背景:抗微生物剂引起宿主微生物组的组成和多样性的扰动。我们旨在比较由口服氢溴酸替比培南酯(一种新型碳青霉烯)和阿莫西林-克拉维酸(一种广泛用于临床实践的口服β-内酰胺-β-内酰胺抑制剂组合)引起的肠道微生物组扰动。
方法:我们进行了第一阶段,单中心,随机化,平行组,评价氢溴酸替比培南酯对人体肠道菌群影响的主动对照试验。18岁或以上的健康参与者在招募期间没有记录的疾病,在卡罗林斯卡大学医院(斯德哥尔摩,瑞典)。研究参与者按性别分层,并以1:1的比例分组随机接受氢溴酸替比培南匹酯(每8小时口服600mg)或阿莫西林-克拉维酸(每8小时口服500mg阿莫西林和125mg克拉维酸)治疗。该研究包括10天的治疗(第1-10天)和4次随访(第14、21、90和180天)。该试验对临床研究者和患者开放标签,但为微生物学研究者蒙面.在所有访问时收集粪便样品。16SrDNA的测序用于测量多样性指标,和定量培养来量化选定的分类群。主要结果是与基线(第1天)相比,样品之间选定分类群的α和β多样性以及菌落形成单位的对数计数的变化,以及在随访期间是否有任何变化恢复。分析是在意向治疗人群中进行的。本研究已在ClinicalTrials.gov(NCT04376554)注册。
结果:该研究于2020年1月23日至2021年4月6日进行。对49名志愿者进行了资格筛选,其中30名可评估参与者(14名男性和16名女性)被分配:氢溴酸替比培南(50%)和阿莫西林-克拉维酸组15名(50%).组间基线特征相似。所有参与者都可以进行完整的随访,和所有参与者,除了一个完成分配的治疗。多样性指标显示在治疗期间相对于基线的显著变化。阿莫西林-克拉维酸组在第4-10天(p≤0·0011)和氢溴酸替比培南酯组在第4-14天(p≤0·0019)观察到丰富度显着下降。同样,阿莫西林-克拉维酸组(第4天,p=0·030)和氢溴酸替比培南酯组(第4-10天,p<0·0001)在治疗期间的均匀度与基线相比显着降低。定量培养物显示肠杆菌显著减少(第4-7天,p≤0·0030),肠球菌属(第4-14天,p=0·025至p<0·0001),双歧杆菌属(第2-4天,p≤0·026),氢溴酸替比培南酯组中的拟杆菌属(第4-10天,p≤0·030)。同样,在阿莫西林-克拉维酸接受者中,在肠杆菌中观察到显着变化(第4-10天,p≤0·048),双歧杆菌属(第2-4天,p≤0·013),和乳杆菌属(第2-4天,p≤0·020)。在β多样性分析中,随访期的样本与基线时的样本没有显着差异(PERMANOVA,p>0·99)。在研究结束时,与基线相比,两组均未观察到显著变化.没有死亡或严重不良事件。
结论:氢溴酸替比培南酯对肠道微生物组的影响与阿莫西林-克拉维酸相似。应注意抗生素在微生物组方面的使用安全性,因为生态失调与健康和疾病相关。
背景:精子疗法。
BACKGROUND: Antimicrobials cause perturbations in the composition and diversity of the host microbiome. We aimed to compare gut microbiome perturbations caused by oral tebipenem pivoxil hydrobromide (a novel carbapenem) and by amoxicillin-clavulanic acid (an orally administered β-lactam-β-lactam inhibitor combination widely used in clinical practice).
METHODS: We did a phase 1, single-centre, randomised, parallel-group, active-control trial to evaluate the effect of tebipenem pivoxil hydrobromide on the human gut microbiota. Healthy participants aged 18 years or older with no documented illnesses during recruitment were enrolled at Karolinska University Hospital (Stockholm, Sweden). Study participants were stratified by sex and block-randomised in a 1:1 ratio to treatment with either tebipenem pivoxil hydrobromide (600 mg orally every 8 h) or amoxicillin-clavulanic acid (500 mg amoxicillin and 125 mg clavulanic acid orally every 8 h). The study included 10 days of treatment (days 1-10) and four follow-up visits (days 14, 21, 90, and 180). The trial was open-label for clinical investigators and patients, but masked for microbiology investigators. Faecal samples were collected at all visits. Sequencing of 16S rDNA was used to measure the diversity metrics, and quantitative culture to quantify selected taxa. The primary outcomes were changes in the α and β diversity and log count of colony-forming units for selected taxa between samples compared with baseline (day 1), and whether any changes reverted during the follow-up period. The analyses were done in the intention-to-treat population. This study was registered with ClinicalTrials.gov (NCT04376554).
RESULTS: The study was conducted between Jan 23, 2020, and April 6, 2021. 49 volunteers were screened for eligibility, among whom 30 evaluable participants (14 men and 16 women) were assigned: 15 (50%) to the tebipenem pivoxil hydrobromide group and 15 (50%) to the amoxicillin-clavulanic acid group. Baseline characteristics were similar between groups. Complete follow-up was available for all participants, and all participants except one completed treatment as assigned. The diversity metrics showed significant changes from baseline during the treatment period. Significant decreases in richness were observed on days 4-10 (p≤0·0011) in the amoxicillin-clavulanic acid group and on days 4-14 (p≤0·0019) in the tebipenem pivoxil hydrobromide group. Similarly, evenness was significantly decreased during treatment in the amoxicillin-clavulanic acid group (day 4, p=0·030) and the tebipenem pivoxil hydrobromide group (days 4-10, p<0·0001) compared with baseline. Quantitative cultures showed significant decreases in Enterobacterales (days 4-7, p≤0·0030), Enterococcus spp (days 4-14, p=0·025 to p<0·0001), Bifidobacterium spp (days 2-4, p≤0·026), and Bacteroides spp (days 4-10, p≤0·030) in the tebipenem pivoxil hydrobromide group. Similarly, in amoxicillin-clavulanic acid recipients, significant changes were observed in Enterobacterales (days 4-10, p≤0·048), Bifidobacterium spp (days 2-4, p≤0·013), and Lactobacillus spp (days 2-4, p≤0·020). Samples from the follow-up period were not significantly different from those at baseline in β diversity analysis (PERMANOVA, p>0·99). By the end of the study, no significant change was observed compared with baseline in either group. There were no deaths or severe adverse events.
CONCLUSIONS: The impact of tebipenem pivoxil hydrobromide on the gut microbiome was similar to that of amoxicillin-clavulanic acid. The safety of antibiotic use with regard to the microbiome should be given attention, as dysbiosis is associated with health and disease.
BACKGROUND: Spero Therapeutics.