Pharmacokinetic-pharmacodynamics Of Intramuscular Florfenicol In Serum And Tissue Cage Fluid Of Swine

PK-PD model, as a basis for antibacterials application, which has importantly theoretical and practical significance to reflect the relationship among drug, host and microorganism. It also can be used to estimate curative effect and formulate optimal dosage regimen clinically. There were some research about the PK-PD model on B-Lactam antibiotics, FQNS, macrolides and aminoglycosides. But no research on Chloromycetin were reported. Florfenicol is the third generation of Chloromycetin and it is widely used in veterinary medicine. It can strengthen antibacterial effect, without inhibiting hemopoiesis and creating aplastic anemia contrast to Chloromyetin. Porcine infectious pleuropneumonia is an elevation touch infectivity respiratory tract disease which almost spread all over the world and caused large loss. Florfenicol is the best drug to treat this disease and widely used in clinic. However abusaging and misusing of Florfenicol lead to drug resistance and caused treatment failure. The drug effect was directly related to the drug concentration of infection site. Florfenicol must have good tissue penetrating in order to reach effective treatment concentration. The tissue penetrating of Florfenicol was studied by tissue cages. Meanwhile, the drug was arrived at lesions tissue by blood stream. The concentration in serum had better relationship with clearance rate of Peripneumonia Actinobacillus. Therefore, this research studied the pharmacodynamics of florfenicol against pleuropneumonia Actinobacillus in vitro and pharmacokinetics of florfenicol in vivo of pigs. Using the Hill equation, PK-PD model was established in serum and tissue cage fluids which could be used to pretest dosage regimen and avoid drug resistance.MIC and MBC of Florfenicol against Peripneumonia Actinobacillus were determined by micro dilution. First, bacterium liquid was prepared and the concentrations of Florfenicol were set to be 128.00,64.00,32.00,16.00,8.00,4.00,2.00,1.00,0.50,0.25,0.125μg/mL, MIC were determined by 96 microwell plate. The first hole get clear which concentration was MIC. Taking high concentration liquid culture from 96 microwell plate being spread on NAD/TSA plates and incubated 24h, the lowest concentration which did not grow colony was MBC. MIC and MBC of Fiorfenicci against Peripneumonia Actinobacillus is 0.5μg/ml and 1μg/ml respectively, which indicates that Fiorfenicol has high bactericidal activity to Peripneumonia Actinobacilius. From the result of killing curves, we can obviously found that bactericidal activity of Fiorfenicol is increasing with the concentration raising. This indicates that Fiorfenicol belongs to concentration dependent antibacterial agents. 10ml plastic centrifuge tube was perforated in surface to make tissue cages. Prior to dosing, two tissue cages per animal, one on each side of cervical part, were inserted surgically under lignoacine local anaesthesia. Five weeks were allowed after insertion of tissue cages to permit wound healing. Six swine received 20mg/kg Fiorfenicol IM into the cervical part. Serum samples were collected at 0,15,30minand1,1.5,2,3,4,6,9,12,15,24,36,48hand tissue cage fluids were collected at 0,1,3,6,9,12,15,24,36,48h. These samples were detected by gas chromatogram with microcell electron capture detector. Serum and tissue cage fluids Fiorfenicol concentration fitted one compartment open model in all animals. The main pharmacokinetics parameters as follows: T_1/2Ka is 1.5±0.76h, T_1/2Kb is 11.16±3.36h, AUC is 24.76±5.36h*μg/mL, Tmax is 2h and Cmax is 5.93±1.63μg/mL in serum; T_1/2Kpen is 4.62±1.19h, T_1/2Kb is 17.35±0.57h, AUC is 49.09±7.04h*μg/mL, Tmax is 12h and Cmax is 3.20±0.89μg/mL in tissue cage fluids. Fiorfenicol was absorbed in blood serum. Fiorfenicol penetrated into tissue cages slowly and eliminated slowly in tissue cages. The ex vivo antibacterial activity of Fiorfenicol in serum and tissue cage fluids against Peripneumonia Actinobacillus was determined at 10 time points: 0, 1,3, 6, 9, 12, 15, 24, 36, 48h after Fiorfenicol dosing. At 1, 3 and 6h point, Fiorfenicol in serum exerted a powerful bactericidal effect which can kill almost all bacteria after 24h incubation. At 9h point, Fiorfenicol in serum has weak antibiotic effects. No inhibitory effects were observed at 12, 15, 24, 36, 48h point in serum. Moreover, At 6, 9, 12, 15, and 24h point, Fiorfenicol in tissue cage fluids exerted a powerful bactericidal effect which can kill almost all bacteria after 24h incubation. At 3h point, Fiorfenicol in tissue cage fluids has weak antibiotic effects. No inhibitory effects were observed at 12, 15, 24, 36, 48h point in tissue cage fluids.PK and PD data assayed by WinNonlin soft indicated that the PK-PD model of Fiorfenicol was Emax model. The relationship between ex vivoAUC_24h/MIC and antibiosis effect were handled using Hill equation. Serum AUC_24h/MIC values required for inhibition of bacterial growth is 23.69, 50% reduction in bacterial count is 24.33, 99.9% reduction in bacterial is 25.96 and elimination of bacteria is 52.33. Corresponding values for tissue cage fluids were almost identical (22.38. 25.31. 26.34. 51.64). Utilizing(?), the lowest aosage is 10.95 mg/kg tobacteriostasis effect.In summary, this topic is the first time to confirm that Florfenicol belongs to concentration-dependent agent and its PK-PD parameters are AUC/MIC and Cmax/MIC. It defmited clinical dosage of florfenicol for treating Porcine infectiousp leuropneumonia. This results offered an evidence to avoid abusing and misusing florfenicol, thus can grow downwards drug fast and save cost for cultivation.