Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium

Abstract

Lung infections with Mycobacterium abscessus, a species of multidrug resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF) where they accelerate inflammatory lung damage leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.Nontuberculous mycobacteria (NTM; referring to mycobacterial species other than M. tuberculosis complex and M. leprae) are ubiquitous environmental organisms that can cause chronic pulmonary infections in susceptible individuals [1,2], particularly those with preexisting inflammatory lung diseases such as cystic fibrosis (CF) [3]. The major NTM infecting CF individuals around the world is Mycobacterium abscessus; a rapidly growing, intrinsically multidrug-resistant species, which can be impossible to treat despite prolonged combination antibiotic therapy [1,[3][4][5], leads to accelerated decline in lung function [6,7], and remains a contraindication to lung transplantation in many centers [3,8,9].Until recently, NTM infections were thought to be independently acquired by individuals through exposure to soil or water [10][11][12]. As expected, previous analyses from the 1990s and 2000s [13][14][15][16] showed that CF patients were infected with unique, genetically diverse strains of M. abscessus, presumably from environmental sources. We used whole genome sequencing at a single UK CF center and identified two clusters of patients (11 individuals in total) infected with identical or near-identical M. abscessus isolates, which social network analysis suggested were acquired within hospital via indirect transmission between patients Phylogenetic analysis of these sequences (using one isolate per patient), supplemented by published genomes from US, France, Brazil, Malaysia, China, and South Korea (Table S1), was performed and analysed in the context of the geographical provenance of isolates ( Figure 1; Figure S1). Within each subspecies, we found multiple examples of deep branches (indicating large genetic differences) between isolates from different individuals, consistent with independent acquisition of unrelated environmental bacteria. However, we also identified multiple clades of near-identical isolates from geographically diverse locations (Figure 1), suggesting widespread transmission of circulating clones within the global CF patient community.To investigate further the relatedness of isolates from different individuals, we a...

Mycobacterium abscessus, a taxonomic puzzle

“…massiliense (M) and M. abscessus subsp. bolletii (B) as independent species.This paper is in clear contradiction with our own recent work [2] published in 2016.The claim of the authors (1st page) that postgenomic analysis 'unambiguously supports the reinstatement of species' seems to us at least highly questionable; in none of the studies they cited in their paper [3][4][5][6][7][8], with the exception of one study [9] done in collaboration with the same authors, is the status of subspecies questioned.A major argument supporting the suggestion of Adekambi et al was published by him in 2008 [10]. The major conclusions of this work were that 1) an rpoB gene similarity 97.7 % correlates with a DNA-DNA Hybridization (DDH) <70 %; and 2) the DDH may be inferred by the formula: 5.98(rpoB similarity)-2516.1.…”

“…The claim of the authors (1st page) that postgenomic analysis 'unambiguously supports the reinstatement of species' seems to us at least highly questionable; in none of the studies they cited in their paper [3][4][5][6][7][8], with the exception of one study [9] done in collaboration with the same authors, is the status of subspecies questioned.…”

Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep

“…Bryant et al recently reported in a study using whole-genome sequencing of isolates from a global collection of clinical isolates that the majority of M. abscessus isolates were dominant circulating clones acquired by transmission between individuals either by fomites or by infectious aerosols and that these clones are associated with worse clinical outcomes and have increased virulence in mouse models thus presenting a serious emerging clinical concern. 69 Identification of NTM is challenging and infection may also easily be missed as organisms are easily overgrown with other bacteria and fungi, and B. cepacia agars have previously been recommended to help with identification. Preece et al have recently reported on their development of a novel agar (RGM medium) that will greatly reduce overgrowth problems and improve the sensitivity of NTM identification.…”

NonTuberculous Mycobacteria Infection and Lung Transplantation in Cystic Fibrosis: A Worldwide Survey of Clinical Practice

“…Importantly, pulmonary infection with M. abscessus complex in people with CF has been associated with accelerated decline in lung function and is of particular clinical concern [4,[8][9][10]. There is also emerging evidence to suggest transmission of M. abscessus complex between individuals with CF [11,12]. NTM PD is challenging to treat requiring multiple antibiotic regimes for a prolonged period of at least 12 months [13,14].…”