4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
4th Department of Internal Medicine, ATTIKON University Hospital, 1 Rimini Street, 124 62, Athens, Greece.
Sci Rep. 2022 Mar 8;12(1):3789. doi: 10.1038/s41598-022-07827-8.
Current knowledge suggests that infection by carbapenem-resistant enterobacteria is preceded by gut colonization. It is hypothesized that colonization is eradicated by non-absorbable antibiotics like rifaximin. We investigated the effect of rifaximin against carbapenem-resistant Klebsiella pneumoniae (CRKP) in vitro and in a mouse model. We studied the in vitro efficacy of rifaximin against 257 CRKP clinical isolates, 188 KPC producers and 69 OXA-48 producers, by minimum inhibitory concentration and time-kill assays. We then developed a model of gut colonization by feeding 30 C57Bl6 mice with 10 cfu of one KPC-KP isolate for 7 days; mice were pre-treated orally with saline, omeprazole or ampicillin. Then, another 60 mice with established KPC-2 gut colonization received orally for 7 consecutive days rifaximin 180 mg/kg dissolved in ethanol and 4% bile or vehicle. On days 0, 3 and 7 stool samples were collected; mice were sacrificed for determination of tissue outgrowth. At a concentration of 1000 μg/ml rifaximin inhibited 84.8% of CRKP isolates. Α 3 × log decrease of the starting inoculum was achieved by 100, 250 and 500 μg/ml of rifaximin after 24 h against 25, 55 and 55% of isolates. Pre-treatment with ampicillin was necessary for gut colonization by KPC-KP. Treatment with rifaximin succeeded in reducing KPC-KP load in stool and in the intestine. Rifaximin inhibits at clinically meaningful gut concentrations the majority of CRKP isolates and is efficient against gut colonization by KPC-KP.
目前的知识表明，耐碳青霉烯肠杆菌的感染是由肠道定植引起的。据推测，定植可以通过利福昔明等不可吸收的抗生素消除。我们研究了利福昔明对体外和小鼠模型中耐碳青霉烯肺炎克雷伯菌（CRKP）的作用。我们通过最低抑菌浓度和时间杀伤试验研究了利福昔明对 257 株 CRKP 临床分离株、188 株 KPC 生产者和 69 株 OXA-48 生产者的体外疗效。然后，我们通过用 10 个 CFU 的一种 KPC-KP 分离株喂养 30 只 C57Bl6 小鼠 7 天来建立肠道定植模型；小鼠用生理盐水、奥美拉唑或氨苄西林进行口服预处理。然后，另外 60 只已经建立了 KPC-2 肠道定植的小鼠连续 7 天口服 180 mg/kg 的利福昔明，溶于乙醇和 4%胆汁或载体。在第 0、3 和 7 天收集粪便样本；处死小鼠以确定组织生长。在 1000 μg/ml 的浓度下，利福昔明抑制了 84.8%的 CRKP 分离株。在 24 小时后，利福昔明的浓度为 100、250 和 500 μg/ml 时，可使起始接种物减少 3 个对数级，对 25、55 和 55%的分离株有效。氨苄西林预处理是 KPC-KP 肠道定植所必需的。利福昔明治疗成功地降低了粪便和肠道中 KPC-KP 的负荷。利福昔明以临床上有意义的肠道浓度抑制大多数 CRKP 分离株，并有效对抗 KPC-KP 的肠道定植。
