Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 233 Records) |
Query Trace: Lockhart E[original query] |
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Sporotrichosis cluster in domestic cats and veterinary technician, Kansas, USA, 2022
Hennessee I , Barber E , Petro E , Lindemann S , Buss B , Santos A , Gade L , Lockhart SR , Sexton DJ , Chiller T , Toda M . Emerg Infect Dis 2024 30 (5) 1053-1055 We describe a feline sporotrichosis cluster and zoonotic transmission between one of the affected cats and a technician at a veterinary clinic in Kansas, USA. Increased awareness of sporotrichosis and the potential for zoonotic transmission could help veterinary professionals manage feline cases and take precautions to prevent human acquisition. |
Potential sexual transmission of antifungal-resistant trichophyton indotineae
Spivack S , Gold JAW , Lockhart SR , Anand P , Quilter LAS , Smith DJ , Bowen B , Gould JM , Eltokhy A , Gamal A , Retuerto M , McCormick TS , Ghannoum MA . Emerg Infect Dis 2024 30 (4) 807-809 We describe a case of tinea genitalis in an immunocompetent woman in Pennsylvania, USA. Infection was caused by Trichophyton indotineae potentially acquired through sexual contact. The fungus was resistant to terbinafine (first-line antifungal) but improved with itraconazole. Clinicians should be aware of T. indotineae as a potential cause of antifungal-resistant genital lesions. |
Expert panel review of skin and hair dermatophytoses in an era of antifungal resistance
Hill RC , Caplan AS , Elewski B , Gold JAW , Lockhart SR , Smith DJ , Lipner SR . Am J Clin Dermatol 2024 Dermatophytoses are fungal infections of the skin, hair, and nails that affect approximately 25% of the global population. Occlusive clothing, living in a hot humid environment, poor hygiene, proximity to animals, and crowded living conditions are important risk factors. Dermatophyte infections are named for the anatomic area they infect, and include tinea corporis, cruris, capitis, barbae, faciei, pedis, and manuum. Tinea incognito describes steroid-modified tinea. In some patients, especially those who are immunosuppressed or who have a history of corticosteroid use, dermatophyte infections may spread to involve extensive skin areas, and, in rare cases, may extend to the dermis and hair follicle. Over the past decade, dermatophytoses cases not responding to standard of care therapy have been increasingly reported. These cases are especially prevalent in the Indian subcontinent, and Trichophyton indotineae has been identified as the causative species, generating concern regarding resistance to available antifungal therapies. Antifungal-resistant dermatophyte infections have been recently recognized in the United States. Antifungal resistance is now a global health concern. When feasible, mycological confirmation before starting treatment is considered best practice. To curb antifungal-resistant infections, it is necessary for physicians to maintain a high index of suspicion for resistant dermatophyte infections coupled with antifungal stewardship efforts. Furthermore, by forging partnerships with federal agencies, state and local public health agencies, professional societies, and academic institutions, dermatologists can lead efforts to prevent the spread of antifungal-resistant dermatophytes. |
Emergence of zoonotic sporotrichosis in Brazil: a genomic epidemiology study
Ribeiro Dos Santos A , Misas E , Min B , Le N , Bagal UR , Parnell LA , Sexton DJ , Lockhart SR , de Souza Carvalho Melhem M , Takahashi JPF , Oliboni GM , Bonfieti LX , Cappellano P , Sampaio JLM , Araujo LS , Alves Filho HL , Venturini J , Chiller TM , Litvintseva AP , Chow NA . Lancet Microbe 2024 BACKGROUND: Zoonotic sporotrichosis is a neglected fungal disease, whereby outbreaks are primarily driven by Sporothrix brasiliensis and linked to cat-to-human transmission. To understand the emergence and spread of sporotrichosis in Brazil, the epicentre of the current epidemic in South America, we aimed to conduct whole-genome sequencing (WGS) to describe the genomic epidemiology. METHODS: In this genomic epidemiology study, we included Sporothrix spp isolates from sporotrichosis cases from Brazil, Colombia, and the USA. We conducted WGS using Illumina NovaSeq on isolates collected by three laboratories in Brazil from humans and cats with sporotrichosis between 2013 and 2022. All isolates that were confirmed to be Sporothrix genus by internal transcribed spacer or beta-tubulin PCR sequencing were included in this study. We downloaded eight Sporothrix genome sequences from the National Center for Biotechnology Information (six from Brazil, two from Colombia). Three Sporothrix spp genome sequences from the USA were generated by the US Centers for Disease Control and Prevention as part of this study. We did phylogenetic analyses and correlated geographical and temporal case distribution with genotypic features of Sporothrix spp isolates. FINDINGS: 72 Sporothrix spp isolates from 55 human and 17 animal sporotrichosis cases were included: 67 (93%) were from Brazil, two (3%) from Colombia, and three (4%) from the USA. Cases spanned from 1999 to 2022. Most (61 [85%]) isolates were S brasiliensis, and all were reported from Brazil. Ten (14%) were Sporothrix schenckii and were reported from Brazil, USA, and Colombia. For S schenckii isolates, two distinct clades were observed wherein isolates clustered by geography. For S brasiliensis isolates, five clades separated by more than 100 000 single-nucleotide polymorphisms were observed. Among the five S brasiliensis clades, clades A and C contained isolates from both human and cat cases, and clade A contained isolates from six different states in Brazil. Compared with S brasiliensis isolates, larger genetic diversity was observed among S schenckii isolates from animal and human cases within a clade. INTERPRETATION: Our results suggest that the ongoing epidemic driven by S brasiliensis in Brazil represents several, independent emergence events followed by animal-to-animal and animal-to human transmission within and between Brazilian states. These results describe how S brasiliensis can emerge and spread within a country. FUNDING: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil; the São Paulo Research Foundation; Productivity in Research fellowships by the National Council for Scientific and Technological Development, and Ministry of Science and Technology of Brazil. |
Evaluation of CHROMagar Candida Plus for the detection of C. auris with a panel of 206 fungal isolates and 83 colonization screening skin-swabs
Bentz ML , Le N , Min B , Nunnally NS , Sullivan V , Tran M , Lockhart SR , Litvintseva A , Berkow EL , Sexton DJ . Microbiol Spectr 2024 e0356423 CHROMagar Candida Plus is a new formulation of chromogenic media designed for the detection and differentiation of major clinical Candida species, including Candida auris. The objective of this study is to evaluate CHROMagar Candida Plus when used according to manufacturer's instructions with a panel of 206 fungal isolates and 83 skin-swab specimens originally collected for C. auris colonization screening. Of the 68 C. auris isolates tested, 66/68 displayed the expected light-blue colony morphology and blue halo within 48 h. None of the remaining 138 non-auris isolates appeared similar to C. auris. CHROMagarCandida Plus was, therefore, inclusive to 97% of 68 C. auris isolates tested and supported visual exclusion of 100% of the 138 non-C. auris isolates tested. For the 83 colonization screening specimens, direct plating onto CHROMagarCandida Plus was 60% sensitive and 100% specific when compared to the enrichment broth gold-standard reference method. In sum, these findings demonstrate the utility of this media when working with isolates but also notable limitations when working with primary skin-swabs specimens when competing yeast species are present.IMPORTANCECandida auris is an emerging fungal pathogen of public health concern. As it continues to spread, it is important to publish evaluations of new diagnostic tools. In this study, we share our experience with a new chromogenic media which can help distinguish C. auris from related species. |
Mortality associated with SARS-CoV-2 in nondomestic felids
Drozd M , Ritter JM , Samuelson JP , Parker M , Wang L , Sander SJ , Yoshicedo J , Wright L , Odani J , Shrader T , Lee E , Lockhart SR , Ghai RR , Terio KA . Vet Pathol 2024 3009858231225500 Between September and November 2021, 5 snow leopards (Panthera uncia) and 1 lion (Panthera leo) were naturally infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) and developed progressive respiratory disease that resulted in death. Severe acute respiratory syndrome coronavirus 2 sequencing identified the delta variant in all cases sequenced, which was the predominant human variant at that time. The time between initial clinical signs and death ranged from 3 to 45 days. Gross lesions in all 6 cats included nasal turbinate hyperemia with purulent discharge and marked pulmonary edema. Ulcerative tracheitis and bronchitis were noted in 4 cases. Histologically, there was necrotizing and ulcerative rhinotracheitis and bronchitis with fibrinocellular exudates and fibrinosuppurative to pyogranulomatous bronchopneumonia. The 4 cats that survived longer than 8 days had fungal abscesses. Concurrent bacteria were noted in 4 cases, including those with more acute disease courses. Severe acute respiratory syndrome coronavirus 2 was detected by in situ hybridization using probes against SARS-CoV-2 spike and nucleocapsid genes and by immunohistochemistry. Viral nucleic acid and protein were variably localized to mucosal and glandular epithelial cells, pneumocytes, macrophages, and fibrinocellular debris. Based on established criteria, SARS-CoV-2 was considered a contributing cause of death in all 6 cats. While mild clinical infections are more common, these findings suggest that some SARS-CoV-2 variants may cause more severe disease and that snow leopards may be more severely affected than other felids. |
Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections.
Gade L , Scheel CM , Pham CD , Lindsley MD , Iqbal N , Cleveland AA , Whitney AM , Lockhart SR , Brandt ME , Litvintseva AP . Eukaryot Cell 2013 12 (5) 677-83 Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection. Here we report development of a novel PCR test that allowed for rapid and specific detection of fungal DNA in cerebrospinal fluid (CSF), other body fluids and tissues of infected individuals. The test relied on direct purification of free-circulating fungal DNA from fluids and subsequent PCR amplification and sequencing. Using this method, we detected Exserohilum rostratum DNA in 123 samples from 114 case-patients (28% of 413 case-patients for whom 627 samples were available), and Cladosporium DNA in one sample from one case-patient. PCR with novel Exserohilum-specific ITS-2 region primers detected 25 case-patients with samples that were negative using broad-range ITS primers. Compared to fungal culture, this molecular test was more sensitive: of 139 case-patients with an identical specimen tested by culture and PCR, E. rostratum was recovered in culture from 19 (14%), but detected by PCR in 41 (29%), showing a diagnostic sensitivity of 29% for PCR compared to 14% for culture in this patient group. The ability to rapidly confirm the etiologic role of E. rostratum in these infections provided an important contribution in the public health response to this outbreak. |
Genomic description of acquired fluconazole- and echinocandin-resistance in patients with serial Candida glabrata isolates
Misas E , Seagle E , Jenkins EN , Rajeev M , Hurst S , Nunnally NS , Bentz ML , Lyman MM , Berkow E , Harrison LH , Schaffner W , Markus TM , Pierce R , Farley MM , Chow NA , Lockhart SR , Litvintseva AP . J Clin Microbiol 2024 e0114023 Candida glabrata is one of the most common causes of systemic candidiasis, often resistant to antifungal medications. To describe the genomic context of emerging resistance, we conducted a retrospective analysis of 82 serially collected isolates from 33 patients from population-based candidemia surveillance in the United States. We used whole-genome sequencing to determine the genetic relationships between isolates obtained from the same patient. Phylogenetic analysis demonstrated that isolates from 29 patients were clustered by patient. The median SNPs between isolates from the same patient was 30 (range: 7-96 SNPs), while unrelated strains infected four patients. Twenty-one isolates were resistant to echinocandins, and 24 were resistant to fluconazole. All echinocandin-resistant isolates carried a mutation either in the FKS1 or FKS2 HS1 region. Of the 24 fluconazole-resistant isolates, 17 (71%) had non-synonymous polymorphisms in the PDR1 gene, which were absent in susceptible isolates. In 11 patients, a genetically related resistant isolate was collected after recovering susceptible isolates, indicating in vivo acquisition of resistance. These findings allowed us to estimate the intra-host diversity of C. glabrata and propose an upper boundary of 96 SNPs for defining genetically related isolates, which can be used to assess donor-to-host transmission, nosocomial transmission, or acquired resistance.IMPORTANCEIn our study, mutations associated to azole resistance and echinocandin resistance were detected in Candida glabrata isolates using a whole-genome sequence. C. glabrata is the second most common cause of candidemia in the United States, which rapidly acquires resistance to antifungals, in vitro and in vivo. |
Peripheral immune responses to filoviruses in a reservoir versus spillover hosts reveal transcriptional correlates of disease
Guito JC , Arnold CE , Schuh AJ , Amman BR , Sealy TK , Spengler JR , Harmon JR , Coleman-McCray JD , Sanchez-Lockhart M , Palacios GF , Towner JS , Prescott JB . Front Immunol 2023 14 1306501 Several filoviruses, including Marburg virus (MARV), cause severe disease in humans and nonhuman primates (NHPs). However, the Egyptian rousette bat (ERB, Rousettus aegyptiacus), the only known MARV reservoir, shows no overt illness upon natural or experimental infection, which, like other bat hosts of zoonoses, is due to well-adapted, likely species-specific immune features. Despite advances in understanding reservoir immune responses to filoviruses, ERB peripheral blood responses to MARV and how they compare to those of diseased filovirus-infected spillover hosts remain ill-defined. We thus conducted a longitudinal analysis of ERB blood gene responses during acute MARV infection. These data were then contrasted with a compilation of published primate blood response studies to elucidate gene correlates of filovirus protection versus disease. Our work expands on previous findings in MARV-infected ERBs by supporting both host resistance and disease tolerance mechanisms, offers insight into the peripheral immunocellular repertoire during infection, and provides the most direct known cross-examination between reservoir and spillover hosts of the most prevalently-regulated response genes, pathways and activities associated with differences in filovirus pathogenesis and pathogenicity. |
Trichophyton indotineae and other terbinafine-resistant dermatophytes in North America
Lockhart SR , Smith DJ , Gold JAW . J Clin Microbiol 2023 61 (12) e0090323 Dermatophyte infections (a.k.a. ringworm, tinea) affect an estimated 20%-25% of the world's population. In North America, most dermatophytoses are caused by Trichophyton rubrum or Trichophyton mentagrophytes species complexes. Severe and antifungal-resistant dermatophytoses are a growing global public health problem. A new species of the T. mentagrophytes species complex, Trichophyton indotineae, has recently emerged and is notable for the severe infections it causes, its propensity for antifungal resistance, and its global spread. In this issue of the Journal of Clinical Microbiology, C. F. Cañete-Gibas, J. Mele, H. P. Patterson, et al. (J Clin Microbiol 61:e00562-23, 2023, https://doi.org/10.1128/JCM.00562-23) summarize the results of speciation and AFST performed on North American dermatophyte isolates received at a fungal diagnostic reference laboratory. Within their collection, 18.6% of isolates were resistant to terbinafine (a first-line oral antifungal for dermatophytoses), and similar proportions of T. rubrum and T. indotineae demonstrated terbinafine resistance. The authors also found that T. indotineae has been present in North America since at least 2017. These findings highlight the importance of increased surveillance efforts to monitor trends in severe and antifungal-resistant dermatophytoses and the need for antifungal stewardship efforts, the success of which is contingent upon improving laboratory capacity for dermatophyte speciation and AFST. |
A conceptual framework for nomenclatural stability and validity of medically important fungi: a proposed global consensus guideline for fungal name changes supported by ABP, ASM, CLSI, ECMM, ESCMID-EFISG, EUCAST-AFST, FDLC, IDSA, ISHAM, MMSA, and MSGERC
de Hoog S , Walsh TJ , Ahmed SA , Alastruey-Izquierdo A , Alexander BD , Arendrup MC , Babady E , Bai FY , Balada-Llasat JM , Borman A , Chowdhary A , Clark A , Colgrove RC , Cornely OA , Dingle TC , Dufresne PJ , Fuller J , Gangneux JP , Gibas C , Glasgow H , Gräser Y , Guillot J , Groll AH , Haase G , Hanson K , Harrington A , Hawksworth DL , Hayden RT , Hoenigl M , Hubka V , Johnson K , Kus JV , Li R , Meis JF , Lackner M , Lanternier F , Leal SM Jr , Lee F , Lockhart SR , Luethy P , Martin I , Kwon-Chung KJ , Meyer W , Nguyen MH , Ostrosky-Zeichner L , Palavecino E , Pancholi P , Pappas PG , Procop GW , Redhead SA , Rhoads DD , Riedel S , Stevens B , Sullivan KO , Vergidis P , Roilides E , Seyedmousavi A , Tao L , Vicente VA , Vitale RG , Wang QM , Wengenack NL , Westblade L , Wiederhold N , White L , Wojewoda CM , Zhang SX . J Clin Microbiol 2023 61 (11) e0087323 The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way. |
Candida auris: a global pathogen that has taken root in Colombia
Escandón P , Lockhart SR , Chow NA , Chiller TM . Biomedica 2023 43 278-287 Candida auris has been recognized as an emerging multidrug-resistant pathogen with a significant public health burden, causing cases of invasive infection and colonization due to its persistence on inanimate surfaces, ability to colonize skin of some patients, and high transmissibility in healthcare settings. The first sporadic report of the isolation of this species from the ear canal of a patient in Asia was in 2009 and reports from other regions of the world soon followed. However, it was not until 2015 that global epidemiological alerts were communicated as a result of an increasing number of reports of invasive infections caused by C. auris in several countries. Colombia was soon added to this list in 2016 after an unusual increase in the number of C. haemulonii isolates was reported, later confirmed as C. auris. Since the issuing of a national alert by the Colombian National Institute of Health together with the Ministry of Health in 2016, the number of cases reported reached over 2,000 by 2022. Colombian isolates have not shown pan resistance to available antifungals, unlike C. auris strains reported in other regions of the world, which leaves patients in Colombia with therapeutic options for these infections. However, increasing fluconazole resistance is being observed. Whole-genome sequencing of Colombian C. auris isolates has enhanced molecular epidemiological data, grouping Colombian isolates in clade IV together with other South American isolates. |
The rapid emergence of antifungal-resistant human-pathogenic fungi
Lockhart SR , Chowdhary A , Gold JAW . Nat Rev Microbiol 2023 21 (12) 818-832 During recent decades, the emergence of pathogenic fungi has posed an increasing public health threat, particularly given the limited number of antifungal drugs available to treat invasive infections. In this Review, we discuss the global emergence and spread of three emerging antifungal-resistant fungi: Candida auris, driven by global health-care transmission and possibly facilitated by climate change; azole-resistant Aspergillus fumigatus, driven by the selection facilitated by azole fungicide use in agricultural and other settings; and Trichophyton indotineae, driven by the under-regulated use of over-the-counter high-potency corticosteroid-containing antifungal creams. The diversity of the fungi themselves and the drivers of their emergence make it clear that we cannot predict what might emerge next. Therefore, vigilance is critical to monitoring fungal emergence, as well as the rise in overall antifungal resistance. |
Public health research priorities for fungal diseases: A multidisciplinary approach to save lives
Smith DJ , Gold JAW , Benedict K , Wu K , Lyman M , Jordan A , Medina N , Lockhart SR , Sexton DJ , Chow NA , Jackson BR , Litvintseva AP , Toda M , Chiller T . J Fungi (Basel) 2023 9 (8) Fungal infections can cause severe disease and death and impose a substantial economic burden on healthcare systems. Public health research requires a multidisciplinary approach and is essential to help save lives and prevent disability from fungal diseases. In this manuscript, we outline the main public health research priorities for fungal diseases, including the measurement of the fungal disease burden and distribution and the need for improved diagnostics, therapeutics, and vaccines. Characterizing the public health, economic, health system, and individual burden caused by fungal diseases can provide critical insights to promote better prevention and treatment. The development and validation of fungal diagnostic tests that are rapid, accurate, and cost-effective can improve testing practices. Understanding best practices for antifungal prophylaxis can optimize prevention in at-risk populations, while research on antifungal resistance can improve patient outcomes. Investment in vaccines may eliminate certain fungal diseases or lower incidence and mortality. Public health research priorities and approaches may vary by fungal pathogen. |
Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project (preprint)
Wilcox E , Harrison SM , Lockhart E , Voelkerding K , Lubin IM , Rehm HL , Kalman L , Funke B . medRxiv 2021 2021.06.09.21258594 Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.Competing Interest StatementThe authors have declared no competing interest.Funding StatementClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: U41HG006834, U41HG009649, U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the following three grants: U24HD093483, U24HD093486, U24HD093487.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study did not involve human subjects and therefore no IRB was required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is included in the figures, tables and supplement included in the manuscript. |
Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses (preprint)
Chow NA , Munoz JF , Gade L , Berkow EL , Li X , Welsh RM , Forsberg K , Lockhart SR , Adam R , Alanio A , Alastruey-Izquierdo A , Althawadi S , Arauz AB , Ben-Ami R , Bharat A , Calvo B , Desnos-Ollivier M , Escandon P , Gardam D , Gunturu R , Heath CH , Kurzai O , Martin R , Litvintseva AP , Cuomo CA . bioRxiv 2020 2020.01.06.896548 Candida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (Clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; Clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single healthcare facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 339 years; outbreak-causing clusters from Clades I, III, and IV originated 34-35 years ago. We observed high rates of antifungal resistance in Clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in Clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris.Importance In less than a decade, C. auris has emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology. |
Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in C. auris (preprint)
Rybak JM , Munoz JF , Barker KS , Parker JE , Esquivel BD , Berkow EL , Lockhart SR , Gade L , Palmer GE , White TC , Kelly SL , Cuomo CA , Rogers PD . bioRxiv 2020 2020.02.18.955534 Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, the fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro. Comparative analysis of comprehensive sterol profiles, [3H]-fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and the relative expression of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene, TAC1B, and a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into the fluconazole-susceptible isolate AR0387, was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in-vitro, and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCE Candida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrate that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole, and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris. |
The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection (preprint)
Singh S , Uppuluri P , Alqarihi A , Elhassan H , French S , Lockhart SR , Chiller T , Edwards JE Jr , Ibrahim AS . bioRxiv 2018 465096 Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host - a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.Author Summary Candida auris has emerged as a major health concern to hospitalized patients and nursing home subjects. C. auris strains display multidrug resistance to current antifungal therapy and cause lethal infections. We have determined that C. auris harbors homologs of C. albicans Als cell surface proteins. The C. albicans NDV-3A vaccine, harboring the N-terminus of Als3p formulated with alum, generates cross-reactive antibodies against C. auris clinical isolates and protects neutropenic mice from hematogenously disseminated C. auris infection. Importantly, the NDV-3A vaccine displays an additive protective effect in neutropenic mice when combined with micafungin. Due to its proven safety and efficacy in humans against C. albicans infection, our studies support the expedited testing of the NDV-3A vaccine against C. auris in future clinical trials. |
Will invasive fungal infections be the Last of Us The importance of surveillance, public-health interventions, and antifungal stewardship
Rodriguez Stewart RM , Gold JAW , Chiller T , Sexton DJ , Lockhart SR . Expert Rev Anti Infect Ther 2023 21 (8) 1-4 The video game-turned-HBO show ‘The Last of Us’ is a fanciful representation of a zombie apocalypse caused by a fungal infection. Although Ophiocordyceps, the ‘zombie fungi’ featured in the show, do not infect vertebrates, the show serves as a reminder that many fungi can cause life-threatening invasive fungal infections (IFIs). Candida and Aspergillus species are the most common and well-known causes of IFIs, but at least 300 species of opportunistic human pathogenic yeasts and molds exist. | | Each year, IFIs are responsible for over 1.5 million deaths globally and, in the United States alone, impose health-care costs ranging from five to seven billion dollars [Citation1,Citation2]. During the COVID-19 pandemic, rates of death from fungal infections have increased [Citation3], and the burden of IFIs is poised to grow given the expanding population of patients living with immunosuppressive conditions (e.g. solid organ and stem cell transplantation), increasing antifungal resistance, and potential climate-change related expansion of the geographic ranges in which pathogenic fungi live. Despite the morbidity and mortality associated with fungal infections and their growing public health importance, we still have much to learn about their diagnosis and management. In this review, we discuss gaps and global disparities in fungal laboratory capacity including antifungal susceptibility testing, the paucity of fungal surveillance, and the importance of antifungal stewardship, all against the backdrop of increasing antifungal resistance and a limited armamentarium of antifungal therapies. |
Low positivity rate and high percentage of nondermatophyte molds in an analysis of 35,257 fungal nail culture results from a United States national commercial laboratory, 2019-2022
Benedict K , Lipner SR , Lockhart SR , Gold JAW . JAAD Int 2023 12 43-45 Onychomycosis is an under-recognized public health topic. Recent US data on laboratory testing and causative organisms are lacking, with the last large analysis performed in 2000.1 Understanding culture testing patterns and species isolated can help characterize disease burden and inform diagnosis and treatment practices. | | We analyzed results of nail fungal cultures ordered during March 1, 2019-March 1, 2022 performed at Labcorp, a major national commercial laboratory, by patient demographics characteristics, region, species, ordering provider type, result timing, and month. |
Notes from the field: First reported U.S. Cases of tinea caused by Trichophyton indotineae - New York City, December 2021-March 2023
Caplan AS , Chaturvedi S , Zhu Y , Todd GC , Yin L , Lopez A , Travis L , Smith DJ , Chiller T , Lockhart SR , Alroy KA , Greendyke WG , Gold JAW . MMWR Morb Mortal Wkly Rep 2023 72 (19) 536-537 Tinea is a common, highly contagious, superficial infection of the skin, hair, or nails caused by dermatophyte molds.* During the past decade, an epidemic of severe, antifungal-resistant tinea has emerged in South Asia because of the rapid spread of Trichophyton indotineae,† a novel dermatophyte species; the epidemic has likely been driven by misuse and overuse of topical antifungals and corticosteroids§ (1,2). T. indotineae infections are highly transmissible and characterized by widespread, inflamed, pruritic plaques on the body (tinea corporis), the crural fold, pubic region, and adjacent thigh (tinea cruris), or the face (tinea faciei) (1). T. indotineae isolates are frequently resistant to terbinafine, a mainstay of tinea treatment (1,3). T. indotineae infections have been reported throughout Asia and in Europe and Canada but have not previously been described in the United States (3). | | On February 28, 2023, a New York City dermatologist notified public health officials of two patients who had severe tinea that did not improve with oral terbinafine treatment, raising concern for potential T. indotineae infection; these patients shared no epidemiologic links. Skin culture isolates from each patient were previously identified by a clinical laboratory as Trichophyton mentagrophytes and were subsequently forwarded to the Wadsworth Center, New York State Department of Health, for further review and analysis. Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis performed during March 2023, identified the isolates as T. indotineae (Supplementary Figure; https://stacks.cdc.gov/view/cdc/127678). Activity related to this investigation was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.¶ |
Epidemiology of implantation mycoses in the United States: an analysis of commercial insurance claims data, 2017-2021
Gold JAW , Smith DJ , Benedict K , Lockhart SR , Lipner SR . J Am Acad Dermatol 2023 89 (2) 427-430 Implantation mycoses, such as eumycetoma, chromoblastomycosis (including | 50 phaeohyphomycotic abscesses), and other deep mycoses (e.g., sporotrichosis, mucormycosis), | 51 constitute a diverse group of fungal neglected tropical diseases that usually develop after traumatic skin | inoculation.1-3 52 Although dermatologists frequently learn about these uncommon conditions during | 53 training, clinical exposure may be limited outside tropical regions. Baseline epidemiologic data on | 54 implantation mycoses might improve clinical recognition and are needed given the potential for climate | change-related expansion of geographic range. | 3 55 Therefore, we estimated prevalence and described | 56 features of U.S. patients diagnosed with implantation mycoses during 1/1/2017–12/31/2021. |
Development of core competencies for field veterinary epidemiology training programs
Pinto J , Dissanayake RB , Dhand N , Rojo-Gimeno C , Falzon LC , Akwar H , Alambeji RB , Beltran-Alcrudo D , Castellan DM , Chanachai K , Guitian J , Hilmers A , Larfaoui F , Loth L , Motta P , Rasamoelina H , Salyer S , Shadomy S , Squarzoni C , Rwego I , Santos CV , Wongsathapornchai K , Lockhart C , Okuthe S , Kane Y , Gilbert J , Soumare B , Dhingra M , Sumption K , Tiensin T . Front Vet Sci 2023 10 1143375 A workforce with the adequate field epidemiology knowledge, skills and abilities is the foundation of a strong and effective animal health system. Field epidemiology training is conducted in several countries to meet the increased global demand for such a workforce. However, core competencies for field veterinary epidemiology have not been identified and agreed upon globally, leading to the development of different training curricula. Having a set of agreed core competencies can harmonize field veterinary epidemiology training. The Food and Agriculture Organization of the United Nations (FAO) initiated a collective, iterative, and participative process to achieve this and organized two expert consultative workshops in 2018 to develop core competencies for field veterinary epidemiology at the frontline and intermediate levels. Based on these expert discussions, 13 competencies were identified for the frontline and intermediate levels. These competencies were organized into three domains: epidemiological surveillance and studies; field investigation, preparedness and response; and One Health, communication, ethics and professionalism. These competencies can be used to facilitate the development of field epidemiology training curricula for veterinarians, adapted to country training needs, or customized for training other close disciplines. The competencies can also be useful for mentors and employers to monitor and evaluate the progress of their mentees, or to guide the selection process during the recruitment of new staff. |
Epidemiology of tinea capitis causative species: an analysis of fungal culture results from a major U.S. national commercial laboratory
Gold JAW , Benedict K , Lockhart SR , Lipner SR . J Am Acad Dermatol 2023 89 (2) 382-384 Tinea capitis (TC), a scalp and hair dermatophytosis, is a common childhood infection.1 US data on the species causing TC are geographically limited or outdated.1, 2, 3, 4 We aimed to describe TC testing practices and causative organisms to improve clinical management. | | We analyzed Labcorp (a major US commercial laboratory) data sent to Centers for Disease Control and Prevention’s National Syndromic Surveillance Program, a collaborative electronic health data sharing effort among Centers for Disease Control and Prevention, health departments, and academic and private sector partners. We identified fungal culture results ordered during March 1, 2019 to October 31, 2022 using Logical Observation Identifiers Names and Codes codes and patients with suspected TC using International Classification of Diseases, 10th Revision code B35.0. We examined patient demographic characteristics, ordering clinical specialty, species, and order month. |
Whole-Genome Sequencing of Candida haemulonii species complex from Brazil and the United States: genetic diversity and antifungal susceptibility.
de Barros Rodrigues DK , Lockhart SR , Berkow EL , Gade L , Bonfietti LX , Gimenes VMF , Ruiz LS , Macioni MB , de Souza Carvalho Melhem M . Med Mycol 2023 61 (4) Candida haemulonii complex species can be multidrug-resistant (MDR) and cause infections such as candidemia. This study determined the genetic relationship between isolates from Brazil and the United States through whole-genome sequencing and performed antifungal susceptibility testing to investigate drug resistance. Contrary to what is widely described, most isolates were susceptible to azoles. However, an atypical susceptibility profile was found in 50% of C. pseudohaemulonii strains including resistance to the three echinocandins. Isolates from both countries formed distinct clusters with wide genetic diversity. Isolates from three hospitals in Brazil were clonal and involved in candidemia cases, pointing to the importance of improving hospital infection control measures and molecular identification. | Candida haemulonii complex species is worldwide distributed and this study aimed to evaluate the resistance to antifungal drugs in cases from Brazil and the United States, and also compare their genetic relationship. Fifty strains were studied, most of them from Brazil were from cases of bloodstream infections while the strains from the United States came from cases of wounds and may be associated with diabetic patients. The vast majority of strains were resistant to amphotericin B, one of the most effective drugs, and susceptible to fluconazole. In addition, 50% of C. pseudohaemulonii strains were resistant to echinocandins. The strains from Brazil and the United States had no genetic relationship and formed two distinct groups. In 3 Brazilian hospitals, strains were clonal indicating an intrahospital transmission. Our findings contribute to guiding therapy in bloodstream fungal infections caused by Candida haemulonii species and alert for nosocomial transmission of this yeast complex species. | eng |
Worsening spread of Candida auris in the United States, 2019 to 2021
Lyman M , Forsberg K , Sexton DJ , Chow NA , Lockhart SR , Jackson BR , Chiller T . Ann Intern Med 2023 176 (4) 489-495 BACKGROUND: Candida auris is an emerging fungal threat that has been spreading in the United States since it was first reported in 2016. OBJECTIVE: To describe recent changes in the U.S. epidemiology of C auris occurring from 2019 to 2021. DESIGN: Description of national surveillance data. SETTING: United States. PATIENTS: Persons with any specimen that was positive for C auris. MEASUREMENTS: Case counts reported to the Centers for Disease Control and Prevention by health departments, volume of colonization screening, and antifungal susceptibility results were aggregated and compared over time and by geographic region. RESULTS: A total of 3270 clinical cases and 7413 screening cases of C auris were reported in the United States through 31 December 2021. The percentage increase in clinical cases grew each year, from a 44% increase in 2019 to a 95% increase in 2021. Colonization screening volume and screening cases increased in 2021 by more than 80% and more than 200%, respectively. From 2019 to 2021, 17 states identified their first C auris case. The number of C auris cases that were resistant to echinocandins in 2021 was about 3 times that in each of the previous 2 years. LIMITATION: Identification of screening cases depends on screening that is done on the basis of need and available resources. Screening is not conducted uniformly across the United States, so the true burden of C auris cases may be underestimated. CONCLUSION: C auris cases and transmission have risen in recent years, with a dramatic increase in 2021. The rise in echinocandin-resistant cases and evidence of transmission is particularly concerning because echinocandins are first-line therapy for invasive Candida infections, including C auris. These findings highlight the need for improved detection and infection control practices to prevent spread of C auris. PRIMARY FUNDING SOURCE: None. |
In vitro activity of the novel antifungal olorofim against Scedosporium And Lomentospora prolificans
Georgacopoulos O , Nunnally N , Law D , Birch M , Berkow EL , Lockhart SR . Microbiol Spectr 2023 11 (1) e0278922 Scedosporium spp. and Lomentospora prolificans are an emerging group of fungi refractory to current antifungal treatments. These species largely affect immunocompromised individuals but can also be lung colonizers in cystic fibrosis patients. Although Scedosporium apiospermum is thought to be the predominant species, the group has been expanded to a species complex. The distribution of species within the S. apiospermum species complex and other closely related species in the United States is largely unknown. Here, we used β-tubulin and ITS sequences to identify 37 Scedosporium isolates to the species level. These Scedosporium isolates as well as 13 L. prolificans isolates were tested against a panel of nine antifungal drugs, including the first in novel class orotimide, olorofim. IMPORTANCE Scedosporium and Lomentospora infections are notoriously hard to treat as these organisms can be resistant to numerous antifungals. The manuscript contributes to our knowledge of the activity of the new antifungal agent olorofim and comparator agents against Lomentospora and against Scedosporium isolates that have been molecularly identified to the species level. The efficacy of olorofim against all species of Scedosporium and Lomentospora was confirmed. |
Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis
Meletiadis J , Andes DR , Lockhart SR , Ghannoum MA , Knapp CC , Ostrosky-Zeichner L , Pfaller MA , Chaturvedi V , Walsh TJ . J Fungi (Basel) 2022 8 (9) Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5−4, indicating no significant pharmacodynamic interactions for all of the strain−combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1−2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found. |
Recurrent candidemia: Trends and risk factors among persons residing in 4 US states, 2011-2018
Seagle EE , Jackson BR , Lockhart SR , Jenkins EN , Revis A , Farley MM , Harrison LH , Schaffner W , Markus TM , Pierce RA , Zhang AY , Lyman MM . Open Forum Infect Dis 2022 9 (10) ofac545 BACKGROUND: Candidemia is a common healthcare-associated infection with high mortality. Estimates of recurrence range from 1% to 17%. Few studies have focused on those with recurrent candidemia, who often experience more severe illness and greater treatment failure. We describe recurrent candidemia trends and risk factors. METHODS: We analyzed population-based candidemia surveillance data collected during 2011-2018. Persons with >1 episode (defined as the 30-day period after a positive Candida species) were classified as having recurrent candidemia. We compared factors during the initial episode between those who developed recurrent candidemia and those who did not. RESULTS: Of the 5428 persons identified with candidemia, 326 (6%) had recurrent infection. Recurrent episodes occurred 1.0 month to 7.6 years after any previous episode. In multivariable logistic regression controlling for surveillance site and year, recurrent candidemia was associated with being 19-44 years old (vs ≥65 years; adjusted odds ratio [aOR], 3.05 [95% confidence interval {CI}, 2.10-4.44]), being discharged to a private residence (vs medical facility; aOR, 1.53 [95% CI, 1.12-2.08]), hospitalization in the 90 days prior to initial episode (aOR, 1.66 [95% CI, 1.27-2.18]), receipt of total parenteral nutrition (aOR, 2.08 [95% CI, 1.58-2.73]), and hepatitis C infection (aOR, 1.65 [95% CI, 1.12-2.43]). CONCLUSIONS: Candidemia recurrence >30 days after initial infection occurred in >1 in 20 persons with candidemia. Associations with younger age and hepatitis C suggest injection drug use may play a modifiable role. Prevention efforts targeting central line care and total parenteral nutrition use may help reduce the risk of recurrent candidemia. |
Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens?
Verweij PE , Arendrup MC , Alastruey-Izquierdo A , Gold JAW , Lockhart SR , Chiller T , White PL . Drug Resist Updat 2022 65 100885 Azole resistance in Aspergillus fumigatus is a One Health resistance threat, where azole fungicide exposure compromises the efficacy of medical azoles. The use of the recently authorized fungicide ipflufenoquin, which shares its mode-of-action with a new antifungal olorofim, underscores the need for risk assessment for dual use of antifungals. |
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