Emergence and Mechanism of Resistance of Tulathromycin Against in a PK/PD Model and the Fitness Costs of 23S rRNA Mutants.

Macrolides are widely used in diseases caused by spp. The new semi-synthetic macrolide antibiotic tulathromycin is currently in wide use for the treatment of respiratory diseases of livestock. The objective of this study was to evaluate the antibacterial effect of tulathromycin against using an pharmacokinetic/pharmacodynamic (PK/PD) model to reveal mechanisms of antibiotic resistance and to evaluate the fitness of drug-resistant strains. In this study, high performance liquid chromatography-tandem mass spectrometry was used to determine drug concentrations for the model after dosing. The peak concentrations were in the range 0.3125-20 μg/mL (1 × MIC-64 × MIC). The ratio of the area under the concentration-time curve (AUC) over 72 h divided by the MIC (AUC/MIC) had the highest correlation with the antibacterial effect of tulathromycin against . Tulathromycin also showed concentration-dependent antimicrobial effects and promoted the emergence of drug-resistant bacteria after being cultured for 168 h and most were mutations in 23S rRNA at site A2058G ( numbering) and only a single isolate was an A2058T ( numbering) mutant. In the presence of reserpine, we determined the MIC of tulathromycin, tilmicosin, tiamulin and tylosin against these drug-resistant bacteria and the strains with efflux pump mechanisms were found among the strains resistant to tilmicosin. Gene expression analysis indicated that the ABC and MATE transporter efflux pump genes RS01935, RS02670, RS01115, RS01970, RS02395 and RS03540 (MATE family efflux transporter) were up-regulated in the three strains ( < 0.05 or < 0.01). These investigations provide guidance for clinical administration of tulathromycin and elucidate the mechanism and fitness cost of drug resistance in .