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A retrospective review of therapeutic failures of miconazole in three patients is presented. Miconazole, a new imidazole derivative, is a broad-spectrum antifungal agent purportedly effective topically, orally, and parenterally against a number of species of fungi. Three patients with the following culturally proven deep fungal infections were treated with miconazole: (i) destructive arthritis (Sporothrix schenckii), (ii) meningoencephalitis (Cryptococcus neoformans), and (iii) disseminated aspergillosis (Aspergillus fumigatus). All the organisms were susceptible in vitro to 1.56 mug or less of miconazole per ml using a broth dilution technique. In each patient, miconazole administered intravenously in dosages of 30 mg/kg per day failed to control or eradicate infection. Miconazole serum levels ranged from <0.5 to 4.35 mug/ml as determined by radial diffusion bioassay. Cerebrospinal fluid levels were virtually undetectable. In one patient (C. neoformans), miconazole was given intraventricularly in doses of 15 mg without response. Therapeutic failures were attributed to suboptimal body fluid levels of miconazole. The reason(s) for such low levels of activity was not clear, but may have been poor penetrance into tissues, in vitro inactivation, and/or unusually rapid excretion. Untoward reactions from miconazole included fever, chills, nausea, vomiting, and phlebitis.
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PMID:Therapeutic failures with miconazole. 35 23

This is the first report from Ethiopia of a case of cryptococcal meningitis in a patient with AIDS. A 20-year-old woman was admitted to Tikur Anbessa Hospital in January 1990 with complaints of generalized pruritic skin lesions of six months, and headache, fever, and poor appetite of three months duration. The headache and low-grade intermittent fever were accompanied by nausea, vomiting, anorexia, and progressive weight loss, without diarrhea. She had had multiple sex partners. Upon admission, after being bedridden for two weeks, she appeared acutely ill and restless. Her temperature was 39.5 degrees Celsius, and she had oral thrush. There was no lymphadenopathy. Widespread, irregular erythematous and whitish macular patches (3 x 5 to 8 x 10 sq. cm in size) with peripheral scaling and tiny vesicles were found on the skin, pubic and perineal regions. She had neck stiffness, but was conscious and well-oriented. Hemoglobin (Hb) was 10.5 g%; the white cell count (WBC) was 3400/cu. mm; the erythrocyte sedimentation rate (ESR) was 92 mm/hr; the platelet count was 175,000/mm; and blood films were negative for hemoparasites. Urinalysis showed 3+ albumin and many pus cells and red cells/HPF. Urine culture was negative, and the VDRL test was nonreactive. Lumbar puncture, which was performed upon arrival, showed clear cerebrospinal fluid (CSF), with normal protein and glucose levels and no cells. CSF culture showed yeast cells, and an India ink preparation was positive for Cryptococcus neoformans. Blood taken for bacterial culture grew yeast cells. Renal and liver function tests, and chest x-rays were normal. A potassium hydroxide (KOH) preparation from a skin snip showed rounded yeast cells. ELISA and Western blot tests were both positive. The patient was given supportive treatment and amphotericin B (0.6 mg/kg daily). Although the fever decreased, the patient's general condition did not improve. She complained of headache, photophobia, nausea, and vomiting. Lumbar puncture was repeated eight days after the start of treatment; CSF culture and India ink preparations were negative. Urea nitrogen (BUN) repeated two weeks later was normal. Four weeks after admission, the patient suddenly vomited massive amounts of fresh blood and died before transfusion could be given. A discussion follows regarding the clinical manifestations, diagnosis, and treatment of this disease, particularly in AIDS patients, with a review of the literature.
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PMID:Cryptococcal meningitis in a young Ethiopian woman with AIDS. 139 20

Fluconazole, a novel triazole antifungal agent, was given orally or intravenously to 10 patients with pulmonary mycosis (7 patients with primary pulmonary cryptococcosis and 3 with pulmonary aspergillosis). Routes of administration were changed in some patients depending on their condition. Two patients from whom foci was removed by surgical operations were excluded from the efficacy assessment. Clinical efficacies in the remaining 8 patients were good in 2 cases and fair in 3 cases of pulmonary cryptococcosis; excellent in 1 case of pneumonia due to Aspergillus; and fair in 1 case and poor in the other case of pulmonary aspergilloma. Side reactions developed in 9 patients who received intravenous drip infusion were nausea or loss of appetite in 3 patients, fever and/or feverish sensation in 3, vascular pain in 1 and diarrhea and eruption in 1. In the patient who reported fever the drug was discontinued and in the patient who complained of pain at the site of injection, dosing was changed to the oral route but was discontinued due to elevated GOT, GPT, Al-P and gamma-GTP. Seven patients who received the drug orally did not report side effects except 2 patients. None of these side effects reported was serious and from the above results, fluconazole was considered to be a useful agent for the treatment of pulmonary mycosis.
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PMID:[Clinical efficacy of fluconazole in the patient with pulmonary mycosis]. 254 Mar 59

Fluconazole is a novel antifungal agent, available in oral and intravenous forms, which was developed by Pfizer Central Research. It is characterized by its long serum half-life (approximately 30 hours) to allow once-a-day dosing and favorable safety profile. Fluconazole was administered orally or intravenously to 166 patients with deep-seated mycosis and it was possible to evaluate clinical efficacies in 99 patients. Clinical cures were obtained in 41 (87.2%) out of 47 cases of candidiasis, in 10 (66.7%) out of 15 cases of cryptococcosis, in 17 (48.6%) out of 35 cases of aspergillosis and in 1 case each (100%) of mucormycosis and mycosis due to an unspecified yeast. Side effects were observed in 10 cases (rash 2, fever 2, abdominal discomfort 1, nausea 1, edema 1, edema/pleural effusion/oliguria 1, finger stiffness 1, hiccup 1) with incidence rate of 6.0%. Drug administrations were discontinued in 4 cases. In general, however, fluconazole was well tolerated. Abnormal changes in laboratory test values due to the drug were observed in 32 cases and incidence rate was 19.3%. These were, however, slight and temporary changes and most of them were in parameters of liver function. It is not clear if these changes were related to the fluconazole administration, because other drugs were concomitantly administered to these cases. These results indicate that fluconazole is an agent with very good potential for the treatment of the systemic deep-seated mycoses.
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PMID:[Clinical study of fluconazole on deep-seated fungal infections]. 254 Mar 69

The clinical course and response to therapy of seven patients with cryptococcosis and AIDS were reviewed. One patient was still in the primary stage of cryptococcosis in AIDS, i.e. the stage that is characterized by the sole cultural detection of Cryptococcus neoformans in the respiratory tract. The other six patients were in the secondary stage, where C. neoformans can be detected from the cerebrospinal fluid (CSF), blood, urine, faeces and other body sites. The main presenting features (headache, fever, nausea) were due to central nervous system involvement, although meningism and mental changes were rarely present, and CSF changes were very subtle. Treatment with amphotericin B and flucytosine was very effective, there being no more growth of fungi in cultures in most cases. Adverse reactions to the drugs used occurred frequently and consisted mainly of anaemia, hepatosis and fever. Diagnosis in the primary stage of cryptococcosis may improve the prognosis.
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PMID:Cryptococcosis in AIDS patients: observations concerning CNS involvement. 291 24

The ascites retention as a complication after ventriculo-peritoneal shunting (V-P shunt) is very rare. In this paper, a case of central nervous cryptococcosis giving rise to ascites after a V-P shunt is presented. A 45-year-old female was referred to Prefectural Gifu Hospital complaining of nausea and disturbance of recent memory. She had no remarkable medical history. CT scan films on admission showed enlarged ventricles except for the fourth ventricle, indicating an obstructed hydrocephalus. Lumbar cerebrospinal fluid (CSF) examinations revealed an increase in cell counts (mostly lymphocytes) and protein content, and positive Pandy and Nonne-Apelt reactions. Based on this information, it was tentatively suggested that she had a certain infection in the central nervous system such as mycosis or tuberculosis etc. Continuous ventricular drainage was performed for about three weeks. During this period, several lumbar and ventricular CSF cultures were negative. Therefore, a V-P shunt operation was performed. However, about seven weeks after the V-P shunt, she developed abdominal distention without any peritoneal signs. Abdominal CT scan films showed an abnormal ascites retention. Laboratory tests revealed positive CRP and increased ESR values. Again, it was suggested that she had not only a central nervous but also a peritoneal infection giving rise to ascites. From samples of ventricular CSF and ascites, cryptococcus neoformans was cultured. The lumbar CSF revealed positive latex agglutination titer for cryptococcal antigen, although the culture was negative. The ascites examination revealed an increase in cell counts (mostly lymphocytes) and protein content, and positive Rivalta and Runneberg reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Central nervous cryptococcosis giving rise to ascites after ventriculo-peritoneal shunting--a case report]. 322 72

A case of cryptococcal meningitis in a patient with the acquired immunodeficiency syndrome (AIDS) is described, as well as the epidemiology, pathogenesis, clinical manifestations, diagnosis, and therapeutic management of the disease. In July 1987 a 38-year-old white man was admitted to the hospital because of confusion, disorientation, and headache. His medical history was notable for a positive human immunodeficiency virus test. Culture of the cerebrospinal fluid was positive for Cryptococcus neoformans. The patient was started on amphotericin B 16 mg/day (0.3 mg/kg/day) intravenously and flucytosine 2 g every six hours (150 mg/kg/day) orally. Despite premedication with diphenhydramine and acetaminophen, he experienced rigors that were treated with hydrocortisone and meperidine. Three weeks later he was discharged on flucytosine 2 g orally every six hours and amphotericin B 50 mg intravenously every other day. One week later the patient developed fever and chills; blood cultures were positive for methicillin-sensitive Staphylococcus aureus, and his peripheral leucocyte count was 1.8 X 10(3)/cu mm. Flucytosine was discontinued, and he was treated with intravenous nafcillin while remaining on amphotericin B. In October the patient complained of nausea, vomiting, weakness, and agitation. A CSF latex agglutination titer for cryptococcal antigen was 1:32. He was treated with amphotericin B 50 mg daily until symptoms resolved and then continued on amphotericin B 50 mg twice weekly. Cryptococcosis is the most common life-threatening fungal infection among AIDS patients. In contrast to immunocompetent hosts, this population invariably develops disseminated disease, with 85% having meningeal involvement. The most effective therapy for cryptococcal meningitis in patients with AIDS has not been established.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Management of cryptococcal meningitis in patients with AIDS. 341 73

Laboratory and clinical study was carried out on miconazole (MCZ), a new synthetic imidazole. The antifungal activity of MCZ was studied and expressed as MICs for clinical isolates. The drug proved to have the highest activity against Cryptococcus neoformans, with MICs of no more than 0.16 micrograms/ml for all isolates of this species. MICs of Torulopsis glabrata were 0.08-5 micrograms/ml for all isolates and those of Candida albicans and Candida tropicalis were 5-20 micrograms/ml for more than 90% of the isolates. Most of other strains were less than 10 micrograms/ml. When 3 healthy adult men were administered each with 200 mg of MCZ by intravenous drip infusion for 1.25 hours, the mean serum MCZ concentration was 1.39 micrograms/ml at the end of the infusion, then decreased rapidly to 0.49 microgram/ml in following 30 minutes, and then decreased gradually to 0.17 microgram/ml 6 hours later. The mean cumulative urinary excretion rate of the drug was as low as 3.0% at this stage. A total of 25 patients with ages of 30-78 years, comprising 17 men and 8 women, were treated with 200-1,800 mg of MCZ daily for 3-93 days. The clinical effectiveness was ascertained in 19 cases among the patients; 9 cases with candidiasis, 3 with cryptococcosis and 7 with aspergillosis. Clinical responses were excellent in 2, good in 9 and poor in 8 cases, and its efficacy rates was 58%. The efficacy rate of the combination therapy with other antifungal agents was 60% in comparison with 57% of MCZ alone. Adverse reactions to the drug such as nausea, vomiting and anorexia were observed in 3 cases (12%). Abnormal changes in laboratory parameters were also observed: 3 patients with elevations of GOT and GPT, and another with eosinophilia.
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PMID:[Laboratory and clinical study of intravenous miconazole]. 359 80

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.
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PMID:Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients. National Institute of Allergy and Infectious Diseases collaborative antifungal study. 629 61

A 58-year-old man was admitted to our hospital with suspicion of aseptic meningitis. He had been well until the day before admission, when he became suffering from headache and nausea. Cerebral spinal fluid (CSF) analysis on admission revealed Cryptococcus neoformans. Neurological examination and brain CT scan showed no abnormality. On the 5th hospital day, he noticed ataxia and weakness in his right extremities and soon fell into drowsy to comatose state. CSF study revealed marked elevation of pleocytosis and oligoclonal IgG bands. The T2 weighted image of brain MRI showed multiple high intensity areas, mainly in the white matter, in cerebellar hemisphere, vermis, left medulla oblongata, left occipital lobe and parieto-occipital lobe. Steroid pulse therapy remarkably improved neurological deficit as well as MRI abnormalities. He became alert at the next day. Ataxia and motor weakness disappeared in a week. Laboratory examination before the pulse therapy revealed impairment of T cell response to mitogens and reduced number of CD8-positive cells. These abnormalities in the cell-mediated immunity were completely corrected by the steroid pulse therapy. It was hypothesized that cryptococcus infection induced the autoimmune mechanism which resulted in the ADEM-like exacerbation.
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PMID:[Acute disseminated encephalomyelitis (ADEM)-like exacerbation in the patients with cryptococcus meningitis treated successfully by steroid pulse therapy]. 866 39


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