Theriot Casey M, Schumacher Cassie A, Bassis Christine M, Seekatz Anna M, Young Vincent B
Department of Internal Medicine/Division of Infectious Diseases, The University of Michigan, Ann Arbor, Michigan, USA
Department of Microbiology and Immunology, The University of Michigan, Ann Arbor, Michigan, USA.
Antimicrob Agents Chemother. 2015 Mar;59(3):1596-604. doi: 10.1128/AAC.04296-14. Epub 2014 Dec 29.
The glycylcycline antibiotic tigecycline was approved in 2005 for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections. Tigecycline is broadly active against both Gram-negative and Gram-positive microorganisms, including Clostridium difficile. Tigecycline has a low MIC against C. difficile in vitro and thus may represent an alternate treatment for C. difficile infection (CDI). To assess the use of tigecycline for treatment of established CDI, 5- to 8-week-old C57BL/6 mice were colonized with C. difficile strain 630. After C. difficile colonization was established, mice (n = 10 per group) were treated with either a 5-day course of tigecycline (6.25 mg/kg every 12 h subcutaneously) or a 5-day course of vancomycin (0.4 mg/ml in drinking water) and compared to infected, untreated control mice. Mice were evaluated for clinical signs of CDI throughout treatment and at 1 week posttreatment to assess potential for disease development. Immediately following a treatment course, C. difficile was not detectable in the feces of vancomycin-treated mice but remained detectable in feces from tigecycline-treated and untreated control mice. Toxin activity and histopathological inflammation and edema were observed in the ceca and colons of untreated mice; tigecycline- and vancomycin-treated mice did not show such changes directly after treatment. One week after the conclusion of either antibiotic treatment, C. difficile load, toxin activity, and histopathology scores increased in the cecum and colon, indicating that C. difficile-associated disease occurred. In vitro growth studies confirmed that subinhibitory concentrations of tigecycline were able to suppress toxin activity and spore formation of C. difficile, whereas vancomycin did not. Taken together, these data show how tigecycline is able to alter C. difficile pathogenesis in a mouse model of CDI.
甘氨酰环素类抗生素替加环素于2005年被批准用于治疗复杂性皮肤和软组织感染以及复杂性腹腔内感染。替加环素对革兰氏阴性和革兰氏阳性微生物均具有广泛活性，包括艰难梭菌。替加环素在体外对艰难梭菌的最低抑菌浓度较低，因此可能是艰难梭菌感染（CDI）的一种替代治疗方法。为了评估替加环素用于治疗已确诊的CDI的效果，将5至8周龄的C57BL/6小鼠用艰难梭菌630菌株进行定植。在艰难梭菌定植建立后，将小鼠（每组n = 10）用为期5天的替加环素疗程（每12小时皮下注射6.25 mg/kg）或为期5天的万古霉素疗程（饮用水中浓度为0.4 mg/ml）进行治疗，并与感染但未治疗的对照小鼠进行比较。在整个治疗过程中和治疗后1周对小鼠进行CDI临床症状评估，以评估疾病发展的可能性。在一个治疗疗程后，万古霉素治疗的小鼠粪便中未检测到艰难梭菌，但替加环素治疗的小鼠和未治疗的对照小鼠粪便中仍可检测到。在未治疗小鼠的盲肠和结肠中观察到毒素活性以及组织病理学炎症和水肿；替加环素和万古霉素治疗的小鼠在治疗后直接未出现此类变化。在任何一种抗生素治疗结束1周后，盲肠和结肠中的艰难梭菌载量、毒素活性和组织病理学评分均升高，表明发生了艰难梭菌相关疾病。体外生长研究证实，亚抑菌浓度的替加环素能够抑制艰难梭菌的毒素活性和孢子形成，而万古霉素则不能。综上所述，这些数据表明替加环素在CDI小鼠模型中能够改变艰难梭菌的发病机制。
