SummaryBackgroundIncreasing numbers of individuals with cystic fibrosis are becoming infected with the multidrug-resistant non-tuberculous mycobacterium (NTM) Mycobacterium abscessus, which causes progressive lung damage and is extremely challenging to treat. How this organism is acquired is not currently known, but there is growing concern that person-to-person transmission could occur. We aimed to define the mechanisms of acquisition of M abscessus in individuals with cystic fibrosis.MethodWhole genome sequencing and antimicrobial susceptibility testing were done on 168 consecutive isolates of M abscessus from 31 patients attending an adult cystic fibrosis centre in the UK between 2007 and 2011. In parallel, we undertook detailed environmental testing for NTM and defined potential opportunities for transmission between patients both in and out of hospital using epidemiological data and social network analysis.FindingsPhylogenetic analysis revealed two clustered outbreaks of near-identical isolates of the M abscessus subspecies massiliense (from 11 patients), differing by less than ten base pairs. This variation represents less diversity than that seen within isolates from a single individual, strongly indicating between-patient transmission. All patients within these clusters had numerous opportunities for within-hospital transmission from other individuals, while comprehensive environmental sampling, initiated during the outbreak, failed to detect any potential point source of NTM infection. The clusters of M abscessus subspecies massiliense showed evidence of transmission of mutations acquired during infection of an individual to other patients. Thus, isolates with constitutive resistance to amikacin and clarithromycin were isolated from several individuals never previously exposed to long-term macrolides or aminoglycosides, further indicating cross-infection.InterpretationWhole genome sequencing has revealed frequent transmission of multidrug resistant NTM between patients with cystic fibrosis despite conventional cross-infection measures. Although the exact transmission route is yet to be established, our epidemiological analysis suggests that it could be indirect.FundingThe Wellcome Trust, Papworth Hospital, NIHR Cambridge Biomedical Research Centre, UK Health Protection Agency, Medical Research Council, and the UKCRC Translational Infection Research Initiative.

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...