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Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC 50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease., Importance: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways., Competing Interests: The authors declare no conflict of interest.

Coccidioides immitis , a pathogenic environmental fungus that causes Valley fever (coccidioidomycosis) primarily in the American Southwest and parts of Central and South America, has emerged over the past 12 years in the Columbia River Basin region, near the confluence with the Yakima River, in southcentral Washington state, USA. An initial autochthonous Washington human case was found in 2010, stemming from a wound derived from soil contamination during an all-terrain vehicle crash. Subsequent analysis identified multiple positive soil samples from the park where the crash occurred (near the Columbia River in Kennewick, WA), and from another riverside location several kilometers upstream from the park location. Intensified disease surveillance identified several more cases of coccidioidomycosis in the region that lacked any relevant travel history to known endemic locales. Genomic analysis of both patient and soil isolates from the Washington cases determined that all samples from the region are phylogenetically closely related. Given the genomic and the epidemiological link between case and environment, C. immitis was declared to be a newly endemic fungus in the region, spawning many questions as to the scope of its presence, the causes of its recent emergence, and what it predicts about the changing landscape of this disease. Here, we review this discovery through a paleo-epidemiological lens in the context of what is known about C. immitis biology and pathogenesis and propose a novel hypothesis for the cause of the emergence in southcentral Washington. We also try to place it in the context of our evolving understanding of this regionally specific pathogenic fungus.

Coccidioidomycosis is a debilitating fungal disease caused by inhalation of arthroconidia. We developed a novel approach for detection of airborne Coccidioides and used it to investigate the distribution of arthroconidia across the Phoenix, Arizona, metropolitan area. Air filters were collected daily from 21 stationary air-sampling units across the area: the first set collected before, during and after a large dust storm on August 25, 2015, and the second over the 45-day period September 25-November 8, 2016. Analysis of DNA extracted from the filters demonstrated that the day of the dust storm was not associated with increase of Coccidioides in air samples, although evidence of the low-level polymerase chain reaction (PCR) inhibition was observed in DNA extracted from samples collected on the day of the dust storm. Testing over 45 days identified uneven geographic distribution suggesting Coccidioides hot spots. In 2016, highest daily concentration of arthroconidia was observed between September 25-October 20, and only sporadic low levels were detected after that. These results provide evidence of seasonality and uneven spatial distribution of Coccidioides in the air. Our results demonstrate that routine air monitoring for arthroconidia is possible and provides an important tool for Coccidioides surveillance, which can address important questions about environmental exposure and human infection., (Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology 2019.)

The full geographic range of coccidioidomycosis is unknown, although it is most likely expanding with environmental change. We report an apparently autochthonous coccidioidomycosis patient from Spokane, Washington, USA, a location to which Coccidioides spp. are not known to be endemic.

A child developed hydrocephalus. Sixteen months later, it was discovered to be a complication of coccidioidal meningitis. The infection's source was uncertain until genomic analysis of the fungal isolate identified its origin to be a visit to Beeville, Texas. Improved national reporting of cases of coccidioidomycosis might reduce diagnostic delays., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Coccidioidomycosis is an emerging fungal infection in Washington, USA, and the epidemiology of the disease in this state is poorly understood. We used whole-genome sequencing to differentiate locally acquired cases in Washington on the basis of the previously identified phylogeographic population structure of Coccidioides spp. Clinical isolates from coccidioidomycosis cases involving possible Washington soil exposure were included. Of 17 human infections with epidemiologic evidence of possible local acquisition, 4 were likely locally acquired infections and 13 were likely acquired outside Washington. Isolates from locally acquired cases clustered within the previously established Washington clade of C. immitis. Genetic differences among these strains suggest multiple environmental reservoirs of C. immitis in the state.

The incidence of reported coccidioidomycosis in the past two decades has increased greatly; monitoring its changing epidemiology is essential for understanding its burden on patients and the healthcare system and for identifying opportunities for prevention and education. We provide an update on recent coccidioidomycosis trends and public health efforts nationally and in Arizona, California, and Washington State. In Arizona, enhanced surveillance shows that coccidioidomycosis continues to be associated with substantial morbidity. California reported its highest yearly number of cases ever in 2016 and has implemented interventions to reduce coccidioidomycosis in the prison population by excluding certain inmates from residing in prisons in high-risk areas. Coccidioidomycosis is emerging in Washington State, where phylogenetic analyses confirm the existence of a unique Coccidioides clade. Additional studies of the molecular epidemiology of Coccidioides will improve understanding its expanding endemic range. Ongoing public health collaborations and future research priorities are focused on characterizing geographic risk, particularly in the context of environmental change; identifying further risk reduction strategies for high-risk groups; and improving reporting of cases to public health agencies.

Unlabelled: Coccidioidomycosis (or valley fever) is a fungal disease with high morbidity and mortality that affects tens of thousands of people each year. This infection is caused by two sibling species, Coccidioides immitis and C. posadasii, which are endemic to specific arid locales throughout the Western Hemisphere, particularly the desert southwest of the United States. Recent epidemiological and population genetic data suggest that the geographic range of coccidioidomycosis is expanding, as new endemic clusters have been identified in the state of Washington, well outside the established endemic range. The genetic mechanisms and epidemiological consequences of this expansion are unknown and require better understanding of the population structure and evolutionary history of these pathogens. Here we performed multiple phylogenetic inference and population genomics analyses of 68 new and 18 previously published genomes. The results provide evidence of substantial population structure in C. posadasii and demonstrate the presence of distinct geographic clades in central and southern Arizona as well as dispersed populations in Texas, Mexico, South America, and Central America. Although a smaller number of C. immitis strains were included in the analyses, some evidence of phylogeographic structure was also detected in this species, which has been historically limited to California and Baja, Mexico. Bayesian analyses indicated that C. posadasii is the more ancient of the two species and that Arizona contains the most diverse subpopulations. We propose a southern Arizona-northern Mexico origin for C. posadasii and describe a pathway for dispersal and distribution out of this region., Importance: Coccidioidomycosis, or valley fever, is caused by the pathogenic fungi Coccidioides posadasii and C. immitis The fungal species and disease are primarily found in the American desert southwest, with spotted distribution throughout the Western Hemisphere. Initial molecular studies suggested a likely anthropogenic movement of C. posadasii from North America to South America. Here we comparatively analyze eighty-six genomes of the two Coccidioides species and establish local and species-wide population structures to not only clarify the earlier dispersal hypothesis but also provide evidence of likely ancestral populations and patterns of dispersal for the known subpopulations of C. posadasii., (Copyright © 2016 Engelthaler et al.)

We used real-time polymerase chain reaction and culture to demonstrate persistent colonization of soils by Coccidioides immitis, an agent of valley fever, in Washington State linked to recent human infections and located outside the endemic range. Whole-genome sequencing confirmed genetic identity between isolates from soil and one of the case-patients., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Coccidioidomycosis ("valley fever") is caused by inhaling spores of the soil-dwelling fungi Coccidioides immitis or Coccidioides posadasii. Most infections are subclinical. When clinical manifestations do occur (typically 1-4 weeks after exposure), they are similar to those associated with influenza or community-acquired pneumonia. Disseminated disease is rare. Residual pulmonary nodules can lead to chronic lung disease. Fluconazole or other triazoles often are used for treatment, but mild cases often resolve without specific therapy. A total of 17,802 cases were reported in the United States in 2012.

Next-generation sequencing enables use of whole-genome sequence typing (WGST) as a viable and discriminatory tool for genotyping and molecular epidemiologic analysis. We used WGST to confirm the linkage of a cluster of Coccidioides immitis isolates from 3 patients who received organ transplants from a single donor who later had positive test results for coccidioidomycosis. Isolates from the 3 patients were nearly genetically identical (a total of 3 single-nucleotide polymorphisms identified among them), thereby demonstrating direct descent of the 3 isolates from an original isolate. We used WGST to demonstrate the genotypic relatedness of C. immitis isolates that were also epidemiologically linked. Thus, WGST offers unique benefits to public health for investigation of clusters considered to be linked to a single source.

Coccidioidomycosis is an infection caused by Coccidioides immitis or C. posadasii. We developed a TaqMan real-time PCR assay that rapidly and accurately differentiates the species. This assay can be used as a tool to improve disease surveillance, increase understanding of the natural history of the infection, and assist in clinical differentiation studies.