Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 49 Records) |
Query Trace: Berkow EL[original query] |
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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. |
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. |
Genomic basis of multidrug-resistance, mating, and virulence in Candida auris and related emerging species (preprint)
Munoz JF , Gade L , Chow NA , Loparev VN , Juieng P , Berkow EL , Farrer RA , Litvintseva AP , Cuomo CA . bioRxiv 2018 299917 Candida auris is an emergent fungal pathogen of rising public health concern due to increasing reports of outbreaks in healthcare settings and resistance to multiple classes of antifungal drugs. While distantly related to the more common pathogens C. albicans and C. glabrata, C. auris is closely related to three rarely observed and often multidrug-resistant species, C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Here, we generated and analyzed near complete genome assemblies and RNA-Seq-guided gene predictions for isolates from each of the four major C. auris clades and for C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Our analyses mapped seven chromosomes and revealed chromosomal rearrangements between C. auris clades and related species. We found conservation of genes involved in mating and meiosis and identified both MTLa and MTLα C. auris isolates, suggesting the potential for mating between clades. Gene conservation analysis highlighted that many genes linked to drug resistance and virulence in other pathogenic Candida species are conserved in C. auris and related species including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11 that confer drug resistance. In addition, we found genetic features of the emerging species that likely underlie differences in virulence and drug response between these and other Candida species, including genes involved in cell wall structure. To begin to characterize the species-specific genes important for antifungal response, we profiled the gene expression of C. auris in response to voriconazole and amphotericin B and found induction of several transporters and metabolic regulators that may play a role in drug resistance. This study provides a comprehensive view of the genomic basis of drug resistance, potential for mating, and virulence in this emerging fungal clade. |
Fungal pathogens as causes of acute respiratory illness in hospitalized veterans: Frequency of fungal positive test results using rapid immunodiagnostic assays
Caceres DH , Rodriguez-Barradas MC , Whitaker M , Jackson BR , Kim L , Surie D , Cikesh B , Lindsley MD , McCotter OZ , Berkow EL , Toda M . J Fungi (Basel) 2023 9 (4) Fungal respiratory illnesses caused by endemic mycoses can be nonspecific and are often mistaken for viral or bacterial infections. We performed fungal testing on serum specimens from patients hospitalized with acute respiratory illness (ARI) to assess the possible role of endemic fungi as etiologic agents. Patients hospitalized with ARI at a Veterans Affairs hospital in Houston, Texas, during November 2016-August 2017 were enrolled. Epidemiologic and clinical data, nasopharyngeal and oropharyngeal samples for viral testing (PCR), and serum specimens were collected at admission. We retrospectively tested remnant sera from a subset of patients with negative initial viral testing using immunoassays for the detection of Coccidioides and Histoplasma antibodies (Ab) and Cryptococcus, Aspergillus, and Histoplasma antigens (Ag). Of 224 patient serum specimens tested, 49 (22%) had positive results for fungal pathogens, including 30 (13%) by Coccidioides immunodiagnostic assays, 19 (8%) by Histoplasma immunodiagnostic assays, 2 (1%) by Aspergillus Ag, and none by Cryptococcus Ag testing. A high proportion of veterans hospitalized with ARI had positive serological results for fungal pathogens, primarily endemic mycoses, which cause fungal pneumonia. The high proportion of Coccidioides positivity is unexpected as this fungus is not thought to be common in southeastern Texas or metropolitan Houston, though is known to be endemic in southwestern Texas. Although serological testing suffers from low specificity, these results suggest that these fungi may be more common causes of ARI in southeast Texas than commonly appreciated and more increased clinical evaluation may be warranted. |
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 |
Genomic description of human clinical Aspergillus fumigatus isolates, California, 2020.
Misas E , Deng JZ , Gold JAW , Gade L , Nunnally NS , Georgacopoulos O , Bentz M , Berkow EL , Litvintseva AP , Chiller TM , Klausner JD , Chow NA . Med Mycol 2023 61 (2) ![]() ![]() Aspergillus fumigatus, an environmental mold, causes life-threatening infections. Studies on the phylogenetic structure of human clinical A. fumigatus isolates are limited. Here, we performed whole-genome sequencing of 24 A. fumigatus isolates collected from 18 patients in U.S. healthcare facilities in California. Single-nucleotide polymorphism (SNP) differences between patient isolates ranged from 187-70 829 SNPs. For five patients with multiple isolates, we calculated the within-host diversities. Three patients had a within-host diversity that ranged from 4-10 SNPs and two patients ranged from 2-16 977 SNPs. Findings revealed highly diverse A. fumigatus strains among patients and two patterns of diversity for isolates that come from the same patient, low and extremely high diversity. | Aspergillus fumigatus is an environmental mold. It can cause a severe infection called aspergillosis in patients with weakened immune systems. We analyzed A. fumigatus DNA from patients at California hospitals. We described genetic diversity between samples from the same patients and among different patients. Our findings provide insight on using genomic sequencing to investigate aspergillosis in hospitals. | eng |
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. |
Molecular Epidemiology of Blastomyces gilchristii Clusters, Minnesota, USA.
Bagal UR , Ireland M , Gross A , Fischer J , Bentz M , Berkow EL , Litvintseva AP , Chow NA . Emerg Infect Dis 2022 28 (9) 1924-1926 ![]() ![]() We characterized 2 clusters of blastomycosis cases in Minnesota, USA, using whole-genome sequencing and single-nucleotide polymorphism analyses. Blastomyces gilchristii was confirmed as the cause of infection. Genomic analyses corresponded with epidemiologic findings for cases of B. gilchristii infections, demonstrating the utility of genomic methods for future blastomycosis outbreak investigations. |
Clinical characteristics, health care utilization, and outcomes among patients in a pilot surveillance system for invasive mold disease-Georgia, United States, 2017-2019
Gold JAW , Revis A , Thomas S , Perry L , Blakney RA , Chambers T , Bentz ML , Berkow EL , Lockhart SR , Lysen C , Nunnally NS , Jordan A , Kelly HC , Montero AJ , Farley MM , Oliver NT , Pouch SM , Webster AS , Jackson BR , Beer KD . Open Forum Infect Dis 2022 9 (7) ofac215 BACKGROUND: Invasive mold diseases (IMDs) cause severe illness, but public health surveillance data are lacking. We describe data collected from a laboratory-based, pilot IMD surveillance system. METHODS: During 2017-2019, the Emerging Infections Program conducted active IMD surveillance at 3 Atlanta-area hospitals. We ascertained potential cases by reviewing histopathology, culture, and Aspergillus galactomannan results and classified patients as having an IMD case (based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [MSG] criteria) or a non-MSG IMD case (based on the treating clinician's diagnosis and use of mold-active antifungal therapy). We described patient features and compared patients with MSG vs non-MSG IMD cases. RESULTS: Among 304 patients with potential IMD, 104 (34.2%) met an IMD case definition (41 MSG, 63 non-MSG). The most common IMD types were invasive aspergillosis (n=66 [63.5%]), mucormycosis (n=8 [7.7%]), and fusariosis (n=4 [3.8%]); the most frequently affected body sites were pulmonary (n=66 [63.5%]), otorhinolaryngologic (n=17 [16.3%]), and cutaneous/deep tissue (n=9 [8.7%]). Forty-five (43.3%) IMD patients received intensive care unit-level care, and 90-day all-cause mortality was 32.7%; these outcomes did not differ significantly between MSG and non-MSG IMD patients. CONCLUSIONS: IMD patients had high mortality rates and a variety of clinical presentations. Comprehensive IMD surveillance is needed to assess emerging trends, and strict application of MSG criteria for surveillance might exclude over one-half of clinically significant IMD cases. |
Rapid Assessment and Containment of Candida auris Transmission in Postacute Care Settings-Orange County, California, 2019.
Karmarkar EN , O'Donnell K , Prestel C , Forsberg K , Gade L , Jain S , Schan D , Chow N , McDermott D , Rossow J , Toda M , Ruiz R , Hun S , Dale JL , Gross A , Maruca T , Glowicz J , Brooks R , Bagheri H , Nelson T , Gualandi N , Khwaja Z , Horwich-Scholefield S , Jacobs J , Cheung M , Walters M , Jacobs-Slifka K , Stone ND , Mikhail L , Chaturvedi S , Klein L , Vagnone PS , Schneider E , Berkow EL , Jackson BR , Vallabhaneni S , Zahn M , Epson E . Ann Intern Med 2021 174 (11) 1554-1562 ![]() ![]() BACKGROUND: Candida auris, a multidrug-resistant yeast, can spread rapidly in ventilator-capable skilled-nursing facilities (vSNFs) and long-term acute care hospitals (LTACHs). In 2018, a laboratory serving LTACHs in southern California began identifying species of Candida that were detected in urine specimens to enhance surveillance of C auris, and C auris was identified in February 2019 in a patient in an Orange County (OC), California, LTACH. Further investigation identified C auris at 3 associated facilities. OBJECTIVE: To assess the prevalence of C auris and infection prevention and control (IPC) practices in LTACHs and vSNFs in OC. DESIGN: Point prevalence surveys (PPSs), postdischarge testing for C auris detection, and assessments of IPC were done from March to October 2019. SETTING: All LTACHs (n = 3) and vSNFs (n = 14) serving adult patients in OC. PARTICIPANTS: Current or recent patients in LTACHs and vSNFs in OC. INTERVENTION: In facilities where C auris was detected, PPSs were repeated every 2 weeks. Ongoing IPC support was provided. MEASUREMENTS: Antifungal susceptibility testing and whole-genome sequencing to assess isolate relatedness. RESULTS: Initial PPSs at 17 facilities identified 44 additional patients with C auris in 3 (100%) LTACHs and 6 (43%) vSNFs, with the first bloodstream infection reported in May 2019. By October 2019, a total of 182 patients with C auris were identified by serial PPSs and discharge testing. Of 81 isolates that were sequenced, all were clade III and highly related. Assessments of IPC identified gaps in hand hygiene, transmission-based precautions, and environmental cleaning. The outbreak was contained to 2 facilities by October 2019. LIMITATION: Acute care hospitals were not assessed, and IPC improvements over time could not be rigorously evaluated. CONCLUSION: Enhanced laboratory surveillance and prompt investigation with IPC support enabled swift identification and containment of C auris. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention. |
Genomic Diversity of Azole-Resistant Aspergillus fumigatus in the United States.
Etienne KA , Berkow EL , Gade L , Nunnally N , Lockhart SR , Beer K , Jordan IK , Rishishwar L , Litvintseva AP . mBio 2021 12 (4) e0180321 ![]() ![]() Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR(34)/L98H (TR(34)) and TR(46)/Y121F/T289A (TR(46)), are widespread across multiple continents and emerging in the United States. We used whole-genome single nucleotide polymorphism (SNP) analysis on 179 nationally represented clinical and environmental A. fumigatus genomes from the United States along with 18 non-U.S. genomes to evaluate the genetic diversity and foundation of the emergence of azole resistance in the United States. We demonstrated the presence of clades of A. fumigatus isolates: clade A (17%) comprised a global collection of clinical and environmental azole-resistant strains, including all strains with the TR(34)/L98H allele from India, The Netherlands, the United Kingdom, and the United States, and clade B (83%) consisted of isolates without this marker mainly from the United States. The TR(34)/L98H polymorphism was shared among azole-resistant A. fumigatus strains from India, The Netherlands, the United Kingdom, and the United States, suggesting the common origin of this resistance mechanism. Six percent of azole-resistant A. fumigatus isolates from the United States with the TR(34) resistance marker had a mixture of clade A and clade B alleles, suggestive of recombination. Additionally, the presence of equal proportions of both mating types further suggests the ongoing presence of recombination. This study demonstrates the genetic background for the emergence of azole resistance in the United States, supporting a single introduction and subsequent propagation, possibly through recombination of environmentally driven resistance mutations. IMPORTANCE Aspergillus fumigatus is one of the most common causes of invasive mold infections in patients with immune deficiencies and has also been reported in patients with severe influenza and severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Triazole drugs are the first line of therapy for this infection; however, their efficacy has been compromised by the emergence of azole resistance in A. fumigatus, which was proposed to be selected for by exposure to azole fungicides in the environment [P. E. Verweij, E. Snelders, G. H. J. Kema, E. Mellado, et al., Lancet Infect Dis 9:789-795, 2009, https://doi.org/10.1016/S1473-3099(09)70265-8]. Isolates with environmentally driven resistance mutations, TR(34)/L98H (TR(34)) and TR(46)/Y121F/T289A (TR(46)), have been reported worldwide. Here, we used genomic analysis of a large sample of resistant and susceptible A. fumigatus isolates to demonstrate a single introduction of TR(34) in the United States and suggest its ability to spread into the susceptible population is through recombination between resistant and susceptible isolates. |
In Vitro Activity of Novel Antifungal Olorofim against Filamentous Fungi and Comparison to Eight Other Antifungal Agents
Georgacopoulos O , Nunnally NS , Ransom EM , Law D , Birch M , Lockhart SR , Berkow EL . J Fungi (Basel) 2021 7 (5) Olorofim is a novel antifungal drug that belongs to the orotomide drug class which inhibits fungal dihydroorotate dehydrogenase (DHODH), thus halting pyrimidine biosynthesis and ultimately DNA synthesis, cell growth and division. It is being developed at a time when many invasive fungal infections exhibit antifungal resistance or have limited treatment options. The goal of this study was to evaluate the in vitro effectiveness of olorofim against a large collection of recently isolated, clinically relevant American mold isolates. In vitro antifungal activity was determined for 246 azole-susceptible Aspergillus fumigatus isolates, five A. fumigatus with TR(34)/L98H-mediated resistance, 19 Rhizopus species isolates, 21 Fusarium species isolates, and one isolate each of six other species of molds. Olorofim minimum inhibitory concentrations (MICs) were compared to antifungal susceptibility testing profiles for amphotericin B, anidulafungin, caspofungin, isavuconazole, itraconazole, micafungin, posaconazole, and voriconazole. Olorofim MICs were significantly lower than those of the echinocandin and azole drug classes and amphotericin B. A. fumigatus wild type and resistant isolates shared the same MIC50 = 0.008 μg/mL. In non-Aspergillus susceptible isolates (MIC ≤ 2 μg/mL), the geometric mean (GM) MIC to olorofim was 0.54 μg/mL with a range of 0.015-2 μg/mL. Olorofim had no antifungal activity (MIC ≥ 2 μg/mL) against 10% of the collection (31 in 297), including some isolates from Rhizopus spp. and Fusarium spp. Olorofim showed promising activity against A. fumigatus and other molds regardless of acquired azole resistance. |
Antifungal activity of nikkomycin Z against Candida auris.
Bentz ML , Nunnally N , Lockhart SR , Sexton DJ , Berkow EL . J Antimicrob Chemother 2021 76 (6) 1495-1497 ![]() BACKGROUND: Nikkomycin Z is a competitive inhibitor of chitin synthase-an enzyme needed for synthesis of the fungal cell wall. Nikkomycin Z shows promise as a treatment for coccidioidomycoses and mixed activity has been described against other fungi and yeast. To our knowledge, it has not previously been tested against the emerging fungal pathogen Candida auris. OBJECTIVES: To determine the in vitro activity of nikkomycin Z against C. auris. METHODS: Nikkomycin Z was tested by broth microdilution against a panel of 100 isolates of genetically diverse C. auris from around the world. RESULTS: Nikkomycin Z showed mixed activity against the tested isolates, with an MIC range of 0.125 to >64 mg/L. The MIC50 and MIC90 were 2 and 32 mg/L, respectively. CONCLUSIONS: These findings suggest nikkomycin Z has in vitro activity against some, but not all isolates of C. auris. |
Categorizing susceptibility of clinical isolates of Candida auris to amphotericin B, caspofungin, and fluconazole utilizing the CLSI M44-A2 disk diffusion method
Nunnally NS , Damm T , Lockhart SR , Berkow EL . J Clin Microbiol 2021 59 (4) We evaluated the CLSI M44ed3E disk diffusion method in comparison with the CLSI M27ed4 broth microdilution method for caspofungin and fluconazole and the Etest method for amphotericin B to categorize susceptibility of 347 clinical isolates of Candida auris Utilizing the zone diameter cutoffs established here we observed the overall categorial agreement between the two methods. For caspofungin, concordant results were observed for 98% of isolates with <1% very major and 1% major errors. For fluconazole, concordant results were observed for 91% of isolates with 1% very major and 8% major errors. For amphotericin B, concordant results were observed for 74% of isolates with <1% very major errors and 25% major errors. The disk diffusion approach provides an accurate method for determining the susceptibility of C. auris for caspofungin and fluconazole, and for identification of at least 75% of amphotericin B-susceptible isolates. |
Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections.
Ghannoum M , Arendrup MC , Chaturvedi VP , Lockhart SR , McCormick TS , Chaturvedi S , Berkow EL , Juneja D , Tarai B , Azie N , Angulo D , Walsh TJ . Antibiotics (Basel) 2020 9 (9) ![]() Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC(50) and MIC(90)) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections. |
Understanding the Emergence of Multidrug-Resistant Candida : Using Whole-Genome Sequencing to Describe the Population Structure of Candida haemulonii Species Complex.
Gade L , Munoz JF , Sheth M , Wagner D , Berkow EL , Forsberg K , Jackson BR , Ramos-Castro R , Escandon P , Dolande M , Ben-Ami R , Espinosa-Bode A , Caceres DH , Lockhart SR , Cuomo CA , Litvintseva AP . Front Genet 2020 11 554 ![]() ![]() The recent emergence of a multidrug-resistant yeast, Candida auris, has drawn attention to the closely related species from the Candida haemulonii complex that include C. haemulonii, Candida duobushaemulonii, Candida pseudohaemulonii, and the recently identified Candida vulturna. Here, we used antifungal susceptibility testing and whole-genome sequencing (WGS) to investigate drug resistance and genetic diversity among isolates of C. haemulonii complex from different geographic areas in order to assess population structure and the extent of clonality among strains. Although most isolates of all four species were genetically distinct, we detected evidence of the in-hospital transmission of C. haemulonii and C. duobushaemulonii in one hospital in Panama, indicating that these species are also capable of causing outbreaks in healthcare settings. We also detected evidence of the rising azole resistance among isolates of C. haemulonii and C. duobushaemulonii in Colombia, Panama, and Venezuela linked to substitutions in ERG11 gene as well as amplification of this gene in C. haemulonii in isolates in Colombia suggesting the presence of evolutionary pressure for developing azole resistance in this region. Our results demonstrate that these species need to be monitored as possible causes of outbreaks of invasive infection. |
Evaluation of nine surface disinfectants against Candida auris using a quantitative disk carrier method: EPA SOP-MB-35
Sexton DJ , Welsh RM , Bentz ML , Forsberg K , Jackson B , Berkow EL , Litvintseva AP . Infect Control Hosp Epidemiol 2020 41 (10) 1-3 We tested 9 disinfectants against Candida auris using the quantitative disk carrier method EPA-MB-35-00: 5 products with hydrogen peroxide or alcohol-based chemistries were effective and 4 quaternary ammonium compound-based products were not. This work supported a FIFRA Section 18 emergency exemption granted by the US Environmental Protection Agency to expand disinfectant guidance for C. auris. |
Performance evaluation of culture-independent SYBR Green Candida auris qPCR diagnostics on anterior nares surveillance swabs
Georgacopoulos O , Nunnally NS , Le N , Lysen C , Welsh RM , Kordalewska M , Perlin DS , Berkow EL , Sexton DJ . J Clin Microbiol 2020 58 (9) Early identification of Candida auris is important for timely implementation of infection prevention and control actions. Here, we evaluated performance of the C. auris-specific SYBR Green qPCR assay on a panel of 70 anterior nares swabs. Enrichment broth culture was used as "gold standard". After performing a receiver operating curve (ROC) to optimize signal threshold, we found perfect agreement between culture and qPCR. Additionally, we found no indication of inhibitors in the anterior nares swabs. |
Mutations in TAC1B : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris.
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 . mBio 2020 11 (3) ![]() ![]() 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, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, 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 analyses of comprehensive sterol profiles, [(3)H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels 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 to show 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 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 to be 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 demonstrated 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. |
Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses.
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 . mBio 2020 11 (2) ![]() ![]() ![]() 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 more than 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 health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 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 health care 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. |
Antifungal susceptibility testing: Current approaches
Berkow EL , Lockhart SR , Ostrosky-Zeichner L . Clin Microbiol Rev 2020 33 (3) SUMMARYAlthough not as ubiquitous as antibacterial susceptibility testing, antifungal susceptibility testing (AFST) is a tool of increasing importance in clinical microbiology laboratories. The goal of AFST is to reliably produce MIC values that may be used to guide patient therapy, inform epidemiological studies, and track rates of antifungal drug resistance. There are three methods that have been standardized by standards development organizations: broth dilution, disk diffusion, and azole agar screening for Aspergillus Other commonly used methods include gradient diffusion and the use of rapid automated instruments. Novel methodologies for susceptibility testing are in development. It is important for laboratories to consider not only the method of testing but also the interpretation (or lack thereof) of in vitro data. |
Bloodstream infections with Candida auris among children in Colombia: Clinical characteristics and outcomes of 34 cases
Berrio I , Caceres DH , Coronell RW , Salcedo S , Mora L , Marin A , Varon C , Lockhart SR , Escandon P , Berkow EL , Rivera S , Chiller T , Vallabhaneni S . J Pediatric Infect Dis Soc 2020 10 (2) 151-154 BACKGROUND: Candida auris is an emerging multidrug-resistant yeast that can cause invasive infections and healthcare-associated outbreaks. Here, we describe 34 cases of pediatric C. auris bloodstream infections (BSIs) identified during July 2014-October 2017 in 2 hospitals in Colombia. METHODS: We conducted a retrospective review of microbiology records for possible C. auris cases in 2 hospitals in Barranquilla and Cartagena. BSIs that occurred in patients aged <18 years confirmed as C. auris were included in this analysis. RESULTS: We identified 34 children with C. auris BSIs. Twenty-two (65%) patients were male, 21% were aged <28 days, 47% were aged 29-365 days, and 32% were aged >1 year. Underlying conditions included preterm birth (26%), being malnourished (59%), cancer (12%), solid-organ transplant (3%), and renal disease (3%). Eighty-two percent had a central venous catheter (CVC), 82% were on respiratory support, 56% received total parenteral nutrition (TPN), 15% had a surgical procedure, and 9% received hemodialysis. Preinfection inpatient stay was 22 days (interquartile range, 19-33 days), and in-hospital mortality was 41%. CONCLUSIONS: Candida auris affects children with a variety of medical conditions including prematurity and malignancy, as well as children with CVCs and those who receive TPN. Mortality was high, with nearly half of patients dying before discharge. However, unlike most other Candida species, C. auris can be transmitted in healthcare settings, as suggested by the close clustering of cases in time at each of the hospitals.Candida auris is an emerging multidrug-resistant yeast that can cause invasive infections and healthcare-associated outbreaks. This report describes 34 cases of pediatric C. auris bloodstream infections, identified in two hospitals in Colombia, South America. |
Population-based active surveillance for culture-confirmed candidemia - four sites, United States, 2012-2016
Toda M , Williams SR , Berkow EL , Farley MM , Harrison LH , Bonner L , Marceaux KM , Hollick R , Zhang AY , Schaffner W , Lockhart SR , Jackson BR , Vallabhaneni S . MMWR Surveill Summ 2019 68 (8) 1-15 PROBLEM/CONDITION: Candidemia is a bloodstream infection (BSI) caused by yeasts in the genus Candida. Candidemia is one of the most common health care-associated BSIs in the United States, with all-cause in-hospital mortality of up to 30%. PERIOD COVERED: 2012-2016. DESCRIPTION OF SYSTEM: CDC's Emerging Infections Program (EIP), a collaboration among CDC, state health departments, and academic partners that was established in 1995, was used to conduct active, population-based laboratory surveillance for candidemia in 22 counties in four states (Georgia, Maryland, Oregon, and Tennessee) with a combined population of approximately 8 million persons. Laboratories serving the catchment areas were recruited to report candidemia cases to the local EIP program staff. A case was defined as a blood culture that was positive for a Candida species collected from a surveillance area resident during 2012-2016. Isolates were sent to CDC for species confirmation and antifungal susceptibility testing. Any subsequent blood cultures with Candida within 30 days of the initial positive culture in the same patient were considered part of the same case. Trained surveillance officers collected clinical information from the medical chart for all cases, and isolates were sent to CDC for species confirmation and antifungal susceptibility testing. RESULTS: Across all sites and surveillance years (2012-2016), 3,492 cases of candidemia were identified. The crude candidemia incidence averaged across sites and years during 2012-2016 was 8.7 per 100,000 population; important differences in incidence were found by site, age group, sex, and race. The crude annual incidence was the highest in Maryland (14.1 per 100,000 population) and lowest in Oregon (4.0 per 100,000 population). The crude annual incidence of candidemia was highest among adults aged >/=65 years (25.5 per 100,000 population) followed by infants aged <1 year (15.8). The crude annual incidence was higher among males (9.4) than among females (8.0) and was approximately 2 times greater among blacks than among nonblacks (13.7 versus 5.8). Ninety-six percent of cases occurred in patients who were hospitalized at the time of or during the week after having a positive culture. One third of cases occurred in patients who had undergone a surgical procedure in the 90 days before the candidemia diagnosis, 77% occurred in patients who had received systemic antibiotics in the 14 days before the diagnosis, and 73% occurred in patients who had had a central venous catheter (CVC) in place within 2 days before the diagnosis. Ten percent were in patients who had used injection drugs in the past 12 months. The median time from admission to candidemia diagnosis was 5 days (interquartile range [IQR]: 0-16 days). Among 2,662 cases that were treated in adults aged >18 years, 34% were treated with fluconazole alone, 30% with echinocandins alone, and 34% with both. The all-cause, in-hospital case-fatality ratio was 25% for any time after admission; the all-cause in-hospital case-fatality ratio was 8% for <48 hours after a positive culture for Candida species. Candida albicans accounted for 39% of cases, followed by Candida glabrata (28%) and Candida parapsilosis (15%). Overall, 7% of isolates were resistant to fluconazole and 1.6% were resistant to echinocandins, with no clear trends in resistance over the 5-year surveillance period. INTERPRETATION: Approximately nine out of 100,000 persons developed culture-positive candidemia annually in four U.S. sites. The youngest and oldest persons, men, and blacks had the highest incidences of candidemia. Patients with candidemia identified in the surveillance program had many of the typical risk factors for candidemia, including recent surgery, exposure to broad-spectrum antibiotics, and presence of a CVC. However, an unexpectedly high proportion of candidemia cases (10%) occurred in patients with a history of injection drug use (IDU), suggesting that IDU has become a common risk factor for candidemia. Deaths associated with candidemia remain high, with one in four cases resulting in death during hospitalization. PUBLIC HEALTH ACTION: Active surveillance for candidemia yielded important information about the disease incidence and death rate and persons at greatest risk. The surveillance was expanded to nine sites in 2017, which will improve understanding of the geographic variability in candidemia incidence and associated clinical and demographic features. This surveillance will help monitor incidence trends, track emergence of resistance and species distribution, monitor changes in underlying conditions and predisposing factors, assess trends in antifungal treatment and outcomes, and be helpful for those developing prevention efforts. IDU has emerged as an important risk factor for candidemia, and interventions to prevent invasive fungal infections in this population are needed. Surveillance data documenting that approximately two thirds of candidemia cases were caused by species other than C. albicans, which are generally associated with greater antifungal resistance than C. albicans, and the presence of substantial fluconazole resistance supports 2016 clinical guidelines recommending a switch from fluconazole to echinocandins as the initial treatment for candidemia in most patients. |
In vitro activity of ibrexafungerp, a novel glucan synthase inhibitor against Candida glabrata isolates with FKS mutations
Nunnally NS , Etienne KA , Angulo D , Lockhart SR , Berkow EL . Antimicrob Agents Chemother 2019 63 (11) Ibrexafungerp is a first in class glucan-synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, and micafungin) by broth microdilution. Results for ibrexafungerp were compared to those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant Candida glabrata isolates. |
Identification of Candida auris using the updated 8.01 VITEK®2 yeast identification system: a multi-laboratory evaluation study.
Ambaraghassi G , Dufresne PJ , Dufresne SF , Vallieres E , Munoz JF , Cuomo CA , Berkow EL , Lockhart SR , Luong ML . J Clin Microbiol 2019 57 (11) ![]() ![]() IntroductionCandida auris is an emerging multidrug-resistant yeast that has been systematically incorrectly identified by phenotypic methods in clinical microbiology laboratories. VITEK(R)2 automated identification system (bioMerieux) recently included C. auris in its database (version 8.01).Material and methodsWe evaluated the performance of VITEK(R)2 (YST ID Card) to identify C. auris and related species. A panel of 44 isolates of Candida species (C. auris, n=35; C. haemulonii, n=5; C. duobushaemulonii, n=4) were tested by three different hospital-based microbiology laboratories.ResultsAmong 35 isolates of C. auris, VITEK(R)2 yielded correct identification in an average of 52% of tested samples. Low discrimination results were obtained in an average of 27% with inability to distinguish between C. auris, C. duobushaemulonii and C. famata. Incorrect identification results were obtained in an average of 21%, the majority (91%) of which were reported as C duobushaemulonii and 9% as C. lusitaniae/C. duobushaemulonii. Proportion of correct identification was not statistically different across different centers (p=0,78). Stratification by genetic clades demonstrated that 100% (n=8) of the strains of the South American clade were correctly identified, compared to 7% (n=10) and 0% (n=4) from the African and East Asian clade respectively. None of the non-auris Candida strains (n=9) were incorrectly identified as C. aurisConclusionOur results show that VITEK(R)2 (version 8.01) yeast identification system has a limited ability to correctly identify C. auris This data suggests that an identification result for C. duobushaemulonii should warrant further testing to rule out C. auris Overall performance of VITEK(R)2 seems to differ according to C. auris genetic clade with the South American isolates yielding the most accurate result. |
Antifungal Susceptibility Testing: The Times They Are A-Changing
Lockhart SR , Berkow EL . Clin Microbiol Newsl 2019 41 (10) 85-90 Antifungal susceptibility testing (AFST) has never been performed as commonly or in as many laboratories as antibacterial susceptibility testing, but strategies may soon change. The pharmaceutical industry is in an unprecedented era of antifungal development, which may alter the utility of, and demand for, AFST. Here, we illustrate an argument for increased AFST capacity, discuss new antifungals that are likely to appear on the market soon, describe the phenomenon of trailing growth that can lead to false interpretation of susceptibility results for Candida spp., and illuminate problems and solutions commonly encountered when performing AFST. |
The fungal Cyp51 specific inhibitor VT-1598 demonstrates in vitro and in vivo activity against Candida auris
Wiederhold NP , Lockhart SR , Najvar LK , Berkow EL , Jaramillo R , Olivo M , Garvey EP , Yates CM , Schotzinger RJ , Catano G , Patterson TF . Antimicrob Agents Chemother 2018 63 (3) Candida auris is an emerging pathogen associated with significant mortality and often multi-drug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 hours post-inoculation with vehicle control, oral VT-1598 (5, 15, and 50 mg/kg once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm, and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 mug/mL and MICs ranging from 0.03 to 8 mug/mL. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival 15 and >21 days for VT-1598 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (1.88 to 3.61 log10 CFU/g reduction) compared to control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris. |
Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species.
Munoz JF , Gade L , Chow NA , Loparev VN , Juieng P , Berkow EL , Farrer RA , Litvintseva AP , Cuomo CA . Nat Commun 2018 9 (1) 5346 ![]() Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLalpha mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade. |
Multidrug-Resistant Aspergillus fumigatus Carrying Mutations Linked to Environmental Fungicide Exposure - Three States, 2010-2017.
Beer KD , Farnon EC , Jain S , Jamerson C , Lineberger S , Miller J , Berkow EL , Lockhart SR , Chiller T , Jackson BR . MMWR Morb Mortal Wkly Rep 2018 67 (38) 1064-1067 ![]() ![]() The environmental mold Aspergillus fumigatus is the primary cause of invasive aspergillosis. In patients with high-risk conditions, including stem cell and organ transplant recipients, mortality exceeds 50%. Triazole antifungals have greatly improved survival (1); however, triazole-resistant A. fumigatus infections are increasingly reported worldwide and are associated with increased treatment failure and mortality (2). Of particular concern are resistant A. fumigatus isolates carrying either TR34/L98H or TR46/Y121F/T289A genetic resistance markers, which have been associated with environmental triazole fungicide use rather than previous patient exposure to antifungals (3,4). Reports of these triazole-resistant A. fumigatus strains have become common in Europe (2,3), but U.S. reports are limited (5). Because of the risk posed to immunocompromised patients, understanding the prevalence of such isolates in patients is important to guide clinical and public health decision-making. In 2011, CDC initiated passive laboratory monitoring for U.S. triazole-resistant A. fumigatus isolates through outreach to clinical laboratories. This system identified five TR34/L98H isolates collected from 2016 to 2017 (6), in addition to two other U.S. isolates collected in 2010 and 2014 and reported in 2015 (5). Four of these seven isolates were reported from Pennsylvania, two from Virginia, and one from California. Three isolates were collected from patients with invasive pulmonary aspergillosis, and four patients had no known previous triazole exposure. A. fumigatus resistant to all triazole medications is emerging in the United States, and clinicians and public health personnel need to be aware that resistant infections are possible even in patients not previously exposed to these medications. |
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