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...

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Funding support: The study was funded by grants from Cystic Fibrosis Foundation Therapeutics USA (BELL14AO) and The Prince Charles Hospital Foundation (MS2014-20). T.J.K. acknowledges National Health and Medical Research Council (NHMRC) Early Career (GNT1088448) and ERS-EU RESPIRE2 Marie Sklodowska-Curie Postdoctoral Research (#4571-2013) Fellowship support. L.D.K. acknowledges an NHMRC Early Career Fellowship (APP1036620) List ONE descriptor number that best classifies the subject of your manuscript: 9.17 Cystic Fibrosis: Translational & Clinical Studies Total word count for the body of the manuscript = 3751 At a Glance Commentary. Scientific Knowledge on the Subject: Pseudomonas aeruginosa is the dominant airways infection in people with cystic fibrosis (CF). People can harbor genetically indistinguishable strains of P. aeruginosa, which suggests that cross infection may be an important mode of transmission, although the mechanisms are not well understand. Droplet nuclei containing P. aeruginosa produced during coughing can remain viable for extended periods, raising the possibility of airborne transmission. The CF Foundation recommends that people with CF wear a surgical mask in communal areas to reduce pathogen acquisition and transmission. What This Study Adds to the Field: This comparative observational study demonstrated that surgical masks and the N95 masks are effective in reducing aerosols containing viable P. aeruginosa 2-metres from source during coughing in people with CF. Short-term use of face masks was well tolerated in people with CF lung disease, with the surgical mask rated more comfortable than the N95 mask. Cough etiquette reduced viable aerosols to a lesser extent than face masks.

Extended-spectrum β-lactamase (ESBL) production and the prevalence of the β-lactamase-encoding gene blaTEM were determined in Prevotella isolates (n = 50) cultured from the respiratory tract of adults and young people with cystic fibrosis (CF). Time–kill studies were used to investigate the concept of passive antibiotic resistance and to ascertain whether a β-lactamase-positive Prevotella isolate can protect a recognised CF pathogen from the action of ceftazidime in vitro. The results indicated that approximately three-quarters (38/50; 76%) of Prevotella isolates produced ESBLs. Isolates positive for ESBL production had higher minimum inhibitory concentrations (MICs) of β-lactam antibiotics compared with isolates negative for production of ESBLs (P < 0.001). The blaTEM gene was detected more frequently in CF Prevotella isolates from paediatric patients compared with isolates from adults (P = 0.002), with sequence analysis demonstrating that 21/22 (95%) partial blaTEM genes detected were identical to blaTEM-116. Furthermore, a β-lactamase-positive Prevotella isolate protected Pseudomonas aeruginosa from the antimicrobial effects of ceftazidime (P = 0.03). Prevotella isolated from the CF respiratory microbiota produce ESBLs and may influence the pathogenesis of chronic lung infection via indirect methods, including shielding recognised pathogens from the action of ceftazidime.