| Summary: | <i>Mycoplasma hyopneumoniae</i> is the major pathogen causing enzootic pneumonia in pigs. <i>M. hyopneumoniae</i> infection can lead to considerable economic losses in the pig-breeding industry. Here, this study established a first-order absorption, one-compartment model to study the relationship between the pharmacokinetics/pharmacodynamics (PK/PD) index of tilmicosin against <i>M. hyopneumoniae</i> in vitro. We simulated different drug concentrations of timicosin in the fluid lining the lung epithelia of pigs. The minimum inhibitory concentration (MIC) of tilmicosin against <i>M. hyopneumoniae</i> with an inoculum of 10<sup>6</sup> CFU/mL was 1.6 μg/mL using the microdilution method. Static time–kill curves showed that if the drug concentration >1 MIC, the antibacterial effect showed different degrees of inhibition. At 32 MIC, the amount of bacteria decreased by 3.16 log<sub>10</sub> CFU/mL, thereby achieving a mycoplasmacidal effect. The <i>M. hyopneumoniae</i> count was reduced from 3.61 to 5.11 log<sub>10</sub> CFU/mL upon incubation for 96 h in a dynamic model with a dose of 40–200 mg, thereby achieving mycoplasmacidal activity. The area under the concentration-time curve over 96 h divided by the MIC (AUC<sub>0–96 h</sub>/MIC) was the best-fit PK/PD parameters for predicting the antibacterial activity of tilmicosin against <i>M. hyopneumoniae</i> (<i>R</i><sup>2</sup> = 0.99), suggesting that tilmicosin had concentration-dependent activity. The estimated value for AUC<sub>0–96 h</sub>/MIC for 2log<sub>10</sub> (CFU/mL) reduction and 3log<sub>10</sub> (CFU/mL) reduction from baseline was 70.55 h and 96.72 h. Four <i>M. hyopneumoniae</i> strains (M1–M4) with reduced sensitivity to tilmicosin were isolated from the four dose groups. The susceptibility of these strains to tylosin, erythromycin and lincomycin was also reduced significantly. For sequencing analyses of 23S rRNA, an acquired A2058G transition in region V was found only in resistant <i>M. hyopneumoniae</i> strains (M3, M4). In conclusion, in an in vitro model, the effect of tilmicosin against <i>M. hyopneumoniae</i> was concentration-dependent and had a therapeutic effect. These results will help to design the optimal dosing regimen for tilmicosin in <i>M. hyopneumoniae</i> infection, and minimize the emergence of resistant bacteria.
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