Pharmacokinetic and pharmacodynamic integration and modeling of acetylkitasamycin in swine for Clostridium perfringens

The aim of this study was to establish an integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach of acetylkitasamycin for designing dosage regimens and decreasing the emergence of drug-resistant bacteria. After oral administration of acetylkitasamycin to healthy and infected pigs at the dose of 50mg/kg body weights (bw), a rapid and sensitive LC-MS/MS method was developed and validated for determining the concentration change of the major components of acetylkitasamycin and its possible metabolite kitasamycin in the intestinal samples taken from the T-shape ileal cannula. The PK parameters, including the integrated peak concentration (C-max), the time when the maximum concentration reached (T-max) and the area under the concentration-time curve (AUC), were calculated by WinNonlin software. The minimum inhibitory concentration (MIC) of 60 C.perfringens strains was determined following CLSI guideline. The in vitro and ex vivo activities of acetylkitasamycin in intestinal tract against a pathogenic strain of C.perfringens type A (CPFK122995) were established by the killing curve. Our PK data showed that the integrated C-max, T-max, and AUC were 14.57-15.81g/ml, 0.78-2.52hR, and 123.84-152.32ghr/ml, respectively. The PD data show that MIC50 and MIC90 of the 60 C.perfringens isolates were 3.85 and 26.45g/ml, respectively. The ex vivo growth inhibition data were fitted to the inhibitory sigmoid E-max equation to provide the values of AUC/MIC to produce bacteriostasis (4.84hr), bactericidal activity (15.46hr), and bacterial eradication (24.99hr). A dosage regimen of 18.63mg/kg bw every 12hr could be sufficient in the prevention of C.perfringens infection. The therapeutic dosage regimen for C.perfringens infection was at the dose of 51.36mg/kg bw every 12hr for 3days. In summary, the dosage regimen for the treatment of C.perfringens in pigs administered with acetylkitasamycin was designed using PK/PD integrate model. The designed dose regimen could to some extent decrease the risk for emergence of macrolide resistance.