Pharmacokinetic/pharmacodynamic relationship of a novel pleuromutilin derivative APTM against Mycoplasma gallisepticum.

Abstract

Mycoplasma gallisepticum (MG) is a primary avian pathogen that causes chronic respiratory disease, leading to significant economic losses in the poultry industry. This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) relationship of a novel pleuromutilin derivative, 14-O-[(4-amino-6-hydroxy-pyrimidine-2-yl) thioacetyl] mutilin (APTM), against MG in a chicken infection model to provide a basis for a rational dosage regimen. The in vitro activity of APTM against MG strain S6 was assessed by determining the minimum inhibitory concentration (MIC) and time-kill kinetics. An intratracheal MG infection model was established in chickens. The pharmacokinetic profile was evaluated after single oral administrations of APTM at 5, 15, and 40 mg/kg. The pharmacodynamic efficacy was determined by quantifying the bacterial reduction in the lungs after three consecutive days of oral treatment with doses ranging from 0 to 40 mg/kg. The PK/PD data were integrated and analyzed using an inhibitory sigmoid Emax model. The MIC of APTM against MG S6 was 0.03125 µg/mL, and in vitro time-kill assays demonstrated concentration-dependent bactericidal activity. In chickens, APTM was rapidly absorbed (T: 0.25-0.5 h), with both Cand AUCexhibiting excellent dose proportionality (R² > 0.99) over the tested range. In the efficacy study, APTM produced a dose-dependent reduction in lung bacterial load, with a maximum mean reduction of 2.80 logCFU/mL observed at the 40 mg/kg dose, indicating a bactericidal effect. The PK/PD indices, AUC/MIC and C/MIC, were both highly correlated with the in vivo antimicrobial effect (R² = 0.9424 and 0.9428, respectively). To achieve a 2-logCFU/mL reduction in bacterial load, the target AUC/MIC value was determined to be 492.75, which corresponds to a calculated daily oral dose of 22 mg/kg. These findings demonstrate the potent efficacy of APTM against MG and provide a quantitative scientific foundation for its therapeutic use in poultry. Specifically, a daily oral dose of 22 mg/kg was identified as the breakpoint for a bactericidal effect (2-log10 reduction), suggesting APTM is a potent candidate for controlling MG infections in poultry.