IMPACT – A One Health collaboration on antibiotic resistance for sustainable change

SINO-SWEDISH INTEGRATED MULTI-SECTORIAL PARTNERSHIP FOR ANTIBIOTIC RESISTANCE CONTAINMENT

IMPACT

PROJEC T SUMMARY

Graphic design: ETC Kommunikation

ANTIBIOTIC RESISTANCE IN BACTERIA is a growing global challenge that affects human and animal health, whilst also threatening welfare, food-safety, productivity and development worldwide. The problem is shared and needs co-operation between countries through a One Health approach to create opportunities for sustainable change. Starting in 2014 with funding for five years, leading Chinese and Swedish researchers in human health, animal health and the environment are collaborating in a project on antibiotic resistance, called IMPACT.

Main areas included in the IMPACT research collabora-tion are:

• knowledge, attitudes and practice concerning human and animal antibiotic use

• distribution of resistant bacteria and genetic elements within the human, animal, environmental and health care sectors

• design, implementation and evaluation of strategies to promote rational use of antibiotics and to limit the spread of antibiotic resistance in all sectors.

ABOUT THE PROJECT

IMPACT – a One Health collaboration on antibiotic resistance for sustainable change

Partner organisationsThe Sino-Swedish integrated multi-sectoral partnership for antibiotic resistance containment (IMPACT) funded from 2014 to 2018 by the Swedish Research Council (VR) and National Natural Science Foundation of China (NSFC).

ChinaZhejiang University (PI)China Agricultural University (co-PI)Shandong University (co-PI)Shandong Academy of Agricultural SciencesShandong Center for Disease Control and Prevention

SwedenPublic Health Agency of Sweden (PI) Karolinska Institutet (co-PI)Linköping University (co-PI)Swedish National Food AgencySwedish National Veterinary Institute

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THIS MIXED METHODS PROJECT aims to deliver a deeper under-standing of the interaction and the overlap of antibiotic resistant bacteria between humans, animals and the envi-ronment. The project also investigates interventions that may lead to sustainable behavioural change for the purpose of informing national and international policies.

Kickoff meeting in Shandong Provence, China 2014.

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One world – One healthThe collaborative effort of multiple

disciplines – working locally, nationally, and globally – to attain optimal health for people, animals and the environment.(AVMA, 2008)

ANTIBIOTIC RESISTANCE IS AN AREA where a ‘one health – one world’ approach is needed to fully understand and deal with the problem. Much is still unknown regarding the emergence of antibiotic resistance and how the spread can be mitigated. Cooperation between countries, between veterinary and human medicine, as well as the environmental sector opens up for new opportunities for sustainable change.

HUMAN

ENVIRONMENTANIMAL

ONE HEALTH

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Data collection l Analyses I Intervention Data collection ll Analyses II

Samples from humans

Samples from pigs

Samples from environment

Antibiotic consumption humans and pigs Prescriptions humans

FGD:s Questionnaires

Identify previous successful

interventions

Define set of interventions

Implement set of interventions

• Microbiological analyses

• Residue analyses

• Molecular analyses

• WGS

Data analyses

Samples from humans

Samples from pigs

FGD:s Questionnaires

• Microbiological analyses

• Molecular analyses

• WGS

Data analysesProcess

evaluation

Joint analyses

Comparisons between

preintervention and postintervention

Clinical isolates

July 2015 August 2015 –August 2016 – July 2017 August 2017 September 2017 –

FGDs, focus group discussions; WGS, whole genome sequencing.

Main components and their relationships

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Collaboration between sectors and countries to achieve a common goal.

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Timeline

Planning phase

Continuous data collection

Qualitative data collection

Baseline cross-sectional data collection

• Establishing specific research questions and methods• Development of study tools• Selection of study sites and basic data collection• Capacity building through workshops

Clinical isolates Collected at the town hospital (MRSA and ESBL- and Carbapenemase-producing Enterobacteriaceae)

Household questionnairesRural residents in 769 households were asked abouttheir knowledge, attitudes and practices regardingantibiotic use and resistance for humans and pigs, and about their health seeking behaviours

Microbiology sampling• Commensal samples were taken at households from humans and from pigs. Analayses focus on carriage of MRSA and ESBL- and Carbapenemase-producing Enterobacteriaceae. • Environmental samples were also taken from drinking water sources, rivers, wastewater, vegeta- bles and soil.

• Six focus group discussions with village residents• Semi-structured interviews with village clinic doctors

2014 2015

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Continuous data collection

Analyses and dissemination

Pilot intervention

Post-intervention cross-sectional data collection

Village clinic prescriptions600 prescriptions per year at each clinic

Household antibiotic useAntibiotic consumption for humans andpigs monitored at 200 households for 15 months

Following the same pattern as the baseline

Data are analysed and results published continuously

• Six intervention villages• Six control villages• One year intervention period

For rural residentsInformation on antibiotics and aspects about antibiotic use and antibiotic resistance in humans, animals and environment:• Audiotapes (three times a week on village speakers)• One lecture every three months• Booklets and poster

For healthcare practitionersTraining programmes for veterinarians and village clinic doctors, once every three months on:• Rational antibiotic use• Infection prevention and control

2016 2017 2018

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Key findings TO ENABLE COLLABORATIVE One Health work,

time must be invested to develop shared concep-tual and contextual frameworks among all resear-chers. Also allocate time for joint planning of the data collection which should link different data types together to allow for integrated analyses across sectors and instruments. [11]

RURAL RESIDENTS GENERALLY have low levels of knowledge about antibiotics (as with other studies in Asia and globally) and their self-reported atti-tudes and practices could lead to both overuse and underuse of antibiotics. Storage of antibio-tics for both human use and pig use is common in households, however most residents are not aware that they are storing antibiotics. [3]

THE ENVIRONMENT PLAYS an important role in the emergence and dissemination of antibiotic resistant bacteria, however, the factors facilitating this development are not yet well understood. Putative transmission routes of CTX-M-producing Escherichia coli to different environmental matrices were evaluated by analysing the genetic relatedness of isolates from bird faeces, pig faeces, drinking water, river sediment, river water and wastewater. The analyses indicate that both plasmid and clonal expansion are important for the dissemination of CTX-M-genes and that wild birds may act as potential vectors across long distances. Regional dissemination between diffe-rent environmental matrices of CTX-M-producing

E. coli increases the exposure risk of humans and animals in the area. [1]

ANTIBIOTIC RESIDUES ARE present in various compartments of the environment. The concen-tration levels of fluoroquinolones in wastewater are estimated to pose biological risks for deve-lopment and selection of antibiotic resistance in bacteria. The concentration of antibiotics in drinking-water and vegetables are estimated to pose no appreciable direct risk to human health through consumption, but might still pose an important indirect risk through contribution to resistance development. [7]

EXTENDED SPECTRUM ß-LACTAMASE (ESBL) producing bacteria carrying genes encoding resistance to last-resort antibiotics carbapenems and colistin are present in wells in rural China, indicating water as a potential source of antibiotic resistance. [10]

KLEBSIELLA PNEUMONIAE is associated with health-care associated infections and has a high capacity to acquire mobile genetic elements such as plasmids containing antibiotic resistance genes. However, data on the occurrence and characteristics of extended spectrum ß-lactamase (ESBL) producing K. pneumoniae in environmental sources are scarce. We show that clinically rele-vant strains of ESBL-producing K. pneumoniae are occurring in environmental sources. [2]

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COMMUNITY-ASSOCIATED MRSA (Methicillin-resistant Staphylococcus aureus) and livestock-associated MRSA, belonging to ST59 and ST9, respectively, were identified in both humans and pigs. The genotypic and phenotypic comparison of isolates indicates that bidirectional transmis-sion of MRSA has occurred between humans and pigs in the study area. [8]

A FIRST REPORT OF MCR-3 AND MCR-3.5 in Escherichia coli in backyard pig husbandry shows that mcr genes are not restricted to pigs from large-scale commercial farms, but also occur in pigs from small-scale backyard holdings. Adequate measures, such as raised awareness of rational use of antibiotics in both animals and humans, prudent use of colistin in pigs for disease treatment and prevention, and good management and hygiene of backyard farming, should be consi-dered to limit the spread of mcr genes. [5]

WE PRESENT A FIRST REPORT of the colistin resis-tance gene mcr-5 in an Aeromonas hydrophila isolate from the faeces of a backyard pig. The ColE-like replication primase in mcr-5-harbouring plasmid pI064-2, which is widely distributed among Enterobacteriaceae, Pseudomonas spp. and aeromonads, indicates that mcr-5 has the potential to disseminate among different bacte-rial species. [4]

OXAZOLIDINONES ARE SOME of the few remaining options for antimicrobial treatment of infections caused by multidrug resistant Gram-positive pathogens, including staphylococci. There is a wide distribution of oxazolidinone resis-tance genes optrA and cfr in household animals in the investigated rural villages, and the presence of optrA and cfr may be explained by co-selection by a number of unrelated antimicrobials. We iden-tified a possibility of transmission of these patho-gens between different house holds within the same village and even between different villages. Furthermore, a first identification of optrA in isolates of Staphylococcus simulans was made. [6]

WE USE A ONE HEALTH approach to address important research questions that individual discipline investigations are unable to. The results obtained should more closely reflect the world in which human health, animal health and the environment are inextricably and intimately interlinked. The data sources include before-after cross-sectional collection of biological samples, demographic information, questionnaires and focus group discussions; longitudinal sampling of prescriptions from village clinics and antibiotic use for pigs and humans in a subset of hous-eholds; and process evaluation data from a pilot One Health intervention package. [9]

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Publications

[1] Zou H, Zheng B, Sun M, Ottoson J, Li Y, Berglund B, Chi X, Ji X, Li X, Stålsby Lundborg C, Nilsson LE. Evaluating dissemination mechanisms of antibiotic-resistant bacteria in rural environments in China by using CTX-M-producing Escherichia coli as an indicator. Microb Drug Resist 2019. Accepted.

[2] Chi X, Berglund B, Zou H, Zheng B, Börjesson S, Ji X, Ottoson J, Stålsby Lundborg C, Li X, Nilsson LE. Character-ization of clinically relevant strains of extended-spectrum β-lactamase-producing Klebsiella pneumoniae occurring in environmental sources in a rural area of China by using whole-genome sequencing. Front Microbiol 2019. Epub 2019 Feb 12. doi: 10.3389/fmicb.2019.00211.

[3] Dyar OJ, Yin J, Ding L, Wikander K, Zhang T, Sun C, Greko C, Sun Q, Stålsby Lundborg C. Antibiotic use in people and pigs: a One Health survey of rural residents’ knowledge, attitudes and practices in Shandong province, China. J An-timicrob Chemother 2018 Oct 1;73(10):2893-2899. Epub 2018 Jul 23. doi: 10.1093/jac/dky240.

[4] Ma S, Sun C, Hulth A, Li J, Nilsson LE, Zhou Y, Börjesson S, Bi Z, Bi Z, Sun Q, Wang Y. Mobile colistin resistance gene mcr-5 in porcine Aeromonas hydrophila. J Antimicrob Chemother 2018 Jul 1;73(7):1777-1780. Epub 2018 Apr 11. doi: 10.1093/jac/dky110.

[5] Li J, Hulth A, Nilsson LE, Börjesson S, Chen B, Bi Z, Wang Y, Schwarz S, Wu C. Occurrence of the mobile colistin resis-tance gene mcr-3 in Escherichia coli from household pigs in

rural area. J Antimicrob Chemother 2018 Jun 1;73(6):1721-1723. Epub 2018 Feb 16. doi: 10.1093/jac/dky038.

[6] Sun C, Zhang P, Ji X, Fan R, Chen B, Wang Y, Schwarz S, Wu C. Presence and molecular characteristics of ox-azolidinone resistance in staphylococci from household animals in rural China. J Antimicrob Chemother 2018 May 1;73(5):1194-1200. Epub 2018 Feb 7. doi: 10.1093/jac/dky009.

[7] Hanna N, Sun P, Sun Q, Li X, Yang X, Ji X, Zou H, Ottoson J, Nilsson LE, Berglund B, Dyar O, Tamhankar AJ, Stålsby Lundborg C. Presence of antibiotic residues in various envi-ronmental compartments of Shandong province in eastern China and its potential for resistance development and ecological and human risk. Environ Int 2018 May;114:131-142. Epub 2018 Mar 2. doi: 10.1016/j.envint.2018.02.003.

[8] Bi Z, Sun C, Börjesson S, Chen B, Ji X, Berglund B, Wang M, Nilsson M, Yin H, Sun Q, Hulth A, Wang Y, Wu C, Bi Z, Nilsson LE. Identical genotypes of community-associat-ed MRSA (ST59) and livestock-associated MRSA (ST9) in humans and pigs in rural China. Zoonoses Public Health 2018 May;65(3):367-371. Epub 2018 Jan 27. doi: 10.1111/zph.12443.

[9] Sun Q, Wang Y, Hulth A, Xiao Y, Nilsson LE, Li X, Bi Z, Liu Y, Yin H, Luo Y, Nilsson M, Sun C, Zhu Y, Zheng B, Chen B, Sun P, Ding L, Xia X, Ottoson J, Löfmark S, Dyar OJ, IMPACT Consortium, Börjesson S, Stålsby Lundborg C. Study proto-col for One Health data collections, analyses and interven-

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tion of the Sino-Swedish Integrated Multi-sectoral Part-nership for Antibiotic Resistance Containment (IMPACT). BMJ Open 2018 Jan 21;8(1):e017832. doi: 10.1136/bmjopen-2017-017832.

[10] Sun P, Bi Z, Nilsson M, Zheng B, Berglund B, Stålsby Lundborg C, Börjesson S, Li X, Chen B, Yin H, Nilsson LE. Occurrence of blaKPC-2, blaCTX-M and mcr-1 in Entero-bacteriaceae from well water in rural China. Antimicrob Agents Chemother 2017 Mar 24;61(4). doi: 10.1128/AAC.02569-16.

[11] Cars O, Xiao Y, Stålsby Lundborg C, Nilsson LE, Shen J, Sun Q, Bi Z, Börjesson S, Greko C, Wang Y, Liu Y, Ottoson J, Li X, Nilsson M, Yin H, Bi Z, Zheng B, Xia X, Chen B, Ding L, Sun P, Dyar OJ, Hulth A, Tomson G. Building bridges to operationalize One Health – a Sino-Swedish collabora-tion to tackle antibiotic resistance. One Health 2016 Sep 17;2:139-143. doi: 10.1016/j.onehlt.2016.09.002.

Conference abstractsDyar OJ, Yin J, Chen B, Nilsson M, Xuewen L, Ottoson J, Sun C, Yin H, Börjesson S on behalf of the IMPACT con-sortium. Risk factors for carriage of resistant bacteria in humans and pigs: a One Health study in rural China. Ac-cepted at 29th European Congress of Clinical Microbiolo-gy and Infectious Diseases, 13-16 April 2019, Amsterdam, Netherlands.

Dyar OJ, Sun C, Chen B, Zheng B, Hulth A on behalf of the IMPACT consortium. Containing antibiotic resistance:

a One Health Chinese-Swedish research collaboration. Poster presented at Prince Mahidol Award Conference (PMAC), 29 January-3 February 2018, Bangkok, Thailand.

Sun C, Bi Z, Wang Y, Chen B, Nilsson LE, Wu C. Identical genotypes of community-associated MRSA (ST59) and livestock-associated MRSA (ST9) in both humans and pigs in rural China. Poster presented at 7th ARAE – Symposium on Antimicrobial Resistance in Animals and the Environ-ment, 26-28 June 2017, Braunschweig, Germany.

Dyar OJ, Ding L, Wikander K, Sun C, Greko C, Sun Q, Stålsby Lundborg C on behalf of the IMPACT consortium. Antibiotic use in rural China: a One Health study of knowl-edge, attitudes and practices. Oral presentation at 27th European Congress of Clinical Microbiology and Infectious Diseases, 22-25 April 2017, Vienna, Austria.

Cars O, Xiao Y, Stålsby Lundborg C, Nilsson LE, Shen J, Sun Q, Bi Z, Börjesson S, Greko C, Wang Y, Liu Y, Ottoson J, Li X, Nilsson M, Yin H, Bi Z, Zheng B, Xia X, Chen B, Ding D, Sun P, Dyar OJ, Hulth A, Tomson G. Building bridges to operationalize One Health – a Sino-Swedish collaboration to tackle antibiotic resistance. Oral presentation at 2nd Annual Conference of the Chinese Consortium of Univer-sities for Global Health (CCUGH) – Advancing Health Sus-tainable Development Goals in China and Globally: Work-ing Together to Meet Challenges, 14-15 October 2016, Duke Kunshan University, Kunshan, Jiangsu, China.

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Colleagues involved in the IMPACT project 2014–2018

Zhejiang University Yonghong Xiao (PI) Lihua GuoChen HuangTianshui NiuPing ShenHao XuXiao YuBeiwen ZhengKai Zhou

Public Health Agency of Sweden Otto Cars (PI) Anette Hulth (PI) Saga AlvringSara ByforsMalin Grape Sonja LöfmarkMartha Melin

China Agricultural University Jianzhong Shen (co-PI)Run FanNansong JiangJiyun LiShizhen MaHongwei RenZhangqi ShenChengtao SunShaolin WangYang WangXi XiaKe XiaoWenjuan Yin

Shandong University Qiang Sun (co-PI)Xiaohui ChiLilu DingXiang JiXuewen LiYao LiuPan SunHuiyu XiaDing YangXiwe YangJia YinQian ZhaoZiyu ZhouHuiyun Zou

Karolinska Institutet Cecilia Stålsby Lundborg (co-PI)Oliver DyarNada HannaGaetano MarroneAshok TamhankarGöran TomsonKarin WikanderTianyang Zhang

Linköping UniversityLennart E Nilsson (co-PI)Björn BerglundMaud NilssonMaria TärnbergHong Yin

Shandong Academy of Agricultural SciencesMing HuBaohua HuangYuqing LiuYanbo Luo

Shandong Center for Disease Control and PreventionZhenqiang Bi Zhenwang BiBaoli Chen Yan LiMiaomiao WangYiqing Zhu

Swedish National Food AgencyMia EgervärnJakob Ottoson

Swedish National Veterinary InstituteStefan BörjessonChristina GrekoMarie Sjölund

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Annual meeting in Uppsala, Sweden 2017.

IMPACT