Integration of PK/PD for dose optimization of aditoprim against Trueperella pyogenes causing endometritis in bovines

Trueperella pyogenes is a major pathogenic organism of bovine uterus causing devastating economic losses. Clinical isolates of T. pyogenes demonstrated severe infection with high rate of disease progression than other pathogenic bacteria of uterus. We aimed to investigate the effectiveness of aditoprim, a novel dihydrofolate reductase inhibitor, based upon the ex-vivo pharmacodynamic analysis by using uterine fluid of cattle. In-vivo pharmacokinetic parameters were measured by high performance liquid choromatography and analyzed by winonline software (version 5.2.1). In-vitro minimum inhibitory concentration, mutant prevention concentration and time kill curves were determined with clinical isolates of Trueperell pyogenes. Our data showed that peak concentration (C_max) and area under the concentration time curve (AUC) were 6551.43 ± 1296.13 and 23585.22 ± 5126.47 μg/mL, respectively. Aditoprim showed potent antimicrobial activity against T. pyogenes (MIC = 0.25 μg/mL) and exhibited the concentration dependent antibacterial effect and produced in-vitro post antibiotic effect which was less than 1 h and increased with concentration. Pharmacodynamics values were modeled with pharmacokinetics parameters (PK/PD modeling) to simulate the efficacy of aditoprim for different dosage regimens. It was concluded that a dose of 2 mg/kg every 12h was expected to reach a bactericidal activity against T. pyogenes in endometritis.