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 patient 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 phenotypically, and genetic determinants of resistance characterised by whole genome sequencing. RESULTS CF and control faecal resistomes differed significantly (P = 0.0003). 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 = 0.0001). 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 analysis supported higher aminoglycoside resistance, with a higher proportion of aminoglycoside-resistant, Gram-negative bacteria (P < 0.0001). Isolated extended spectrum beta lactamase (ESBL)-positive Escherichia coli from CF stool exhibited phenotypic resistance to tobramycin and gentamicin. Genomic analysis showed co-localisation of both aminoglycoside resistance and ESBL genes, consistent with MDR emergence 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.

中文翻译：

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囊性纤维化肠道是多重耐药病原体的潜在来源

背景技术耐多药（MDR）病原体的出现对全球健康构成了深刻的威胁。CF 患者的抗生素累积暴露量是所有患者组中最高的，包括至关重要的最后一线药物。虽然几乎没有证据表明气道病原体中的抗生素耐药性会导致 CF 患者的临床结果更差，但由于 CF 护理，非呼吸系统中可能出现的 MDR 病原体对更广泛的人群构成潜在的健康威胁，包括家人和照顾者。方法 对 19 名 CF 成人和 16 名健康成人对照的粪便进行宏基因组测序，以评估粪便抗性组和基于培养的分析。从表型上鉴定出抗性分离株，以及以全基因组测序为特征的抗性遗传决定因素。结果 CF 和对照粪便抗性组显着不同 (P = 0.0003)。CF 中映射到移动遗传元件的读取比例显着更高（P = 0.014），并且组成显着不同（P = 0.0001）。值得注意的是，CF 患者显示出更高的质粒介导氨基糖苷修饰基因 ant(6)-Ib、aac(6')-Ip 和 aph(3')-IIIa (P < 0.01)。基于培养的分析支持更高的氨基糖苷类耐药性，其中耐氨基糖苷类的革兰氏阴性菌比例更高（P < 0.0001）。从 CF 粪便中分离出的超广谱 β 内酰胺酶 (ESBL) 阳性大肠杆菌表现出对妥布霉素和庆大霉素的表型耐药性。基因组分析显示氨基糖苷类抗性和 ESBL 基因共定位，这与通过水平基因转移出现的 MDR 一致。结论 成人 CF 肠道微生物组中潜在的可传播耐药性的携带远大于健康个体，并可能导致 MDR 病原体的出现和传播。