Feasibility of Pharmacy-based Research Opportunity to Enhance Community Testing and Surveillance (PROTECTS).

BACKGROUND: Approximately 89% of the US population lives within five miles of a community pharmacy, which provides a network of geographically distributed recruitment nodes for testing and surveillance of infection and disease. OBJECTIVES: Establish feasibility of Pharmacy-based Research Opportunities To Enhance Community Testing and Surveillance (PROTECTS) in the context of SARS-CoV-2 infection in a community pharmacy setting with University of Kentucky serving as the coordinating center and research hub for sample analysis. METHODS: Two community pharmacies in Kentucky served as community-based recruitment sites to assess SARS-CoV-2 exposure through longitudinal (5 visits over 56 days) collection of nasal swabs and blood samples from subjects. RESULTS: Fifty subjects were recruited between May 2022 and December 2023 for longitudinal sample collection. Three phases of recruitment were investigated by first establishing standard operating procedures in an urban pharmacy, then expanding recruitment at a second pharmacy in a rural setting, and finally increasing recruitment at the urban pharmacy. During the first phase of recruitment, 12 participants were recruited. Of these participants, two never scheduled a visit after the initial screening. The median time for study completion from first to last visit within this phase was 59 days (IQR: 56-68 days). During the second phase of recruitment, eight of nine participants completed all five visits. The median time to complete all visits was 105 days (IQR: 98-112 days). During the ongoing third phase, 29 subjects were recruited, and 19 participants completed all required visits and the remainder continue to schedule follow-up appointments. CONCLUSION: Community pharmacies have a significant role in promoting public health. The geographic distribution of community pharmacies makes them appealing locations for recruitment of outpatient cohorts for local surveillance of infections and chronic inflammatory conditions with opportunities for broad implementation of this project for clinical trials in underserved communities.

Isavuconazole in the Treatment of Chronic Forms of Coccidioidomycosis.

Coccidioidomycosis is a fungal infection with a range of clinical manifestations. Currently used antifungal agents exhibit variable efficacy and toxicity profiles that necessitate evaluation of additional therapeutic options. Improvement was observed in the majority of patients treated with isavuconazole, with clinical failures observed only in those with coccidioidal meningitis.

Controversies in the Management of Central Nervous System Coccidioidomycosis.

Central nervous system infection with Coccidioides spp. is fatal if untreated and complications occur even when therapy is directed by experienced clinicians. We convened a panel of clinicians experienced in the management of coccidioidal meningitis to summarize current controversies and provide consensus for the management of this difficult infection.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Isavuconazole in the Treatment of Coccidioidal Meningitis.

Patients with coccidioidal meningitis require lifelong antifungal therapy. Cumulative toxicity and lack of antifungal efficacy require salvage therapy in the treatment of some patients. In a retrospective review of nine patients with coccidioidal meningitis treated with isavuconazole, successful therapy was seen in three patients and stable disease was confirmed in six patients. Isavuconazole may be a useful addition to the therapeutic choices currently available for coccidioidal meningitis.

Evaluation of Amphotericin B Lipid Formulations for Treatment of Severe Coccidioidomycosis.

Patients with severe coccidioidomycosis infections are often treated with either amphotericin B lipid complex (ABLC) or liposomal amphotericin B (L-AmB). Outcome data with these agents in severe coccidioidomycosis cases are currently lacking. The purpose of this study is to evaluate the efficacy and toxicity of ABLC and L-AmB in treating severe coccidioidomycosis. A retrospective pre-post study design was employed. Chart reviews were completed from 1 January 2005 to 31 December 2014 for all patients who received lipid-based amphotericin B. Inclusion criteria included having a follow-up complement fixation (CF) titer or a treatment emergent adverse event (TEAE) prior to follow-up. Patients with meningeal involvement and pregnant patients were excluded. Treatment outcomes were assessed based on documented completion of therapy as well on symptoms, complement fixation titer, and changes to laboratory monitoring parameters. A total of 108 patients were identified, 69 of whom met the inclusion criteria. There were no statistical differences in demographics or disease burden in those that received ABLC and those that received L-AmB, except that those who received L-AmB were more likely to have previously diagnosed chronic kidney disease (nL-AmB = 4, 12.5% vs nABLC = 0, 0.0%; P = 0.042) and to have a lower creatinine clearance at the start of therapy (L-AmB = 79.6 mg/dl versus ABLC = 100.4 mg/dl; P = 0.008). Successful treatment was achieved in 27 (73.0%) of ABLC patients and 22 (68.8%) of L-AmB patients (P = 0.700). Amphotericin B was discontinued due to documented completion of therapy for 17 (45.9%) ABLC patients and 18 (56.3%) L-AmB patients (P = 0.553). Acute kidney injury (AKI) was the documented reason of treatment cessation for 10 (27.0%) ABLC and 1 (3.1%) L-AmB patient (P = 0.007). ABLC and L-AmB both appear to be equally efficacious in the treatment of severe coccidioidomycosis. L-AmB may have less renal toxicity than ABLC and may be the preferred agent in baseline renal impairment.

Coccidioidal Meningitis: A Review on Diagnosis, Treatment, and Management of Complications.

PURPOSE OF REVIEW: This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy. RECENT FINDINGS: Ho et al. described the preparation and administration of intrathecally delivered amphotericin B deoxycholate. Thompson et al. described possible benefits of controversial adjuvant corticosteroid therapy for secondary prevention of vasculitic infarction secondary to CM. CM was universally fatal until the advent of intrathecal amphotericin B deoxycholate therapy, the introduction of which changed the natural history of the disease in much the same way as penicillin changed the natural history of bacterial meningitis. Although there was still significant morbidity, survival rates drastically increased to approximately 70%. The introduction of azole therapy has decreased the side effects and burden of treatment but without a significant change in CM-related mortality and morbidity compared with the use of intrathecal amphotericin B deoxycholate therapy.

Intrathecal Amphotericin B: A 60-Year Experience in Treating Coccidioidal Meningitis.

Coccidioidal meningitis (CM) is a devastating complication of coccidioidomycosis. Since the late 1950s, intrathecal (IT) amphotericin B deoxycholate (AmBd) has been successfully used to treat and often cure this disease, reducing mortality rates from 100% to approximately 30%. The introduction of azoles further revolutionized the treatment of coccidioidal infections. However, IT AmBd remains the only known curative option in the management of CM. While the use of IT AmBd is well described in many articles, few discuss the actual methods behind preparation, titration, and dosing strategies utilized. The practitioners at Kern Medical (Bakersfield, California) have >60 years of experience in the utilization of IT AmBd and the treatment of CM. This article describes the practice experience in the treatment of CM, preparation of IT AmBd, and the different dosing strategies used in regard to route of administration (ie, cisternal, lumbar, ventricular).

Adjunctive Corticosteroid Therapy in the Treatment of Coccidioidal Meningitis.

Coccidioidal meningitis (CM) has high morbidity, and adjunctive measures to improve outcomes are needed. Using an established multicenter retrospective cohort study of CM (N = 221), we found that patients receiving adjunctive corticosteroids had a significant reduction in secondary cerebrovascular events (P = .0049). Those with CM-associated cerebrovascular events (8%) may benefit from short-term corticosteroids.

Executive Summary: 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Call for a California coccidioidomycosis consortium to face the top ten challenges posed by a recalcitrant regional disease.

Coccidioidomycosis ('Valley Fever'), caused by the inhalation of the fungus Coccidioides, remains a recalcitrant health problem in large parts of California. The incidence and severity of the disease continues to rise in many parts of the state. In this manuscript, we highlight unanswered questions about the disease. Specifically, the extent of disease burden, genetic determinants of host susceptibility, diagnostic and treatment guidelines, natural reservoirs of the pathogens, antifungal drug resistance, and fungal determinants of mild or severe disease are all areas awaiting in depth investigations. We also recommend establishment of a California Coccidioidomycosis Registry to improve clinical care and translational research.

Hypoxemic Respiratory Failure and Coccidioidomycosis-Associated Acute Respiratory Distress Syndrome.

Background: Severe coccidioidomycosis presenting with respiratory failure is an uncommon manifestation of disease. Current knowledge of this condition is limited to case reports and small case series. Methods: A retrospective multicenter review of patients with coccidioidomycosis-associated acute respiratory distress syndrome (CA-ARDS) was conducted. It assessed clinical and laboratory variables at the time of presentation, reviewed the treatment course, and compared this cohort with a national database of patients with noncoccidioidomycosis ARDS. Survivors and nonsurvivors of coccidioidomycosis were also compared to determine prognostic factors. Results: In this study, CA-ARDS (n = 54) was most common in males, those of Hispanic ethnicity, and those with concurrent diabetes mellitus. As compared with the PETAL network database (Prevention and Early Treatment of Acute Lung Injury; n = 1006), patients with coccidioidomycosis were younger, had fewer comorbid conditions, and were less acidemic. The 90-day mortality was 15.4% for patients with coccidioidomycosis, as opposed to 42.6% (P < .0001) for patients with noncoccidioidomycosis ARDS. Patients with coccidioidomycosis who died, as compared with those who survived, were older, had higher APACHE II scores (Acute Physiology and Chronic Health Evaluation), and did not receive corticosteroid therapy. Conclusions: CA-ARDS is an uncommon but morbid manifestation of infection. When compared with a national database, the overall mortality appears favorable vs other causes of ARDS. Patients with CA-ARDS had a low overall mortality but required prolonged antifungal therapy. The utility of corticosteroids in this condition remains unconfirmed.

Asymptomatic Coccidioidal Meningitis Relapse: A Demon in Disguise.

Coccidioides spp is a soil-dwelling, dimorphic fungus that causes coccidioidomycosis. It is endemic to the western hemisphere. Although primarily a respiratory disease, it can also cause a myriad of clinical manifestations, from asymptomatic disease to meningitis. In fact, Coccidioides species is probably the most common etiologic agent of long-term meningitis in California and Arizona. Early diagnosis and treatment are critical to avoid fatal complications. With treatment, the cerebral spinal fluid analysis may return to normal. Relapse of coccidioidal meningitis is usually suspected with recurrence of meningitis symptoms. The patient is a 53-year-old man with a 2-decade history of coccidioidal meningitis who was diagnosed with an asymptomatic relapse of coccidioidal meningitis.

A Case of Coccidioidal Meningitis With Biofilm Obstructing VP Shunt Due to Cutibacterium acnes.

Herein described is a case of biofilm obstructing ventriculoperitoneal shunt due to Cutibacteirum acnes infection in a patient with coccidioidal meningitis. Cutibacterium acnes infects and obstructs cerebral shunts by the production of biofilm; however, diagnosis is usually missed by routine aerobic cultures. Obtaining anaerobic cultures routinely in patients with foreign body implants leading to central nervous system infections could prevent a missed diagnosis of this pathogen. Penicillin G is the first-line treatment.

A Clinicopathological Categorization System for Clinical Research in Coccidioidomycosis.

A wide array of clinical manifestations follow infection with Coccidioides immitis or Coccidioides posadasii, ranging from asymptomatic infection to life-threatening pulmonary disease or extrapulmonary dissemination and meningitis. Epidemiological studies require consistent definitions of cases and their comparative clinical features. Understanding host and pathogen determinants of the severity of coccidioidomycosis also requires that specific clinical features (such as coccidioidal meningitis) and their overlap be precisely defined and quantified. Here we propose a system for categorization of outcomes of coccidioidomycosis in individuals who are not overtly immunocompromised that harmonizes clinical assessments during translational research of this increasingly common disease.

Coccidioidal Pulmonary Cavitation: A New Age.

Coccidioides species are thermally dimorphic fungi found in geographically defined areas of the Western Hemisphere. The primary portal of entry is respiratory, with symptomatic pneumonic diseases as the most common presentation. Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis. This study aims to explore the spectrum of coccidioidal cavities and the evaluation and management in a cohort of patients seen at Kern Medical over the last 12 years.

Evidence for additional FREM1 heterogeneity in Manitoba oculotrichoanal syndrome.

PURPOSE: Manitoba Oculotrichoanal (MOTA) syndrome is an autosomal recessive disorder present in First Nations families that is characterized by ocular (cryptophthalmos), facial, and genital anomalies. At the commencement of this study, its genetic basis was undefined. METHODS: Homozygosity analysis was employed to map the causative locus using DNA samples from four probands of Cree ancestry. After single nucleotide polymorphism (SNP) genotyping, data were analyzed and exported to PLINK to identify regions identical by descent (IBD) and common to the probands. Candidate genes within and adjacent to the IBD interval were sequenced to identify pathogenic variants, with analyses of potential deletions or duplications undertaken using the B-allele frequency and log(2) ratio of SNP signal intensity. RESULTS: Although no shared IBD region >1 Mb was evident on preliminary analysis, adjusting the criteria to permit the detection of smaller homozygous IBD regions revealed one 330 Kb segment on chromosome 9p22.3 present in all 4 probands. This interval comprising 152 SNPs, lies 16 Kb downstream of FRAS1-related extracellular matrix protein 1 (FREM1), and no copy number variations were detected either in the IBD region or FREM1. Subsequent sequencing of both genes in the IBD region, followed by FREM1, did not reveal any mutations. CONCLUSIONS: This study illustrates the utility of studying geographically isolated populations to identify genomic regions responsible for disease through analysis of small numbers of affected individuals. The location of the IBD region 16 kb from FREM1 suggests the phenotype in these patients is attributable to a variant outside of FREM1, potentially in a regulatory element, whose identification may prove tractable to next generation sequencing. In the context of recent identification of FREM1 coding mutations in a proportion of MOTA cases, characterization of such additional variants offers scope both to enhance understanding of FREM1's role in cranio-facial biology and may facilitate genetic counselling in populations with high prevalences of MOTA to reduce the incidence of this disorder.

A reformulated spherule-derived coccidioidin (Spherusol) to detect delayed-type hypersensitivity in coccidioidomycosis.

The ability of spherule-derived coccidioidin containing 0.4 % phenol and 0.0001 % thimerosal in buffered saline to induce delayed-type hypersensitivity (DTH) was evaluated in four separate studies. The skin test antigen was titrated in 20 adult volunteers with a recent history of pulmonary coccidioidomycosis using intradermal doses of 0.4, 0.8, and 1.6 µg of antigen, based on total dry weight. Based on these data, a dose of 1.27 µg was shown to elicit a mean ± SEM induration response of 23.5 ± 2.3 mm at 48 h, similar to the 23.6-mm response after 48 h of the U. S. Reference coccidioidin last tested approximately 13 years ago. The 1.27 µg dose in 0.1 mL of the spherule-derived antigen (Spherusol) was then examined in three separate groups of adult volunteers to determine the sensitivity and specificity of the product. Fifty-nine of 60 individuals living in a non-endemic area for coccidioidomycosis were skin test negative to Spherusol. Twelve subjects with a recent history of pulmonary histoplasmosis were skin test negative to Spherusol. Finally, 51 of 52 individuals with a recent diagnosis of acute pulmonary coccidioidomycosis were skin test positive to Spherusol. Within this group, prior therapy with fluconazole did not appear to reduce the reactivity to Spherusol. No serious adverse events were observed in the four studies. From these data, Spherusol was found to be safe and has an overall observed sensitivity and specificity of ≥ 98 % in detecting DTH in coccidioidomycosis.

Disseminated Coccidioidomycosis: Cutaneous, Soft Tissue, Osseous, and "Shotgun Intraparenchymal" Brain Disease.

Coccidioidomycosis is a disease found in the southwestern United States and caused by inhalation of arthroconidia of Coccidioides immitis and posadasii. Although the disease is most commonly asymptomatic or respiratory, it has a propensity to disseminate to any tissue in the body with the most common being skin, bone, joints, and central nervous system. This case demonstrates the dissemination of coccidioidomycosis to several foci along with a rare form of parenchymal dissemination with an unusual neuroradiological finding.