New ß-glucan inhibitors as antifungal drugs.

INTRODUCTION: New classes of synthetic and semi-synthetic ß-glucan inhibitors have recently emerged, providing analogs that, in some cases, have been proven to have a high degree of activity against fungi, offering the prospect of alternatives to the commercially available lipopeptide/echinocandin agents caspofungin, micafungin and anidulafungin. AREA COVERED: This review covers applications disclosing compound classes that include synthetic pyridazinone analogs, bicyclic heteroaryl ring compounds, aniline derivates, and semi-synthetic echinocandin and enfumafungin derivatives. MK-3118 is an analog of the natural product enfumafungin that, in particular, shows promise as it has a spectrum of activity comparable with caspofungin but has the advantageous property of oral bioavailability. EXPERT OPINION: The diversity of chemical classes in the present review, which have demonstrable activity against ß-glucan and the prospect of oral bioavailability, offers hope that safe and effective antifungal drugs will emerge and be commercialized. Of particular note, the Merck compound MK-3118, with solid evidence of efficacy based on preclinical data, has moved into clinical trials.

The public health impact of coccidioidomycosis in Arizona and California.

The numbers of reported cases of coccidioidomycosis in Arizona and California have risen dramatically over the past decade, with a 97.8% and 91.1% increase in incidence rates from 2001 to 2006 in the two states, respectively. Of those cases with reported race/ethnicity information, Black/African Americans in Arizona and Hispanics and African/Americans in California experienced a disproportionately higher frequency of disease compared to other racial/ethnic groups. Lack of early diagnosis continues to be a problem, particularly in suspect community-acquired pneumonia, underscoring the need for more rapid and sensitive tests. Similarly, the inability of currently available therapeutics to reduce the duration and morbidity of this disease underscores the need for improved therapeutics and a preventive vaccine.

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.

An archived lot of coccidioidin induces specific coccidioidal delayed-type hypersensitivity and correlates with in vitro assays of coccidioidal cellular immune response.

No test for assessing cellular immune response in coccidioidomycosis is currently available in the United States. In the present study, we tested 49 healthy subjects living in the coccidioidal endemic region with a 1:55.8 dilution of a single lot of coccidioidin archived since the 1970s. In this group, 23 evaluable subjects demonstrated >/=5 mm of induration at 24, 48 or 72 h, with a mean+/-SEM maximum induration of 18.4+/-4.0 mm. The induration results among 14 subjects reactive at 24 h were compared to those from 179 individuals in an historical cohort studied in the 1980s using a reference lot of coccidioidin. Results were within 5% and not significantly different (P=0.924). The maximum induration response of all evaluable subjects correlated significantly with the results of in vitro tests of coccidioidal cellular immunity using supernatant interferon-gamma concentration and CD69 expression on T cells (Spearman rank correlation coefficients 0.69 and 0.68, respectively; P<0.01 for both). These data suggest that archived coccidioidin retains its potency and specificity and that in vitro test of coccidioidal immunity may have utility in the measurement of coccidioidal cellular immunity.

An overview of antifungal drugs and their use for treatment of deep and superficial mycoses in animals.

Fungal infections are often challenging to manage, given the limited numbers of therapeutics and a general lack of applicable clinical literature for their use in a given animal species. This article reviews some of the underlying principles that can affect the therapeutic outcome for a given antifungal, and provides specific information from the literature that is intended to highlight the distinctive properties of the most commonly used antifungals in veterinary medicine to better facilitate their successful application in clinical practice.

Comparison of susceptibility of fungal isolates to lufenuron and nikkomycin Z alone or in combination with itraconazole.

OBJECTIVE: To evaluate and compare the in vitro antifungal properties of lufenuron and nikkomycin Z against isolates of Coccidioides immitis and Aspergillus fumigatus when used singly and in combination with the azole antifungal agent itraconazole. SAMPLE POPULATION: 3 clinical isolates of A fumigatus and the Silveira strain of C immitis. PROCEDURE: The fungal isolates were tested in vitro for susceptibility to the single and combination of compounds by use of microtiter-format susceptibility methods. Minimum inhibitory concentration end points were determined visually, and the contents of representative wells were examined microscopically for evidence of morphologic effects on fungi. RESULTS: No evidence of inhibition, either by susceptibility testing or direct microscopic examination of treated cells, was obtained with lufenuron under experimental conditions. In contrast, nikkomycin Z, a known inhibitor of fungal chitin synthesis, had potent activity against C immitis when used singly. A synergistic interaction between nikkomycin Z and itraconazole was found against isolates of both species tested. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of our in vitro data, lufenuron does not appear to possess antifungal properties.