| Swine streptococcosis is an infectious zoonosis caused by diffetent serogroups of Streptococcus suis, many countries has reported this disease recent years, and it is largely endanger the pig industry in the world. Tylosin is usually used in the treatment of bacterial respiratory disease because of its rapid absorption, high bioavailability and extended spectrum of antibacterial activity. Tylosin is widely used to treat swine streptococcosis in veterinary, and made a great contribution to the healthy development of swine industry. However, drug is abused seriously in clinical, that cause the drug can’t chieve the best efficy, and lead to the emergence of bacteria resistance. We research in the in vitro and ex vivo pharmacodynamics of tylosin against streptococcus suis, and pharmacokinetics of tylosin after intramuscular administrated at a dose rate of10mg/kg in healthy swine and S. suis infectious swine. Then integrated the pharmacokinetics and pharmacodynamics, and established the PK-PD model according to the Sigmiod Emax equation. We predicted the optimal dosing regimen of tylosin to treat swine streptococcosis, it could achieve the best efficy and treat swine streptococcosis, reduced the bacteria resistance and extended the life of tylosin in swine industry.1Pharmacodynamics of tylosin against S. suisMIC and MBC of tylosin against Streptocuccus suis CVCC606were determined in broth and serum by the micro dilution method. The MIC is0.25μg/mL, and MBC is1μg/mL, and they are the same in broth and serum. It indicates that tylosin has a well bactericidal activity to streptococcus suis. MPC is1μg/mL, which was determined by the plat method. Let S. suis expose to different concentrations of tylosin solutions, then remove the drug after1h and2h, and calculate the PAE of tylosin against Streptococcus suis. The PAEs of Streptococcus suis exposed to2MIC and4MIC tylosin for1h are1.43h and2.15h,3.43h and4.21h respectively for2h, which indicate that tylosin has a prolonged PAE to S. suis. The in vitro bacterial killing curves were esblished to determine the rate and extent of bacterial killing by tylosin against S. suis in broth and serum. According to the bacterial killing profile, the antibacterial activity of tylosin against S. suis is abviously time-dependent, when increasing the time bacteria exposed in the drug increasing the antibacterial effect. The killing curves also show weak concentration-denpendent antibacterial activity, increasing drug concentration increasing the rate of killing. That can confirm that the PK-PD paramerer of tylosin against S. suis is AUC/MIC according to the bacterial killing curve and the PAEs. The ex vivo antibacterial activity of tylosin against streptococcus suis was determined as follows:added10μL stationary phase bacterial culture to0.5mL volumes of serum to give a final concentration of approximately1X106CFU/mL.50μL samples was collected to determine viable counts at the pre-determined times. The ex vivo antibacterial activity of tylosin illustrate that tylosin in serum from healthy swine exerted powerful anti-bacterial effect in0.5,1,1.5,2,3and4h point, extended weak antimicrobial effects in0.17,0.33and6h point, no inhibitory effects were abserved at8,10and12h point. And antibacterial activity in serum from S. suis infentious swine were the same as samples from healthy swine except0.33h samples extended powerful bacterial effect.2Pharmacokinetics of tylosin in healthy swine and S. suis infectious swineSwine were inoculated subcutaneously to establish experimental model of swine streptococcosis. Serum samples were collected at0,10,20,30min,1,1.5,2,3,4,6,8,10and12h after the swine were intramuscular administration at a dose rate of10mg/kg. Part of the serum were detected the concentrations of tylosin by HPLC, and the others were used to determine the ex vivo antibacterial activity of tylosin. Pharmacokinetics parameters were calculated by Winnonlin software. The PK result showed that tylosin fit one compartment open model in healthy swine and S. suis infectious swine after IM administration. The main pharmacokinetics parameters of tylsin in healthy swine are as follows:ka=0.521h-1, ke=0.518h-1, AUC=10.804h·μg/mL, Tmax=1.948h, Cmax=2.056μg/mL, MRT=3.588h. They show that tylosin is absorpt quickly, and rearches the peak concentration soon. The main pharmacokinetics parameters of tylosin in the S. suis infectious swine as follows:ka=0.759h-1, ke=0.634h-1, AUC=10.297h·μg/mL, Tmax=1.578h, Cmax=2.372μg/mL, MRT=3.353h, and the parameters ka, ke, T1/2ka and Tmaxin healthy and S. suis infectious swine show significant difference. The result show that tylosin is absorpt and eliminated more quickly in the swine with S.suis, reached the peak concentration earlier.3Data analysis and the establishment of PK-PD modelIntegration of in vivo pharmacolinetics data with MIC deterimined in vitro provided mean value of AUC/MIC, Cmax/MIC and T>MIC,43.216,8.900,4.339for serum from healthy swine after IM dosing respectively, and41.188,9.768,7.136for serum from swine with S. suis. PK and PD data were combined by Winnonlin software to establish a PK-PD model, the model was described as Sigmoid Emax model. The relationship between ex vivo AUC/MIC and antibacterial effect were handled using Sigmiod Emax equation. For healthy swine, the AUC/MIC value for serum required for bacteriostatic action is26.276; For swine with S. suis, the AUC/MIC value reached30.631when tylosin killing90%bacteria, and tylosin show bacterial action (99.9%reduction for bacteria) when AUC/MIC is115.315. The dosage was calculated by the equation for dosage regimen, the rational dosage for tylosin treating swine streptococcosis is6.298-27.997mg/kg.In summary the antibacterial activity of tylosin against streptococcus suis is obviously time-dependent and weak concentration-dependent at the same time, AUC/MIC is its optimal PK-PD parameter. Tylosin is absorpt and eliminated more quickly, rearch the peak concentration earlier in swine with streptococcus suis. PK-PD model of tylosin against S. suis in vivo can be described as Sigmiod Emax model by Winnonlin software. We established the rational dosage regimen for tylosin for treating swine streptococcosis, which could reduce bacterial resistance and save the cost for farmers. |
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