal meningitis in Africa is apparently associated with higher rates of neurological complications and death than is such disease in developed countries of the world.

AIDS-Related Opportunistic Infections↗
PubMed1994

Cryptococcal meningitis in Lilongwe and Blantyre, Malawi.

Infection with Human Immunodeficiency Virus is widespread in Malawi and cryptococcal meningitis is a common problem in those with AIDS. A review of microbiology laboratory records in Lilongwe and Blantyre between July 1991 and January 1993 identified 31 patients with cryptococcal meningitis. Diagnosis was based on a positive India ink stain of CSF and/or culture of Cryptococcus neoformans. There were 16 men (median age 38 years) and 15 women (median age 28 years) in the investigation. The median duration of symptoms was 2 weeks. The clinical presentation was varied, the most frequent features being headache (97%), neck stiffness (74%), fever (61%) and altered consciousness (58%). CSF WBC count, glucose and protein concentrations were non-specific. Most patients could not afford anti-cryptococcal chemotherapy and their median survival time after diagnosis was 4 days. Patients who could afford such treatment survived for up to several months. Diagnosis is useful for prognostic reasons and may save patients unnecessary treatment if tuberculous meningitis is the alternative diagnosis. Cryptococcal antigen detection tests may improve diagnostic accuracy. The problem of cryptococcal meningitis is likely to become increasingly common as HIV infection becomes more widespread.

AIDS-Related Opportunistic Infections↗
PubMed1998

Cryptococcal meningitis in human immunodeficiency virus-infected patients in Harare, Zimbabwe.

A prospective observational study was conducted over a 10-month period to determine the clinical and laboratory manifestations of cryptococcal meningitis in Zimbabwe, a country where antifungal agents are not widely available. Eighty-nine patients with cryptococcal meningitis (median age, 34 years; range, 11-63 years; 56 males) were identified from 406 patients for whom a clinical diagnosis of meningitis had been made. All patients tested were positive for antibody to human immunodeficiency virus. Cryptococcal meningitis was the first AIDS-defining illness in 88% of patients. Typical presentations were headache, mental impairment, and meningism (median duration, 14 days; range, 1-180 days). The median CD4+ cell count was 70/microL (range, 0-651/microL). The cumulative median survival from the time of diagnosis was 14 days (range, 0-233 days); 22% of patients survived for >30 days. Independent indicators of a good prognosis were not identified. This study provides a unique basis for the development of novel management strategies for patients with cryptococcal meningitis who reside in resource-poor countries.

AIDS-Related Opportunistic Infections↗
PubMed1985

Effects of cyclosporine in experimental cryptococcal meningitis.

We studied the effects of cyclosporine on experimental cryptococcal meningitis. Like cortisone, cyclosporine depressed the highly effective defense mechanisms of normal rabbits against inoculated Cryptococcus neoformans, causing them to develop progressive, fatal cryptococcal meningitis. Unlike cortisone, which causes a striking reduction in leukocytes in cerebrospinal fluid, cyclosporine depressed mononuclear cell function rather than numbers. Interleukin 2, a primary target for the immunodepressive action of cyclosporine, appears to be of central importance in central nervous system defenses against cryptococci. The findings suggest that humans receiving cyclosporine are likely to suffer increased incidence of cryptococcal infection.

Animals↗
PubMed1995

Successful treatment of cryptococcal meningitis with amphotericin B colloidal dispersion: report of four cases.

Four patients with cryptococcal meningitis were treated with amphotericin B colloidal dispersion because of nephrotoxicity from prior treatment with conventional amphotericin B. The limited experience presented here suggests that amphotericin B colloidal dispersion is efficacious for the treatment of cryptococcal meningitis, despite being undetectable in cerebrospinal fluid, and offers a potential therapeutic alternative for patients who cannot tolerate conventional amphotericin B.

AIDS-Related Opportunistic Infections↗
PubMed1998

[Chronic Cryptococcal meningitis with CSF oligoclonal IgG band in a patient with Claude syndrome].

We described a 61-year-old man who was diagnosed as having chronic cryptococcal meningitis, while he was hospitalized with Claude syndrome. The patient was admitted because of acute onset of gait disturbance. He had a tendency to fall down to his left side since he awoke in the morning of August 12, 1995. On admission, he was mentally alert, showing a right oculomotor nerve palsy, gaze-evoked horizontal nystagmus in the left eye on the left lateral gaze, and incoordination of the left upper and lower extremities. In addition, he fell to the left side on standing up with feet together and with eyes closed. He had mild wild-based gait with a tendency to fall down to the left on tandem gait. Babinski sign was present on the left side. He did not have fever, nor meningeal signs, nor sensory abnormalities. X-ray films of the chest showed multiple nodular shadows consistent with pneumoconiosis. Cranial X-ray computed tomography and magnetic resonance imaging revealed a small lesion in the paramedian area of the midbrain on the right, consistent with an infarct. Cerebral arteriography revealed a stenosis in the proximal portion of the right posterior cerebral artery. Cerebrospinal fluid (CSF) showed a moderate mononuclear cell predominant pleocytosis, a moderate elevation of total protein, slightly reduced glucose values. Although the culture and India ink preparation of CSF were negative for cryptococcus in repeated studies, its antigen was positive both in the serum and CSF. In addition, the CSF showed an oligoclonal IgG band which was predominantly K type. After the antigen of Cryptococcus neoformans was added to the CSF in vitro, the oligoclonal IgG band was absorbed completely. The patient was treated with fluconazole (FLCZ), which did not cause any improvement of the CSF abnormalities, so that FLCZ was replaced by 5-flucytosine (5-FC). Since the CSF abnormalities moderately improved with 5-FC, he was discharged on December 21, 1995. After the 5-FC was discontinued, the CSF results slowly worsened over several months without any signs and symptoms of meningitis. He was hospitalized again on October 28, 1996 for treatment with both 5-FC and amphotericin B. Although the CSF abnormalities improved markedly, the meningitis was not cured. After he was discharged on February 1, 1997, he was treated with both 5-FC and FLCZ. Although his CSF abnormalities worsened mildly, he remained afebrile without meningeal signs and symptoms and led an ordinary life. In our patient it remained undetermined whether the Claude syndrome was caused by arteriosclerotic infarction, or vasculitis due to cryptococcal meningitis, or both. Asymptomatic chronic cryptococcal meningitis as observed in our patients is unusual. In addition, this is the second case after Porter et al (1977) that the oligoclonal IgG band in CSF proved to be related to cryptococcal infection.

Biomarkers↗
PubMed1997

Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis.

OBJECTIVE: Amphotericin B deoxycholate initial therapy and fluconazole maintenance therapy is the treatment of choice for AIDS-associated cryptococcal meningitis. However, the administration of amphotericin B is associated with considerable toxicity. A potential strategy for reducing the toxicity and increasing the therapeutic index of amphotericin B is the use of lipid formulations of this drug. DESIGN AND METHODS: HIV-infected patients with cryptococcal meningitis were randomized to treatment with either liposomal amphotericin B (AmBisome) 4 mg/kg daily or standard amphotericin B 0.7 mg/kg daily for 3 weeks, each followed by fluconazole 400 mg daily for 7 weeks. During the first 3 weeks, clinical efficacy was assessed daily. Mycological response was primarily evaluated by cerebrospinal fluid (CSF) cultures at days 7, 14, 21 and 70. RESULTS: Of the 28 evaluable patients, 15 were assigned to receive AmBisome and 13 to receive amphotericin B. Baseline characteristics were comparable. The time to and the rate of clinical response were the same in both arms. AmBisome therapy resulted in a CSF culture conversion within 7 days in six out of 15 patients versus one out of 12 amphotericin B-treated patients (P = 0.09), within 14 days in 10 out of 15 AmBisome patients versus one out of nine amphotericin B patients (P = 0.01), and within 21 days in 11 out of 15 AmBisome patients versus three out of eight amphotericin B patients (P = 0.19). When Kaplan-Meier estimates were used to compare time to CSF culture conversion, AmBisome was more effective (P < 0.05; median time between 7 and 14 days for AmBisome versus > 21 days for amphotericin B). AmBisome was significantly less nephrotoxic. CONCLUSIONS: A 3-week course of 4 mg/kg AmBisome resulted in a significantly earlier CSF culture conversion than 0.7 mg/kg amphotericin B, had equal clinical efficacy and was significantly less nephrotoxic when used for the treatment of primary episodes of AIDS-associated cryptococcal meningitis.

AIDS-Related Opportunistic Infections↗
PubMed1996

Treatment of experimental cryptococcal meningitis with fluconazole: impact of dose and addition of flucytosine on mycologic and pathophysiologic outcome.

Fluconazole is effective in the therapy of cryptococcal meningitis in patients with AIDS. The optimal dosage of fluconazole and the impact of combination with flucytosine are not known. In this study, rabbits with experimental cryptococcal meningitis were given fluconazole at low, intermediate, or high dose or in combination with a low or intermediate dose of flucytosine. Serial cerebrospinal fluid (CSF) examinations showed that all three doses of fluconazole and low-dose fluconazole in combination with intermediate-dose flucytosine were effective in reducing CSF cryptococcal titer, lactate, white blood cell count, and cryptococcal antigen (CRAG) titers. The intermediate and high doses of fluconazole reduced CSF fungal (P < .05) and CRAG (P < .001) titers earlier than low-dose fluconazole alone or in combination with flucytosine. Only the highest dose of fluconazole reduced brain edema after 7 days. In this model of cryptococcal meningitis, there was evidence of a dose response with fluconazole but no in vivo synergism with flucytosine.

Animals↗