Acetylkitamycin

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 50 mg/kg body weights (bw), a rapid and sensitiveLC–MS/MSmethod 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. ThePKparameters, including the integrated peak concentration (Cmax), the time when the maximum concentration reached (Tmax) and the area under the concentration–time curve (AUC), were calculated by WinNonlin software. The minimum inhibitory concentration (MIC) of 60C. perfringensstrains was determined followingCLSIguideline. The in vitro and ex vivo activities of acetylkitasamycin in intestinal tract against a pathogenic strain ofC. perfringenstype A (CPFK122995) were established by the killing curve. OurPKdata showed that the integratedCmax,Tmax, andAUCwere 14.57–15.81 μg/ml, 0.78–2.52 hR, and 123.84–152.32 μg hr/ml, respectively. ThePDdata show thatMIC50andMIC90of the 60C. perfringensisolates were 3.85 and 26.45 μg/ml, respectively. The ex vivo growth inhibition data were fitted to the inhibitory sigmoidEmaxequation to provide the values ofAUC/MICto produce bacteriostasis (4.84 hr), bactericidal activity (15.46 hr), and bacterial eradication (24.99 hr). A dosage regimen of 18.63 mg/kg bw every 12 hr could be sufficient in the prevention ofC. perfringensinfection. The therapeutic dosage regimen forC. perfringensinfection was at the dose of 51.36 mg/kg bw every 12 hr for 3 days. In summary, the dosage regimen for the treatment ofC. perfringensin pigs administered with acetylkitasamycin was designed usingPK/PDintegrate model. The designed dose regimen could to some extent decrease the risk for emergence of macrolide resistance.

Streptococcus suis (S. suis) causes severe respiratory diseases in pigs and is also an important pathogen causing hidden dangers to public health and safety. Acetylkitasamycin is a new macrolide agent that has shown good activity to Gram-positive cocci such as Streptococcus. The purpose of this study was to perform pharmacokinetic–pharmacodynamic (PK-PD) modeling to formulate a dosing regimen of acetylkitasamycin for treatment of S. suis and to decrease the emergence of acetylkitasamycin-resistant S. suis. The minimal inhibitory concentration (MIC) of 110 S. suis isolates was determined by broth micro dilution method. The MIC50 of the 55 sensitive S. suis isolates was 1.21 μg/mL. The strain HB1607 with MIC close to MIC50 and high pathogenicity was used for the PK-PD experiments. The MIC and MBC of HB1607 in both MH broth and pulmonary epithelial lining fluid (PELF) was 1 and 2 μg/mL, respectively. The liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration change of acetylkitasamycin in piglet plasma and PELF after intragastric administration of a single dose of 50 mg/kg b.w. acetylkitasamycin. The PK parameters were calculated by WinNolin software. The PK data showed that the maximum concentration (Cmax), peak time (Tmax), and area under the concentration–time curve (AUC) were 9.84 ± 0.39 μg/mL, 4.27 ± 0.19 h and 248.58 ± 21.17 h·μg/mL, respectively. Integration of the in vivo PK data and ex vivo PD data, an inhibition sigmoid Emax equation was established. The dosing regimen of acetylkitasamycin for the treatment S. suis infection established as 33.12 mg/kg b.w. every 12 h for 3 days. This study provided a reasonable dosing regimen for a new drug used in clinical treatment, which can effectively be used to treat S. suis infection and slow down the generation of drug resistance.