Antibacterial activity of combined aditoprim and sulfamethoxazole against Escherichia coli from swine and a dose regimen based on pharmacokinetic-pharmacodynamic modeling.

Abstract

The mortality of livestock caused by pathogenic Escherichia coli (E. coli) still accounts for a large proportion of deaths in large-scale production and reproduction, which causes devastating economic losses to the pig breeding industry. The aims of this study were to investigate the antibacterial activity of combined aditoprim (ADP) and sulfamethoxazole (SMZ) against clinical isolates of E.coli from pigs and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to formulate the optimal dose of ADP/SMZ for the treatment of pig colibacillosis. Blood and ileum fluid samples were collected at different times after single intramuscular injection of ADP/SMZ (5/25mg/kg b.w.) to healthy pigs and E.coli-infected pigs. Concentrations of ADP and SMZ in plasma and ileum fluid were analyzed by HPLC. The peak concentration (Cmax ) and the area under the concentration-time curve (AUC0-24h ) in ileum fluid of healthy pigs were 1.76±0.27µg/ml and 18.92±2.87µg·h/ml for ADP and 19.15±2.63µg/ml and 125.70±11.86µg·h/ml for SMZ, respectively. Cmax and AUC0-24h in ileum fluid of infected pigs were 1.88±0.13µg/ml and 15.12±0.75µg·h/ml for ADP and 19.71±3.68µg/ml and 133.92±17.14µg·h/ml for SMZ, respectively. The minimum inhibitory concentrations (MICs) of combined ADP and SMZ (ADP/SMZ) against 185 strains of E.coli from pigs were determined. The MIC50 and MIC90 of ADP/SMZ were 0.5/2.5 and 4/20µg/ml, respectively. The MIC of the selected pathogenic E.coli SHC28 was 0.5/2.5µg/ml in Mueller-Hinton broth and 0.25/1.25µg/ml in ileum fluid, respectively. In vitro, the mutant prevention concentration, the post-antibiotic effect, growth, and time-killing curves in vitro and ex vivo of ADP/SMZ against the isolate SHC28 were assayed for PD studies. The results showed that ADP/SMZ exhibited strong concentration-dependent antimicrobial activity against E.coli. After integrating the in vivo pharmacokinetic parameters of infected pigs and ex vivo PD data using the sigmoid Emax (Hill) equation, the AUC24h /MIC values in ileum fluid for bacteriostatic, bactericidal, and bacterial eradication were 18.84, 65.39, and 110.68h, respectively. In conclusion, a dosage of 3.45/17.25mg/kg ADP/SMZ by intramuscular injection daily for 3 consecutive days may be sufficient to treat swine colibacillosis due to E.coli with a MIC of 0.5/2.5µg/ml.