To evaluate the microbiological safety of tilmicosin on human intestinal microflora, four chemostat models of healthy human colonic ecosystems were exposed to tilmicosin (0, 0.436, 4.36, and 43.6 μg/mL) for 7 days. Prior to and during drug exposure, three microbiological endpoints were monitored daily including short-chain fatty acids, bacterial counts and macrolide susceptibility. Colonization resistance of each community was determined by 3 successive daily challenges of Salmonella typhimurium. Genes associated with virulence and macrolide resistance in Enterococcus faecalis were determined by PCR. Transcriptional expression of the virulence gene (gelE) in E. faecalis was determined by real-time RT-PCR. Our results showed that different concentrations of tilmicosin did not disrupt the colonization resistance in each chemostat. During exposure to 4.36 and 43.6 μg/mL tilmicosin, the Bacteroides fragilis population was significantly decreased while the proportion of resistant Enterococci increased. After long-term exposure to the highest concentration (43.6 μg/mL) of tilmicosin, the gelE gene was significantly up-regulated in the high-level macrolide resistant strains that also contained the ermB resistance gene. This study was the first of its kind to evaluate the microbiological toxicity of tilmicosin using a chemostat model. These findings also provide new insight into the co-occurrence of macrolide resistance and virulence in E. faecalis under tilmicosin selective pressure.

College of Life Science Yangtze University Jingzhou Hubei China; Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products Huazhong Agricultural University Wuhan Hubei 430070 China

National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues Huazhong Agricultural University Wuhan Hubei 430070 China

National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues Huazhong Agricultural University Wuhan Hubei 430070 China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products Huazhong Agricultural University Wuhan Hubei 430070 China

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