Back to the future – Diagnostic considerations in a growth promoters-free industry 回到未来 —不用生长促进剂的养殖业的兽医诊断 Fabio Vannucci (法比奥.万努奇)
Back to the future – Diagnostic considerations in a growth promoters-free industry
回到未来 —不用生长促进剂的养殖业的兽医诊断
Fabio Vannucci (法比奥.万努奇)
Outline
• History历史
• EU experiences欧盟经验
o Disease incidence发病率
• USA scenario美国情况
o Diagnostics诊断
• USA and EU: compare/contrast 美国和欧盟:对比/比较
• Considerations for future scenarios将来的注意事项
Overview 概要
• Use of antimicrobial growth promoter (AGP) 抗菌生长促进剂(AGP)的使用
- Late 1940s: Chickens fed with fermentation waste from tetracycline production as a source of vit B12 20世纪40年代后期:鸡饲喂生产四环素发酵废弃物作为维生素B12的来源
Overview History历史
- Better growth performance due to residual tetracycline: “Animal protein factor”
由于残留四环素”动物蛋白因子”,产生更好的生长成绩。
- Early 1950 (Cunha et al, Luecke et al): 20世纪50年代早期
o The effect of vitamin B12, animal protein factor and streptomycin on the growth of young pigs
维生素B12、动物蛋白因子和链霉素对仔猪的生长产生影响。
• Use of antimicrobial growth promoter and antimicrobial resistance 使用抗菌促生产剂和耐药性
Overview History历史
- Inaction (UK and other EU countries): tylosin, spiramycin, avoparcin… 无行动(英国和其他欧盟国家):泰乐菌素、螺旋霉素、阿伏霉素...
- Action (Sweden): consumers → Federation of Swedish Farmers → ban in 1986 行动(瑞典):消费者→瑞典农民联合会→1986年禁止
- Mid 1960 (UK): Multi-drug-resistant salmonella 60年代(英国):多重耐药性沙门氏菌
- “Sufficient sound basis for action” 采取行动的充分可靠依据”
- Recommendations for using on animal feed:饲料中使用抗生素的建议 o Little or none application for therapeutic purposes in human or animals在人和动物上少用或不用治疗用抗生素。
o Not impair the efficacy of a prescribed therapeutic drugs through development of resistance 通过耐药性的形成,但不破坏处方治疗药物的疗效
o Tylosin should be available only for therapeutic purposes 泰乐菌素应该只提供给治疗用。
• Use of antimicrobial growth promoter and antimicrobial resistance 使用抗菌促生长剂和耐药性
Overview History历史
- Vancomycin (glycopeptide antimicrobial): discovered early 1960s 万古霉素(糖肽类抗生素):发现20世纪60年代初 o 1980s: widely used in humans for treatment of resistant Gram positive bacteria
80年代广泛应用用于治疗人的耐药革兰氏阳性菌。 o 1993: Vancomycin resistant enterococci isolated from humans and animals (Bates et al 1993)
1993年从人和动物分离出耐万古霉素肠球菌 Not been used in food animal食品动物中没有使用 o Cross-resistance with Avoparcin: commonly used for growth promotion in food animal与阿伏霉素有交叉耐药:常用于食品动物促生长
EU banned in 1997 欧盟1997明禁用 - AGP termination 动物生长促进剂(AGP)停用时间
Sweden瑞典: 1986 Norway挪威: 1995 Switzerland瑞士: 1999 Finland芬兰: 1999 Denmark丹麦: 2000 EU欧盟: 2006
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何测量发病率(AGP禁用前后)
- Indirect method for occurrence of disease 疾病发生的间接方法 o Antimicrobial usage ONLY for therapeutic or preventive purposes (assumption after AGP ban) 假设禁用AGP后,抗生素仅用在治疗或预防上
o Recording antimicrobial usage for a given clinical syndrome记录针对指定临床综合征使用的抗生素
- Production data: mortality, ADG, Feed conversion生产数据:死亡率\平均日增重\饲料转化
- Diagnostic data (lab accessions)诊断数据(实验室病例) o High specificity but questionable sensitivity 高特异性,但敏感性有问题 o Confounders - emerging disease, surveillance, detection vs disease 混杂因素 - 新出现疾病,监测,检测 VS 疾病
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何测量发病率(AGP禁用前后)
Denmark丹麦
- Production data: mortality, ADG, Feed conversion 生产数据:平均日增重,平均日增重,饲料转化率
平均日增重
死亡率
断奶猪禁用促生长剂
时间(年)
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何测量发病率(AGP禁用前后)
- Overall trends on antimicrobial consumption (therapeutic use) 抗生素使用(治疗用)的总体趋势
Sweden瑞典 Norway挪威
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何评估发病率(AGP禁用前后)
- Overall trends on antimicrobial consumption (therapeutic use) 抗生素使用(治疗用)的总体趋势
Denmark丹麦 Netherlands荷兰
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何评估发病率(AGP禁用前后)
- Age groups 年龄组
Sweden (1986) – first 4 years after 瑞典(1986年)—禁用AGP后的头4年
o Increase post-weaning diarrhea (> 1.5% mortality) 增加断奶后腹泻(>1.5%死亡率)
o 5-6 more days to reach 25 kg 达25Kg体重增加5-6天
o ↓ 1.5% feed efficiency in finishers育肥阶段饲料转化率↓ 1.5%
母猪和仔猪 断奶仔猪
育肥猪 总体,校正后
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何评估发病率(AGP禁用前后)
- Antimicrobial classes (Denmark) 抗生素分类(丹麦)
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何评估发病率(AGP禁用前后)
- Antimicrobial classes (Netherlands) 抗生素分类(荷兰)
Switzerland
瑞士
Overview European experiences: disease incidence 欧洲经验:发病率
• How to measure disease incidence (before/after AGP ban)? 如何评估发病率(AGP禁用前后)
- Clinical signs, age group, # days and animals treated 临床症状\年龄组,动物治疗和天数
腹泻
月: 相对于不用AGP
肺炎
关节炎 消瘦
其他疾病
治疗比例
• Enteric pathogens after AGP ban 上 禁用AGP后的肠道病原
o Significant increase in diarrhea (nursery) 保育腹泻明显增加
- Post-weaning diarrhea: β-hemolytic E. coli 断奶后腹泻: β溶血大肠杆菌
- Spirochetal colitis (Brachyspira pilosicoli) 螺旋体结肠炎(多毛结肠短螺旋体)
- Clinical ileitis (Lawsonia intracellularis) 临床回肠炎(胞内罗松菌)
• ↓50-120g ADG 平均日增重↓50-120g • ~ 7 additional days from weaning to 30Kg断奶至30K多7天
Overview European experience: disease incidence 欧洲经验:发病率
Weber et al (2016), 24th IPVS
1 days 5 days 2 weeks 3 weeks 5 weeks 10 weeks 28 weeks Adult
Escherichia coli大肠杆菌
Brachyspiral colitis螺旋体结肠炎
Lawsonia intracellularis胞内罗松菌
Neonatal亲生 Nursery保育 Finishing育肥
Overview
Autolysis自溶 Non-autolysis非自溶
USA Scenario: Diagnostics美国情况:诊断
• Enterotoxigenic Escherichia coli (ETEC)肠毒大肠杆菌
o Post-weaning diarrhea: β-hemolytic E. coli 断奶后腹泻: β溶血大肠杆菌
o High morbidity and variable mortality高发病率和死亡率差异大
Overview
o Virulence毒力 - Fimbria (F18, F4) + Enterotoxins (LT, STa, STb, EAST1, Stx2e, AIDA)
纤毛(F18,F4)+ 肠毒素(LT, STa, STb, EAST1, Stx2e)
- Stx2e: Sudden death (CNS signs may be present) 突然死亡(中枢神经症状可能会出现)
USA Scenario: Diagnostics美国情况:诊断 β-溶血
α-溶血 γ-溶血
• Enterotoxigenic Escherichia coli (ETEC) 肠毒大肠杆菌
Overview USA Scenario: Diagnostics美国情况:诊断
UMN-VDL: Enterotoxigenic E. coli 2010-2016 (n=2206) 明大-兽医诊断实验室-肠毒大肠杆菌 2010-2016(2206例)
Overview
F18 F4
Neg
Others (F41, F5, F6)
F18.LT
F18.STb
F18.STX2e
F4.LT
F4.STa F4.STb
F4. STa.STb
F4.LT.STa.STb
Weber et al (2016), 24th IPVS
USA Scenario: Diagnostics美国情况:诊断
UMN-VDL: Antimicrobial susceptibility (2006-2016)抗生素敏感性
Overview β-
hem
olyt
ic E
. col
i β-溶
血大
肠杆
菌
Ampicillin氨苄青霉素
Enrofloxacin恩诺沙星 Trimethoprim/SulphaTMP/磺胺 Gentamicin庆大霉素 Neomycin新霉素 Florfenicol氟苯尼考
Sulpha磺胺
Oxytetracycline土霉素
Tiamulin泰妙灵 Chlortetracycline金霉素
USA Scenario: Diagnostics美国情况:诊断
• Brachyspiral colitis短螺旋属结肠炎
Overview
“B. suanatina” Swine Swine dysentery-like “B. hampsonii” Swine Swine dysentery-like
Strongly
β-hemolytic
Weakly
β-hemolytic
USA Scenario: Diagnostics美国情况:诊断
弱β-溶血
强β-溶血
种类 主要宿主 主要疾病
UMN-VDL: B. pilosicoli isolation (2011-2016)多毛结肠短螺旋体的分离
Overview
0
1
2
3
4
5
6
7
8
9
Num
ber o
f B. p
ilosi
coli
USA Scenario: Diagnostics美国情况:诊断
UMN-VDL: Antimicrobial susceptibility (2009-2013)抗生素敏感性
Overview USA Scenario: Diagnostics美国情况:诊断
卡巴氧 沃尼妙林 泰妙灵 强力霉素 林可霉素 泰乐菌素
Sweden: Antimicrobial susceptibility (AGP free scenario) 瑞典:抗生素敏感性(无AGP情况)
Overview USA Scenario: Diagnostics美国情况:诊断
• Proliferative enteropathy (ileitis): Lawsonia intracellularis 增生性肠炎(回肠炎):胞内罗松菌
Overview
o Endemically distributed worldwide流行分布于全世界
o Classically affected growing-finishing pigs 常见于生长育肥猪爱影响
0
10
20
30
40
50
60
70
2 5 7 10 13 16 19 22Weeks周
0
10
20
30
40
50
60
70
5 7 10 13 16 19 22Weeks周
Feca
l PC
R粪
便PC
R
Sero
logy
血清
学
o Clinical presentation (Acute/Chronic/Subclinical) 临床表明(急性/慢性/亚临床)
USA Scenario: Diagnostics美国情况:诊断
• Proliferative enteropathy (ileitis): Lawsonia intracellularis 增生性肠炎(回肠炎):胞内罗松菌 o Clinical/subclinical PCR threshold to justify the treatment (?) 临床/亚临床 PCR检测来证实处理(?)
Overview
1.00E+00
1.00E+01
1.00E+02
1.00E+03
1.00E+04
1.00E+05
1.00E+06
1.00E+07
1.00E+08
1.00E+09
1.00E+10
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Log 1
0 Law
soni
a in
trac
ellu
laris
bac
teria
/g fe
ces
Ct value Ct值
UMN-VDL
- One Log10 increase in LI load increases OR for a pig to have a low growth rate by 2 times
USA Scenario: Diagnostics美国情况:诊断
Overview
UMN-VDL: Lawsonia intracellularis PCR detection - 2013-2016 (n=3577)明大-兽医诊断实验室:胞内罗松菌的PCR检测-2013-2016(3577例)
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
10/3/2013 4/21/2014 11/7/2014 5/26/2015 12/12/2015 6/29/2016
Ct v
alue
25%
34%
41%
USA Scenario: Diagnostics美国情形:诊断
Overview
UMN-VDL: Antimicrobial susceptibility抗生素敏感性
USA Scenario: Diagnostics美国情形:诊断
• Increasing of enteric bacterial infection (not much respiratory)肠道细菌感染增加(呼吸道菌增加不多)
Overview USA and EU: compare/contrast 美国和欧洲:比较/对比
o Porcine Respiratory Disease Complex (PRDC)猪呼吸首综合征 - Success controlling primary triggers – vaccination, elimination 成功控制的主要手段--免疫,净化
o Microbiome complexity 微生物的复杂性
o Porcine Enteric Disease Complex (PEDC) – What the heck?猪肠道疾
病综合征--到底怎么回事 - Enteric bacteria as primary cause肠道细菌是主要的原因 - Synergism: Rotavirus – Clostridium perfringens, E.coli (?) 协同:轮状病毒 - 产气荚膜梭菌,大肠杆菌(?)
Overview
Europe欧洲 United States美国 Weaning age断奶日龄 28-30 days 21 days PRRS status蓝耳状况 Neg (some countries)阴 Pos阳 Pig/farm density猪/场密度 Low/variable低/差异大 High高 Lawsonia vaccine usage罗松菌疫苗使用情况 Low低 Widely used使用广 Carbadox卡巴氧 Banned禁止 Widely used*使用广
Zinc oxide氧化锌 Partial restrictions部分地方限用
Widely used使用广
USA and EU: compare/contrast 美国和欧洲:比较/对比
• Management/alternative strategies管理/备选策略
• Systematic approach to measure disease incidence系统方法评估发病率
• Scale matters 规模方面
• AGP ban (EU)禁用AGP(欧盟) – Enteric bacterial pathogens (diarrhea): When to act (?) 肠道细菌病原
(腹泻):什么时候开始采取措施(?) • Lawsonia PCR positive: “how much” to justify treatment (?) and for how long (?)罗松菌PCR阳性:”多少”需要确认治疗(?)和治疗多久(?)
• Beta-hemolytic E coli with virulence factor + diarrhea β-溶血大肠杆菌带有毒力因子引起腹泻
Outline Considerations for future scenarios 将来的注意要点
– Followed by additional regulation → Long term benefits 接着是更多的监管→长期受益
• Denmark (Yellow card regulations)丹麦(黄牌规章制度) • Germany (DART, German Antibiotic Resistance Strategy)德国(DART,德国耐药性策略)
• Netherlands (Netherlands Veterinary Medicines Authority - SDa)荷兰(荷兰兽药管理局-SDa)
Outline
• Talking about additional regulation…谈论更多的监管...
Considerations on future scenarios 将来的注意要点
©2014 Regents of the University of Minnesota. All rights reserved. The University of Minnesota is an equal opportunity educator and employer.
• Dr. Peter Davies
• Dr. Connie Gebhart
• Dr. Julio Alvarez
Aknowledgements Acknowledgements 致谢
Fabio Vannucci [email protected]