Langdon Amy, Schwartz Drew J, Bulow Christopher, Sun Xiaoqing, Hink Tiffany, Reske Kimberly A, Jones Courtney, Burnham Carey-Ann D, Dubberke Erik R, Dantas Gautam
The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Clinical Research Training Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Genome Med. 2021 Feb 16;13(1):28. doi: 10.1186/s13073-021-00843-9.
Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non-C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI.
An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one (N = 16) or two doses of RBX2660 (N = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms.
Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted.
Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others.
ClinicalTrials.gov, NCT01925417 ; registered on August 19, 2013.
一旦抗生素耐药菌在肠道微生物群中定植，它们就会在宿主体内引发感染，并传播给其他人及环境。目前，尚无有效方法可减少或预防抗生素耐药菌的定植。肠道微生物群恢复可预防艰难梭菌感染（CDI）复发。微生物群恢复的另一个潜在应用是抑制非艰难梭菌多重耐药菌，并全面降低肠道微生物群中抗生素耐药基因（耐药组）的丰度。本研究旨在表征基于微生物群的研究性疗法RBX2660在递送至复发性CDI患者后，对肠道微生物群的组成和丰度、耐药组以及多重耐药菌携带情况的影响。
在美国11个中心开展了一项关于RBX2660治疗复发性CDI的安全性和有效性的开放标签、多中心临床试验。对其中29例接受一剂（N = 16）或两剂RBX2660（N = 13）的复发性CDI受试者的粪便标本进行了二次分析。在治疗前及治疗后长达6个月的时间间隔内采集粪便样本，并通过三种方式进行分析：（1）16S rRNA基因测序以分析微生物分类组成；（2）全基因组鸟枪法测序以分析功能途径和抗生素耐药组含量；（3）选择性和差异性细菌培养，随后对分离株进行基因组测序以纵向追踪多重耐药菌。
通过加权UniFrac距离测量，RBX2660成功预防CDI复发与患者微生物群与供体微生物群的分类趋同相关。RBX2660在给药后2个月内显著降低了抗生素耐药肠杆菌科细菌的丰度。粪便抗生素耐药基因携带量的减少与供体微生物群植入的程度直接相关。
基于微生物群的疗法可降低受体肠道微生物组中的耐药基因丰度和耐药菌数量。这种方法可能会降低患者体内耐药菌引起感染的风险，以及耐药基因或病原体传播给他人的风险。
ClinicalTrials.gov，NCT01925417；于2013年8月19日注册。
