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

Abstract

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) in infected chicks was 0.10 h, elimination half-life (T) was 4.23 h. The areas under the concentration-time curve at 24 h (AUC) 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) 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 LogCFU/mL, respectively, achieving a bactericidal effect. Through PK/PD fitting, the target values corresponding to reducing the lung mycoplasma load by 3 LogCFU/mL of AUC/MIC and C/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.