喹赛多抗菌作用及对猪短螺旋体性痢疾的治疗作用研究
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摘要
防治动物疾病、改善生产性能药物的开发,对养殖业具有重要意义。喹赛多正是处于开发中的具有抗菌促生长作用的喹噁啉类新品种。已有研究表明,喹赛多毒性作用小,安全性高,具有较好的开发应用前景。已有的药效学研究发现喹赛多对多种畜禽和水产动物均有改善生长性能,降低腹泻率的作用,并可预防猪和鸡的大肠杆菌病。体外药敏试验也表明喹赛多对多种常见致病菌有较强的抗菌作用,特别对大肠杆菌、沙门氏杆菌、巴氏杆菌、猪丹毒杆菌、金黄色葡萄球菌、柱状嗜纤维菌、迟缓爱德华氏菌、猪痢疾短螺旋体等的作用较强。然而,目前喹赛多抗菌作用的研究尚缺乏系统性,细菌种类和数量较局限,临床控制疾病的研究也很少,其更多的抗菌作用和临床应用价值有待进一步开发。本试验扩大了体外药敏试验菌种的种类和数量,建立喹赛多在猪、鸡、鱼体的抗菌谱,并根据体外药敏结果进行了喹赛多对猪痢疾的Ⅱ期临床治疗试验,为喹赛多的进一步推广应用提供科学依据。
1喹赛多的体外抗菌试验
采用倍比稀释法测定喹赛多对猪、鸡、鱼等来源的19个属35种96株常见致病菌的最小抑菌浓度和最小杀菌浓度,主要参考标准为CLSI制定相关文件,并以金霉素、喹乙醇、杆菌肽锌和磺胺二甲氧嘧啶为对照药物。由于体内细菌基本处于无氧或缺氧的环境,因而也对兼性厌氧菌在厌氧条件下的药敏作用进行了测定。结果表明,喹赛多是一种对革兰氏阴性菌和革兰氏阳性菌均有较好作用的广谱抗菌剂。对大部分细菌的作用好于或等于对照药物喹乙醇、杆菌肽锌和磺胺二甲氧嘧啶,差于盐酸金霉素。
喹赛多对猪源致病菌,标准条件下,其主要敏感菌为猪痢疾短螺旋体、产气荚膜梭菌和巴氏杆菌,特别是前两者的MIC和MBC值在0.031～1 gg/mL之间,巴氏杆菌的MIC90和MBC90为8μg/mL和32μg/mL。中度敏感菌为霍乱沙门氏菌、大肠杆菌、丹毒丝菌和链球菌,MIC值为8～128μg/mL,MBC值为32->128μg/mL。对兼性厌氧菌在无氧条件下,喹赛多对大肠杆菌、巴氏杆菌、霍乱沙门氏菌和丹毒丝菌的抗菌活性可提高4-64倍,主要敏感菌为巴氏杆菌、大肠杆菌、霍乱沙门氏菌和丹毒丝菌,MIC为0.125～4 gg/mL,MBC为0.5～64 gg/mL；中度敏感菌为链球菌,MIC和MBC值为16～64μg/mL和32～128μg/mL。
喹赛多对鸡源致病菌,标准条件下,其主要敏感菌为空肠弯曲杆菌、产气荚膜梭菌和巴氏杆菌,特别是前两者的MIC值和MBC值在0.25～1μg/mL和1-32μg/mL,巴氏杆菌的MIC值和MBC值为2-4μg/mL和16～32 gg/mL；中度敏感菌为沙门氏菌、大肠杆菌和金黄色葡萄球菌,MIC为4-32 gg/mL,MBC为16～128μg/mL；对粪肠球菌和屎肠球菌则不敏感。对兼性厌氧菌在无氧条件下,喹赛多对沙门氏菌、大肠杆菌和肠球菌的抗菌活性可提高8-16倍,主要敏感菌为巴氏杆菌、大肠杆菌和鸡沙门氏菌,MIC为1-4μg/mL,MBC为4-32μg/mL；中度敏感菌为粪肠球菌和屎肠球菌,MIC和MBC为8-16μg/mL和64μg/mL。
喹赛多对鱼源致病菌,标准条件下,主要敏感菌为大肠杆菌、柱状黄杆菌,但对后者仅有抑菌作用,无杀菌作用；中度敏感菌为鲁克氏耶尔森氏菌、金黄色葡萄球菌、无乳链球菌和结核分枝杆菌,MIC为2-32 gg/mL,MBC为32～128μg/mL；对荧光假单胞菌、鲍曼不动杆菌、气单胞菌、鲶鱼爱德华氏菌和河弧菌不敏感。对兼性厌氧菌在无氧条件下,喹赛多对气单胞菌(除肠型点状气单胞菌)、河弧菌、鲍曼不动杆菌和鲁克氏耶尔森菌的敏感性可提高8～256倍,主要敏感细菌为气单胞菌(除肠型点状气单胞菌)、河弧菌、鲁克氏耶尔森菌、鲍曼不动杆菌和无乳链球菌,MIC为0.5-8μg/mL,MBC为1-16μg/mL；不敏感菌为荧光假单胞菌、肠型点状气单胞菌和鲶鱼爱德华氏菌。
喹赛多对其它源致病菌,在有氧条件下,敏感菌为鼠伤寒沙门氏菌,MIC和MBC为8μg/mL和>128μg/mL；中度敏感菌为小结肠耶尔森氏菌和奇异变形杆菌,MIC和MBC为32 gg/mL和128 gg/mL；对铜绿假单胞菌不敏感。厌氧条件下,奇异变形杆菌的抑菌作用提高了8倍,主要敏感菌为鼠伤寒沙门氏菌和奇异变形杆菌,MIC和MBC为4-8μg/mL和32-64μg/mL,中度敏感菌为小结肠耶尔森氏菌,MIC和MBC为16μg/mL和64μg/mL；不敏感菌为绿脓假单胞菌。
2喹赛多对猪痢疾的治疗试验
体重约为15kg的健康断奶仔猪随机分为7组,每组10头。其中,空白组不攻毒也不给药；阴性组进行人工攻毒,不作治疗；药物对照组进行人工攻毒后,用100 ppm和200 ppm的喹乙醇混饲治疗；试验组分为喹赛多的高(400 ppm)、中(200 ppm)、低(100 ppm)三个剂量组,人工攻毒后混饲给药治疗。用猪痢疾短螺旋体攻毒后,经过7-13天的潜伏期,各攻毒组有7-9头猪出现血便,此时开始混饲给药,每天饲喂两次,对治疗初期毫不吃食的猪采取当次当量喂服的方式,食欲好转和食欲差的猪仍任其自由采食。各给药组达100%治愈时停药,再继续观察两周。对治疗效果从临床表现、治愈率、复发率、生长性能、血液生理生化指标和病理变化的多个方面进行考查。
用药期间,各用药组动物的食欲、精神和粪便状况随着用药时间的延长逐渐好转。喹赛多400 ppm组的疗程最短,在治疗的第6天便可达到100%的治愈,且不复发；喹赛多200 ppm组的疗效也较好,用药6天后也能使治愈率达到80%以上；喹赛多100ppm组的疗程则较长,病情容易反复,需要两周时间使治愈率控制在80%以上。而对照药物喹乙醇200 ppm组的疗效与喹赛多400 ppm组相当,好于200 ppm的喹赛多,喹乙醇100 ppm组与喹赛多100 ppm组疗效相当。
喹赛多400 ppm组的日增重和肉料比最高,比空白组日增重和肉料比提高了5.2%和22.2%；喹赛多200 ppm组的日增重和肉料比与空白组相当,而喹乙醇的日增重和肉料比为空白组的25.4%和30.6%；喹赛多100 ppm组的日增重和肉料比是空白组的74.0%和80.6%,喹乙醇100 ppm组的日增重和肉料比是空白组的55.6%和58.3%；阴性组动物体重基本呈负增长。
血液生理生化指标和病理学观察认为喹赛多400 ppm的剂量对肾脏和水盐代谢有轻度影响,但在临床没有任何表现,其生长性能有显著提高,可认为其没有明显副作用；喹乙醇200 ppm对肾和肾上腺有一定的损伤,对肝脏和水盐代谢有轻度影响,在临床上有饮积水和同栏动物尿液的现象,并且生长性能下降,副作用较明显。
总之,喹赛多临床治疗猪痢疾的推荐剂量为200～400 ppm。建议以200-400ppm的混饲剂量用于症状明显的猪群；以100 ppm的混饲剂量用于预防和临床治防,或者用于治愈后的巩固过程。
综上所述,本课题参考了美国食品药品管理局(FDA)的抗菌药物的微生物资料要求和抗微生物药物临床评价指南等相关文件,及我国农业部颁发的实验临床试验技术规范,建立了喹赛多在多种动物的抗菌谱,评价了喹赛多对猪痢疾的Ⅱ期临床治疗效果,为喹赛多在畜禽和水产动物的合理应用提供了理论依据。喹赛多在在畜禽和水产生产中抗菌作用好,又能够起到促生长作用,具有广阔的应用前景。
Exploitation of new antimicrobial growth promoter is important to the aquaculture industry. Cyadox is a developing candidate of quinoxalines. Existing research demonstrated that cyadox has low toxicity, good safety, and has good prospects for development and application. Pharmacodynamic studies showed that cyadox can promote the growth of livestock, poultry and aquatic animals, reduce diarrhea frequencies, and be effective for prevention of E. coli infection in piglets and broilers. Some studies on antibacterial activity of cyadox in vitro have indicated that cyadox was active to many pathogens, especially Escherichia coli, Salmonella spp., Staphylococcus aureus, Pasteurella multocida, Erysipelothrix rhuriopathiae, Flavobacterim columnare, Edwardsiella tarda, Brachyspira hyodysenteriae and so on. The antibacterial activity of cyadox is similar to or stronger than olaquindox. However, the existing antibacterial data are lack of systematization, and the type and quantity of bacteria are limited, and the research on control disease is too little, so some new antibacterial activity and clinical value of cyadox need a further study. This antimicrobial susceptibility tests expanded the type and quantity of bacteria in vitro, built up the antimicrobial spectra of livestock, poultry and aquatic animals, and according to the result in vitro carried on approach II clinical study on the therapeutic effect of cyadox on swine dysentery, all of which will provide the scientific basis for the further application of this drug.
1 In vitro antimicrobial activity of cyadox
The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of cyadox against 96 strains bacteria from35 species in 19 genus, isolated from pigs, poultry and fishes, were evaluated by twofold dilution methods recommended by Clinical and Laboratory Standards Institute (CLSI). The control drug including chlortetracycline, olaquindox, bacitracin zinc and sulfadimidine. Since it's an anaerobic or anoxic environment in vivo, the antimicrobial activity of facultative anaerobes in anaerobic condition was determined, too. The results showed that cyadox was a broad-spectrum antibacterial agent which has a good effect on gram-negative and gram-positive bacteria. The antibacterial activity of cyadox was stronger than or similar to that of olaquindox, stronger than that of bacitracin zinc and sulfadimidine, and weaker than that of chlortetracycline.
The antimicrobial spectrum of cyadox against pathogens isolated from pigs were as follows. Under standard conditions, susceptible bacteria were Brachyspira hyodysenteria, Clostridium perfringen and Pasteurella multocida, the MICs and MBCs of former two were 0.031～1μg/mL, and the MlCc90 and MBC90 of Pasteurella multocida were 8μg/mL and 32μg/mL, respectively. Intermediate bacteria were Salmonella choleraesui, Escherichia coil, Erysipelothrix rhuriopathiae and Streptococcus, MICs were 8～128μg/mL and MBCs were 32～>128μg/mL, respectively. Under anaerobic conditions, the antibacterial activity were enhanced by 4-64 times on Escherichia coil, Pasteurella multocida, Salmonella choleraesui and Erysipelothrix. Susceptible bacteria were Pasteurella multocida, Escherichia coil, Salmonella choleraesui and Erysipelothrix, MICs were 0.125～4μg/mL, MBC were 0.5～64μg/mL. Intermediate bacteria was Streptococcus, MICs and MBCs were 16～64μg/m and 32～128μg/mL, respectively.
The antimicrobial spectrum of cyadox against pathogens isolated from poultry were as follows. Under, standard conditions, susceptible bacteria were Campylobacter jejuni, Clostridium perfringen and Pasteurella multocida, MICs and MBCs of the former two were 0.25～1μg/mL and 1μg/mL, the MIC and MBC of Pasteurella multocida were 2-4μg/mL and 16～32μg/mL, respectively. Intermediate bacteria were Salmonella pullorum, Escherichia coil and Staphylococcus aureus, MICs were 8～32μg/mL, MBCs were 16～128μg/mL. Nonsusceptible bacteria were Enterococcu faecalis and Enterococcu faecium. Under anaerobic conditions, the antibacterial activity were enhanced by 8-16 times on Salmonella spp., Escherichia coil and Enterococcus spp.. Susceptible bacteria are Pasteurella multocida, Escherichia coil and Salmonella spp., MICs were 1～4μg/mL, MBCs were 4～32μg/mL. Intermediate bacteria were Enterococcu faecalis and Enterococcu faecium, MICs and MBCs were 8～16μg/mL and 64μg/mL, respectively.
The antimicrobial spectrum of cyadox against common pathogens isolated from fishes were as follows. Under standard conditions, susceptible bacteria were Escherichia coil and Flavobacterim columnare, but there were no killing effect for Flavobacterim columnare. Intermediate bacteria were Yersinia ruckeri, Staphylococcus aureus, Streptococcus agalactiae and Mycobacterium tuberculosis, MICs were 2～32μug/mL, MBCs were 32～128μg/mL. Nonsusceptible bacteria were Pseudomonas fluorescent, Acinetobacter baumannii, Aeromonas spp. (including A. hydrophila, A. veronii, A. jandaei, A. caviae and A. sobria and A. punctata), Edwardsiell ictaluri and Vibrio fluvialis. Under anaerobic conditions, the antibacterial activity were enhanced by 8-256 times on Aeromonas spp. (exclude Aeromonas punctata), Vibrio fluvialis, Acinetobacter baumannii and Yersinia ruckeri. Susceptible bacteria were Aeromonas spp. (exclude A. punctata), Vibrio fluvialis, Yersinia ruckeri, Vibrio fluvialis and Streptococcus agalactiae, MICs were 0.5～8μg/mL, MBCs were 1～16μg/mL. Nonsusceptible bacteria were Pseudomonas fluorescent, Aeromonas punctata and Edwardsiell ictaluri.
Antimicrobial susceptibility of cyadox against pathogenic bacteria isolated from others were as follows. Under standard conditions, susceptible bacteria were Salmonella typhimurium, MICs were 8μg/mL, MBCs were>128μg/mL. Intermediate bacteria are Yersinia enterocolitica and Proteus mirabilis, MICs and MBCs were 32μg/mL and 128μg/mL; Nonsusceptible bacteria is Pseudomonas pyocyanea. Under anaerobic conditions, the antibacterial activity were enhanced by 8 times on Proteus mirabilis. Susceptible bacteria is Salmonella typhimurium and Proteus mirabilis, MICs and MBCs were 4-8μg/mL and 32-64μg/mL, respectively. Intermediate bacteria were Yersinia enterocolitica, MIC and MBC were 16μg/mL and 64μg/mL, respectively; Nonsusceptible bacterium was Pseudomonas pyocyanea.
2 Therapeutic effect of cyadox on swine dysentery
Seventy crossbred piglets weighing～15kg were randomly divided into 7 treatments with ten replications (pens) each. Blank group, without artificial challenge nor administration. Negative control group, with artificial challenge, but not administration. Positive control groups, fed with olaquindox at 100 ppm and 200 ppm after the artificial challenge were successful. Experimental groups, fed with cyadox at 400 ppm,200 ppm and 100 ppm after the artificial challenge were successful. The average incubation period infection with B. hyodysenteriae is 7～13 days, when 7～9 piglets began to excrete with haemorrhagic diarrhoea, the treatment would begin as administration by fed, two times per day. Meanwhile, some those piglets did not eat any feed would be treated by oral medication, those with improved appetite or poor appetite still administration by fed. Stop administration when the groups had a 100% cure rate, and continued to observe two weeks. Evaluated the therapeutic effect with the clinical manifestation, cure rate, relapse rate, growth performance, blood biochemical indices and pathological examination.
During administration, the appetite, mental status and fecal index of treatment group were gradually improved. Cyadox 400 ppm group had the shortest course of treatment, after 6 days of treatment the cure rate was 100%, and not relapse; Cyadox 200 ppm group had a good effect also, medication for 6 days also achieved more than 80% cure rate; Cyadox 100 ppm group had a long course of treatment for some dysentery repeat, and took two weeks to achieve more than 80% cure rate. Olaquindox 200 ppm group had an similar efficacy as cyadox 400 ppm group, better than cyadox 200 ppm group. Olaquindox 100 ppm group had a similar efficacy as cyadox 100 ppm group.
Cyadox 400 ppm group had the highest Average Daily Gain (ADG) and Gain/Feed (G/F), the ADG and G/F were increased by 5.2% and 22.2% than blank group. Cyadox 200 ppm group was similar with blank group, while the ADG and G/F of olaquindox 200 ppm group were decreased to 25.4% and 30.6% of blank group. The ADG and G/F of cyadox 100 ppm group were decreased to 74.0% and 80.6% of blank group, olaquindox 100 ppm group were decreased to 55.6% and 58.3% of blank group. Negative growth was showed in negative group.
The blood parameters and pathological examination indicated cyadox 400 ppm had a mild impact on water and salt metabolism and kidney, but there were no any clinical manifestations, and the growth performance had been significantly improved, so it could be considered no significant side effects. The 200 ppm olaquindox group suffered a moderate damage on kidney and adrenal and a mild negatively affected on water and salt metabolism and liver. The animals in this group would like drink ground water and urine of fellow, and had a decreased growth performance, so the side effects of 200 ppm olaquindox diet was obvious.
In short, the therapeutic dose of cyadox recommended for swine dysentery is 200～400 ppm. We suggest taking 200～400 ppm cyadox for treatment by fed; 100 ppm dose for the prevention and metaphylaxis, or the process of consolidation after curing.
In summary, this subject had referred the "Microbiological Data for Systemic Antibacterial Drug Products—Development, Analysis, and Presentation", "Developing Antimicrobial Drugs—General Considerations for Clinical Trials" formulated by Food and Drug Administration (FDA) and "Experimental Clinical Trial Technology Standard" issued by China Ministry of Agriculture, and established the antimicrobial spectra in a variety of animals, evaluate the phaseⅡclinical study of cyadox on the therapeutic effect on swine dysentery, and gave scientific guidance for the reasonable use of cyadox in livestock, poultry and aquatic animals. Cyadox will have a broad application prospect for it's good effect in animal production.
1喹赛多的体外抗菌试验
采用倍比稀释法测定喹赛多对猪、鸡、鱼等来源的19个属35种96株常见致病菌的最小抑菌浓度和最小杀菌浓度,主要参考标准为CLSI制定相关文件,并以金霉素、喹乙醇、杆菌肽锌和磺胺二甲氧嘧啶为对照药物。由于体内细菌基本处于无氧或缺氧的环境,因而也对兼性厌氧菌在厌氧条件下的药敏作用进行了测定。结果表明,喹赛多是一种对革兰氏阴性菌和革兰氏阳性菌均有较好作用的广谱抗菌剂。对大部分细菌的作用好于或等于对照药物喹乙醇、杆菌肽锌和磺胺二甲氧嘧啶,差于盐酸金霉素。
喹赛多对猪源致病菌,标准条件下,其主要敏感菌为猪痢疾短螺旋体、产气荚膜梭菌和巴氏杆菌,特别是前两者的MIC和MBC值在0.031～1 gg/mL之间,巴氏杆菌的MIC90和MBC90为8μg/mL和32μg/mL。中度敏感菌为霍乱沙门氏菌、大肠杆菌、丹毒丝菌和链球菌,MIC值为8～128μg/mL,MBC值为32->128μg/mL。对兼性厌氧菌在无氧条件下,喹赛多对大肠杆菌、巴氏杆菌、霍乱沙门氏菌和丹毒丝菌的抗菌活性可提高4-64倍,主要敏感菌为巴氏杆菌、大肠杆菌、霍乱沙门氏菌和丹毒丝菌,MIC为0.125～4 gg/mL,MBC为0.5～64 gg/mL；中度敏感菌为链球菌,MIC和MBC值为16～64μg/mL和32～128μg/mL。
喹赛多对鸡源致病菌,标准条件下,其主要敏感菌为空肠弯曲杆菌、产气荚膜梭菌和巴氏杆菌,特别是前两者的MIC值和MBC值在0.25～1μg/mL和1-32μg/mL,巴氏杆菌的MIC值和MBC值为2-4μg/mL和16～32 gg/mL；中度敏感菌为沙门氏菌、大肠杆菌和金黄色葡萄球菌,MIC为4-32 gg/mL,MBC为16～128μg/mL；对粪肠球菌和屎肠球菌则不敏感。对兼性厌氧菌在无氧条件下,喹赛多对沙门氏菌、大肠杆菌和肠球菌的抗菌活性可提高8-16倍,主要敏感菌为巴氏杆菌、大肠杆菌和鸡沙门氏菌,MIC为1-4μg/mL,MBC为4-32μg/mL；中度敏感菌为粪肠球菌和屎肠球菌,MIC和MBC为8-16μg/mL和64μg/mL。
喹赛多对鱼源致病菌,标准条件下,主要敏感菌为大肠杆菌、柱状黄杆菌,但对后者仅有抑菌作用,无杀菌作用；中度敏感菌为鲁克氏耶尔森氏菌、金黄色葡萄球菌、无乳链球菌和结核分枝杆菌,MIC为2-32 gg/mL,MBC为32～128μg/mL；对荧光假单胞菌、鲍曼不动杆菌、气单胞菌、鲶鱼爱德华氏菌和河弧菌不敏感。对兼性厌氧菌在无氧条件下,喹赛多对气单胞菌(除肠型点状气单胞菌)、河弧菌、鲍曼不动杆菌和鲁克氏耶尔森菌的敏感性可提高8～256倍,主要敏感细菌为气单胞菌(除肠型点状气单胞菌)、河弧菌、鲁克氏耶尔森菌、鲍曼不动杆菌和无乳链球菌,MIC为0.5-8μg/mL,MBC为1-16μg/mL；不敏感菌为荧光假单胞菌、肠型点状气单胞菌和鲶鱼爱德华氏菌。
喹赛多对其它源致病菌,在有氧条件下,敏感菌为鼠伤寒沙门氏菌,MIC和MBC为8μg/mL和>128μg/mL；中度敏感菌为小结肠耶尔森氏菌和奇异变形杆菌,MIC和MBC为32 gg/mL和128 gg/mL；对铜绿假单胞菌不敏感。厌氧条件下,奇异变形杆菌的抑菌作用提高了8倍,主要敏感菌为鼠伤寒沙门氏菌和奇异变形杆菌,MIC和MBC为4-8μg/mL和32-64μg/mL,中度敏感菌为小结肠耶尔森氏菌,MIC和MBC为16μg/mL和64μg/mL；不敏感菌为绿脓假单胞菌。
2喹赛多对猪痢疾的治疗试验
体重约为15kg的健康断奶仔猪随机分为7组,每组10头。其中,空白组不攻毒也不给药；阴性组进行人工攻毒,不作治疗；药物对照组进行人工攻毒后,用100 ppm和200 ppm的喹乙醇混饲治疗；试验组分为喹赛多的高(400 ppm)、中(200 ppm)、低(100 ppm)三个剂量组,人工攻毒后混饲给药治疗。用猪痢疾短螺旋体攻毒后,经过7-13天的潜伏期,各攻毒组有7-9头猪出现血便,此时开始混饲给药,每天饲喂两次,对治疗初期毫不吃食的猪采取当次当量喂服的方式,食欲好转和食欲差的猪仍任其自由采食。各给药组达100%治愈时停药,再继续观察两周。对治疗效果从临床表现、治愈率、复发率、生长性能、血液生理生化指标和病理变化的多个方面进行考查。
用药期间,各用药组动物的食欲、精神和粪便状况随着用药时间的延长逐渐好转。喹赛多400 ppm组的疗程最短,在治疗的第6天便可达到100%的治愈,且不复发；喹赛多200 ppm组的疗效也较好,用药6天后也能使治愈率达到80%以上；喹赛多100ppm组的疗程则较长,病情容易反复,需要两周时间使治愈率控制在80%以上。而对照药物喹乙醇200 ppm组的疗效与喹赛多400 ppm组相当,好于200 ppm的喹赛多,喹乙醇100 ppm组与喹赛多100 ppm组疗效相当。
喹赛多400 ppm组的日增重和肉料比最高,比空白组日增重和肉料比提高了5.2%和22.2%；喹赛多200 ppm组的日增重和肉料比与空白组相当,而喹乙醇的日增重和肉料比为空白组的25.4%和30.6%；喹赛多100 ppm组的日增重和肉料比是空白组的74.0%和80.6%,喹乙醇100 ppm组的日增重和肉料比是空白组的55.6%和58.3%；阴性组动物体重基本呈负增长。
血液生理生化指标和病理学观察认为喹赛多400 ppm的剂量对肾脏和水盐代谢有轻度影响,但在临床没有任何表现,其生长性能有显著提高,可认为其没有明显副作用；喹乙醇200 ppm对肾和肾上腺有一定的损伤,对肝脏和水盐代谢有轻度影响,在临床上有饮积水和同栏动物尿液的现象,并且生长性能下降,副作用较明显。
总之,喹赛多临床治疗猪痢疾的推荐剂量为200～400 ppm。建议以200-400ppm的混饲剂量用于症状明显的猪群；以100 ppm的混饲剂量用于预防和临床治防,或者用于治愈后的巩固过程。
综上所述,本课题参考了美国食品药品管理局(FDA)的抗菌药物的微生物资料要求和抗微生物药物临床评价指南等相关文件,及我国农业部颁发的实验临床试验技术规范,建立了喹赛多在多种动物的抗菌谱,评价了喹赛多对猪痢疾的Ⅱ期临床治疗效果,为喹赛多在畜禽和水产动物的合理应用提供了理论依据。喹赛多在在畜禽和水产生产中抗菌作用好,又能够起到促生长作用,具有广阔的应用前景。
Exploitation of new antimicrobial growth promoter is important to the aquaculture industry. Cyadox is a developing candidate of quinoxalines. Existing research demonstrated that cyadox has low toxicity, good safety, and has good prospects for development and application. Pharmacodynamic studies showed that cyadox can promote the growth of livestock, poultry and aquatic animals, reduce diarrhea frequencies, and be effective for prevention of E. coli infection in piglets and broilers. Some studies on antibacterial activity of cyadox in vitro have indicated that cyadox was active to many pathogens, especially Escherichia coli, Salmonella spp., Staphylococcus aureus, Pasteurella multocida, Erysipelothrix rhuriopathiae, Flavobacterim columnare, Edwardsiella tarda, Brachyspira hyodysenteriae and so on. The antibacterial activity of cyadox is similar to or stronger than olaquindox. However, the existing antibacterial data are lack of systematization, and the type and quantity of bacteria are limited, and the research on control disease is too little, so some new antibacterial activity and clinical value of cyadox need a further study. This antimicrobial susceptibility tests expanded the type and quantity of bacteria in vitro, built up the antimicrobial spectra of livestock, poultry and aquatic animals, and according to the result in vitro carried on approach II clinical study on the therapeutic effect of cyadox on swine dysentery, all of which will provide the scientific basis for the further application of this drug.
1 In vitro antimicrobial activity of cyadox
The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of cyadox against 96 strains bacteria from35 species in 19 genus, isolated from pigs, poultry and fishes, were evaluated by twofold dilution methods recommended by Clinical and Laboratory Standards Institute (CLSI). The control drug including chlortetracycline, olaquindox, bacitracin zinc and sulfadimidine. Since it's an anaerobic or anoxic environment in vivo, the antimicrobial activity of facultative anaerobes in anaerobic condition was determined, too. The results showed that cyadox was a broad-spectrum antibacterial agent which has a good effect on gram-negative and gram-positive bacteria. The antibacterial activity of cyadox was stronger than or similar to that of olaquindox, stronger than that of bacitracin zinc and sulfadimidine, and weaker than that of chlortetracycline.
The antimicrobial spectrum of cyadox against pathogens isolated from pigs were as follows. Under standard conditions, susceptible bacteria were Brachyspira hyodysenteria, Clostridium perfringen and Pasteurella multocida, the MICs and MBCs of former two were 0.031～1μg/mL, and the MlCc90 and MBC90 of Pasteurella multocida were 8μg/mL and 32μg/mL, respectively. Intermediate bacteria were Salmonella choleraesui, Escherichia coil, Erysipelothrix rhuriopathiae and Streptococcus, MICs were 8～128μg/mL and MBCs were 32～>128μg/mL, respectively. Under anaerobic conditions, the antibacterial activity were enhanced by 4-64 times on Escherichia coil, Pasteurella multocida, Salmonella choleraesui and Erysipelothrix. Susceptible bacteria were Pasteurella multocida, Escherichia coil, Salmonella choleraesui and Erysipelothrix, MICs were 0.125～4μg/mL, MBC were 0.5～64μg/mL. Intermediate bacteria was Streptococcus, MICs and MBCs were 16～64μg/m and 32～128μg/mL, respectively.
The antimicrobial spectrum of cyadox against pathogens isolated from poultry were as follows. Under, standard conditions, susceptible bacteria were Campylobacter jejuni, Clostridium perfringen and Pasteurella multocida, MICs and MBCs of the former two were 0.25～1μg/mL and 1μg/mL, the MIC and MBC of Pasteurella multocida were 2-4μg/mL and 16～32μg/mL, respectively. Intermediate bacteria were Salmonella pullorum, Escherichia coil and Staphylococcus aureus, MICs were 8～32μg/mL, MBCs were 16～128μg/mL. Nonsusceptible bacteria were Enterococcu faecalis and Enterococcu faecium. Under anaerobic conditions, the antibacterial activity were enhanced by 8-16 times on Salmonella spp., Escherichia coil and Enterococcus spp.. Susceptible bacteria are Pasteurella multocida, Escherichia coil and Salmonella spp., MICs were 1～4μg/mL, MBCs were 4～32μg/mL. Intermediate bacteria were Enterococcu faecalis and Enterococcu faecium, MICs and MBCs were 8～16μg/mL and 64μg/mL, respectively.
The antimicrobial spectrum of cyadox against common pathogens isolated from fishes were as follows. Under standard conditions, susceptible bacteria were Escherichia coil and Flavobacterim columnare, but there were no killing effect for Flavobacterim columnare. Intermediate bacteria were Yersinia ruckeri, Staphylococcus aureus, Streptococcus agalactiae and Mycobacterium tuberculosis, MICs were 2～32μug/mL, MBCs were 32～128μg/mL. Nonsusceptible bacteria were Pseudomonas fluorescent, Acinetobacter baumannii, Aeromonas spp. (including A. hydrophila, A. veronii, A. jandaei, A. caviae and A. sobria and A. punctata), Edwardsiell ictaluri and Vibrio fluvialis. Under anaerobic conditions, the antibacterial activity were enhanced by 8-256 times on Aeromonas spp. (exclude Aeromonas punctata), Vibrio fluvialis, Acinetobacter baumannii and Yersinia ruckeri. Susceptible bacteria were Aeromonas spp. (exclude A. punctata), Vibrio fluvialis, Yersinia ruckeri, Vibrio fluvialis and Streptococcus agalactiae, MICs were 0.5～8μg/mL, MBCs were 1～16μg/mL. Nonsusceptible bacteria were Pseudomonas fluorescent, Aeromonas punctata and Edwardsiell ictaluri.
Antimicrobial susceptibility of cyadox against pathogenic bacteria isolated from others were as follows. Under standard conditions, susceptible bacteria were Salmonella typhimurium, MICs were 8μg/mL, MBCs were>128μg/mL. Intermediate bacteria are Yersinia enterocolitica and Proteus mirabilis, MICs and MBCs were 32μg/mL and 128μg/mL; Nonsusceptible bacteria is Pseudomonas pyocyanea. Under anaerobic conditions, the antibacterial activity were enhanced by 8 times on Proteus mirabilis. Susceptible bacteria is Salmonella typhimurium and Proteus mirabilis, MICs and MBCs were 4-8μg/mL and 32-64μg/mL, respectively. Intermediate bacteria were Yersinia enterocolitica, MIC and MBC were 16μg/mL and 64μg/mL, respectively; Nonsusceptible bacterium was Pseudomonas pyocyanea.
2 Therapeutic effect of cyadox on swine dysentery
Seventy crossbred piglets weighing～15kg were randomly divided into 7 treatments with ten replications (pens) each. Blank group, without artificial challenge nor administration. Negative control group, with artificial challenge, but not administration. Positive control groups, fed with olaquindox at 100 ppm and 200 ppm after the artificial challenge were successful. Experimental groups, fed with cyadox at 400 ppm,200 ppm and 100 ppm after the artificial challenge were successful. The average incubation period infection with B. hyodysenteriae is 7～13 days, when 7～9 piglets began to excrete with haemorrhagic diarrhoea, the treatment would begin as administration by fed, two times per day. Meanwhile, some those piglets did not eat any feed would be treated by oral medication, those with improved appetite or poor appetite still administration by fed. Stop administration when the groups had a 100% cure rate, and continued to observe two weeks. Evaluated the therapeutic effect with the clinical manifestation, cure rate, relapse rate, growth performance, blood biochemical indices and pathological examination.
During administration, the appetite, mental status and fecal index of treatment group were gradually improved. Cyadox 400 ppm group had the shortest course of treatment, after 6 days of treatment the cure rate was 100%, and not relapse; Cyadox 200 ppm group had a good effect also, medication for 6 days also achieved more than 80% cure rate; Cyadox 100 ppm group had a long course of treatment for some dysentery repeat, and took two weeks to achieve more than 80% cure rate. Olaquindox 200 ppm group had an similar efficacy as cyadox 400 ppm group, better than cyadox 200 ppm group. Olaquindox 100 ppm group had a similar efficacy as cyadox 100 ppm group.
Cyadox 400 ppm group had the highest Average Daily Gain (ADG) and Gain/Feed (G/F), the ADG and G/F were increased by 5.2% and 22.2% than blank group. Cyadox 200 ppm group was similar with blank group, while the ADG and G/F of olaquindox 200 ppm group were decreased to 25.4% and 30.6% of blank group. The ADG and G/F of cyadox 100 ppm group were decreased to 74.0% and 80.6% of blank group, olaquindox 100 ppm group were decreased to 55.6% and 58.3% of blank group. Negative growth was showed in negative group.
The blood parameters and pathological examination indicated cyadox 400 ppm had a mild impact on water and salt metabolism and kidney, but there were no any clinical manifestations, and the growth performance had been significantly improved, so it could be considered no significant side effects. The 200 ppm olaquindox group suffered a moderate damage on kidney and adrenal and a mild negatively affected on water and salt metabolism and liver. The animals in this group would like drink ground water and urine of fellow, and had a decreased growth performance, so the side effects of 200 ppm olaquindox diet was obvious.
In short, the therapeutic dose of cyadox recommended for swine dysentery is 200～400 ppm. We suggest taking 200～400 ppm cyadox for treatment by fed; 100 ppm dose for the prevention and metaphylaxis, or the process of consolidation after curing.
In summary, this subject had referred the "Microbiological Data for Systemic Antibacterial Drug Products—Development, Analysis, and Presentation", "Developing Antimicrobial Drugs—General Considerations for Clinical Trials" formulated by Food and Drug Administration (FDA) and "Experimental Clinical Trial Technology Standard" issued by China Ministry of Agriculture, and established the antimicrobial spectra in a variety of animals, evaluate the phaseⅡclinical study of cyadox on the therapeutic effect on swine dysentery, and gave scientific guidance for the reasonable use of cyadox in livestock, poultry and aquatic animals. Cyadox will have a broad application prospect for it's good effect in animal production.
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