The cystic fibrosis gut as a potential source of multidrug resistant pathogens

Abstract

Background: The emergence of multidrug resistant (MDR) pathogens represents a profound threat to global health. Individuals with CF have amongst the highest cumulative antibiotic exposure of any pa- tient group, including to critically-important last-line agents. While there is little evidence that antibiotic resistance in airway pathogens results in worse clinical outcomes for CF patients, the potential emergence of MDR pathogens in non-respiratory systems, as a consequence of CF care, represents a potential health threat to the wider population, including family and carers. Methods: Stool from 19 adults with CF and 16 healthy adult controls was subjected to metagenomic sequencing, to assess faecal resistome, and culture-based analysis. Resistant isolates were identified phe- notypically, and genetic determinants of resistance characterised by whole genome sequencing. Results: CF and control faecal resistomes differed significantly ( P = 0.0 0 03). The proportion of reads that mapped to mobile genetic elements was significantly higher in CF ( P = 0.014) and the composition was significantly different ( P = 0.0 0 01). Notably, CF patients displayed higher carriage of plasmid-mediated aminoglycoside-modifying genes ant (6)-Ib, aac (6 ′ )-Ip, and aph (3 ′ )-IIIa ( P < 0.01). Culture-based analy- sis supported higher aminoglycoside resistance, with a higher proportion of aminoglycoside-resistant, Gram-negative bacteria ( P < 0.0 0 01). Isolated extended spectrum beta lactamase (ESBL)-positive Es- cherichia coli from CF stool exhibited phenotypic resistance to tobramycin and gentamicin. Genomic anal- ysis showed co-localisation of both aminoglycoside resistance and ESBL genes, consistent with MDR emer- gence through horizontal gene transfer. Conclusions: The carriage of potentially transmissible resistance within the adult CF gut microbiome is considerably greater than in healthy individuals and could contribute to the emergence and dissemination of MDR pathogens.