Antimicrbial resistance Basic principles P-A Beleil Unit n Bilgical Mnitring Seminar n Antimicrbial Resistance and the veterinary and fd sectr 7 th March 2013 Beijing, China Outline Antimicrbial resistance, a glbal threat! Antimicrbial resistance in relatin t fd safety Tackling antimicrbial resistance! 1
Outline Antimicrbial resistance, a glbal threat Antimicrbial resistance in relatin t fd safety Tackling antimicrbial resistance Antimicrbial agents/antimicrbials Chemical cmpunds that kill r inhibit the grwth f micrrganisms The term antimicrbials used t refer t antibacterial agents, whether prduced naturally r synthetically r semi-synthetically Primary tls fr treating infectius diseases Medicine revlutinized in the 1940 s Pneumnia, sepsis, meningitis, severe wund infectins Supprting tls f many mdern medical practices Organ transplantatin, chemtherapy fr cancer, rthpedic surgery 2
Antimicrbial Resistance (AMR) The antimicrbials used in fd-prducing animals are frequently the same, r belng t the same classes as thse used in human medicine Undesirable side effect f antimicrbial use Cntinuus psitive selectin f resistant bacterial clnes: Pathgenic bacteria Cmmensal bacteria Envirnmental bacteria Mdificatin in the ppulatin structure f micrbial cmmunities Unpredictable cnsequences fr human health! Antimicrbial Resistance Varius Mechanisms f Resistance 3
Antimicrbial Resistance Genetic medium Intrinsic Resistance Acquired Resistance Chrmsmal Resistance: nvel genetic mutatin in DNA Hrizntal gene transfer: Acquisitin f mbile genetic elements harbring resistance genes Absence f target Lw affinity target Lw permeability Efflux mechanisms Mdificatin f target Inactivatin f drug Mdificatin f target Efflux mechanisms VerticalTransmissin Generally mnresistance Hrizntal Transmissin Multiple resistance Antimicrbial Resistance Hrizntal transfer f genetic material Dnr Bacteria Cnjugatin f plasmid Transfrmatin f free DNA Recipient Bacteria Transpsn Integrn Transpsitin Transductin Epidemilgy f AMR is made mre cmplicated by the ability f genes respnsible fr such resistance t spread between different types f bacteria 4
Clinical Resistance vs. Bilgical Resistance Clinical Resistance Situatins where antimicrbials, that nrmally inhibit certain types f bacteria, n lnger have the desired effect Clinically resistant islate tlerate higher cncentratins that thse t be btained in viv The degree f resistance shwn is assciated with a high likelihd f therapeutic failure Clinical breakpint Defined against a backgrund f clinically-relevant data Therapeutic indicatin Clinical respnse data Dsing schedules Pharmackinetics Pharmacdynamics May alter with changes in circumstances e.g. alteratins in dsing regime, drug frmulatin, patient factrs etc. 9 Clinical Resistance vs. Bilgical Resistance Micrbilgical Resistance WILD-TYPE BACTERIAL POPULATION Naïve, susceptible wildtype ppulatin N acquired r mutatinal resistance mechanisms are present t the antimicrbial in questin NON WILD-TYPE BACTERIAL POPULATION Acquired r mutatinal resistance mechanisms are present t the antimicrbial in questin Reduced susceptibility t a given antimicrbial agent Epidemilgical cut-ff values nt altered by changing circumstances T achieve ptimum sensitivity fr early detectin f acquired resistance and emergence f resistance ECOFFS shuld be used in mnitring scheme f AMR in zntic and indicatr rganisms in animals and fd 10 5
Interpretative Criteria fr Resistance EUCAST has defined Clinical Breakpints and ECOFFs 11 Antimicrbial Resistance Single Resistance A bacterium has a single resistance t ne antimicrbial cmpund C-Resistance A bacterium is resistant t several cmpunds f the same family Crss-Resistance A bacterium has a mechanism f resistance which decreases sensitivity fr cmpunds f different antimicrbial families e.g. multi-drug efflux pumps can cause crss-resistance t a wide range f structurally hetergeneus cmpunds including antimicrbials Multiple Resistance A bacterium has several mechanisms f resistance which decrease sensitivity t different antimicrbial family Crss-selectin / C-selectin (+ heavy metals, bicids) 6
Why AMR is increasing/diffusing wrldwide? Selectin Pressure & Gegraphic Spread Use f antimicrbials in humans, animals and plants anywhere in the wrld affects everyne! Antimicrbial use Lcal survival f resistant strains Diffusin f Resistance Diffusin f resistant bacteria acrss sectrs, settings and gegraphical brders Travelling humans Traded animals and fd Envirnmental cntaminatin Outline Antimicrbial resistance, a glbal threat Antimicrbial resistance in relatin t fd safety Antimicrbial use in fd prductin Antimicrbial resistance as a fd safety prblem Tackling antimicrbial resistance 7
Why AMR are used in fd prductin? Intrduced in veterinary medicine in the 1940 s Therapy / Disease preventin / Grwth prmtin The same classes f antimicrbials are used in animals as thse used medicinally in humans! Why AMR are used in fd prductin? In fd-prducing animals T treat respiratry and enteric infectins f intensively fed animals Especially during the early part f an animal s life Briler chickens / pst-weaning piglets / veal calves T treat infectins in individual animals caused by bacterial pathgens Mastitis in dairy cws, cmmn infectins in cws with a high milk utput Glbal increase in intensive fish farming Antimicrbials added t fish fdstuffs t treat bacterial infectins Cntrl f different diseases in plants with certain antimicrbials 8
Antimicrbial Grwth Prmters (AGPs) Antimicrbials added t the feed f terrestrial fd animals in subtherapeutic cncentratins t imprve grwth Intrduced glbally fr rutine use in intensively raised fd animals explsive increase in the verall use f antimicrbials The UK gvernment s Swann Reprt f 1969 Cncern grew abut cntinuus increase f AMR during 80 s and 90 s Use f antimicrbials in fd prducing animals culd pse a risk t human health, wing t the diffusin f resistance via the fd-chain AGP use represents health risks due t develpment and diffusin f crss-resistance t antimicrbials used t treat humans Antimicrbial Grwth Prmters (AGPs) Withdrawing avparcin as an AGP in fd animals A glycpeptide similar t vancmycin, a last resrt antimicrbial in human medicine Use f avparcin as an AGP in fd prducing animals in Eurpe Vancmycin-resistant enterccci (VRE) in cmmensal flra f: Fd animals and meat theref Healthy peple Crss-resistance between avparcin and vancmycin Transfer f VRE frm fd derived frm avparcin-expsed animals In 1997, the EU banned avparcin Since 2006, all AGPs have been withdrawn frm the EU 9
Antimicrbial Grwth Prmters (AGPs) Effect n the ccurrence f resistance fllwing withdrawal f AGPs Reductin f VRE in fd animals and the general ppulatin Antimicrbial cnsumptin in fd animals Fd-prducing animals are frequently subjected t heard treatment with antimicrbials Frequency t expsure t antimicrbials is usually high, specially where AGPs are used Large prprtin f animal ppulatins expsed during mst f their lifespan Veterinary usage f antimicrbials may be relatively lw! Experience f Nrdic cuntries in Eurpe Plicies t restrict antimicrbial use and strengthen disease preventin Better knwledge f antimicrbial use is needed! Mst cuntries have n system t mnitr antimicrbial use in animals Lack f reliable and cmparable data In the EU, EMA wrks fr develping a harmnised apprach: ESVAC 10
Antimicrbial resistance, a fd safety issue Therapeutic and nn-therapeutic use f antimicrbials Land fd-prducing animals (e.g. pultry, cattle, pigs) Aquaculture (e.g. fish, shrimps) Effluents Sil Cntact with fd animals (e.g. farm dwellers) Wildlife Wells, Rivers, Streams Fd: Meat and dairy prducts Fish and shrimps Vegetables and Fruits Cmpanin animals Effluents Humans Critically Imprtant Antimicrbials WHO list Critically Imprtant Antimicrbials fr human medicine Quinlnes / 3 rd - and 4 th -generatin Cephalsprins / Macrlides T supprt mre cmprehensive assessment f risks Ptential develpment f resistance in pathgens in animals Ptential diffusin f resistant bacteria r their genes frm animals t peple OIE list Antimicrbials f veterinary imprtance: Antimicrbial classes shared with WHO list Antimicrbials are essential fr treating and cntrlling infectius disease in animals Animal health has a substantial effect n fd safety and fd security, bth f which substantially affect human health Antimicrbials are a cmmn-prperty resurce fr bth human and veterinary medicine 11
Antimicrbial resistance in Salmnella spp. (1) Fd may be an imprtant reservir f resistant Salmnella Beef, prk, pultry prducts, dairy prducts, eggs and fresh prduce Fd-brne disease caused by resistant Salmnella well dcumented In the EU, Natinal Cntrl Prgrammes (NCPs) f Salmnella in pultry sectrs Quinlne resistance Increase f quinlne resistance in Salmnella f animal and fd rigins Subsequent increase in human infectins Cephalsprin resistance ESBL- / AmpC-prducing Salmnella rise cncerns Human infectins with cephalsprin-resistant Salmnella related t freign travel Transfer f resistance alng the fd chain increasingly cmmn Antimicrbial resistance in Salmnella spp. (2) Multiresistant S. Typhiumurium rganisms Emergence f several clnes f S. Typhimurium since the early 1960 s Resistant t a wide range f antimicrbials, including critically imprtant antimicrbials fr human medicine Definitive Phage Types (DTs) 29, 204, 193 and 104 Emergence f mnphasic S. Typhimurium since the late 1990 s Adverse cnsequences fr human health Higher frequency and duratin f hspital stays Lnger illness Higher risk f invasive infectin Higher risk f death 12
Antimicrbial resistance in Campylbacter Campylbacterisis is a very frequent fd-brne znsis When therapy is required, macrlides and flurquinlnes are used Campylbacter easily acquires resistance t antimicrbials Quinlne resistance Intrductin f flurquinlne use Emergence and rise f resistance Adverse health and ecnmic effects f quinlne-resistant Campylbacter infectin Use f flurquinlnes in fd animals Resistance in human Campylbacter Macrlide resistance C. jejuni in pultry vs. C. cli in pigs Resistance t macrlides causes delays and failure in treatment, and need fr alternative antibitics Antimicrbial resistance in E. cli E. cli strains can harbur resistance genes that may be transferred t human adapted bacteria r pathgens during passage thrugh intestine Treatment failure: prlnged illness duratin and increased severity ESBL-prducing E. cli Exhibit transferable resistance t 3 rd - and 4 th -generatin cephalsprins May exhibit resistance t ther first-line antimicrbials, flurquinlnes Have emerged wrldwilde in hspitals and the cmmunity Islated frm fd-prducing animals: cattle, pultry, briler chickens Chicken meat and the envirnment culd be imprtant surces 13
Outline Antimicrbial resistance, a glbal threat Antimicrbial resistance in relatin t fd safety Tackling antimicrbial resistance Tackling antimicrbial resistance The need t act is urgent! T preserve the effectiveness f the antimicrbials Effrts t cntain AMR Reducing unnecessary use f antimicrbials Strengthening mnitring f antimicrbial use and resistance Prmting prudent use Interrupting the diffusin f resistant strains Imprving infectin cntrl and preventive measures Vaccinatins Hygiene Bisecurity Prmting innvatin and research n new drugs 14
Thank yu fr yur attentin! 15