Pharmacokinetic/pharmacodynamic relationship of a novel pleuromutilin derivative p-furoylamphenmulin against Mycoplasma gallisepticum in vivo in chickens

Mycoplasma gallisepticum ( M. gallisepticum , MG ) is the primary pathogen of chronic respiratory disease ( CRD ) in chickens and leads to pneumonia and air sacculitis in infected chickens and a corresponding economic loss for the poultry industry. The pleuromutilins have excellent anti-mycoplasmal activity and we evaluated the in vivo activity of a new derivative 22-((4-((2-furan-1-yl)acetamido)phenyl)thio) deoxypleuromutilin ( p- furoylamphenmulin ) against M. gallisepticum . A plasma pharmacokinetic ( PK ) study and an in vivo pharmacodynamic ( PD ) study of p -furoylamphenmulin were performed using an M. gallisepticum -infected chicken model. Based on the PK/PD results, a preliminary recommended dose was calculated. The minimum inhibitory concentration ( MIC ) of p -furoylamphenmulin against M. gallisepticum was 0.001953125 μg/mL. PK results indicated that the absorption half-life ( T 1/2ka ) in infected chicks was 0.10 h, elimination half-life ( T 1/2kel ) was 4.23 h. The areas under the concentration-time curve at 24h ( AUC 24h ) for 5, 40, and 80 mg/kg single-dose injections were 1.49, 10.15, and 18.56 μg·h/mL, respectively. The peak concentrations ( C max ) of 5, 40, and 80 mg/kg were 0.56, 5.79, and 9.53 μg/mL, respectively. The PD results indicated that at doses of 70 and 80 mg/kg, the mycoplasmal counts in lungs decreased by 3.39 and 3.28 Log 10 CFU/mL, respectively, achieving a bactericidal effect. Through PK/PD fitting, the target values corresponding to reducing the lung mycoplasma load by 3 Log 10 CFU/mL of AUC 24h /MIC and C max /MIC were 8288.29 h and 4299.30, respectively, and the calculated dosage using formula (2) was 62.64 mg/kg, under the regimen of intramuscular injection once every 24 h for 3 consecutive days. In addition, the effect of high-dose p -furoylamphenmulin on the relief of air sac lesions was significant. These results provide a basis for developing and applying p -furoylamphenmulin and provide a preliminary medication regimen.