Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru

Nathavitharana, Ruvandhi R.; Shi, Cynthia X.; Chindelevitch, Leonid; Calderón, Róger; Zhang, Zibiao; Galea, Jerome T; Contreras, Carmen; Yataco, Rosa; Lecca, Leonid; Becerra, Mercedes C.; Murray, Megan; Cohen, Ted

doi:10.3201/eid2311.170077

Cited by 10 publications

(6 citation statements)

References 14 publications

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“…Nathavitharana et al 2017 demonstrated polyclonal TB primarily in drug resistant TB. [48] Our observations of statistically significant association of drug resistance with polyclonality reiterate the same findings. CAS lineage contributed to nearly half of the baseline cultures and more of the subsequently grown cultures.…”

Section: Plos Onesupporting

confidence: 86%

Mycobacterium tuberculosis polyclonal infections through treatment and recurrence

Pandey

Bhatnagar²,

Sachdeva

et al. 2020

PLoS ONE

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Background Mixed/polyclonal infections due to different genotypes are reported in Tuberculosis. The current study was designed to understand the fate of mixed infections during the course of treatment and follow-up and its role in disease pathogenesis. Methods Sputum samples were collected on 0,1,2,3,6,12 and 24 months from 157 treatment-naïve patients, cultures subjected to Drug-Susceptibility-testing (MGIT 960), spoligotyping, MIRU-VNTR and SNP genotyping. All isolated colonies on thin layer agar (7H11) were subjected to spoligotyping. Findings One thirty three baseline cultures were positive (133/157, 84.7%), 43(32.3%) had mixture of genotypes. Twenty-four of these patients (55.8%) showed change in genotype while six showed different drug-susceptibility patterns while on treatment. Twenty-three (53.5%) patients with polyclonal infections showed resistance to at least one drug compared to 10/ 90 (11.1%) monoclonal infections (P<0.0001). Eight patients had recurrent TB, two with a new genotype and two with altered phenotypic DST. Conclusions The coexistence of different genotypes and change of genotypes during the same disease episode, while on treatment, confirms constancy of polyclonal infections. The composition of the mixture of genotypes and the relative predominance may be missed by culture due to its limit of detection. Polyclonal infections in TB could be a rule rather than exception and challenges the age-old dogma of reactivation/reinfection.

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Section: Plos Onesupporting

confidence: 86%

Mycobacterium tuberculosis polyclonal infections through treatment and recurrence

Pandey

Bhatnagar²,

Sachdeva

et al. 2020

PLoS ONE

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“…An implicit assumption of this model is that hosts are colonized by clonal pathogen populations that lack genetic variation due to due to bottlenecks that occur during transmission (7,(12)(13)(14)(15). However, hosts can also be colonized by multiple strains of the same pathogen species, giving rise to polyclonal pathogen populations (16)(17)(18)(19). Polyclonal populations contain both novel genetic variation that is acquired in situ and pre-existing variation that reflects differences between the co-colonizing strains.…”

Section: Main Textmentioning

confidence: 99%

Polyclonal pathogen populations accelerate the evolution of antibiotic resistance in patients

Caballero

Wheatley

Kapel

et al. 2021

Preprint

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Antibiotic resistance poses a global health threat, but the within-host drivers of resistance remain poorly understood. Pathogen populations are often assumed to be clonal within hosts, and resistance is thought to emerge due to selection for de novo variants. Here we show that pulmonary populations of the opportunistic pathogen P. aeruginosa are often polyclonal. Crucially, resistance evolves rapidly in patients colonized by polyclonal populations through selection for pre-existing resistant strains. In contrast, resistance evolves sporadically in patients colonized by monoclonal populations due to selection for novel resistance mutations. However, strong trade-offs between resistance and fitness occur in polyclonal populations that can drive the loss of resistant strains. In summary, we show that the within-host diversity of pathogen populations plays a key role in shaping the emergence of resistance in response to treatment.One sentence summaryAntibiotic resistance evolves quickly in patients colonized by polyclonal pathogen populations.

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“…In this way, the number of repeats at each VNTR locus can be determined using different DNA sizing techniques for comparing isolates. It was found that 50 studies used VNTR-typing to detect M. tuberculosis MSIs, where 28 studies used it as the sole discriminatory method for this purpose (Allix et al, 2004 ; Shamputa et al, 2004 ; Umubyeyi et al, 2007 ; Fang et al, 2008 ; Hofmann-Thiel et al, 2009 ; Mokrousov et al, 2009 ; Stavrum et al, 2009 ; Dickman et al, 2010 ; Mulenga et al, 2010 ; Cohen et al, 2011 ; Gardy et al, 2011 ; Navarro et al, 2011 , 2015 ; Cerezo et al, 2012 ; Furphy et al, 2012 ; Huyen et al, 2012 ; Hingley-Wilson et al, 2013 ; Muwonge et al, 2013 ; Peng et al, 2013 ; Biffa et al, 2014 ; Chaoui et al, 2014 ; Lamine-Khemiri et al, 2014 ; Zetola et al, 2014 ; Barletta et al, 2015 ; Mei et al, 2015 ; Pang et al, 2015 ; Shin et al, 2015 , 2018 ; Ssengooba et al, 2015 ; Streit et al, 2015 ; Wang et al, 2015 ; Zheng et al, 2015 ; Antusheva et al, 2016 ; Hajimiri et al, 2016 ; Hu et al, 2016 ; Egbe et al, 2017 ; Farmanfarmaei et al, 2017 ; Ghielmetti et al, 2017 ; Kamakoli et al, 2017 , 2019 , 2020a , b ; Khosravi et al, 2017 ; Kontsevaya et al, 2017 ; Nathavitharana et al, 2017 ; Sadegh et al, 2017 ; Silva-Pereira et al, 2019 ; Abascal et al, 2020 ; Baik et al, 2020 ; Sichewo et al, 2020 ). In addition, 24-locus MIRU-VNTR was the most commonly used method for detecting M. tuberculosis MSIs, and nearly all (47/50, 94.0%) of the reports used some form...…”

Section: Resultsmentioning

confidence: 99%

“…It was also our intention to help clarify true MSIs as compared to similar events such as re-infection, relapses, and microevolution. While polyclonal infection may refer to microevolution, some studies have also used the term to describe infections that fit the criteria of an MSI (Adams et al, 2012 ; Fujita et al, 2014 ; Farmanfarmaei et al, 2017 ; Kamakoli et al, 2017 , 2020b ; Nathavitharana et al, 2017 ). Due to this lack of consensus regarding the terminology used in the literature and to be consistent in our study, we have selected definitions to describe the different events ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Methods for Detecting Mycobacterial Mixed Strain Infections–A Systematic Review

et al. 2020

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Mixed strain infection (MSI) refers to the concurrent infection of a susceptible host with multiple strains of a single pathogenic species. Known to occur in humans and animals, MSIs deserve special consideration when studying transmission dynamics, evolution, and treatment of mycobacterial diseases, notably tuberculosis in humans and paratuberculosis (or Johne's disease) in ruminants. Therefore, a systematic review was conducted to examine how MSIs are defined in the literature, how widespread the phenomenon is across the host species spectrum, and to document common methods used to detect such infections. Our search strategy identified 121 articles reporting MSIs in both humans and animals, the majority (78.5%) of which involved members of the Mycobacterium tuberculosis complex, while only a few (21.5%) examined non-tuberculous mycobacteria (NTM). In addition, MSIs exist across various host species, but most reports focused on humans due to the extensive amount of work done on tuberculosis. We reviewed the strain typing methods that allowed for MSI detection and found a few that were commonly employed but were associated with specific challenges. Our review notes the need for standardization, as some highly discriminatory methods are not adapted to distinguish between microevolution of one strain and concurrent infection with multiple strains. Further research is also warranted to examine the prevalence of NTM MSIs in both humans and animals. In addition, it is envisioned that the accurate identification and a better understanding of the distribution of MSIs in the future will lead to important information on the epidemiology and pathophysiology of mycobacterial diseases.

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Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru

Cited by 10 publications

References 14 publications

Mycobacterium tuberculosis polyclonal infections through treatment and recurrence

Mycobacterium tuberculosis polyclonal infections through treatment and recurrence

Polyclonal pathogen populations accelerate the evolution of antibiotic resistance in patients

Methods for Detecting Mycobacterial Mixed Strain Infections–A Systematic Review

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