Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles.

The use of voriconazole, a trifluorinated antifungal, has been associated with the development of fluoride excess and periostitis/exostoses. We evaluated a cohort of patients on long-term triazole therapy and found that other fluorinated triazoles (fluconazole and posaconazole) conferred no risk for the development of hyperfluorosis and its complications in our cohort.

Early treatment with fluconazole may abrogate the development of IgG antibodies in coccidioidomycosis.

BACKGROUND: We have observed a number of patients who fail to develop coccidioidal complement fixing (CF) antibody (immunoglobulin [IgG]) after the initiation of early antifungal therapy. Although this is the first description of this phenomenon in mycology, a precedent for the abrogation of the immune response has been observed in other conditions, including primary syphilis and primary Lyme disease. METHODS: We conducted a retrospective case-control study to determine any patient-specific risk factors associated with this observation. Additionally, in vitro analysis of the coccidioidal CF (IgG) antigen (Cts1) was performed after Coccidioides was grown under escalating fluconazole concentrations. RESULTS: Seventeen patients persistently positive for coccidioidal IgM antibodies without developing an IgG response (cases) were compared with 64 consecutive patients who did develop coccidioidal CF (IgG) antibodies (controls). Early treatment with antifungals (within 2 weeks of symptom onset) was associated with an abrogation of IgG antibody production (P < .001). With immunodiffusion testing, control serum demonstrated a lack of IgG seroreactivity when Coccidioides posadasii grown in the presence of escalating fluconazole doses (0.5-128 µg/mL) was used as the antigen; however, control serum remained seroreactive for the presence of IgM. The coccidioidal IgG antigen (Cts1) was shown to be diminished when cultures were grown in the presence of fluconazole, lending further in vitro plausibility to our findings. CONCLUSIONS: The abrogation of an IgG response in patients treated early in the course of coccidioidal infection may complicate serodiagnosis and epidemiologic studies, and further study to determine the potential clinical implications should be performed.

Safety, antigenicity, and efficacy of a recombinant coccidioidomycosis vaccine in cynomolgus macaques (Macaca fascicularis).

The safety, immunogenicity and efficacy of recombinant Ag2/PRA106 + CSA chimeric fusion protein (CFP) vaccine in ISS/Montanide adjuvant-administered intramuscular (IM) was assessed in adult female cynomolgus macaques challenged with Coccidioides posadasii. Animals received three immunizations with either 5 microg CFP, 50-microg CFP, or adjuvant alone and were challenged 4 weeks following the final immunization. Although significant antibody response was produced in response to vaccination, there were no discernable adverse effects, suggesting that the vaccine was well tolerated. Upon intratracheal challenge, all animals showed evidence of disease. Two animals that received 5-microg doses of CFP were euthanatized prior to the study's end because of severe symptoms. Animals vaccinated with 50-microg doses of CFP showed evidence of enhanced sensitization compared to adjuvant controls and animals vaccinated with 5-microg doses of CFP. This was based on higher serum anti-CFP titers, enhanced secretion of interferon-gamma (IFN-gamma) from stimulated bronchoalveolar lavage mononuclear cells (BALMC), reduced pulmonary radiologic findings following intratracheal challenge, reduced terminal complement fixation titers, and reduced necropsy findings. Overall the vaccine was well tolerated, induced sensitization, and resulted in a protective response when given at the higher 50-microg dose. Additional experiments may be needed to optimize the vaccination and to confer greater protection against lethal challenge.

Molecular cloning and expression of a cDNA encoding a Coccidioides posadasii Cu,Zn superoxide dismutase identified by proteomic analysis of the coccidioidal T27K vaccine.

Previous studies have demonstrated that the coccidioidal T27K vaccine preparation is protective in mice against respiratory challenge using Coccidioides posadasii (C. posadasii) arthroconidia. Proteomic methods have been employed to define the molecular components within the vaccine. This method has led to the identification of novel and previously uncharacterized coccidioidal proteins including a Cu,Zn superoxide dismutase. A two-dimensional gel of the T27K vaccine was run and spots were excised for mass spectrometric analysis. One peptide was obtained from the T27K gel that matched a TIGR C. posadasii 2.0 gene index tentative consensus sequence, TC1072, which is similar to fungal Cu,Zn superoxide dismutase. Activity assays performed with native PAGE gels of the T27K vaccine showed that the vaccine contains superoxide dismutase. The cDNA encoding the enzyme has been cloned and sequenced and expressed as a recombinant protein.