Interaction of fluconazole and cyclosporine.
Explore the source record for details and available documents.
Antifungal Agents↗
Biomedical subjects
A M Sugar
Publications and source records attributed to A M Sugar.
Fungal peritonitis complicating continuous ambulatory peritoneal dialysis: successful treatment with fluconazole, a new orally active antifungal agent.
Explore the source record for details and available documents.
Adult↗
Effect of cilofungin (LY121019), a fungal cell wall synthesis inhibitor, on interactions of Candida albicans with human neutrophils.
The effects of cilofungin, a lipopeptide antifungal agent active against several species of Candida, on human neutrophil candidacidal activity were investigated. While no increase or decrease in neutrophil killing of blastospores was observed when cilofungin was simultaneously incubated with neutrophils and yeasts, preincubation of yeasts with serum containing cilofungin resulted in approximately 90% decrease in killing of five of six strains. Attachment/phagocytosis of these strains was unchanged from controls. We conclude that cilofungin interferes with opsonization of most strains of C. albicans, resulting in a marked decrease in neutrophil candidacidal activity, a phenomenon which may be of significance in vivo in certain tissues where access to antibodies and/or complement is limited.
Antifungal Agents↗
Characterization of murine bronchoalveolar macrophage respiratory burst: comparison of soluble and particulate stimuli.
Stimulation of the respiratory burst of murine bronchoalveolar macrophages obtained by lung lavage was studied using four different stimuli and different assay conditions. One soluble stimulus, phorbol myristate acetate (PMA), two intracellular particles, zymosan and Blastomyces dermatitidis conida, and one extracellular particle, B. dermatitidis yeast, were incubated with either freshly obtained macrophages in suspension or 2- and 48-hour macrophage monolayers. Suspension cultures were incubated with stimuli for 90 minutes and monolayers for 10 minutes before O2- was assayed. PMA did not elicit O2- production in macrophage suspensions or 2-hour macrophage monolayers, but 48-hour macrophage monolayers exhibited a 13-fold increase above control values (P = .0001). On the other hand, zymosan elicited an increase in O2- production in both suspensions and monolayers, although monolayers incubated for 48 hours produced almost fourfold more O2- than the other systems (P = .025). Opsonization had no effect on the ability of zymosan to elicit respiratory burst. B. dermatitidis conidia resulted in a two- to threefold increase in O2- production in macrophage suspensions and a five- to eightfold increase in 48-hour monolayers, representing significantly less respiratory burst stimulation than with either zymosan or PMA. Similarly, B. dermatitidis yeasts demonstrated similar submaximal stimulation of O2-, 3-4 times that over control values, and again this was less than zymosan and PMA. We conclude that 1) freshly obtained murine bronchoalveolar macrophages do not respond to PMA with an increase in O2- production, but that responsiveness is evident after 48 hours of incubation in monolayers; 2) B. dermatitidis conidia and yeasts do not stimulate respiratory burst activity to the same degree as zymosan or PMA; and 3) opsonization of zymosan is not necessary for stimulation of the murine bronchoalveolar macrophage oxidative burst, confirming previous data that functional complement receptors are not present on these cells.
Animals↗
In vitro activity of LY121019 against Candida species and Torulopsis glabrata.
Explore the source record for details and available documents.
Antifungal Agents↗
Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome.
PURPOSE: Because of the increasing numbers of patients with acquired immunodeficiency syndrome (AIDS) who will require treatment for cryptococcosis and because of the problems associated with long-term administration of intravenous amphotericin B, an alternative therapeutic approach in the form of an efficacious and easily administered oral antifungal drug would be of great benefit. Fluconazole, a new triazole antifungal agent, represents such an alternative. We therefore conducted an open, non-randomized trial of oral fluconazole as maintenance suppressive therapy of disseminated cryptococcosis in patients with AIDS. PATIENTS AND METHODS: Twenty patients with AIDS, 19 of whom had cryptococcal meningitis, were studied. Patients were followed for up to 21 months. All patients received amphotericin B as primary therapy, from 20 to 257 days prior to entry (500 to 5,080 mg total dose). Eight also received flucytosine. After administration of amphotericin B for acute disseminated cryptococcosis, and prior to initiation of fluconazole therapy, Cryptococcus neoformans was isolated from the cerebrospinal fluid (CSF) in two patients and from the blood in one patient. Fluconazole was given once daily, in doses of 50 to 200 mg/day. RESULTS: Following initiation of fluconazole, results of CSF and blood cultures continued to be negative, except for the CSF culture in one patient who had a relapse in the 32nd week of therapy. Fluconazole therapy has been successfully continued in nine patients, for a median of 11 months (nine to 21 months). Seven patients died; five had no evidence of active cryptococcosis at the time of death. Two patients had a relapse, although the CSF culture showed growth of the fungus in only one patient. One patient was lost to follow-up after five months of therapy and one was unevaluable. Fluconazole had to be discontinued in only one patient in whom thrombocytopenia developed, and then resolved when the drug was stopped. CONCLUSION: We conclude that oral fluconazole represents a significant advance in the management of cryptococcal meningitis and should be useful in the long-term suppressive therapy of this opportunistic infection in patients with AIDS.
Acquired Immunodeficiency Syndrome↗
Experimental blastomycosis pneumonia in mice by infection with conidia.
We describe a murine model of acute blastomycosis pneumonia induced by Blastomyces dermatitidis conidia. Anesthetized mice were infected by placing a droplet containing conidia suspended in sterile saline on the nares and allowing the suspension to be aspirated into the lungs. Conidia were obtained from mycelia derived from the yeast forms of two well characterized strains of B. dermatitidis, ATCC 26199 and 26197. ATCC 26199 yeast and conidia were highly virulent in BALB/cByJ mice whereas both forms of ATCC 26197 were incapable of causing disease in 60 days. Conidia and yeasts of the virulent strain caused pathologic changes primarily in the lungs, whereas no abnormalities were seen in the lungs, or elsewhere, in mice infected with the a virulent strain. Small numbers of ATCC 26199 yeast forms were found in scattered foci in liver and kidneys, but no inflammatory reaction surrounded the fungus. This murine model of acute blastomycosis pneumonia mimics the acute disease in humans and is initiated with the naturally infectious particle.
Animals↗
Ketoconazole treatment of coccidioidal meningitis.
Fifteen patients with coccidioidal meningitis were treated with high doses of ketoconazole for up to 4 years. Five patients were treated with ketoconazole alone. One clinically failed, one developed hepatotoxicity, and three achieved remission of meningitis. One patient received intrathecal AMB in addition to ketoconazole for only 2 weeks before continuing on ketoconazole alone. He improved, but discontinued ketoconazole because of nausea and vomiting, and suffered a lethal relapse. Nine patients received ketoconazole in combination with prolonged courses of intrathecal AMB. Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. The clinical responses appeared to be similar in patients receiving high-dose ketoconazole, either alone or combined with AMB, suggesting that there is no clinically significant antagonism of the drugs. Nausea and vomiting are significant limitations of high-dose ketoconazole. Ketoconazole alone is effective in some patients with coccidioidomycotic meningitis.
Amphotericin B↗
Systemic fungal infections: diagnosis and treatment. I. Paracoccidioidomycosis.
Paracoccidioidomycosis is the designation for the disease caused by the dimorphic fungus Paracoccidioides brasiliensis. It is a disease of great importance in Latin America and constitutes an important diagnosis for consideration in patients from endemic areas who have pulmonary or systemic disease compatible with fungal infection. In the laboratory, basic work has uncovered important interactions between the fungus and the human sex steroid system. These studies may have important implications in our approach to this and other infectious diseases.
Antifungal Agents↗
Rapid diagnosis of nocardiosis with an enzyme immunoassay.
Diagnosis of nocardiosis is often delayed because of the frequently nonspecific nature of the illness and because of the long incubation period required to isolate the organism in the microbiology laboratory. Past experience with serological methods for diagnosing nocardiosis have met with little success, primarily because there was no suitable antigen. Using a previously identified Nocardia asteroides-specific protein, we developed an enzyme immunoassay for the rapid diagnosis of nocardiosis. We evaluated sera from 22 patients with nocardiosis, 83 hospitalized controls, and 21 patients with tuberculosis. Twenty (91%) of the sera from patients with nocardiosis had titers of antibody greater than or equal to 1:256, whereas all of the sera from controls and from patients with tuberculosis had titers less than 1:256. This assay represents a highly sensitive and specific serodiagnostic tool for evaluating patients with possible nocardiosis.
Antibodies, Bacterial↗
Pharmacology and toxicity of high-dose ketoconazole.
One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.
Clinical Trials as Topic↗
Identification of a common immunodominant protein in culture filtrates of three Nocardia species and use in etiologic diagnosis of mycetoma.
Diagnosis of systemic nocardiosis has been hampered by difficulty in the rapid isolation and identification of the organism and by the frequent need for invasive biopsies. We show that a 55,000-Mr protein previously found in Nocardia asteroides is also present in N. brasiliensis and N. caviae culture filtrates. We also used the antigen in a dot blot assay to identify patients infected with N. brasiliensis. Sera from patients with mycetoma secondary to N. brasiliensis (n = 6) or Actinomadura madurae (n = 2) and 10 hospitalized controls were tested. Six (100%) of the sera from the patients with nocardial mycetoma had positive dot blots to purified antigen, whereas all 10 of the control sera were negative. Serum from one of two patients infected with A. madurae also reacted with the antigen. Thus, the 55-kilodalton protein appears to be produced by three medically important species of Nocardia and is useful when used in an immunoblot assay for identifying patients infected with these organisms.
Antibodies, Bacterial↗
Fungicidal activity of murine broncho-alveolar macrophages against Blastomyces dermatitidis.
The fungicidal activity of murine broncho-alveolar macrophages (BAM) against the yeast form of a virulent strain of Blastomyces dermatitidis was studied in the small-volume wells of a Terasaki plate. In a 4-h fungicidal assay, significant killing (16-33%) of the fungus by unstimulated BAM was demonstrated with BAM from normal mice and from mice rendered immune to lethal infection with B. dermatitidis. No significant differences between the activity of BAM from these two sources could be identified. Addition of 10% autologous normal or immune serum did not augment the macrophage fungicidal activity. Simultaneous experiments with peritoneal macrophages (PM) also gave reproducible killing of the yeast form in the wells of the Terasaki plate, but in the larger wells of microtitration plates, PM showed no significant fungicidal activity. On the other hand, BAM had similar fungicidal activity against B. dermatitidis in Terasaki and microtitration-plate wells. The modest fungicidal activity of BAM from immune mice against B. dermatitidis suggests that the resistance of immune mice to respiratory challenge is likely to be based on some augmentation of this first line of defence.
Animals↗
Herpes zoster ophthalmicus and granulomatous angiitis. An ill-appreciated cause of stroke.
The syndrome of granulomatous angiitis related to varicella zoster virus infection often manifests as herpes zoster ophthalmicus followed by contralateral hemiplegia. Forty-five cases have been reported to date, and the authors' experience with two additional cases seen in a one-year period is described. Given the frequency of both stroke and herpes zoster ophthalmicus in an aging population, the authors postulate that granulomatous angiitis is underdiagnosed. There is need for increased awareness of this disease by the non-neurologist. Diagnostic and therapeutic considerations are reviewed.
Acyclovir↗
Comparative activities of UK-49,858 and amphotericin B against Blastomyces dermatitidis infections in mice.
UK-49,858, a new antifungal triazole derivative, was compared with amphotericin B in the treatment of pulmonary infections by Blastomyces dermatitidis in male BALB/cByJ mice. Administration of UK-49,858 in daily doses of 25 or 50 mg/kg for 21 days gave 30 and 100% survival rates, respectively. These results compared with 100% mortality in infected controls and 100% survival among mice treated with amphotericin B. UK-49,858 did not eradicate the fungus from the lungs of surviving animals, while amphotericin B effected sterilization of the lungs in 66% of the survivors.
Amphotericin B↗
Candida rugosa in immunocompromised infection. Case reports, drug susceptibility, and review of the literature.
Candida rugosa was isolated from two patients. One patient had acute leukemia and developed invasive disease due to this yeast on two occasions while granulocytopenic. Her infection was eventually cured after treatment with amphotericin B. In another immunocompromised patient, the yeast was isolated from the sputum in the presence of a pulmonary infiltrate, but there was no other evidence for a pathogenic role. Antifungal susceptibility testing of the first patient's isolate and three environmental isolates showed all four to be susceptible to amphotericin B, miconazole, and flucytosine, and only the patient isolate was resistant to ketoconazole. These results suggest possibilities for therapy in future encounters. It appears that C. rugosa, a common pathogen in cattle, can be pathogenic in humans under the appropriate circumstances.
Aged↗
Antibody response in human nocardiosis: identification of two immunodominant culture-filtrate antigens derived from Nocardia asteroides.
An ammonium sulfate precipitate derived from a culture filtrate of Nocardia asteroides contained 20-30 protein subunits, as identified by gel electrophoresis. Western blot analysis of these proteins (obtained from serum samples from patients with systemic nocardiosis) revealed that all of the 17 samples reacted with a subunit of a protein with an apparent molecular weight of 55,000 and that 11 of the 17 samples reacted with a subunit with a molecular weight of 31,000. In contrast, only two of 25 serum samples obtained from healthy controls or patients hospitalized without nocardial or mycobacterial disease reacted with these subunits. Sera from 21 patients infected with Mycobacterium tuberculosis, a historically troublesome cross-reactive group, failed to react with either the 55,000 or the 31,000 molecular weight subunit. The presence of only two protein subunits that reacted with sera from humans with nocardiosis suggests that these molecules may have use as diagnostic reagents or probes of the immunologic reaction to Nocardia.
Antibodies, Bacterial↗
Enhanced oxidative burst in immunologically activated but not elicited polymorphonuclear leukocytes correlates with fungicidal activity.
Polymorphonuclear neutrophils (PMN) induced locally in immune mice by intraperitoneal injection of antigen exhibit enhanced fungicidal activity compared with PMN elicited with thioglycolate. The mechanism of the differences in these PMN populations was studied. Sublethal infection was used to produce immunity to Blastomyces dermatitidis. A correlation was sought between the ability of PMN to kill, or not kill, B. dermatitidis and the production of the oxidative burst, as measured by luminol-enhanced chemiluminescence (CL). Although elicited PMN cocultured with Candida albicans produced a burst of CL and were candidacidal, killing did not occur when PMN were cocultured with B. dermatitidis. Lack of killing of B. dermatitidis by elicited PMN correlated with lack of stimulation of a brisk oxidative burst. In contrast to elicited PMN, PMN induced by B. dermatitidis antigen responded to this fungus with a burst of CL and a significant reduction of inoculum CFU (80%). Furthermore, these PMN when cocultured with C. albicans produced an enhanced burst of CL, and killing was enhanced compared with that by elicited PMN, e.g., 86 versus 58%. The CL burst and killing of B. dermatitidis by antigen-induced PMN was abrogated in the presence of catalase, implying a critical role for hydrogen peroxide. Partial but significant depression of CL and killing in the presence of dimethyl sulfoxide, a hydroxyl radical scavenger, identified hydroxyl radical, or its metabolites, as a toxic product(s) responsible for a significant fraction of fungicidal activity. These results indicate that the metabolic activity and microbicidal activity of PMN can be altered (enhanced) at the site of an immunological reaction and thus could constitute an important factor in resistance.
Animals↗