Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study

Abstract

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.

Investigation of the population structure of Mycobacterium abscessus complex strains using 17-locus variable number tandem repeat typing and the further distinction of Mycobacterium massiliense hsp65 genotypes

“…bolletii (Leao et al, 2011). However, wholegenome sequencing supported the separation as three subspecies (Bryant et al, 2013). We concur that there has been some debate in the literature regarding the taxonomy of these organisms (Harris & Kenna, 2014).…”

“…According to previous molecular investigations in CF patient groups, M. abscessus complex isolates from the majority of individual patients were indistinguishable by both nine-locus VNTR analysis and the Diversilab rep-PCR typing method; moreover, the same strain or genotype was found with no apparent epidemiological links (Harris et al, 2012). Whole-genome sequencing demonstrated that the clustering strains might be more transmissible in CF patient groups (Bryant et al, 2013). According to reports of global epidemiological studies, MLST is useful for the global comparison of strains; the most prevalent sequence types were ST1 (CC5; M. abscessus isolates) and ST23 (CC3; M. massiliense isolates), and these sequence types were found from Europe and Brazil in different years (Macheras et al, 2014).…”

Changing Epidemiology of the Respiratory Bacteriology of Patients With Cystic Fibrosis

“…Recent evidence of patient-to-patient transmission including the role of airborne transmission has heightened this concern. 36,37 From 2010 to 2012, when robust data in the CFFPR were available, the prevalence of all species of NTM and of MAC increased.…”

Infection Prevention and Control Guideline for Cystic Fibrosis: 2013 Update

“…Notably, wholegenome sequencing was used to assess transmission of NTM between individuals with and without CF. 65,66 The slow mutation rate of NTM is another reason for the need for wholegenome sequencing methods with these pathogens.…”