Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial

OBJECTIVE: To compare the efficacy of fluconazole with amphotericin B plus flucytosine in the treatment of cryptococcal meningitis. DESIGN: Patients were randomly assigned to oral fluconazole, 400 mg/d, for 10 weeks or to amphotericin B, 0.7 mg/kg body weight daily for 1 week, then three times weekly for 9 weeks combined with flucytosine, 150 mg/kg d, in four divided doses. SETTING: Los Angeles County-University of Southern California Medical Center. PATIENTS: Between 15 February and 7 December 1988, 42 patients had evidence of their first episode of cryptococcal meningitis, of whom 21 participated in the trial. All patients enrolled were men with the acquired immunodeficiency syndrome (AIDS) except one woman who was receiving prednisone therapy and was excluded from the final analysis. RESULTS: Of 14 patients with AIDS assigned to fluconazole, 8 (57%; 95% CI, 29% to 82%) failed; none of the 6 patients with AIDS failed who were assigned to amphotericin B plus flucytosine therapy (0%; CI, 0% to 46%) (Fisher exact test, P = 0.04). The mean duration of positive cerebrospinal fluid cultures was 40.6 +/- 5.4 days in patients receiving fluconazole and 15.6 +/- 6.6 days in patients receiving amphotericin B plus flucytosine (Mann-Whitney test, P = 0.02). Overall, 4 patients assigned to fluconazole therapy died whereas no patient assigned to amphotericin B plus flucytosine therapy died (Fisher exact test, P = 0.27). CONCLUSION: Amphotericin B used in combination with flucytosine has superior mycologic and clinical efficacy compared with fluconazole for the treatment of cryptococcal meningitis in patients with AIDS.     

Initial treatment with amphotericin B plus rifampin in the acute treatment of cryptococcal meningitis in aids

The result of initial treatment with amphotericin B (0.7 mg/kg/day) plus rifampin (600 mg/day) for 2 weeks, followed by fluconazole (400 mg/day) for 8 weeks in the acute treatment of cryptococcal meningitis in AIDS is reported. There were 10 patients in the study: at 2 weeks, all had made a clinical response and cerebrospinal fluid was sterile in 4 patients; at 10 weeks, all had negative cerebrospinal fluid cultures. Serious side effects were not detected.     

Experimental chemotherapy of histoplasmosis in nude mice

Nude (nu/nu) mice were infected with Histoplasma capsulatum and treated with varying doses of 3 drug regimens: oral ambruticin, intraperitoneal amphotericin B, and amphotericin B plus oral rifampin. Therapy with amphotericin B alone was the most effective regimen. High-dose ambruticin (50 mg/kg of body weight every 8 hours) led to significantly prolonged survival compared to that of untreated control animals, but no long-term cures. Addition of rifampin produced no benefit and might actually have decreased the efficacy of amphotericin B; this combination may be deleterious in a setting of immunodeficiency.     

Clinical profile of disseminated cryptococcal infection–a case series

ObjectiveTo study disseminated cryptococcal infection in a tertiary care hospital in Southern India.MethodsThe clinical profile of 12 disseminated cryptococcosis patients with the age group of 28-52 years was retrospectively analyzed.Results7(58.3%) presented with fever < 30 days and 3(25%) > 30 days whereas 2(16.7%) did not have fever. All the 12(100%) had headache, 2(16.7%) had altered sensorium, one (8%) seizure. 5(41.7%) had diarrhea and vomiting. 6(50%) had oral candidiasis, and anemia. 9(75%) had elevated erythrocyte sedimentation rate (ESR). 6(50%) had neck stiffness. Cerebrospinal fluid (CSF) pressure was elevated in all 12(100%) patients. Blood culture positive for Cryptococcus neoformans(C. neoformans) in 11(91.7%) and CSF culture positive in all 12 (100%), one (8%) had urine culture positive. India ink preparation was positive in 10(83.3%). CD4 count was less than 50/microl in 4 (33.3%), between 50-100 in 6(50%) and 2(16.7%) in the range of 100-200. 6(50%) were treated with parenteral amphotericin B (0.7 mg/kg/d) during intensive phase followed by oral fluconazole 400 mg/d for 8 weeks then maintenance oral fluconazole 200 mg/d. 5(41.6%) were treated with fluconazole alone. 8(66.7%) improved and 4(33.3%) patients died. Among those who succumbed to the illness, 2(16.7%) received amphotericin and fluconazole, 2(16.7%) patients received fluconazole alone.ConclusionsDisseminated cryptococcosis can cause considerable mortality in HIV patients and immunocompromised non- HIV individuals. At times, its presentation closely mimics that of Tuberculosis. Early diagnosis and appropriate treatment should be started as early as possible.     

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.     

Hepatosplenic cat-scratch disease in children: selected clinical features and treatment.

We reviewed 19 cases of hepatosplenic cat-scratch disease at Texas Children's Hospital (Houston). The range of the patients' ages was 2 years 4 months to 11 years 8 months. The chief complaint was fever for all patients. The duration of fever before diagnosis was 7 to 56 days (mean, 22 days). Abdominal pain was present in 13 patients (68%). Thirteen children were treated with rifampin alone, and three received rifampin therapy plus gentamicin or trimethoprim-sulfamethoxazole. Once rifampin therapy was initiated alone or in combination, improvement was noted within 1 to 5 days (mean, 2.6 days) for patients who had had prolonged fever the duration of which before rifampin therapy averaged 3 weeks. The most common dosage and duration for our patients were 20 mg/[kg x d] every 12 hours and 14 days, respectively. Rifampin should be considered in the initial antimicrobial treatment of hepatosplenic cat-scratch disease.     

A prospective study of AIDS-associated cryptococcal meningitis in Thailand treated with high-dose amphotericin B

OBJECTIVE: To assess kinetic of cryptococci in the cerebrospinal fluid (CSF) and outcome of AIDS-associated cyptococcal meningitis after high-dose amphotericin B. PATIENTS AND METHODS: A prospective study involving Thai adults (n=106) with cryptococcal meningitis associated with AIDS was conducted to determine the kinetic of cryptococci in CSF and prognostic factors affecting survival after high-dose amphotericin B (0.7 mg/kg/day) followed by oral azole treatment. Cerebrospinal fluids were collected for cryptococcal count and culture at weekly intervals for at least 2 weeks or until CSF cultures were negative for cryptococci. All patients were followed monthly for 1 year or until death in order to detect relapse or occurrence of any other opportunistic infection. RESULTS: A total of 106 AIDS patients with cryptococcal meningitis were enrolled. The geometric mean (range) total and viable cryptococcal counts in CSF on admission were 430,000 (1000 to 3.4 x 10(7)) and 31,000 (10 to 1.4 x 10(7)) per ml, respectively. Both total and viable cryptococcal counts declined monoexponentially with an elimination half life of 4 days. The cumulative CSF yeast clearance rates were 38% and 56% at 2 and 4 weeks, respectively. Early death was associated significantly with previous history of weight loss [relative risk (RR)=2.2; 95% CI, 1.2-3.9], Glasgow Coma Score <13 (RR=2.33; 95% CI, 1.55-3.50), and hypoalbuminaemia (P<0.001). Later mortality was associated delayed CSF yeast clearance (RR=3.6; 95% CI, 1.9--6.4) and relapse (RR=3.9; 95% CI, 1.4-10.8). CONCLUSION: High-dose amphotericin B was not as effective as previously thought. Cumulative mortality at 2 weeks, 4 weeks and 1 year were 16%, 24% and 76%, respectively.     

Early mycological treatment failure in AIDS-associated cryptococcal meningitis.

Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.     

Diagnosis and successful treatment of fusariosis in the compromised host

We present six cases of fusariosis caused by Fusarium solani that were diagnosed over a three-year period in 166 adult patients undergoing chemotherapy for acute leukemia. Necrotic skin lesions were evident in four patients, fungemia in three, and a deep cellulitis around a great toe nail at the time of a febrile illness in two. The mean minimal inhibitory concentration (MIC) of amphotericin B was 3.3 micrograms/mL and of miconazole, 5.3 micrograms/mL; all isolates were resistant to 5-fluorocytosine. All patients received amphotericin B (1.0-1.5 mg/kg per d) plus 5-fluorocytosine. In contrast to results found in the literature, five patients had resolution of their infections, and the one patient who died had necropsy evidence of disseminated fusariosis. Review of our cases and of the literature did not reveal a definitive source for the organism or its portal of entry. Fusarium spp. must be recognized as opportunistic pathogens that cause a potentially fatal infection in compromised patients.     

Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis

OBJECTIVE: To determine the median response time to therapy with vancomycin alone or with vancomycin plus rifampin in patients with methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. DESIGN: Cohort analysis of a randomized study. SETTING: University medical center. PATIENTS: Forty-two consecutive patients with MRSA endocarditis were randomly assigned to receive either vancomycin (group I) or vancomycin plus rifampin (group II) for 28 days. MEASUREMENTS: Clinical signs and symptoms were recorded, and blood cultures were obtained daily to determine the duration of bacteremia. MAIN RESULTS: The median duration of bacteremia was 9 days (7 days for group I and 9 days for group II). The median duration of fever for all patients and for each treatment group was 7 days. Six patients failed therapy, including three patients who died 5, 6, and 9 days after therapy was started, respectively. The other three patients who failed therapy required valve surgery on days 2, 22, and 27, respectively. Although patients had sustained bacteremia, no unusual complications were seen in either treatment group, and most patients responded to continued antibiotic therapy. CONCLUSIONS: Slow clinical response is common among patients with MRSA endocarditis who are treated with vancomycin or vancomycin plus rifampin. Nevertheless, few complications appear to be related solely to this sustained bacteremia.     

Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment

Between 1 January 1981 and 1 December 1984, 34 of 396 patients with the acquired immunodeficiency syndrome (AIDS) developed cryptococcal infections. Twenty-six cases are reviewed. Twenty-two patients had brain or meningeal disease; the others had pulmonary disease (2 patients), pericarditis (1 patient), and antigenemia (1 patient). During treatment, 3 patients died of cryptococcosis and 3 died of other causes. Fifteen patients were followed for more than 6 weeks after treatment. Of 8 patients who received no additional amphotericin B, 4 had relapses and died of cryptococcosis within 6 months, 3 died of other causes, and 1 survived. Of 7 patients who received maintenance therapy with amphotericin B, none had relapses, 3 died of other causes, and 4 survived. Our data suggest that maintenance therapy with amphotericin may be needed to prevent relapse in patients with AIDS.     

Hepatosplenic candidiasis: successful treatment with fluconazole

PURPOSE: To determine if fluconazole is effective treatment for hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine treatment. PATIENTS AND METHODS: Six patients (ages 3 to 44) with acute leukemia and hepatosplenic candidiasis who did not respond to prior antifungal therapy were treated with fluconazole. RESULTS: All six patients had fever and three had nausea and vomiting; computed tomographic (CT) scan showed lucencies in the liver in six, lucencies in the spleen in five, and lucencies in the kidneys in three. Prior therapy with 1.6 to 4 g of amphotericin B in the five adults and 526 mg of amphotericin B in the child (with the addition of flucytosine in four) failed to improve clinical symptoms or lucencies in the liver, spleen, and kidneys seen on CT scan. Fluconazole was given at a dose of 200 to 400 mg daily (70 to 100 mg in the child) for 2 to 14 months. All patients had resolution of fever and other symptoms in 2 to 8 weeks. Improvement of the lesions noted on CT scan was seen in 4 to 8 weeks in all patients. Total resolution of lesions noted on CT scan occurred by 4 weeks in two patients, but took 4 to 5 months for three patients and 13 months for one patient. Three patients had relapse of their acute leukemia and two died, presumably cured of their candidiasis. Two patients underwent successful bone marrow transplantation without relapse of their candidiasis. CONCLUSION: Fluconazole appears to be useful in the treatment of hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine therapy.     

Therapy of cryptococcosis with a combination of flucytosine and amphotericin B.

In a prospective study from May 1971 to November 1973, 20 consecutive patients with a diagnosis of disseminated cryptococcosis were treated for six weeks with a combination of amphotericin B (20 mg daily) intravenously and flucytosine (150 mg/kg daily) orally. Fifteen patients has culturally docummented Cryptococcus neoformans meningitis, and three died of infection early in therapy. Of the remaining 12 patients, eight were alive and well eight to 34 months after therapy, and four died of other causes. None of the surviving patients has relapsed. Hematologic complications developed in nine patients, three of whom had no underlying lymphoreticular disorder or therapy with known cytotoxic agents. Renal insufficiency of mild degree occurred in only six patients. A shorter period of hospitalization and reduction in toxicity of amphotericin B suggest that combined therapy is a safe and efficacious alternative to other regimens.     

Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen. Rifampin, ethambutol, clofazimine, and ciprofloxacin. The California Collaborative Treatment Group.

OBJECTIVE: To determine the quantitative microbiologic response and the clinical response of patients with Mycobacterium avium complex bacteremia and AIDS to an oral antimycobacterial regimen. DESIGN: A phase II, multicenter clinical trial. SETTING: Four university-affiliated medical centers. PATIENTS: Forty-one patients with HIV infection who had at least two consecutive blood cultures positive for M. avium complex and who had not received previous antimycobacterial therapy were enrolled in the study. Thirty-one patients were evaluable with regard to the efficacy of the oral regimen. INTERVENTIONS: Patients received a combination of orally administered rifampin (600 mg), ethambutol (15 mg/kg body weight), clofazimine (100 mg once daily), and ciprofloxacin (750 mg twice daily) for 12 weeks. Parenterally administered amikacin, 7.5 mg/kg daily for 4 weeks after the first 4 weeks of oral therapy, was used at the discretion of the individual investigator. MEASUREMENTS: Clinical symptoms, Karnofsky scores, and adverse events were monitored. Colony counts for M. avium complex were determined. MAIN RESULTS: The mean logarithmic (log) baseline colony count decreased from 2.1 to 0.7 after 4 weeks of oral therapy (P less than 0.001). Suppression of bacteremia was sustained throughout therapy. Thirteen patients (42%) became culture negative during therapy. The mean duration of treatment was 9.7 weeks. Nineteen evaluable patients (61%) completed 12 weeks of therapy. Adverse reactions to one or more agents were common. CONCLUSIONS: A rapid reduction in symptoms and bacteremia can be achieved as early as week 2 of therapy using an oral regimen of rifampin, ethambutol, clofazimine, and ciprofloxacin. Colony counts rose dramatically after therapy was discontinued, suggesting that more prolonged periods of therapy are necessary to eradicate systemic infection.     

Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases

No controlled trials of therapy for invasive aspergillosis have been done. This review appraises 2,121 cases reported in 497 articles in the literature and analyzes 440 courses of treatment of infection at various body sites in 379 patients. The exclusion of early failures of therapy skews the results toward a favorable outcome. The rate of response to amphotericin B is 55%. Mortality from pulmonary aspergillosis in bone marrow transplant recipients exceeds 94% regardless of therapy, as does that from cerebral aspergillosis in all hosts. Amphotericin B (1 mg/[kg.d]) with flucytosine lowers mortality in neutropenic patients with pulmonary aspergillosis who did not receive a bone marrow transplant; relapse is common. Surgical debridement of aspergillus maxillary sinusitis is usually curative in nonimmunocompromised patients, whereas it increases mortality among neutropenic patients. Valve replacement is essential for aspergillus endocarditis. Both vitrectomy and intravitreal amphotericin B treatment are essential for aspergillus endophthalmitis. Flucytosine is somewhat useful clinically. Itraconazole shows efficacy in the treatment of pulmonary, skeletal, and pericardial aspergillosis. Although liposomal amphotericin B is less toxic than standard preparations of the drug, relevant data are limited. The proposed potentiation of amphotericin B by rifampin is unsupported by clinical data. Despite "conventional" therapy, mortality from invasive aspergillosis remains high; new approaches must be investigated.     

Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. California Collaborative Treatment Group

OBJECTIVE: To determine the efficacy of combination drug therapy for disseminated Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Prospective, nonrandomized, before-after comparison. SETTING: Outpatient clinics at three university medical centers. PATIENTS: Seventeen patients with at least two consecutive blood cultures positive for M. avium complex who had not been previously treated with antituberculous medications. Fifteen of the seventeen patients completed at least 4 weeks of treatment. INTERVENTION: Patients received daily intravenous amikacin (7.5 mg/kg body weight) for the first 4 weeks plus the following oral medications for at least 12 weeks: ciprofloxacin, 750 mg twice daily; ethambutol, 1000 mg daily; and rifampin, 600 mg daily. MEASUREMENTS AND MAIN RESULTS: The baseline geometric mean colony count from blood cultures decreased from 537/mL to 14/mL (P less than 0.001) after 4 weeks of therapy. The microbiologic suppression was sustained while on treatment and was associated with a decrease in systemic symptoms related to M. avium complex infection. Premature withdrawal from treatment (less than 12 weeks) occurred in 7 of 17 patients. The commonest reasons for early withdrawal were gastrointestinal intolerance and hepatic toxicity. CONCLUSIONS: Mycobacterial load and systemic symptoms in patients with AIDS and disseminated M. avium complex infection can be effectively reduced by a regimen containing amikacin, ethambutol, rifampin, and ciprofloxacin.     

Efficacy of amphotericin B colloidal dispersion in the treatment of Mediterranean visceral leishmaniasis in immunocompetent adult patients

Twelve immunocompetent adults with Mediterranean visceral leishmaniasis (VL) were treated with amphotericin B colloidal dispersion (ABCD; 2 mg/kg/d for 7 d). All patients showed rapid clinical response without significant adverse events. Two weeks after therapy they were parasitologically cured and no relapses occurred during 6 months. ABCD is a valid alternative in the management of Mediterranean VL in adult patients.     

隐球菌性脑膜炎26例临床分析

目的 总结隐球菌性脑膜炎的资料,提高对隐球菌性脑膜炎的认识。方法 回顾性总结近20年（1981年10月至2001年9月）隐球菌性脑膜炎的一般资料,诊断及治疗情况。结果 共26例患者,其中男12例,女14例,年龄5－62岁,平均35．6岁,有基础疾病者16例,其中系统红斑狼疮（SLE）9例,人类免疫缺陷病毒感染或艾滋病（HIV／AIDS）4例,其他疾病3例;有明确鸽子接触史者12例;误诊结核性脑膜炎者5例,狼疮脑病者6例;墨汁染色找到隐球菌者23例（23／26）,乳胶凝集试验抗原阳性20例（20／20）。颅内压明显增高＞300mm H2O者15例,脑室扩大行侧脑室引流者9例;12例给予两性霉素B（AmpB) 5氟胞嘧啶,6例又同时加氟康唑治疗,5例AmpB 氟康唑,1例单纯应用AmpB治疗。AmpB最大用量：AmpB10.05g 脂质体两性霉素B20g,平均用量2.6g;治愈17例,好转4例,死亡或自动出院5例。同时发现近5年隐球菌性脑膜炎病例数明显增多。结论 近年来,隐球菌性脑膜炎发病率明显增高,可能和免疫抑制剂和糖皮质激素的应用及HIV／AIDS增多有关,减少病死的关键在于提高早期诊断率,治疗仍首选AmpB加5氟胞嘧啶,侧脑室引流可减少AmpB的用量,提高治愈率,缩短疗程。