valnemulin and Escherichia-coli-Infections

Pharmacokinetic and pharmacodynamic (PK/PD) indices against Mycoplasma gallisepticum (MG) S6 were investigated in an ex vivo PK/PD model following oral administration of valnemulin to chickens co-infected with M. gallisepticum and Escherichia coli. The minimum inhibitory concentrations (MICs) for valnemulin against MG S6 in artificial medium and chicken serum were determined. In vitro time-killing curves were established according to a series of multiples of the MIC value in an artificial medium, and ex vivo time-killing curves were established in serum samples obtained from infected chickens at different time points after oral administration with an initial titer of 1 × 10(6) color change units (CCU)/mL MG S6. The sigmoid Emax model was used to provide 24 h area under concentration-time curve/minimum inhibitory concentration ratios (AUC0-24h/MIC) for mycoplasmastasis, mycoplasmacidal activity and mycoplasmal elimination, respectively. The inoculum size and micro or macro methods exhibited little effect on MIC determination of MG, whereas matrix had a large effect. The rapid killing activity observed in in vitro time-killing curves seems to indicate that valnemulin was mycoplasmacidal and concentration dependent against MG. The AUC0-24h/MIC ratio for mycoplasmacidal activity and mycoplasmal elimination was 1321 h and 1960 h, respectively. A dosage regimen of 12.4 mg/kg/day and 18.3 mg/kg/day valnemulin was calculated for mycoplasmacidal activity and mycoplasmal elimination against MG S6, respectively.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Chickens; Diterpenes; Escherichia coli; Escherichia coli Infections; Half-Life; Microbial Sensitivity Tests; Mycoplasma gallisepticum; Mycoplasma Infections; Poultry Diseases

A Mycoplasma gallisepticum-Escherichia coli mixed infection model was developed in broiler chickens, which was applied to pharmacokinetics of valnemulin in the present experiment. The velogenic M. gallisepticum standard strain S6 was rejuvenated to establish the animal model, and the wild E. coli strain O78 was injected as supplementary inoculum to induce chronic respiratory disease in chickens. The disease model was evaluated based on its clinical signs, histopathological examination, bacteriological assay, and serum plate agglutination test. The pharmacokinetics of valnemulin in infected chickens was determined by intramuscular (i.m.) injection and oral administration (per os, p.o.) of a single dose of 10 mg/kg body weight (BW). Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry. The plasma concentration-time curve of valnemulin was analyzed using the noncompartmental method. After the i.m. administration, the mean values of Cmax , Tmax , AUClast , MRT, CLβ /F, Vz /F, and t1⁄2β , were 27.94 μg/mL, 1.57 h, 171.63 μg·h/mL, 4.51 h, 0.06 L/h/kg, 0.56 L/kg, and 6.50 h, respectively. By contrast, the corresponding values after p.o. administration were 5.93 μg/mL, 7.14 h, 47.60 μg·h/mL, 9.80 h, 0.22 L/h/kg, 3.35 L/kg, and 10.60 h. The disposition of valnemulin was retarded in infected chickens after both modes of extravascular administration as compared to the healthy controls. More attention should be given to monitoring the therapeutic efficacy and adverse effects of mixed infection because of higher required plasma drug concentration and enlarged AUC with valnemulin treatment.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Chickens; Coinfection; Diterpenes; Escherichia coli Infections; Half-Life; Mycoplasma gallisepticum; Mycoplasma Infections; Poultry Diseases