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Use and misuse of antimicrobials on farms: Ecological and health impact Juan J Carrique-Mas Oxford University Clinical Research Unit Ho Chi Minh City,

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Presentation on theme: "Use and misuse of antimicrobials on farms: Ecological and health impact Juan J Carrique-Mas Oxford University Clinical Research Unit Ho Chi Minh City,"— 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

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

3 The ‘Confusogram’ J. F. Prescott et al. (2000) Antimicrobial Therapy in Veterinary Medicine ?????

4 The VAC system in Vietnam Source: FAO (2004)

5 Pig farmsChicken farmsHumans Human and farm density in SE Asia* * Sources: LEAD and FAO (2000, 2006) Animal protein consumption: Vietnam Fish and shrimp production in Vietnam (2004 to 2011)

6 Antimicrobial use in animal production S. Page and P. Gautier (2012), Rev. sci. tech. Off. int. Epiz., 2012, 31 (1), 145-188

7 Post antimicrobial effects 7 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) 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: 278-294 Fate of antimicrobials Fate of antimicrobial resistant bacteria Fate of resistant genes Interaction with environmental bacteria?

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 qnr encoded in plasmids detected in Aeromonas spp. ARG integrated in gene-transfer elements (plasmids, transposons, integrons) the highest risk ARG detected in bacteria from environmentally pristine locations, indicating dissemination † J. Martinez (2009). Proc. R. Soc. B. 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?

10 Confirmed hospital-acquired Acinetobacter baumannii infections, respiratory patients, ICU (HTD, HCMC (Vietnam) (2000-2014) Source: James I. Campbell, OUCRU-HCMC

11 AMR in E. coli in humans and chickens in the Mekong Delta Tien Giang

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

13 13 Class of antimicrobial Name of antimicrobial No. (%) formulations containing the product (N=157) No. (%) farms using (N=208) TetracyclinesDoxycycline, oxytetracycline, tetracycline57 (36.3%)53 (25.5%) PolypeptidesColistin48 (30.6%)41 (19.7%) MacrolidesTylosin, tilmicosin, erythromycin, spiramycin40 (25.5%)40 (19.2%) PenicillinsAmpicillin, amoxicillin41 (26.1%)34 (16.3%) QuinolonesFlumequine, oxolinic acid, norfloxacin, enrofloxacin22 (14.0%)19 (9.1%) Aminoglycosides Spectinomycin, neomycine, gentamicin, apramycin, streptomycin 19 (12.1%)19 (9.1%) PhenicolsFlorfenicol, thiamphenicol14 (8.9%)12 (5.8%) Sulphonamides/ trimethoprim Sulfamethoxazole, sulphadimidine, sulphadimetoxine, sulphadimerazine, trimethoprim 12 (7.6%)12 (5.8%) LincosamidesLincomycin4 (2.5%) PleuromutilinTiamulin1 (0.6%)1 (0.5%) Antimicrobial agents used in chicken farming, TG

14 Antimicrobial formulations, TG Penicillin Polypeptide Macrolides Tetracyclines Quinolones Phenicols Aminoglycosides Sulphonamides Lincosamides Pleuromutilins No. administrations Penicillins 6331141 Polipeptides 22511348 Macrolides 32554140 Tetracyclines 136757 Quinolones 20122 Phenicols 814 Aminoglycosides11319 Sulphonamides 312 Lincosamides 14 Pleuromutilin 1 100/157 (64% products were ‘mixes’ of 2 or more antimicrobials) tylosin tartrate, trimethoprim, sulphadiazine, sulphamethoxazole

15 VariableLevel All farms (N=208) Number of antimicrobial products used over study period 040.9% 1 >118.3% Method of administration Water82% Feed9% Feed and water4% Type of administrationProphylaxis84% Treatment12% Both4% TimingOn arrival34% Continuously18% Periodic29% Other19% Advice given byDrug seller56% District veterinarian18% Friend/neighbour12% Sales person12% Other2% AMU on chicken farms, Tien Giang

16 Antimicrobial consumption in relation to chicken production 16 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, hh342,890409,850 0.007141.8 30.4 (±15.6)901.2 (±622.8) CG, sm3447,970128,250 0.3742.7 5.3 (±1.5)167.5 (±63.9) CT, hh364,505268,295 0.01759.5 5.6 (±1.4)327.8 (±122.4) CT, sm3650,23056,700 0.8861.1 18.6 (±7.2)193.1 (±57.3) MT, hh342,29058,310 0.03925.5 26.4 (±17.2)413.8 (±256.4) MT, sm3452,50073,300 0.7161.4 4.7 (±1.9)156.6 (±63.7) All 208160,385994,7050.16115.1 (±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

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

19 Antimicrobial resistance in E. coli (non-selective plates) VIBRE Project

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

21 12345 ---C--TE-STX----AMP-AMC---C-------AMP-----------AMP- ---C--TE-STX----- 1-----TE------ 2---C--TE-----AMP- 3----------AMP- XX 3---C--TE-----AMP- 5---C--TE-STX----AMP- X Matching: 3/50 (6%) Human and chicken E. coli AMR patterns (I)

22 DistancesNo. calculationsMedian [75% IQR] Chicken vs. farmer a 201 2.76 [2.07-3.40] Chicken vs. rural control b 199 3.12 [2.52-4.04] Chicken vs. urban control c 97 3.47 [2.68-4.15] Farmer vs. Rural control d 196 3.02 [2.40-3.89] Farmer vs. Urban control e 95 3.20 [2.52-4.22] Rural vs. Urban control f 97 3.25 [2.36-4.24] Comparisons of E. coli patterns from humans and chickens

23 Antimicrobial resistance in pig pathogens

24 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 White bar: day-old, grey bar: mid production, black bar: end of production Longitudinal studies on AMR in pig and chicken farms E. coliEnterococcus spp.

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

27 ProductDisinfectant class Percent farms using (%) (N=208) 1QAC68.2 2Peroxygen-based3.4 3Halogen-Releasing agent 13.4 4Halogen-Releasing agent 21.9 5Other23.0 Use of QAC in chicken farms

28 Adaptation experiments to QAC Expose 10 5 cfu/ml of bacteria to 0.5MIC (37 o C, 18-20h) Stabilise bacteria in MHB without disinfectant (37 o C, 5h) Calibrate suspension to 10 5 cfu/ml and transfer to new MHB supplemented with 0.75 MIC QAC disinfectant Stabilise bacteria in MHB without disinfectant for 5h at 37 o C Expose bacteria to step-wise increase concentration of disinfectant Until no growth observed, the highest concentration of disinfectant that bacteria can survive were used Determine MIC for each isolate

29 Study IDTECNAMPCIPCTSXTC AD01-cSSSSISS AD01-pSSRSISI AD01-efSIRSISS AD02-cSSSSISS AD02-pRSRSRSS AD02-efSSRSISS AD03-cSSSSISS AD03-pRSRIRSI AD03-efRIRSRSS AD04-cSSSSISI AD04-pRSRSRSI AD04-efRIRSRSI AD09-cSSSSISS AD09-pISRSISS AD09-efIIRSRII AD10-cSSSSISS AD10-pISRIRSR AD10-efISRSRSI Cross-resistance QAC and antimicrobials c = control; p = post adaptation; ef= after treating with PAβN

30 The link between AMU and AMR is uncontroversial 30 Chantziaras et al (2014) Journal of Antimicrobial Chemotherapy, 69: 827-834.

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

32 Priorities for research….and for policy Understand why and where antimicrobials are used in agriculture –Increase awareness –Change attitudes and behaviours 1.Carry out farming with less antimicrobials 2. If antimicrobials are used, limit their impact on animals and their environment Surveillance of AMU and AMR: –Monitoring of antimicrobial use and ARG 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

34 Thanks for your attention! jcarrique-mas@oucru.org


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