Comparative pharmacokinetics of florfenicol in healthy and Pasteurella multocida‐infected Gaoyou ducks

Pasteurella multocida is the causative agent of fowl cholera, and florfenicol (FF) has potent antibacterial activity against P. multocida and is widely used in the poultry industry. In this study, we established a P. multocida infection model in ducks and studied the pharmacokinetics of FF in serum and lung tissues after oral administration of 30 mg/kg bodyweight. The maximum concentrations reached (C_max) were lower in infected ducks (13.88 ± 2.70 μg/ml) vs. healthy control animals (17.86 ± 1.57 μg/ml). In contrast, the mean residence time (MRT: 2.35 ± 0.13 vs. 2.27 ± 0.18 hr) and elimination half‐life (T_½β: 1.63 ± 0.08 vs. 1.57 ± 0.12 hr) were similar for healthy and diseased animals, respectively. As a result, the area under the concentration curve for 0–12 hr (AUC_0–12 hr) for FF in healthy ducks was significantly greater than that in infected ducks (49.47 ± 5.31 vs. 34.52 ± 8.29 μg hr/ml). The pharmacokinetic differences of FF in lung tissues between the two groups correlated with the serum pharmacokinetic differences. The C_max and AUC_0–12 hr values of lung tissue in healthy ducks were higher than those in diseased ducks. The concentration of FF in lung tissues was approximately 1.2‐fold higher than that in serum both in infected and healthy ducks indicating that FF is effective in treating respiratory tract infections in ducks.     

鸭源多杀性巴氏杆菌在人工感染雏鸭体内的动态研究

为探索多杀性巴氏杆菌在雏鸭体内的动态病理变化,用小鼠复壮鸭源多杀性巴氏杆菌,经测定其滴鼻途径的LD50=1×10-4.5/0.2 mL,口服途径的LD50=1×10-2.375/0.2mL.用100 LD50剂量,以口服、滴鼻途径分别感染雏鸭,于感染后6 h、12 h、18 h和24 h取心、肝、肺、肾及胸腺进行组织活菌计数.口服和滴鼻感染后12 h,从胸腺、肝、心、肺检测到生长繁殖的病原菌,18 h从口服感染组的肾脏检出目标菌,24 h从滴鼻组的肾脏检出目标菌.口服感染12 h,胸腺中菌数最高,达5.33×103 CFU/g,依次是肝、肺、心、肾.滴鼻感染12h,肺中菌数最高,达5.00×103 CFU/g,依次是胸腺、肝、心、肾.24 h均以胸腺菌数最高.表明检测体内鸭巴氏杆菌抗原或分离病原菌,首选器官是胸腺和肺,其次是肝、心.同时取心、肝、肺、肾、脾、胸腺、法氏囊、腺胃和十二指肠制作病理切片.消化道途径感染出现病变的最早时间是侵入后6 h,呼吸道途径感染出现病变的时间小于6 h.口服途径感染雏鸭后6 h,各器官都表现以充血为主要特征的轻微病理变化,6 h～12 h表现以细胞肿胀、开始细胞变性为特征的病理变化.12 h～18 h表现细胞变性加剧,开始核浓缩、核碎裂为特征的病理变化.18 h～24 h表现核浓缩、核碎裂加剧,细胞溶解的细菌损伤病理,以及淋巴细胞浸润、免疫器官网状内皮细胞增生相伴的免疫损伤.滴鼻途径的病理变化与口服途径相似,但病理进程有所提前.鸭多杀性巴氏杆菌对胸腺、脾、法氏囊等免疫器官造成病理损伤,以胸腺和脾脏的损伤较为严重.     

Comparative pharmacokinetics of marbofloxacin in healthy and Mannheimia haemolytica infected calves

The pharmacokinetics of marbofloxacin were investigated in healthy (n=8) and Mannheimia haemolytica naturally infected (n=8) Simmental ruminant calves following intravenous (i.v.) and intramuscular (i.m.) administration of 2 mg kg(-1) body weight. The concentration of marbofloxacin in plasma was measured using high performance liquid chromatography with ultraviolet detection. Following i.v. administration of the drug, the elimination half-life (t(1/2 beta)) and mean residence time (MRT) were significantly longer in diseased calves (8.2h; 11.13 h) than in healthy ones (4.6 h; 6.1 h), respectively. The value of total body clearance (CL(B)) was larger in healthy calves (3 ml min(-1) kg(-1)) than in diseased ones (1.3 ml min(-1) kg(-1)). After single intramuscular (i.m.) administration of the drug, the elimination half-life, mean residence time (MRT) and maximum plasma concentration (C(max)) were higher in diseased calves (8.0, 12 h, 2.32 microg ml(-1)) than in healthy ones (4.7, 7.4 h, 1.4 microg ml(-1)), respectively. The plasma concentrations and AUC following administration of the drug by both routes were significantly higher in diseased calves than in healthy ones. Protein binding of Marbofloxacin was not significantly different in healthy and diseased calves. The mean value for MIC of marbofloxacin for M. haemolytica was 0.1+/-0.06 microg ml(-1). The C(max)/MIC and AUC(24)/MIC ratios were significantly higher in diseased calves (13.0-64.4 and 125-618 h) than in healthy calves (8-38.33 and 66.34-328 h). The obtained results for surrogate markers of antimicrobial activity (C(max)/MIC, AUC/MIC and T > or = MIC) indicate the excellent pharmacodynamic characteristics of the drug in diseased calves with M. haemolytica, which can be expected to optimize the clinical efficacy and minimize the development of resistance.     

甲砜霉素在感染多杀性巴氏杆菌鸡体内的药物动力学

30只健康杂交肉鸡随机分成3组,每组10只,雌雄各半,分别进行健康鸡静脉注射、健康和巴氏杆菌感染鸡口服给药的药动学研究。静注和口服的给药剂量按体质量分别为15mg/kg和30mg/kg。以反相HPLC测定血浆中甲砜霉素的质量浓度,药物浓度-时间数据用3P97药动学程序软件处理。健康鸡单剂量静注给药后,血药浓度-时间数据符合无吸收二室开放模型,其主要动力学参数分别为:V(c)为(0.58±0.09)L/kg,t1/2α(0.11±0.03)h,t1/2β(0.95±0.18)h,AUC为(11.99±0.90)mg/(L.h),CL(s)为(1.26±0.10)L/(kg.h)。健康鸡和巴氏杆菌感染鸡单剂量口服给药血药浓度-时间数据均符合一级吸收一室开放模型。健康鸡口服给药的主要动力学参数分别为:Lagtime(0.04±0.02)h,t1/2ka(0.16±0.08)h,t1/2ke(1.64±0.22)h,T(peak)(0.57±0.18)h,C(max)(6.34±0.56)mg/L,AUC为(19.02±1.48)mg/(L.h),F为79.32%。巴氏杆菌感染鸡口服给药的主要动力学参数分别为:Lagtime(0.07±0.02)h,t1/2ka(0.54±0.26)h,t1/2ke(1.74±0.27)h,T(peak)(1.31±0.39)h,C(max)(5.28±0.73)mg/L,AUC为(21.75±1.03)mg/(L.h),F90.70%。与健康鸡相比,甲砜霉素在感染鸡的t1/2(ka)、T(peak)和Lag-time显著延长(P0.05或P0.01),且比健康鸡具有更高的生物利用度。但甲砜霉素在巴氏杆菌感染鸡体内的消除速度未受影响。     

Atrophic rhinitis in New Zealand white rabbits infected with Pasteurella multocida

Atrophic rhinitis was detected in New Zealand White rabbits when upper respiratory tract disease was evaluated during a vaccine field trial for the prevention of pasteurellosis. Of 52 adult rabbits euthanatized and necropsied, 26 (50%) had evidence of turbinate atrophy. Atrophy was detected in 77% of rabbits with Pasteurella multocida infection only, 71% of rabbits with concurrent P multocida and Bordetella bronchiseptica infections, and 6% of rabbits with B bronchiseptica infection only. Grossly, turbinate atrophy was characterized by a mild to severe loss or diminution in the maxilloturbinates. Histologically, turbinate bones were small and irregular in thickness and had numerous osteoclasts and osteoblasts. A neutrophilic exudate filled the nasal passages, and infiltrates of neutrophils and lymphocytes were detected in the mucosa and submucosa of the nasal turbinates. Rhinitis was significantly (P less than 0.001) associated with turbinate atrophy. Isolates of P multocida from rabbits with turbinate atrophy were serotype A:12.     

Antibacterial efficacy and pharmacokinetic studies of ciprofloxacin on Pasteurella multocida infected rabbits

Twenty four isolates of Pasteurella multocida were taken from 74 diseased rabbits which suffered from respiratory manifestations with an incidence 35.1%. All isolated strains were identified biochemically and serologically as Pasteurella multocida type 3. The in vitro sensitivity test proved that Ciprofloxacin was the most effective antibiotic which was used for treatment of diseased rabbits. There was no isolation of Pasteurella multocida organism from all treated rabbits with Ciprofloxacin which can eliminate the causative organism, and control the infection within the examined rabbit colony. The kinetics of Ciprofloxacin, a fluoroquinolone, was studied after multiple oral and I/V dose of 20 mg/kg b. wt. In healthy rabbits and in those diseased with Pasteurella multocida Ciprofloxacin was given at a dose (20 mg kg-1/day) orally for successive 5 days. Serum levels reached their peak Tmax, at 2.321 and 2.524 hrs. in healthy and infected rabbits after oral administration, with absorption half-life (t0.5 (ab)) of 1.22 and 2.41 hrs. and elimination half-life (t0.5 (B)) of 2.24 and 1.28 hour respectively. Following I/V injection the kinetics of Ciprofloxacin follow two compartment model with (t0.5 (B)) 1.201 and 0.82 hour for normal and infected rabbits, (Vd (area)) of 0.653 and 0.563 L/kg and total body clearance CL(B) of 0.385 and 0.358 L/kg/hr respectively. High tissue concentrations of the drug were recorded in the kidneys, lung, spleen, liver, and muscle of diseased rabbits, while in healthy animal group the highest concentrations were achieved in kidney, liver, lung, spleen, and muscle. The high Ciprofloxacin tissue concentrations indicate that the Ciprofloxacin may be an excellent drug for treating urinary and respiratory tract infections.     

替米考星治疗人工感染巴氏杆菌病仔猪试验

研究了国产替米考星注射用药对人工感染多杀性巴氏杆菌病猪的治疗效果,用断奶仔猪进行试验,为临床使用提供了依据.结果表明,替米考星治疗急性猪肺疫效果确实, 推荐剂量为10 mg/kg体重.     

Reduced microbicidal activity of peripheral mononuclear phagocytic cells infected with Pasteurella multocida

Pasteurella multocida inhibits the uptake and killing of Candida albicans and P. multocida by avian mononuclear phagocytic cells. The toxic outer membrane protein of P. multocida, which has been previously described, also inhibited the uptake and killing of C. albicans. Antibody specific for the toxic outer membrane protein reversed this effect resulting not only in an increase in uptake of C. albicans and P. multocida, but also in intracellular killing of P. multocida. This antibody, however, only partially restored killing of C. albicans. These data support the hypothesis that P. multocida is capable of intracellular survival in avian mononuclear phagocytic cells and that the toxic outer membrane protein is totally or partly responsible for this occurrence.     

Pharmacokinetics of sulfadimidine and its N4-acetyl metabolite in healthy and diseased rabbits infected with Pasteurella multocida

The pharmacokinetics of sulfadimidine (SDM) and its N4-acetyl metabolite (N4SDM) were investigated after intravenous bolus injection of a single dose (200 mg/kg) of SDM in normal and diseased New Zealand white rabbits. The apparent distribution volume at steady state, total body clearance and elimination half-life of SDM in normal animals were 0.7 +/- 0.3 l/kg, 0.57 +/- 0.24 l/kg/h and 1.6 +/- 1.3 h, respectively. Of the administered dose, 62.1% was metabolized by N4-acetylation, and 12.7 +/- 1.1 and 2.8 +/- 1.8% of the dose was excreted as free drug by the kidney and gastrointestinal tract, respectively. The 'apparent' formation and elimination half-lives of N4SDM were 0.6 +/- 0.4 and 2.2 +/- 1.1 h, respectively. The metabolite was eliminated mainly by excretion through the kidney. There was no significant effect of acute pasteurellosis on the pharmacokinetics of either SDM or N4SDM in rabbits.     

Comparative susceptibility of caponized and uncaponized tom turkeys to Pasteurella multocida.

When susceptibility to virulent Pasteurella multocida was compared, there was no significant (P greater than 0.05) difference between caponized and uncaponized tom turkeys. Neither was there any significant (P greater than 0.05) difference between the surviving caponized and uncaponized toms in the development of serum anti-P. multocida antibody. However, at 28 weeks of age, the average live body weight of the caponized toms was significantly (P less than 0.05) lower than that of the uncaponized toms. Turkeys were caponized when 9 weeks old, and different groups were exposed to P. multocida when 13, 18, 23, and 28 weeks old.     

Deoxyribonucleic acids from Pasteurella multocida and Pasteurella haemolytica]

Pasteurella multocida and P. haemolytica strains contain between 1.5 and three per cent phosphorus, between nine and 14 per cent nitrogen, between two and four per cent DNA, and between five and 18 per cent RNA, the precise figures depending on culturing conditions. High-molecular DNA may be isolated by means of bacteriolysis, using deoxycholate or dodecylsulphate and the usual steps of purification, with yield and purity differing by strains. DNA with sufficient purity can be obtained from Sepharose 2 B by gel chromatography. The isolated DNA yields were characterised, base values being between 37 and 38 per cent GC for P. haemolytica and between 41 and 48 per cent GC for P. multocida. Highly suitable precursors to DNA synthesis for tritium labelling are 3H-thymidine, which is incorporated in excess of 3H-thymine by a factor of 255, as well as 3H-uracil, with its activity being recovered also from the pyrimidine bases of DNA via pyrimidine biosynthesis.     

产毒素多杀性巴氏杆菌的鉴定

采用菌落多重PCR方法对分离保存的28株多杀性巴氏杆菌进行种型和毒素基因的检测,结果表明,菌株C51-6、M-4和P-2237为产毒素多杀性巴氏杆菌,菌株C51-6和P-2237为荚膜血清D型,菌株M-4为荚膜血清A型。同时用金黄色葡萄球菌抑制试验、中性吖啶黄沉淀试验和豚鼠皮肤坏死试验对PCR方法进行了验证。基于对甘露醇、卫茅醇、山梨醇、海藻糖的发酵能力和产生鸟氨酸脱羧酶的特性,3株菌株鉴定为多杀性巴氏杆菌多杀亚种。