Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS2 9JT, UK.
J Antimicrob Chemother. 2012 Oct;67(10):2434-7. doi: 10.1093/jac/dks243. Epub 2012 Jun 21.
We previously demonstrated that 7 days of oritavancin instillation effectively treats Clostridium difficile infection (CDI) in a human gut model. Oritavancin may be more effective than vancomycin due to apparently increased activity against spores. We compared the efficacy of shortened dosing duration (4 days) of oritavancin and vancomycin for CDI treatment using the gut model.
Clindamycin induced CDI in two triple-stage chemostat gut models primed with pooled human faeces and C. difficile ribotype 027 spores. Oritavancin (64 mg/L twice daily) or vancomycin (125 mg/L four times daily) was instilled for 4 days and the effects on C. difficile proliferation and toxin production, and gut microflora were determined.
Both oritavancin and vancomycin reduced toxin to undetectable levels. Recurrent C. difficile germination occurred 20 days after vancomycin instillation, with high-level toxin production. Oritavancin reduced C. difficile counts to around the detection limit for the remainder of the experiment, with spores undetectable from day 1 of instillation. Toxin production was reduced to below detectable levels, but was sporadically seen later, despite no evidence of germination. Both oritavancin and vancomycin instillation led to only modest effects on gut microflora.
Shortened courses of oritavancin and vancomycin effectively treated CDI in a human gut model, but evidence of recurrence was observed following vancomycin instillation. Oritavancin exposure inhibited the recovery of C. difficile spores, as previously described. Shortened antibiotic exposure minimizes disruption to the gut microflora. These data indicate the possible value of a 4 day oritavancin dosing regimen for CDI treatment.
我们之前的研究表明，7 天的奥他万古霉素滴注治疗能够有效地治疗人体肠道模型中的艰难梭菌感染（CDI）。奥他万古霉素可能比万古霉素更有效，因为它对孢子的活性似乎增加了。我们比较了使用肠道模型治疗 CDI 时缩短奥他万古霉素和万古霉素的治疗时间（4 天）的疗效。
克林霉素诱导的 CDI 在两个三阶段恒化器肠道模型中进行，这些模型用混合人类粪便和艰难梭菌 027 型孢子预先接种。奥他万古霉素（64mg/L，每日两次）或万古霉素（125mg/L，每日四次）滴注 4 天，测定其对艰难梭菌增殖和毒素产生以及肠道微生物群的影响。
奥他万古霉素和万古霉素均可将毒素降低至无法检测的水平。万古霉素滴注 20 天后再次发生艰难梭菌发芽，高水平毒素产生。奥他万古霉素将艰难梭菌计数降低至实验其余时间的检测限以下，滴注第 1 天就无法检测到孢子。毒素产生降低至无法检测的水平，但后来仍偶有出现，尽管没有发芽的证据。奥他万古霉素和万古霉素滴注对肠道微生物群的影响都不大。
缩短奥他万古霉素和万古霉素的疗程可有效治疗人体肠道模型中的 CDI，但万古霉素滴注后观察到复发的证据。奥他万古霉素暴露抑制了艰难梭菌孢子的恢复，如前所述。缩短抗生素暴露可最大限度地减少对肠道微生物群的破坏。这些数据表明，奥他万古霉素 4 天给药方案可能对 CDI 治疗有价值。
