The PK/PD Integration and Resistance of Tilmicosin against Mycoplasma hyopneumoniae

Zilong Huang; Zixuan Hu; Haorui Zheng; Xirui Xia; Xiaoyan Gu; Xiangguang Shen; Hong Yang; Huanzhong Ding

doi:10.3390/pathogens9060487

The PK/PD Integration and Resistance of Tilmicosin against Mycoplasma hyopneumoniae

Pathogens. 2020 Jun 19;9(6):487. doi: 10.3390/pathogens9060487.

Authors

Zilong Huang¹, Zixuan Hu¹, Haorui Zheng¹, Xirui Xia¹, Xiaoyan Gu¹, Xiangguang Shen¹, Hong Yang², Huanzhong Ding¹

Affiliations

¹ Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, South China Agriculture University, 483 Wushan Road, Guangzhou 510642, China.
² School of life science and engineering, Foshan University, Foshan 510642, China.

Abstract

Mycoplasma hyopneumoniae is the major pathogen causing enzootic pneumonia in pigs. M. hyopneumoniae 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 M. hyopneumoniae 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 M. hyopneumoniae with an inoculum of 10⁶ 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 log₁₀ CFU/mL, thereby achieving a mycoplasmacidal effect. The M. hyopneumoniae count was reduced from 3.61 to 5.11 log₁₀ 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_{0-96 h}/MIC) was the best-fit PK/PD parameters for predicting the antibacterial activity of tilmicosin against M. hyopneumoniae (R² = 0.99), suggesting that tilmicosin had concentration-dependent activity. The estimated value for AUC_{0-96 h}/MIC for 2log₁₀ (CFU/mL) reduction and 3log₁₀ (CFU/mL) reduction from baseline was 70.55 h and 96.72 h. Four M. hyopneumoniae 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 M. hyopneumoniae strains (M3, M4). In conclusion, in an in vitro model, the effect of tilmicosin against M. hyopneumoniae was concentration-dependent and had a therapeutic effect. These results will help to design the optimal dosing regimen for tilmicosin in M. hyopneumoniae infection, and minimize the emergence of resistant bacteria.

Keywords: Mycoplasma hyopneumoniae; enzootic pneumonia; in vitro dynamic model; pharmacodynamic; pharmacokinetic; resistance; tilmicosin.