Hetero-resistance: an under-recognised confounder in diagnosis and therapy?

Rinder, Heinz

doi:10.1099/0022-1317-50-12-1018

Cited by 46 publications

(13 citation statements)

References 13 publications

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“…However with the advent of molecular testing the term is also used to describe the co-occurrence of wild-type and resistance-associated mutations in a single isolate [12, 13, 15]. This molecular heteroresistance has been described in TB for a limited number of drugs [12, 15, 16] but its prevalence and phenotypic implications across multiple drug resistance-associated genes using a sensitive NGS method is less clear. We focused this study on MDR-TB, because of the likely use of amplicon-based NGS in this scenario, plus resistant strains have revealed high rates of heteroresistance [12].…”

Section: Introductionmentioning

confidence: 99%

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis

et al. 2017

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Amplicon-based Next Generation Sequencing (NGS) is an emerging method for Mycobacterium tuberculosis drug susceptibility testing (DST) but has not been well described. We examined 158 clinical multidrug-resistant M. tuberculosis isolates via NGS of 11 resistance-associated gene regions covering 3519 nucleotides. Across these gene regions, complete resistance or heteroresistance (defined as 1%-99% mutation) was present in at least one isolate in 6.3% of loci. The number of isolates with heteroresistance was highest for gyrA codon 94, rpoB codons 526 and 531, and embB codons 306, 372 and 406 (range 11–26% of isolates exhibited heteroresistance). 57% of MDR strains had heteroresistance of one or more recognized resistance-associated mutation. Heteroresistant loci generally exhibited high or low degrees of mutation (>90% or <10%). The deep sensitivity of NGS for detecting low level pncA heteroresistance appeared to improve genotypic-phenotypic PZA susceptibility correlations over that of Sanger. NGS demonstrates that heteroresistance in TB in the regions of key genes is common and will need to be bioinformatically managed. The clinical significance of such heteroresistance is unclear, and further study of pncA should be pursued.

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Section: Introductionmentioning

confidence: 99%

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis

et al. 2017

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“…Heteroresistance is defined as the phenotypic manifestation of both drug resistance and susceptibility in mixed populations of a single clinical isolate (77). The two resistant VGI strains R1413F and R1412F each showed a different pattern of genome change compared with those of their parental strains.…”

Section: Resultsmentioning

confidence: 99%

Genome Variation in Cryptococcus gattii, an Emerging Pathogen of Immunocompetent Hosts

D’Souza

Kronstad

Taylor

et al. 2011

mBio

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192

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Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.IMPORTANCE Isolates of Cryptococcus gattii are currently causing an outbreak of cryptococcosis in western North America, and most of the cases occurred in the absence of coinfection with HIV. This pattern is therefore in stark contrast to the current global burden of one million annual cases of cryptococcosis, caused by the related species Cryptococcus neoformans, in the HIV/AIDS population. The genome sequences of two outbreak-associated major genotypes of C. gattii reported here provide insights into genome variation within and between cryptococcal species. These sequences also provide a resource to further evaluate the epidemiology of cryptococcal disease and to evaluate the role of pathogen genes in the differential interactions of C. gattii and C. neoformans with immunocompromised and immunocompetent hosts.

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“…However, its relevance to infection and resistance has remained unclear, and even its definition has been debated. We use the term clonal heteroresistance to distinguish the phenomenon we describe from the blanket term heteroresistance, which is often used to refer to mixed populations of genetically distinct bacteria 31–34 . We show that clonal heteroresistance, in addition to mediating lethal infection in the presence of antibiotic, can also go undetected and cause unexplained treatment failure during in vivo infection (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae

et al. 2016

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Antibiotic resistance is a major public health threat, further complicated by unexplained treatment failures caused by bacteria that appear antibiotic susceptible. We describe an Enterobacter cloacae isolate harbouring a minor subpopulation that is highly resistant to the last-line antibiotic colistin. This subpopulation was distinct from persisters, became predominant in colistin, returned to baseline after colistin removal and was dependent on the histidine kinase PhoQ. During murine infection, but in the absence of colistin, innate immune defences led to an increased frequency of the resistant subpopulation, leading to inefficacy of subsequent colistin therapy. An isolate with a lower-frequency colistin-resistant subpopulation similarly caused treatment failure but was misclassified as susceptible by current diagnostics once cultured outside the host. These data demonstrate the ability of low-frequency bacterial subpopulations to contribute to clinically relevant antibiotic resistance, elucidating an enigmatic cause of antibiotic treatment failure and highlighting the critical need for more sensitive diagnostics.

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Hetero-resistance: an under-recognised confounder in diagnosis and therapy?

Cited by 46 publications

References 13 publications

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis

Genome Variation in Cryptococcus gattii, an Emerging Pathogen of Immunocompetent Hosts

Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae

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