Perrin-Guyomard Agnès, Poul Jean-Michel, Laurentie Michel, Sanders Pascal, Fernández A Haydée, Bartholomew Mary
Agence Française de Sécurité Sanitaire des Aliments, Laboratoire d'études et de Recherches sur les Médicaments Vétérinaires et les Désinfectants, BP 90203, 35302 Fougères cedex, France.
Regul Toxicol Pharmacol. 2006 Jun;45(1):66-78. doi: 10.1016/j.yrtph.2006.02.002. Epub 2006 Mar 24.
The ecological impact of different doses of ciprofloxacin was investigated in an experimental germ-free rat model into which human fecal flora was inoculated. Animals received oral doses (gavage) of 0, 0.25, 2.5, and 25 mg/kg body weight (bw) of ciprofloxacin once daily for 5 weeks. All doses of ciprofloxacin significantly reduced aerobic populations. Elimination of Enterobacteriaceae and reduction of bifodibacteria were noticed in the group treated with 25 mg/kg of the antibiotic. The rest of the intestinal flora was not affected. These effects were reversible after the treatment ended. The percentage of resistant enterococci increased in rats treated with 2.5 and 25 mg/kg; however, this increase was not statistically significant. There was a significant (P < 0.05) emergence of ciprofloxacin-resistant Bacteroides fragilis group with 25 mg/kg bw, which is equivalent to a human therapeutic dosage of the antibiotic. The MIC values and the percentage of resistance remained elevated 2 weeks after the end of treatment in this anaerobic population. Although sub-populations of enterococci and Enterobacteriaceae showed decreased susceptibility after ciprofloxacin administration, resistance was not evident. The ability of an exogenous strain of Salmonella to colonize the intestine of animals treated with 25 mg/kg of ciprofloxacin confirmed that the drug disrupted the colonization barrier effect of the indigenous flora at the high dose level tested. No changes in the metabolic parameters occurred during the antibiotic treatment. The results obtained in the HFA rat model were similar to those obtained in our previous study using the HFA mice model where ciprofloxacin at 0.125, 1.25, and 12.5 mg/kg bw induced a decrease of enterococci and Enterobacteriaceae populations. The high dose of ciprofloxacin also induced a decrease in bifidobacteria counts, an increase in levels of resistant B. fragilis group and a significant (P < 0.05) disruption of the colonization resistance of the barrier flora in HFA mice.
在接种了人类粪便菌群的无菌大鼠实验模型中，研究了不同剂量环丙沙星的生态影响。动物每天经口灌胃给予0、0.25、2.5和25mg/kg体重的环丙沙星，持续5周。所有剂量的环丙沙星均显著降低了需氧菌数量。在给予25mg/kg抗生素治疗的组中，观察到肠杆菌科细菌的清除和双歧杆菌数量的减少。肠道其余菌群未受影响。治疗结束后，这些影响是可逆的。用2.5和25mg/kg治疗的大鼠中，耐环丙沙星肠球菌的百分比增加；然而，这种增加在统计学上并不显著。给予25mg/kg体重的环丙沙星时，出现了显著（P<0.05）的脆弱拟杆菌群对环丙沙星耐药的情况，这相当于该抗生素的人类治疗剂量。在该厌氧菌群中，治疗结束2周后，最低抑菌浓度（MIC）值和耐药百分比仍保持升高。尽管给予环丙沙星后肠球菌和肠杆菌科的亚群显示敏感性降低，但耐药性并不明显。用25mg/kg环丙沙星治疗的动物中，外源沙门氏菌菌株在肠道定植的能力证实，在测试的高剂量水平下，该药物破坏了本土菌群的定植屏障作用。在抗生素治疗期间，代谢参数未发生变化。在人类粪便菌群相关（HFA）大鼠模型中获得的结果与我们之前使用HFA小鼠模型的研究结果相似，在HFA小鼠模型中，0.125、1.25和12.5mg/kg体重的环丙沙星导致肠球菌和肠杆菌科数量减少。高剂量的环丙沙星还导致双歧杆菌数量减少、脆弱拟杆菌群耐药水平增加以及HFA小鼠屏障菌群定植抗性的显著（P<0.05）破坏。
