scholarly journals Cryptococcus gattii Species Complex as an Opportunistic Pathogen: Underlying Medical Conditions Associated with the Infection

mBio ◽  
2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Dong-Hoon Yang ◽  
Matthew R. England ◽  
Helene Salvator ◽  
Seher Anjum ◽  
Yoon-Dong Park ◽  
...  
Keyword(s):  
Species Complex ◽  
Opportunistic Pathogen ◽  
Cryptococcus Gattii ◽  
Infection Frequency ◽  
Immunocompromised Patients ◽  
Medical Conditions ◽  
Content Type ◽  
High Infection

The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people.

scholarly journals Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for the Cryptococcus neoformans-Cryptococcus gattii Species Complex Using the CLSI M27-A3 Broth Microdilution Method

2014 ◽  
Vol 59 (1) ◽  
pp. 666-668 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. Chowdhary ◽  
G. M. Gonzalez ◽  
J. Guinea ◽  
F. Hagen ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Multicenter Study ◽  
Species Complex ◽  
Cryptococcus Gattii ◽  
Broth Microdilution ◽  
Wild Type ◽  
Content Type ◽  
Microdilution Method ◽  
Cutoff Values ◽  
Broth Microdilution Method

ABSTRACTEpidemiological cutoff values (ECVs) of isavuconazole are not available forCryptococcusspp. The isavuconazole ECVs based on wild-type (WT) MIC distributions for 438Cryptococcus neoformansnongenotyped isolates, 870 isolates of genotype VNI, and 406Cryptococcus gattiiisolates from six laboratories and different geographical areas were 0.06, 0.12, and 0.25 μg/ml, respectively. These ECVs may aid in detecting non-WT isolates with reduced susceptibilities to isavuconazole.

scholarly journals The Complexities of Nocardia Taxonomy and Identification

2017 ◽  
Vol 56 (1) ◽  
Author(s):  
Patricia S. Conville ◽  
Barbara A. Brown-Elliott ◽  
Terry Smith ◽  
Adrian M. Zelazny
Keyword(s):  
Type Species ◽  
Species Complex ◽  
Nocardia Asteroides ◽  
Immunocompromised Patients ◽  
Group Level ◽  
Content Type ◽  
Complex Group ◽  
Taxonomic History ◽  
Human Infections ◽  
Aerobic Actinomycetes

ABSTRACT Nocardia species are a complex group of organisms considered to belong to the aerobic actinomycetes. Of the validly described species, many have been implicated as the cause of serious human infections, especially in immunocompromised patients. The genus has a complicated taxonomic history; this is especially true for Nocardia asteroides, the type species of the genus and previously the most frequently reported nocardial taxon from human specimens. We provide background on the current taxonomy of Nocardia, with a focus on clinically relevant species, and discuss the currently available methods used to accurately identify isolates to the species, complex, or group level.

scholarly journals Genome Evolution and Innovation across the Four Major Lineages of Cryptococcus gattii

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Rhys A. Farrer ◽  
Christopher A. Desjardins ◽  
Sharadha Sakthikumar ◽  
Sharvari Gujja ◽  
Sakina Saif ◽  
...  
Keyword(s):  
Positive Selection ◽  
Species Complex ◽  
Cryptococcus Gattii ◽  
Genomic Variation ◽  
Pulmonary Infections ◽  
Copper Transporter ◽  
Mitochondrial Recombination ◽  
Content Type ◽  
Multidrug Transporters ◽  
Gene Expansion

ABSTRACT Cryptococcus gattii is a fungal pathogen of humans, causing pulmonary infections in otherwise healthy hosts. To characterize genomic variation among the four major lineages of C. gattii (VGI, -II, -III, and -IV), we generated, annotated, and compared 16 de novo genome assemblies, including the first for the rarely isolated lineages VGIII and VGIV. By identifying syntenic regions across assemblies, we found 15 structural rearrangements, which were almost exclusive to the VGI-III-IV lineages. Using synteny to inform orthology prediction, we identified a core set of 87% of C. gattii genes present as single copies in all four lineages. Remarkably, 737 genes are variably inherited across lineages and are overrepresented for response to oxidative stress, mitochondrial import, and metal binding and transport. Specifically, VGI has an expanded set of iron-binding genes thought to be important to the virulence of Cryptococcus, while VGII has expansions in the stress-related heat shock proteins relative to the other lineages. We also characterized genes uniquely absent in each lineage, including a copper transporter absent from VGIV, which influences Cryptococcus survival during pulmonary infection and the onset of meningoencephalitis. Through inclusion of population-level data for an additional 37 isolates, we identified a new transcontinental clonal group that we name VGIIx, mitochondrial recombination between VGII and VGIII, and positive selection of multidrug transporters and the iron-sulfur protein aconitase along multiple branches of the phylogenetic tree. Our results suggest that gene expansion or contraction and positive selection have introduced substantial variation with links to mechanisms of pathogenicity across this species complex. IMPORTANCE The genetic differences between phenotypically different pathogens provide clues to the underlying mechanisms of those traits and can lead to new drug targets and improved treatments for those diseases. In this paper, we compare 16 genomes belonging to four highly differentiated lineages of Cryptococcus gattii, which cause pulmonary infections in otherwise healthy humans and other animals. Half of these lineages have not had their genomes previously assembled and annotated. We identified 15 ancestral rearrangements in the genome and over 700 genes that are unique to one or more lineages, many of which are associated with virulence. In addition, we found evidence for recent transcontinental spread, mitochondrial genetic exchange, and positive selection in multidrug transporters. Our results suggest that gene expansion/contraction and positive selection are diversifying the mechanisms of pathogenicity across this species complex.

scholarly journals Literature-Based Gene Curation and Proposed Genetic Nomenclature for Cryptococcus

2014 ◽  
Vol 13 (7) ◽  
pp. 878-883 ◽  
Author(s):  
Diane O. Inglis ◽  
Marek S. Skrzypek ◽  
Edward Liaw ◽  
Venkatesh Moktali ◽  
Gavin Sherlock ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Functional Data ◽  
Scientific Literature ◽  
Research Community ◽  
Cryptococcus Gattii ◽  
Immunocompromised Patients ◽  
Genome Database ◽  
Content Type ◽  
Central Source ◽  
Gene Information

ABSTRACTCryptococcus, a major cause of disseminated infections in immunocompromised patients, kills over 600,000 people per year worldwide. Genes involved in the virulence of the meningitis-causing fungus are being characterized at an increasing rate, and to date, at least 648Cryptococcusgene names have been published. However, these data are scattered throughout the literature and are challenging to find. Furthermore, conflicts in locus identification exist, so that named genes have been subsequently published under new names or names associated with one locus have been used for another locus. To avoid these conflicts and to provide a central source ofCryptococcusgene information, we have collected all publishedCryptococcusgene names from the scientific literature and associated them with standardCryptococcuslocus identifiers and have incorporated them into FungiDB (www.fungidb.org). FungiDB is a panfungal genome database that collects gene information and functional data and provides search tools for 61 species of fungi and oomycetes. We applied these published names to a manually curated ortholog set of allCryptococcusspecies currently in FungiDB, includingCryptococcus neoformansvar.neoformansstrains JEC21 and B-3501A,C. neoformansvar.grubiistrain H99, andCryptococcus gattiistrains R265 and WM276, and have written brief descriptions of their functions. We also compiled a protocol for gene naming that summarizes guidelines proposed by members of theCryptococcusresearch community. The centralization of genomic and literature-based information forCryptococcusat FungiDB will help researchers communicate about genes of interest, such as those related to virulence, and will further facilitate research on the pathogen.

scholarly journals Genetic and Genomic Analyses Reveal Boundaries between Species Closely Related to Cryptococcus Pathogens

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Andrew Ryan Passer ◽  
Marco A. Coelho ◽  
Robert Blake Billmyre ◽  
Minou Nowrousian ◽  
Moritz Mittelbach ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Species Complex ◽  
Chromosomal Rearrangements ◽  
Fungal Species ◽  
Cryptococcus Gattii ◽  
Species Boundaries ◽  
Small Scale ◽  
Content Type ◽  
Fungal Lineage ◽  
Genomic Analyses

ABSTRACT Speciation is a central mechanism of biological diversification. While speciation is well studied in plants and animals, in comparison, relatively little is known about speciation in fungi. One fungal model is the Cryptococcus genus, which is best known for the pathogenic Cryptococcus neoformans/Cryptococcus gattii species complex that causes >200,000 new human infections annually. Elucidation of how these species evolved into important human-pathogenic species remains challenging and can be advanced by studying the most closely related nonpathogenic species, Cryptococcus amylolentus and Tsuchiyaea wingfieldii. However, these species have only four known isolates, and available data were insufficient to determine species boundaries within this group. By analyzing full-length chromosome assemblies, we reappraised the phylogenetic relationships of the four available strains, confirmed the genetic separation of C. amylolentus and T. wingfieldii (now Cryptococcus wingfieldii), and revealed an additional cryptic species, for which the name Cryptococcus floricola is proposed. The genomes of the three species are ∼6% divergent and exhibit significant chromosomal rearrangements, including inversions and a reciprocal translocation that involved intercentromeric ectopic recombination, which together likely impose significant barriers to genetic exchange. Using genetic crosses, we show that while C. wingfieldii cannot interbreed with any of the other strains, C. floricola can still undergo sexual reproduction with C. amylolentus. However, most of the resulting spores were inviable or sterile or showed reduced recombination during meiosis, indicating that intrinsic postzygotic barriers had been established. Our study and genomic data will foster additional studies addressing fungal speciation and transitions between nonpathogenic and pathogenic Cryptococcus lineages. IMPORTANCE The evolutionary drivers of speciation are critical to our understanding of how new pathogens arise from nonpathogenic lineages and adapt to new environments. Here we focus on the Cryptococcus amylolentus species complex, a nonpathogenic fungal lineage closely related to the human-pathogenic Cryptococcus neoformans/Cryptococcus gattii complex. Using genetic and genomic analyses, we reexamined the species boundaries of four available isolates within the C. amylolentus complex and revealed three genetically isolated species. Their genomes are ∼6% divergent and exhibit chromosome rearrangements, including translocations and small-scale inversions. Although two of the species (C. amylolentus and newly described C. floricola) were still able to interbreed, the resulting hybrid progeny were usually inviable or sterile, indicating that barriers to reproduction had already been established. These results advance our understanding of speciation in fungi and highlight the power of genomics in assisting our ability to correctly identify and discriminate fungal species.

scholarly journals Species in the Cryptococcus gattii Complex Differ in Capsule and Cell Size following Growth under Capsule-Inducing Conditions

mSphere ◽  
2016 ◽  
Vol 1 (6) ◽  
Author(s):  
Kenya E. Fernandes ◽  
Christine Dwyer ◽  
Leona T. Campbell ◽  
Dee A. Carter
Keyword(s):  
Cell Wall ◽  
New Species ◽  
Cell Size ◽  
Fungal Pathogen ◽  
Species Complex ◽  
Cryptococcus Gattii ◽  
Clinical Infection ◽  
Content Type ◽  
Diagnosis And Prognosis ◽  
Capsule Size

ABSTRACT Infections with the fungal pathogen Cryptococcus gattii have been increasing in recent years. Recently, four different species have been described within C. gattii, which correspond to four previously known molecular genotypes (VGI to VGIV). Examining traits related to infection and disease is important for determining whether these different species have clinical relevance. This study examined variation in attributes that are important for infecting and surviving in the host, including tolerance to various stresses, yeast cell size, and the amount of polysaccharide capsule that covers the cell. The cell size and capsule size were significantly different and inversely correlated across the species. Thermotolerance was highest in C. deuterogattii (VGII), the only species known to cause outbreaks, while most strains of the species C. bacillisporus (VGIII) and C. tetragattii (VGIV) grew poorly at 37°C. These findings argue for increased acceptance of the new species and may be useful for informing diagnosis and prognosis in clinical infection. Cryptococcus gattii causes invasive fungal infections that have been increasing in incidence and global distribution in recent years. The major molecular genotypes of C. gattii that were previously classified as VGI to VGIV have recently been described as four new species: C. gattii (VGI), C. deuterogattii (VGII), C. bacillisporus (VGIII), and C. tetragattii (VGIV). The main driver for their classification has been phylogeny, and phenotypic diversity has not yet been extensively characterized. This study examines variation in attributes related to virulence and pathogenicity, including capsule thickness, cell size, tolerance to temperature, oxidative and osmotic stress, and cell wall integrity. A capsule induction agar using diluted Sabouraud medium revealed significant differences in capsule and cell size across the C. gattii species complex and produced irregularly shaped elongated cells in a number of strains. C. gattii/VGI strains possessed the largest capsules of all species but had smaller cells, while C. deuterogattii/VGII strains possessed the largest cells of all species but had smaller capsules. Overall thermotolerance was highest in C. deuterogattii/VGII strains, while a number of C. bacillisporus/VGIII, and C. tetragattii/VGIV strains had substantially reduced growth at 37°C. There was no significant difference among species in their tolerances to oxidative or osmotic stresses, and there was no evidence for defects in cell wall integrity in strains producing irregular cells. These data support the division of the C. gattii species complex into distinctly identified species and suggest underlying reasons for their differences in virulence, epidemiology, and host preference. IMPORTANCE Infections with the fungal pathogen Cryptococcus gattii have been increasing in recent years. Recently, four different species have been described within C. gattii, which correspond to four previously known molecular genotypes (VGI to VGIV). Examining traits related to infection and disease is important for determining whether these different species have clinical relevance. This study examined variation in attributes that are important for infecting and surviving in the host, including tolerance to various stresses, yeast cell size, and the amount of polysaccharide capsule that covers the cell. The cell size and capsule size were significantly different and inversely correlated across the species. Thermotolerance was highest in C. deuterogattii (VGII), the only species known to cause outbreaks, while most strains of the species C. bacillisporus (VGIII) and C. tetragattii (VGIV) grew poorly at 37°C. These findings argue for increased acceptance of the new species and may be useful for informing diagnosis and prognosis in clinical infection.

scholarly journals The Primary Target Organ of Cryptococcus gattii Is Different from That of Cryptococcus neoformans in a Murine Model

mBio ◽  
2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Popchai Ngamskulrungroj ◽  
Yun Chang ◽  
Edward Sionov ◽  
Kyung J. Kwon-Chung
Keyword(s):  
Cryptococcus Neoformans ◽  
Blood Brain Barrier ◽  
Opportunistic Pathogen ◽  
Lung Infection ◽  
Cryptococcus Gattii ◽  
Brain Barrier ◽  
Hiv Patients ◽  
Content Type ◽  
Blood Brain ◽  
The Brain

ABSTRACTCryptococcosis is caused by the opportunistic pathogenCryptococcus neoformansor by the primary pathogenCryptococcus gattii. Epidemiological studies suggest that patients infected withC. gattiimainly present with pulmonary disease, while those infected withC. neoformanscommonly manifest meningoencephalitis. We compared the pathogenesis of the two species using theC. neoformansH99 andC. gattiiR265 strains in a murine inhalation model.C. neoformansgrew faster in the brain and caused death by meningoencephalitis, whileC. gattiigrew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v. ) inoculation of 104cells via the tail vein, however,C. gattiiproduced severe meningoencephalitis, demonstrating thatC. gattiicells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% ofC. gattii-infected mice, compared to 60% of mice infected withC. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected withC. gattii.C. neoformanscells grew 10 to 100 times faster thanC. gattiicells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation ofC. gattii, therefore, may be partly due to an unknown factor(s) in the host’s blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection.IMPORTANCEWhileCryptococcus neoformansis the most common cause of fatal meningoencephalitis, especially in HIV patients,Cryptococcus gattiicauses disease mainly in non-HIV patients. Clinical studies revealed that most patients infected withC. gattiiVGII strains have lung infections with minimal brain involvement. Despite extensive clinicopathological studies on cryptococcosis in animal models, only a few have includedC. gattii. We compared the pathogenesis of the two species in mice using an inhalation model. Similar to infection in humans, even thoughC. gattiican cross the blood-brain barrier, it failed to cause fatal meningoencephalitis but caused fatal lung infection. We show that growth ofC. gattiiin mouse blood is significantly slower than that ofC. neoformansand that a secondary protective phenomenon, though weak, manifests itself only inC. gattiiinfection. Our study provides a model for understanding the clinicopathological differences between these two closely genetically related pathogens.

scholarly journals Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Amphotericin B and Flucytosine

2012 ◽  
Vol 56 (6) ◽  
pp. 3107-3113 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. Chowdhary ◽  
M. Cuenca-Estrella ◽  
A. Fothergill ◽  
J. Fuller ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Species Complex ◽  
Acquired Resistance ◽  
International Study ◽  
Resistance Mechanisms ◽  
Cryptococcus Gattii ◽  
Wild Type ◽  
Content Type ◽  
Cutoff Values

ABSTRACTClinical breakpoints (CBPs) are not available for theCryptococcus neoformans-Cryptococcus gattiispecies complex. MIC distributions were constructed for the wild type (WT) to establish epidemiologic cutoff values (ECVs) forC. neoformansandC. gattiiversus amphotericin B and flucytosine. A total of 3,590 amphotericin B and 3,045 flucytosine CLSI MICs forC. neoformans(including 1,002 VNI isolates and 8 to 39 VNII, VNIII, and VNIV isolates) and 985 and 853 MICs forC. gattii, respectively (including 42 to 259 VGI, VGII, VGIII, and VGIV isolates), were gathered in 9 to 16 (amphotericin B) and 8 to 13 (flucytosine) laboratories (Europe, United States, Australia, Brazil, Canada, India, and South Africa) and aggregated for the analyses. Additionally, 442 amphotericin B and 313 flucytosine MICs measured by using CLSI-YNB medium instead of CLSI-RPMI medium and 237 Etest amphotericin B MICs forC. neoformanswere evaluated. CLSI-RPMI ECVs for distributions originating in ≥3 laboratories (with the percentages of isolates for which MICs were less than or equal to ECVs given in parentheses) were as follows: for amphotericin B, 0.5 μg/ml forC. neoformansVNI (97.2%) andC. gattiiVGI and VGIIa (99.2 and 97.5%, respectively) and 1 μg/ml forC. neoformans(98.5%) andC. gattiinontyped (100%) and VGII (99.2%) isolates; for flucytosine, 4 μg/ml forC. gattiinontyped (96.4%) and VGI (95.7%) isolates, 8 μg/ml for VNI (96.6%) isolates, and 16 μg/ml forC. neoformansnontyped (98.6%) andC. gattiiVGII (97.1%) isolates. Other molecular types had apparent variations in MIC distributions, but the number of laboratories contributing data was too low to allow us to ascertain that the differences were due to factors other than assay variation. ECVs may aid in the detection of isolates with acquired resistance mechanisms.

scholarly journals Continental Drift and Speciation of the Cryptococcus neoformans and Cryptococcus gattii Species Complexes

mSphere ◽  
2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Arturo Casadevall ◽  
Joudeh B. Freij ◽  
Christopher Hann-Soden ◽  
John Taylor
Keyword(s):  
South America ◽  
Cryptococcus Neoformans ◽  
Species Complex ◽  
Continental Drift ◽  
Pathogenic Fungi ◽  
Cryptococcus Gattii ◽  
Evolutionary Divergence ◽  
Temporal Separation ◽  
Content Type ◽  
Species Complexes

ABSTRACT Genomic analysis has placed the origins of two human-pathogenic fungi, the Cryptococcus gattii species complex and the Cryptococcus neoformans species complex, in South America and Africa, respectively. Molecular clock calculations suggest that the two species separated ~80 to 100 million years ago. This time closely approximates the breakup of the supercontinent Pangea, which gave rise to South America and Africa. On the basis of the geographic distribution of these two species complexes and the coincidence of the evolutionary divergence and Pangea breakup times, we propose that a spatial separation caused by continental drift resulted in the emergence of the C. gattii and C. neoformans species complexes from a Pangean ancestor. We note that, despite the spatial and temporal separation that occurred approximately 100 million years ago, these two species complexes are morphologically similar, share virulence factors, and cause very similar diseases. Continuation of these phenotypic characteristics despite ancient separation suggests the maintenance of similar selection pressures throughout geologic ages.

scholarly journals Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

2012 ◽  
Vol 56 (11) ◽  
pp. 5898-5906 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. I. Aller ◽  
E. Canton ◽  
L. R. Castañón-Olivares ◽  
A. Chowdhary ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Species Complex ◽  
Acquired Resistance ◽  
Cryptococcus Gattii ◽  
Yeast Nitrogen Base ◽  
Wild Type ◽  
Nitrogen Base ◽  
Content Type ◽  
Rpmi Medium ◽  
Cutoff Values

ABSTRACTEpidemiological cutoff values (ECVs) for theCryptococcus neoformans-Cryptococcus gattiispecies complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to 5,733 CLSI MICs forC. neoformans(including isolates of molecular type VNI [MICs for 759 to 1,137 isolates] and VNII, VNIII, and VNIV [MICs for 24 to 57 isolates]) and 705 to 975 MICs forC. gattii(including 42 to 260 for VGI, VGII, VGIII, and VGIV isolates) were gathered in 15 to 24 laboratories (Europe, United States, Argentina, Australia, Brazil, Canada, Cuba, India, Mexico, and South Africa) and were aggregated for analysis. Additionally, 220 to 359 MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium forC. neoformanswere evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included ≥95% of the modeled WT population, were as follows: fluconazole, 8 μg/ml (VNI,C. gattiinontyped, VGI, VGIIa, and VGIII), 16 μg/ml (C. neoformansnontyped, VNIII, and VGIV), and 32 μg/ml (VGII); itraconazole, 0.25 μg/ml (VNI), 0.5 μg/ml (C. neoformansandC. gattiinontyped and VGI to VGIII), and 1 μg/ml (VGIV); posaconazole, 0.25 μg/ml (C. neoformansnontyped and VNI) and 0.5 μg/ml (C. gattiinontyped and VGI); and voriconazole, 0.12 μg/ml (VNIV), 0.25 μg/ml (C. neoformansandC. gattiinontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 μg/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.

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