Heine Henry S, Bassett Jennifer, Miller Lynda, Hartings Justin M, Ivins Bruce E, Pitt M Louise, Fritz David, Norris Sarah L, Byrne W Russell
Division of Bacteriology, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702-5011, USA.
Antimicrob Agents Chemother. 2007 Apr;51(4):1373-9. doi: 10.1128/AAC.01050-06. Epub 2007 Feb 12.
An anthrax spore aerosol infection mouse model was developed as a first test of in vivo efficacy of antibiotics identified as active against Bacillus anthracis. Whole-body, 50% lethal dose (LD50) aerosol challenge doses in a range of 1.9x10(3) to 3.4x10(4) CFU with spores of the fully virulent Ames strain were established for three inbred and one outbred mouse strain (A/J, BALB/c, C57BL, and Swiss Webster). The BALB/c strain was further developed as a model for antibiotic efficacy. Time course microbiological examinations of tissue burdens in mice after challenge showed that spores could remain dormant in the lungs while vegetative cells disseminated to the mediastinal lymph nodes and then to the spleen, accompanied by bacteremia. For antibiotic efficacy studies, BALB/c mice were challenged with 50 to 100 LD50 of spores followed by intraperitoneal injection of either ciprofloxacin at 30 mg/kg of body weight (every 12 h [q12h]) or doxycycline at 40 mg/kg (q6h). A control group was treated with phosphate-buffered saline (PBS) q6h. Treatment was begun 24 h after challenge with groups of 10 mice for 14 or 21 days. The PBS-treated control mice all succumbed (10/10) to inhalation anthrax infection within 72 h. Sixty-day survival rates for ciprofloxacin and doxycycline-treated groups were 8/10 and 9/10, respectively, for 14-day treatment and 10/10 and 7/10 for 21-day treatment. Delayed treatment with ciprofloxacin initiated 36 and 48 h postexposure resulted in 80% survival and was statistically no different than early (24 h) postexposure treatment. Results using this mouse model correlate closely with clinical observations of inhalational anthrax in humans and with earlier antibiotic studies in the nonhuman primate inhalational anthrax model.
建立了炭疽芽孢气溶胶感染小鼠模型，作为对已鉴定出对炭疽芽孢杆菌有活性的抗生素进行体内疗效的首次测试。对于三种近交系和一种远交系小鼠品系（A/J、BALB/c、C57BL和瑞士韦伯斯特），用完全有毒力的埃姆斯菌株的芽孢确定了全身50%致死剂量（LD50）气溶胶攻击剂量，范围为1.9×10³至3.4×10⁴CFU。BALB/c品系进一步发展成为抗生素疗效模型。对攻击后小鼠组织负荷的时间进程微生物学检查表明，芽孢可在肺部保持休眠状态，而繁殖细胞则扩散至纵隔淋巴结，然后扩散至脾脏，并伴有菌血症。对于抗生素疗效研究，用50至100 LD50的芽孢攻击BALB/c小鼠，随后腹腔注射30 mg/kg体重的环丙沙星（每12小时一次[q12h]）或40 mg/kg的强力霉素（q6h）。对照组每6小时用磷酸盐缓冲盐水（PBS）处理一次。在攻击后24小时开始治疗，每组10只小鼠，持续治疗天或21天。PBS处理的对照小鼠在72小时内全部死于吸入性炭疽感染。环丙沙星和强力霉素治疗组在14天治疗时的60天生存率分别为8/10和9/10，在21天治疗时分别为10/10和7/10。暴露后36小时和48小时开始的环丙沙星延迟治疗导致80%的生存率，在统计学上与暴露后早期（24小时）治疗无差异。使用该小鼠模型得到的结果与人类吸入性炭疽的临床观察结果以及在非人类灵长类动物吸入性炭疽模型中早期的抗生素研究结果密切相关。
