Deshpande Abhishek, Hurless Kelly, Cadnum Jennifer L, Chesnel Laurent, Gao Lihong, Chan Luisa, Kundrapu Sirisha, Polinkovsky Alexander, Donskey Curtis J
Department of Infectious Diseases, Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Antimicrob Agents Chemother. 2016 Jun 20;60(7):3988-93. doi: 10.1128/AAC.02590-15. Print 2016 Jul.
The use of oral vancomycin or metronidazole for treatment of Clostridium difficile infection (CDI) may promote colonization by health care-associated pathogens due to disruption of the intestinal microbiota. Because the macrocyclic antibiotic fidaxomicin causes less alteration of the intestinal microbiota than vancomycin, we hypothesized that it would not lead to a loss of colonization resistance to vancomycin-resistant enterococci (VRE) and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae (ESBL-Kp). Mice (8 per group) received orogastric saline, vancomycin, or fidaxomicin daily for 5 days at doses resulting in stool concentrations in mice similar to those measured in humans. The mice were challenged with 10(5) CFU of orogastric VRE or ESBL-Kp on day 2 of treatment and concentrations of the pathogens in stool were monitored. The impact of drug exposure on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. In comparison to saline controls, oral vancomycin promoted establishment of high-density colonization by VRE and ESBL-Kp in stool (8 to 10 log10 CFU/g; P < 0.001), whereas fidaxomicin did not (<4 log10 CFU; P > 0.5). Vancomycin treatment resulted in significant reductions in enterococci, Bacteroides spp., and Clostridium leptum, whereas the population of aerobic and facultative Gram-negative bacilli increased; deep-sequencing analysis demonstrated suppression of Firmicutes and expansion of Proteobacteria during vancomycin treatment. Fidaxomicin did not cause significant alteration of the microbiota. In summary, in contrast to vancomycin, fidaxomicin treatment caused minimal disruption of the intestinal microbiota and did not render the microbiota susceptible to VRE and ESBL-Kp colonization.
口服万古霉素或甲硝唑用于治疗艰难梭菌感染（CDI）时，可能会因肠道微生物群的破坏而促进医疗保健相关病原体的定植。由于大环抗生素非达霉素对肠道微生物群的改变比万古霉素小，我们推测它不会导致对耐万古霉素肠球菌（VRE）和产超广谱β-内酰胺酶肺炎克雷伯菌（ESBL-Kp）的定植抗性丧失。小鼠（每组8只）连续5天每天经口给予生理盐水、万古霉素或非达霉素，剂量使其粪便浓度与人类测量值相似。在治疗第2天，用10⁵CFU经口给予的VRE或ESBL-Kp对小鼠进行攻击，并监测粪便中病原体的浓度。通过培养、对选定厌氧菌的实时PCR和深度测序来测量药物暴露对微生物群的影响。与生理盐水对照组相比，口服万古霉素促进了VRE和ESBL-Kp在粪便中的高密度定植（8至10 log₁₀CFU/g；P<0.001），而非达霉素则未促进（<4 log₁₀CFU；P>0.5）。万古霉素治疗导致肠球菌、拟杆菌属和纤细梭菌显著减少，而需氧和兼性革兰氏阴性杆菌数量增加；深度测序分析表明，万古霉素治疗期间厚壁菌门受到抑制，变形菌门扩张。非达霉素未引起微生物群的显著改变。总之，与万古霉素相比，非达霉素治疗对肠道微生物群的破坏最小，且未使微生物群易受VRE和ESBL-Kp定植的影响。
