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Juan J Carrique-Mas Oxford University Clinical Research Unit

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Presentation on theme: "Juan J Carrique-Mas Oxford University Clinical Research Unit"— Presentation transcript:

1 Use and misuse of antimicrobials on farms: Ecological and health impact
Juan J Carrique-Mas Oxford University Clinical Research Unit Ho Chi Minh City, Vietnam Biodiversity and Health Symposium Phnom Penh, 17 November 2014 Good morning. It is a pleasure to be in PP introducing this very relevant topic.

2 Agenda AMR: A complex ‘ecohealth’ problem
Economic development and animal production The ‘ecological web’ of AMR Other AMR co-selecting environmental pollutants Data from current projects (OUCRU-VN): Antimicrobial consumption Transmission of AMR between humans and animals The way forward Future projects In my presentation I will introduce the problem of AMR – emphasizing its complexity. Use of Ams are interlinked with animal production and economic development. I will present the ecological web of AMR. I will briefly introduce to the issue of other co-selecting pollutants. Then some results from on-going projects in VN that hopefully will help document the issues, both on AM consumption on farms and transmission between humans and animals Finally some suggestions as to where to move on from here.

3 The ‘Confusogram’ ????? This diagramme comes from a book by Dr Prescott of Guelph University in Canada. In another publication it was referred as a confusogram. It highlights the complex webs of circulation of AMR. It is a One Health issue, probably more than any other. The overwhelming majority of research on the right side, hospitals and communities. Over the last 15 years or so emphasis on the food producing animals. Clearly the greatest research gaps on research relate to the environment. J. F. Prescott et al. (2000) Antimicrobial Therapy in Veterinary Medicine

4 The VAC system in Vietnam
We can see an example of this web in some producting systems in Asia. For example in Vietnam, the VAC system, stands for garden, pond, and animal pen which is an efficient way of recycling byproducts and manure, but also for facilitating AMR. Source: FAO (2004)

5 Human and farm density in SE Asia*
Animal protein consumption: Vietnam Fish and shrimp production in Vietnam (2004 to 2011) Human and farm density in SE Asia* Pig farms Chicken farms Humans These maps are now a little bit old, but show how the densities of humans, chicken and pigs are inter-related. Of the countries in the Indochina Peninsula, probably VN has the highest population densities, mostly in the Deltas and the cities of Ha Noi and HCMC. An important characteristic is the rapid observed increase in animal protein consumption, fuelled by fish (now VN is one of the first fish consuming countries in Asia), followed by pigs and poultry * Sources: LEAD and FAO (2000, 2006)

6 Antimicrobial use in animal production
Fundamental differences in the use of AM in humans and animals. Use in animal production is almost always related to groups of animals, except in the case of injectable drugs (most common in pigs only, but rare in aquaculture and poultry). Growth promotion, prophylactic and methaphylactic use, treatment. In human medicine treatment is the most common use. Some travellers have the habit of having doxacycline in developing countries. S. Page and P. Gautier (2012), Rev. sci. tech. Off. int. Epiz., 2012, 31 (1),

7 Post antimicrobial effects
Fate of antimicrobials Fate of antimicrobial resistant bacteria Fate of resistant genes Interaction with environmental bacteria? Fate of antimicrobials Distribution at sub-inhibitory concentrations Fate of antimicrobial resistant bacteria Pathogens and commensals Direct transfer from host to host Indirect transfer (food, water, environmental pathways) This slide summarises the main impacts of the use of AM: It concerns that availability of the antimicrobial that may keep promoting AMR after its intended aid. As a result of AMU you generate AMR bacteria that may reach humans or other individuals not treated. Now the most recent concern is that a lot of the AMR promoted during the use of AM is in the form of AMR genes that can cross beyond bacterial species. Fate of resistant genes Vertical transfer Horizontal transfer between unrelated bacteria *Adapted from Da Costa et al. (2013) Int. J. Environ. Res. Public Health 2013, 10:

8 AMR and environmental bacteria
Environmental bacteria >95% of the earth’s microbiome Naturally produce antimicrobials as signalling molecules at low concentrations Naturally multi-drug resistant Most plasmid-mediated ARG originate from the environment i.e. qnr from waterborne bacteria Since 1950’s humans have manufactured antimicrobials and used them at industrial levels, this results in unprecedented levels of exposure of the earth’s microbiome to antimicrobials

9 Ecological concerns Commensal, pathogenic flora, and ARG interact with environmental organisms in certain hotspots Farm, hospital ARG integrated in gene-transfer elements (plasmids, transposons, integrons) the highest risk ARG can be maintained in the absence of antimicrobial selective pressure and co-selected due to other stressors (siderophores, toxins, heavy metals, biocides) Do changes in the natural ecosystems as a consequence of human activities accelerate evolution towards AMR? ARG detected in bacteria from environmentally pristine locations, indicating dissemination qnr encoded in plasmids detected in Aeromonas spp. † J. Martinez (2009). Proc. R. Soc. B.

10 Confirmed hospital-acquired Acinetobacter baumannii infections, respiratory patients, ICU (HTD, HCMC (Vietnam) ( ) Source: James I. Campbell, OUCRU-HCMC

11 AMR in E. coli in humans and chickens in the Mekong Delta
Tien Giang I will be presenting some studies we have been carried out to investigate AMU in poultry farms, and AMR in chickens and humans

12 VIBRE Project Rural areas (3 districts) Urban areas (1 city)
Chicken farm Use of antimicrobials Food habits Use of antimicrobials Food habits Knowledge and use of antimicrobials: Bio-security Non-farmers (N=204) Not involved in poultry farming Matched by commune, age/sex to farmer Urban inhabitants (N=102) Not involved in poultry farming Living in urban centre of My Tho Chicken farms (N=204) Development of AMR E. coli ? Transfer of AMR? Use of antimicrobials Contact with chickens Food habits Chicken farmers (N=204) Transfer of AMR?

13 Antimicrobial agents used in chicken farming, TG
Class of antimicrobial Name of antimicrobial No. (%) formulations containing the product (N=157) No. (%) farms using (N=208) Tetracyclines Doxycycline, oxytetracycline, tetracycline 57 (36.3%) 53 (25.5%) Polypeptides Colistin 48 (30.6%) 41 (19.7%) Macrolides Tylosin, tilmicosin, erythromycin, spiramycin 40 (25.5%) 40 (19.2%) Penicillins Ampicillin, amoxicillin 41 (26.1%) 34 (16.3%) Quinolones Flumequine, oxolinic acid, norfloxacin, enrofloxacin 22 (14.0%) 19 (9.1%) Aminoglycosides Spectinomycin, neomycine, gentamicin, apramycin, streptomycin 19 (12.1%) Phenicols Florfenicol, thiamphenicol 14 (8.9%) 12 (5.8%) Sulphonamides/ trimethoprim Sulfamethoxazole, sulphadimidine, sulphadimetoxine, sulphadimerazine, trimethoprim 12 (7.6%) Lincosamides Lincomycin 4 (2.5%) Pleuromutilin Tiamulin 1 (0.6%) 1 (0.5%) Studies show that over the last 90 days a total of 28 formulations had been used. Some of them include critically important antimicrobials such as colistin, quinolones and aminoglycosides.

14 Antimicrobial formulations, TG
Penicillin Polypeptide Macrolides Tetracyclines Quinolones Phenicols Aminoglycosides Sulphonamides Lincosamides Pleuromutilins No. administrations Penicillins 6 33 1 41 Polipeptides 2 5 3 48 25 4 40 13 7 57 20 22 8 14 19 12 Pleuromutilin tylosin tartrate, trimethoprim, sulphadiazine, sulphamethoxazole 100/157 (64% products were ‘mixes’ of 2 or more antimicrobials)

15 AMU on chicken farms, Tien Giang
Variable Level All farms (N=208) Number of antimicrobial products used over study period 40.9% 1 >1 18.3% Method of administration Water 82% Feed 9% Feed and water 4% Type of administration Prophylaxis 84% Treatment 12% Both Timing On arrival 34% Continuously 18% Periodic 29% Other 19% Advice given by Drug seller 56% District veterinarian Friend/neighbour Sales person 2% We collect data on AMU on these farms

16 Antimicrobial consumption in relation to chicken production
Stratum No. farms sampled No. chickens sampled No. chickens (census) Fraction sampled (%) Sampling weight Milligrams of active compound used per week per chicken (±SE) Grams of active compound per 1,000 chickens produced CG, hh 34 2,890 409,850 0.007 141.8 30.4 (±15.6) 901.2 (±622.8) CG, sm 47,970 128,250 0.374 2.7 5.3 (±1.5) 167.5 (±63.9) CT, hh 36 4,505 268,295 0.017 59.5 5.6 (±1.4) 327.8 (±122.4) CT, sm 50,230 56,700 0.886 1.1 18.6 (±7.2) 193.1 (±57.3) MT, hh 2,290 58,310 0.039 25.5 26.4 (±17.2) 413.8 (±256.4) MT, sm 52,500 73,300 0.716 1.4 4.7 (±1.9) 156.6 (±63.7) All 208 160,385 994,705 0.161 15.1 (±4.0) 358.1 (±113.5)

17 What’s on the menu? Colistin: 120 mg/Kg Neomycin: 400 mg/Kg
Florfenicol: 60mg/Kg Kitasamycin: 300 mg/Kg In Vietnam, most commercial animal feed rations are medicated How easy it is to calculate the amount of AM necessary to produce pork

18 AMR testing in E. coli Disc diffusion test 1 ampicillin (10µg) 2
ceftriaxone (30µg) 3 ceftazidime (30µg) 4 chloramphenicol (30µg) 5 ciprofloxacin (1µg) 6 ciprofloxacin (5µg) 7 trimethoprim-sulphamethoxazole (1.25 µg /23.75µg) 8 gentamicin (10µg) 9 amikacin (30µg) 10 meropenem (10µg) 11 amoxicillin-clavulanic acid (20/10µg) 12 tetracycline (30µg) Disc diffusion test

19 Antimicrobial resistance in E
Antimicrobial resistance in E. coli (non-selective plates) VIBRE Project These can be taken as ‘randomly selected colonies from farmers and chickens’.

20 Diversity among chicken and human E. coli
N=5 colonies per study subject Shannon-Weaver diversity index (H) Shannon-Weaver index (H)

21 Human and chicken E. coli AMR patterns (I)
1 2 3 4 5 ---C--TE-STX----AMP- AMC---C AMP- AMP- ---C--TE-STX----- -----TE------ ---C--TE-----AMP- X Matching: 3/50 (6%)

22 Comparisons of E. coli patterns from humans and chickens
Distances No. calculations Median [75% IQR] Chicken vs. farmer a 201 2.76 [ ] Chicken vs. rural control b 199 3.12 [ ] Chicken vs. urban control c 97 3.47 [ ] Farmer vs. Rural control d 196 3.02 [ ] Farmer vs. Urban control e 95 3.20 [ ] Rural vs. Urban control f 3.25 [ ]

23 Antimicrobial resistance in pig pathogens

24 AMR among pig pathogens (n=53)
Source: Severe disease in piglets in southern Vietnam: main bacterial aetiologies and antimicrobial resistance. J. Campbell et al, 2014 (in preparation)

25 Longitudinal studies on AMR in pig and chicken farms
Differences in the dynamics of AMR depending on the type of farming. Here we see results of AMR testing against a number of antimicrobials for one pig and poultry farm at three time points. E. coli Enterococcus spp. White bar: day-old, grey bar: mid production, black bar: end of production

26 Environmental stressors and AMR: Quaternary ammonium compounds (QAC)

27 Use of QAC in chicken farms
Product Disinfectant class Percent farms using (%) (N=208) 1 QAC 68.2 2 Peroxygen-based 3.4 3 Halogen-Releasing agent 1 4 Halogen-Releasing agent 2 1.9 5 Other 23.0 (in the cleaning process and in occupied animal houses) QAC products represented 68.2% of all disinfectants used in Tien Giang province Benkocid represented 56.7% The cross-resistance of QAC and antibiotics could be achieved by linkage of different resistance mechanisms on the same plasmid, transposon or integron or any combination of these [4]. Many bacteria acquire resistance to QACs by changing the composition of their membrane proteins, LPS, fatty acids [6, 9], cell surface hydrophobicity

28 Adaptation experiments to QAC
Determine MIC for each isolate Expose 105 cfu/ml of bacteria to 0.5MIC (37oC, 18-20h) Stabilise bacteria in MHB without disinfectant (37oC, 5h) Calibrate suspension to 105cfu/ml and transfer to new MHB supplemented with 0.75 MIC QAC disinfectant Stabilise bacteria in MHB without disinfectant for 5h at 37oC Expose bacteria to step-wise increase concentration of disinfectant Until no growth observed, the highest concentration of disinfectant that bacteria can survive were used

29 Cross-resistance QAC and antimicrobials
Study ID TE CN AMP CIP CT SXT C AD01-c S I AD01-p R AD01-ef AD02-c AD02-p AD02-ef AD03-c AD03-p AD03-ef AD04-c AD04-p AD04-ef AD09-c AD09-p AD09-ef AD10-c AD10-p AD10-ef c = control; p = post adaptation; ef= after treating with PAβN

30 The link between AMU and AMR is uncontroversial
Chantziaras et al (2014) Journal of Antimicrobial Chemotherapy, 69:

31 A vociferous skeptical minority
WoK quoted >350 times!!!

32 Priorities for research….and for policy
Carry out farming with less antimicrobials If antimicrobials are used, limit their impact on animals and their environment Understand why and where antimicrobials are used in agriculture Increase awareness Change attitudes and behaviours Surveillance of AMU and AMR: Monitoring of antimicrobial use and ARG Applied research Understand impact of antimicrobial use on the environmental (AM, ARG, bacteria) Intervention studies to reduce AMU Technical solutions to limit impact.. and test them!

33 Acknowledgements Zoonoses Group ITU, CTU, Microbiology, Enterics Group
Mr. Trung Nguyen Vinh Dr. Ngo T. Hoa Mr. James Campbell Dr. Constance Schultsz Sub-Department of Animal Health Tien Giang, Dong Thap Hospital Tropical Diseases HCMC Funding: ZoNMW / WOTRO (The Netherlands) (VIBRE Project) The Wellcome Trust Add pictures

34 Thanks for your attention!

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