Cost-effectiveness of a potential vaccine for Coccidioides immitis.
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Coccidioidomycosis, a systemic fungal infection, affects Americans living in the Southwest. We evaluated the cost- effectiveness of a potential vaccine against Coccidioides immitis. Using a decision model we developed, we estimate that among children, vaccination would saved 1.9 quality-adjusted life days (QALD) and $33 per person. Among adults, screening followed by vaccination would save 0.5 QALD per person and cost $62,000 per quality adjusted life year gained over no vaccination. If the birth cohort in highly endemic counties of California and Arizona were immunized in 2001, 11 deaths would be averted and $3 million would be saved (in net present value) over the lifetime of these infants. Vaccination of adults to prevent disseminated coccidioidomycosis would provide a modest health benefit similar in magnitude to other vaccines but would increase net expenditures. Vaccination of children in highly endemic regions would provide a larger health benefit and would reduce total health care expenditures. (+info)
Comparative study of the reaction mechanism of family 18 chitinases from plants and microbes.
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Hydrolytic mechanisms of family 18 chitinases from rice (Oryza sativa L.) and Bacillus circulans WL-12 were comparatively studied by a combination of HPLC analysis of the reaction products and theoretical calculation of reaction time-courses. All of the enzymes tested produced beta-anomers from chitin hexasaccharide [(GlcNAc)(6)], indicating that they catalyze the hydrolysis through a retaining mechanism. The rice chitinases hydrolyzed predominantly the fourth and fifth glycosidic linkages from the nonreducing end of (GlcNAc)(6), whereas B. circulans chitinase A1 hydrolyzed the second linkage from the nonreducing end. In addition, the Bacillus enzyme efficiently catalyzed transglycosylation, producing significant amounts of chitin oligomers larger than the initial substrate, but the rice chitinases did not. The time-courses of (GlcNAc)(6) degradation obtained by HPLC were analyzed by theoretical calculation, and the subsite structures of the rice chitinases were identified to be (-4)(-3)(-2)(-1)(+1)(+2). From the HPLC profile of the reaction products previously reported [Terwisscha van Scheltinga et al. (1995) Biochemistry 34, 15619-15623], family 18 chitinase from rubber tree (Hevea brasiliensis) was estimated to have the same type of subsite structure. Theoretical analysis of the reaction time-course for the Bacillus enzyme revealed that the enzyme has (-2)(-1) (+1)(+2)(+3)(+4)-type subsite structure, which is identical to that of fungal chitinase from Coccidioides immitis [Fukamizo et al. (2001) Biochemistry 40, 2448-2454]. The Bacillus enzyme also resembled the fungal chitinase in its transglycosylation activity. Minor structural differences between plant and microbial enzymes appear to result in such functional variations, even though all of these chitinases are classified into the identical family of glycosyl hydrolases. (+info)
Delayed-type hypersensitivity responses to a cell wall fraction of the mycelial phase of Coccidioides immitis.
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A skin test-active fraction was isolated from the mycelial-phase cell walls of Coccidioides immitis. This alkali-soluble, water-soluble antigen (C-ASWS) elicited positive reactions in 22 of 24 (92%) of the Coccidioides-sensitized guinea pigs whereas only 14 (54%) of the same guinea pigs reacted to commercial coccidioidin (BioCox). None of the 21 Histoplasma-sensitized guinea pigs cross-reacted with the C-ASWS antigen. Footpad tests in mice actively infected with Coccidioides further established the efficacy of the C-ASWS antigen in eliciting a delayed-type hypersensitivity response. One-microgram doses of C-ASWS produced reactions comparable to 100-mug doses of nondialyzable coccidioidin (Smith's lot 64 D4). The C-ASWS fractions isolated from three different C. immitis strains showed similar reactivity in terms of the number of positive reactions produced in Coccidioides-sensitized guinea pigs. However, the induration responses (diameter in millimeters) elicited by the C-ASWS fraction of one strain were significantly less than those elicited by the C-ASWS fractions of the other two C. immitis strains. (+info)
In vitro and in vivo activities of posaconazole against Coccidioides immitis.
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Posaconazole (SCH 56592) was tested against 25 strains of Coccidioides immitis to determine their in vitro susceptibilities. The geometric mean 48-h MIC of posaconazole (POSA) was 0.5 microg/ml, the MIC range was 0.25 to 1 microg/ml, and the MIC at which 50% of the isolates tested are inhibited (MIC50) and the MIC90 were 0.5 and 1 microg/ml, respectively. The geometric mean 48-h MIC of itraconazole (ITRA) was 0.23 microg/ml, the MIC range was 0.125 to 0.5 microg/ml, and the MIC50 and MIC90 were both 0.25 microg/ml. Two strains of C. immitis were selected for in vivo studies on the basis of the POSA 48-h MICs for the isolates. POSA orally administered at 0.01, 0.1, 0.5, 1, 5, and 10 mg/kg of body weight/day was compared with ITRA administered at 10 and 30 mg/kg three times a day. The spleens and livers of mice that died or survived to day 50 were removed to measure the fungal burdens. Mice had >or=90% survival when they were treated with >or=0.5 mg of POSA per kg or 30 mg of ITRA per kg. Cultures of whole spleens and livers from mice treated with 10 mg of POSA per kg showed >or=70% sterilization. No sterilization of whole spleens and livers from mice treated with ITRA was seen. POSA displayed potent in vivo activity against the two strains of C. immitis tested. (+info)
In vitro activities of free and lipid formulations of amphotericin B and nystatin against clinical isolates of Coccidioides immitis at various saprobic stages.
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We investigated the susceptibilities of hyphal, mixed hyphal, ungerminated arthroconidial, and germinated arthroconidial populations of Coccidioides immitis to lipid formulations of amphotericin B and nystatin and their conventional preparations, utilizing the National Committee for Clinical Laboratory Standards M38-P broth macrodilution method. The differences in effects of the three different growth stages of the saprobic phase of C. immitis on the MIC/minimum lethal concentration (MLC) ratio were not statistically significant for any of the antifungal agents tested. These results suggest that either inocula could be used for in vitro susceptibility studies with C. immitis. (+info)
Biofilm on ventriculo-peritoneal shunt tubing as a cause of treatment failure in coccidioidal meningitis.
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We describe a case of recurrent coccidioidal meningitis in which a fungal biofilm on the tip of ventriculo-peritoneal shunt tubing was likely responsible for a 4-year persistence of Coccidioides immitis, despite the patient's taking an adequate dosage of fluconazole. Fungal biofilms should be considered as a cause for treatment failure and fungal persistence, especially when artificial prostheses or indwelling catheters are present. (+info)
Protection of mice against Coccidioides immitis intranasal infection by vaccination with recombinant antigen 2/PRA.
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Subcutaneous vaccination with recombinant antigen 2/PRA (rAg2/PRA) protected BALB/c mice against intranasal infection with Coccidioides immitis. Subcutaneously vaccinated C57BL/6 mice and intranasally vaccinated BALB/c mice were protected against larger numbers of infecting spores. Weight loss correlated with lethality, but histologic appearance did not. These studies support rAg2/PRA vaccination to prevent coccidioidomycosis. (+info)
Localization within a proline-rich antigen (Ag2/PRA) of protective antigenicity against infection with Coccidioides immitis in mice.
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Subunits of a proline-rich coccidioidal antigen (Ag2/PRA) of Coccidioides immitis were analyzed by comparison as vaccines in mice. The optimal dose of plasmid vaccine encoding full-length Ag2/PRA was determined to be between 10 and 100 microg. Mice vaccinated with plasmids encoding amino acids (aa) 1 to 106 were as protective as full-length Ag2/PRA (aa 1 to 194). The subunit from aa 27 to 106 was significantly but less protective. Plasmids encoding aa 90 to 151 or aa 90 to 194 were not protective. Analogous results were obtained with recombinant vaccines of the same amino acid sequences. In addition, mixtures of aa 90 to 194 with either aa 1 to 106 or aa 27 to 106 did not enhance protection compared to the active single-recombinant subunits alone. Humoral response of total immunoglobulin G (IgG) and subclasses IgG1 and IgG2a were detectable in subunit vaccinations but at significantly (100-fold) lower concentrations than after vaccination with plasmids encoding full-length Ag2/PRA. Since virtually all protection by vaccination with full-length Ag2/PRA can be accounted for in the first half of the protein (aa 1 to 106), this subunit could make a multicomponent vaccine more feasible by reducing the quantity of protein per dose and the possibility of an untoward reactions to a foreign protein. (+info)