Risk profile on antimicrobial resistance transmissible from food animals to humans

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transmissible from food animals to humans


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Risk prole onanimicrobial resisanceransmissible from food

animals o humansP.L. Geenen, M.G.J. Koene, H. Blaak, A.H. Havelaar, A.W. van de Giessen

This report contains an erratum d.d. 28/02/2011 on the last page


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Colophon

This report is published by the National Institute o Public Health and the Environment (RIVM). Thereport describes the results o the research project ABRES-vet-med, which is part o the researchprogramme ABRES. This project is carried out by a project group o expertise institutes and

coordinated by the Centre or Inectious Disease Control (CIb) on behal o the Department oKnowledge and Innovation o the Ministry o Economic Afairs, Agriculture and Innovation. Theresearch project was carried out under the supervision o the supervisory commiee ABRES. Thedigital version o this report is available on the website o the RIVM (www.rivm.nl). The suggestedcitation o the report is: Geenen, PL, Koene, MGJ, Blaak, H, Havelaar, AH, van de Giessen, AW. Riskprole on antimicrobial resistance transmissible rom ood animals to humans. RIVM-rapport330334001, 2010.

Authors:P.L. Geenen, M.G.J. Koene, H. Blaak, A.H. Havelaar, A.W. van de Giessen

Project group:Members o the ABRES-vet-med project group:Centre or Inectious Disease Control, RIVMH. Blaak, P.L. Geenen, A.W. van de Giessen, M.A. Leverstein-van Hall , A.H. HavelaarM.N. Mulders, A.J. de Neeling, A.M. de Roda Husman

Faculty o Veterinary Medicine, Utrecht UniversityJ.A. Wagenaar

Central Veterinary Institute, Wageningen URD.J. Mevius, M.G.J. Koene

University Medical Centre Utrecht

M.A. Leverstein-van Hall

Academic Hospital MaastrichtE.E. Stobberingh

Supervisory commiee:Members o the supervisory commiee ABRES:H. Bekman, PVE, E.J. de Boer, VWS-PG, A. Meijering, EL&I-DKI, M. Moelands, EL&I-AKVP.H.A. Mlder, Denkavit, G.T.J.M. Theunissen, VWS-VGP, C.W. Zwitser, EL&I-VDC

Photograph ront page:ESBL phenotypic screening test A.H.A.M van Hoek

RIVM 2010Parts o this publication may be reproduced, provided acknowledgement is given to the NationalInstitute or Public Health and the Environment, along with the title and year o publication.


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Risk prole on antimicrobial resistance transmissible rom ood animals to humans | 3

Summary

Since their introduction in the 1940s, antimicrobials havesubstantially reduced the human disease burden. As a sideefect, their extensive use has resulted in selection anddissemination o antimicrobial resistant bacteria, whichreduces the ecacy o initial treatment o inections andlimits treatment options aer diagnosis. In ood animalproduction, antimicrobial drugs are widely used andantimicrobial resistance is increasing in both zoonotic andcommensal bacteria. This has raised concerns about therisks o transmission o resistant zoonotic bacteria (directhazards) and resistance genes (indirect hazards) rom ood

animals to humans and the consequences or health careand public health. This report presents a risk prole toinorm risk managers on the current knowledge on thesepotential health hazards as a rst step in the riskmanagement process. Two direct and one indirect hazardwere selected to serve as examples in this risk prole,these are: quinolone-resistant Campylobacterjejuni (direct hazard); livestock-associated (LA-)MRSA (direct hazard); extended-spectrum beta-lactamase (ESBL-) producing

bacteria (indirect hazards).

A summary o relevant inormation with respect to theirrisk or human health is given below.

Quinolone-resistantCampylobacter

In the last decades, quinolone resistance in Campylobacterisolates rom poultry and human cases has increasedstrongly and was ound to be directly related to the use oquinolones in poultry production. There is sucientevidence o a causal relationship based on temporal,geographic, and epidemiological associations. Similar tosensitive bacteria, quinolone-resistant Campylobacterismainly transmied through consumption and preparationo broiler meat, but the role o other pathways is

increasingly recognised. There are no indications thatdirect contact with ood animals or handling meat poses asignicant risk.Campylobacterprimarily causes acute gastroenteritis thatusually is sel-limiting; there are no indications that illnessdifers between cases with quinolone-resistant andsusceptible strains. Antimicrobial resistance is notexpected to increase the risk o chronic sequelae such asGuillain-Barr syndrome, reactive arthritis, irritable bowelsyndrome and inammatory bowel disease. Antimicrobialtreatment is only indicated or severely diseased orimmunocompromised patients. As a result o the high

level o resistance in Campylobacter; quinolones areexcluded or empiric treatment o gastroenteritis inprimary health care as well as in hospitals. It is estimatedthat approximately 79,000 symptomatic Campylobacterinections occur annually and approximately 50% o these

inections, i.e. 40,000 cases, are caused by quinolone-resistant strains. There are no indications that the diseaseburden has increased as a consequence o quinoloneresistance and the healthcare costs are similar to those orsusceptible Campylobacterinections. Social consequencesand risk perception have not been studied.Control o quinolone-resistant Campylobacteris similar tocontrol o susceptible Campylobacterand may includecontrol o inection in primary production combined withpost-harvest measures, such as improved slaughterhygiene as well as scheduled processing combined with

decontamination measures. Banning the use ouoroquinolones in poultry may not solve the problem; inthe USA such a ban has not resulted in reduceduoroquinolone resistance in human clinical isolates in therst years aer the ban. Several AMR-RAs are available orquinolone-resistant Campylobacterspp. They all show that(uoro)quinolone use in the ood animal reservoircontributes to resistance in humans, but the human healthimpact seems to be relatively small.

Livestock-associated MRSA (LA-MRSA)

LA-MRSA was rst discovered in 2005 and is now

spreading throughout the Dutch intensive livestockarming sectors. The majority o strains derived rom oodanimals were o sequence type 398.There is sucientevidence o a causal relationship between human clinicalisolates and isolates rom ood animals based ontemporal, geographic, epidemiological, and geneticassociations. Direct contact with live ood animals is themain transmission route rom ood animals to humans.Identied risk groups include pig and veal armers andtheir amilies, as well as veterinarians and slaughterhouseworkers. The carriage rate among pig and veal armers inthe Netherlands is approximately 30%; the risk o carriageincreases with intensity and duration o animal contact.

Person-to-person transmission is limited, which reducesthe risk o secondary spread and limits hospital outbreaks.There are no indications that the presence o LA-MRSA onmeat is a risk or public health or or ood handlers.LA-MRSA mainly causes skin or so tissue inections, butis also capable o causing invasive inections. In recentyears, approximately 100 LA-MRSA inections werereported annually, which constitutes 10-15% o all MRSAinections. Reported clinical cases o LA-MRSA concernedoccupational groups in direct contact with livestock,patients with other underlying diseases, elderly patients,and patients that underwent surgery. LA-MRSA is

multidrug resistant, which reduces treatment options. Thedisease burden and cost o illness (COI) o MRSA have notbeen quantied, but are likely to have increased with therise o LA-MRSA inections. There are no indications thatthe individual disease burden o LA-MRSA difers rom


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4 | Risk prole on antimicrobial resistance transmissible rom ood animals to humans

HA-MRSA. MRSA patients are ound to experiencepsychological problems due to stigmatization andisolation. Risk perception has not been studied.Currently, there are no specic LA-MRSA control optionsoutside healthcare, except or general initiatives inhusbandry to reduce the use o antimicrobials. Potentialcontrol measures in primary production include purchaseo MRSA-negative animals, restrictive use o antibioticsand thorough cleaning and disinection; the efect o thesemeasures is yet unquantied. Control options to preventtransmission to proessionals include adaptations inanimal production systems and the use o personalprotection measures to reduce exposure to live arm

animals and their environment. Personal protectionmeasures are theoretically efective, but i not properlyapplied may increase the risk o colonization. There are noantimicrobial resistance risk assessments (AMR-RA)available or LA-MRSA; or most risk questions analyticalepidemiological studies combined with microbialsubtyping may suce.

ESBL-producing bacteria

Extended-spectrum beta-lactamases (ESBLs) are enzymesthat render Gram-negative bacteria resistant to beta-lactam antimicrobials and are inhibited by beta-lactamase

inhibitors. They are an important reason or ailure oinitial cephalosporin treatment o inections caused byESBL-producing bacteria. Since the beginning o thiscentury, the number o ESBL-producing bacteria isincreasing in human as well as veterinary isolates, inparticular rom poultry. The CTX-M type ESBL is currentlymost widespread among humans. ESBL-genes are usuallylocated on plasmids that can be transerred betweenbacterial species. These plasmids oen carry otherantimicrobial resistance genes as well, rendering thebacteria multidrug-resistant.There is sucient evidence o an association betweenplasmids and the ESBL resistance genes they carry in

human clinical isolates and in poultry isolates based ontemporal, genetic, and epidemiological associations butthe evidence is currently too limited to conclude aboutcausal relationships. Recent data suggest that bothoodborne transmission and direct contact play a role inthe transmission rom ood animals to humans. In a pilotstudy, aecal carriage among Dutch broiler armers wasound to occur requently (6 positive out o 18). The risk othe presence o ESBL-producing bacteria on meat orpublic health or proessional ood handlers is unclear.Extensive, laborious inection control measures are takenin the hospital seing to prevent dissemination o

ESBL-producing bacteria. Alternative treatment optionsare limited, more expensive and may requirehospitalization. It is estimated that in 2009, approximately5400 urinary tract inections (UTI) cases in general practicepatients were caused by ESBL-producing E. coli. In addition,

there are an estimated 500 invasive inections by ESBL-producing bacteria reported in 2009. Knowledge on therisk actors or carriage and inection is limited. Identiedrisk actors are previous admission to health-care acilities,antimicrobial drugs usage, travelling to high-endemiccountries and the presence o ESBL-positive amilymembers. The disease burden and cost o illness have notyet been quantied, but are likely to be substantial andincreasing. The social consequences and risk perceptionhave not been investigated.The voluntarily decision o Dutch veterinarians to stopusing cephalosporins in poultry is the single currentcontrol option in place. Potential options in primary

production are restrictive use o antibiotics and thoroughcleaning and disinection; the efect o these measures isyet unclear. In Canada, a temporary stop on usingcephalosporins in poultry was efective in reducing theprevalence o ESBL-producing bacteria on poultry meat.Conductance o an AMR-RA would be helpul in addressingthe problem o ESBL-producing bacteria, but has not beenperormed yet.

Recommendations

Based on the inormation collected, the ollowingrecommendations are made:

to rene or make beer use o the current humansurveillance systems to enable monitoring o microbialresistance hazards aributed to the ood animalreservoir;

to initiate research to ll in the identied knowledgegaps and involving risk assessors when determiningnational research agendas on antimicrobial resistance;

to initiate a risk assessment on ESBL-producing bacteria.


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Samenvating

Sinds hun introductie in de jaren 40 van de vorige eeuwhebben antibiotica substantieel bijgedragen aan hetverminderen van de ziektelast bij de mens. Het intensievegebruik van deze middelen hee echter ook een negatieefect; hierdoor vindt selectie en verspreiding vanresistente bacterin plaats, waardoor de initilebehandeling van sommige bacterile inecties minderefectie is en de opties voor behandeling na het stellenvan de diagnose beperkt zijn. In de dierhouderij wordenantibiotica veelvuldig gebruikt waardoor ook hier deantibioticaresistentie toeneemt, zowel bij zonotische als

bij commensale bacterin. Dit hee geleid tot bezorgdheidover de risicos van overdracht van resistente zonotischebacterin (directe gevaren) en resistentiegenen (indirectegevaren) van voedselproducerende dieren naar de mensen de mogelijke gevolgen daarvan voor devolksgezondheid en de gezondheidszorg. Dit rapportbevat een risicoproel, hetgeen bedoeld is omrisicomanagers te inormeren over de beschikbare kennismet betrekking tot dit potentile gezondheidsrisico, alseen eerste stap in het proces van risicomanagement. Driegevaren (twee directe en n indirecte) dienen alsvoorbeeld in dit risicoproel, dit zijn:

quinolone-resistente Campylobacterjejuni, (direct gevaar); veegerelateerde MRSA (v-MRSA), (direct gevaar); ESBL-producerende bacterin, (indirect gevaar).

Hieronder volgt een samenvaing van relevanteinormatie betrefende hun risicos voor de humanegezondheid.

Quinolone-resistenteCampylobacterjejuni

In de agelopen decennia is de resistentie tegenquinolonen bij Campylobacter-isolaten van pluimvee enpatinten sterk gestegen en werd er een directe relatiemet het gebruik van quinolonen in de pluimveesector

aangetoond. Tijdgerelateerde, geograsche enepidemiologische associaties leveren voldoende bewijsvoor een oorzakelijk verband. Quinolone-resistenteCampylobacterwordt, net als gevoelige Campylobacter,voornamelijk overgedragen door consumptie en bereidingvan kippenvlees; dat andere transmissieroutes ook een rolspelen wordt in toenemende mate onderkend. Er zijn geenindicaties dat mensen in direct contact metvoedselproducerende dieren o in de vleesverwerkendeindustrie een verhoogd risico lopen.Campylobacterveroorzaakt in de eerste plaats een acutegastro-enteritis die gewoonlijk zelimiterend is; er zijn

geen indicaties dat er verschil is tussen de ziekteveroorzaakt door quinolone-resistente en -gevoeligestammen. Naar verwachting zal antibioticaresistentie hetrisico op chronische complicaties, zoals het Guillain-Barr-syndroom, reactieve artritis, het prikkelbare darm-

syndroom en inammatoire darmziekten, niet verhogen.Het gebruik van antibiotica is alleen gendiceerd voorernstig zieke o immuungecompromieerde patinten. Alsgevolg van het hoge resistentieniveau van Campylobacterishet gebruik van quinolonen voor de initile behandelingvan gastro-enteritis uitgesloten in zowel deeerstelijnsgezondheidszorg als ziekenhuizen. Geschatwordt dat ongeveer 79.000 symptomatischeCampylobacter-inecties per jaar plaatsvinden en ongeveer50% van deze inecties (40.000 gevallen) wordtveroorzaakt door quinolone-resistente stammen. Er zijn

geen aanwijzingen dat de ziektelast is toegenomen alsgevolg van quinolone-resistentie en de kosten van degezondheidszorg zijn dan ook vergelijkbaar met die voorgevoelige Campylobacter-inecties. De sociale gevolgen enrisicoperceptie zijn niet onderzocht.De opties voor de bestrijding van quinolone-resistenteCampylobacterzijn dezelde als die voor de bestrijding vangevoelige Campylobacteren omvaen zowel hetterugdringen van de besmeing in de primaireproductiesector als maatregelen met betrekking tot hetslachtproces, zoals verbetering van de slachthygine en decombinatie van logistiek slachten met decontaminatie. Er

zijn aanwijzingen dat het verbieden van het gebruik vanuoroquinolonen bij pluimvee het probleem niet oplost; inde VS hee een dergelijk verbod niet geleid tot eenverminderde uoroquinolone-resistentie vanpatintenisolaten in de daaropvolgende jaren. Voorquinolone-resistente Campylobacterzijn verschillende riskassessments beschikbaar. Ze tonen aan dat het gebruikvan (uoro)quinolonen bij voedselproducerende dierenbijdraagt aan resistentie bij de mens, maar de impact opde humane gezondheid lijkt relatie klein te zijn.

Veegerelateerde MRSA (v-MRSA)

V-MRSA werd voor het eerst ontdekt in 2005 en komt nu

wijdverspreid voor in de Nederlandse intensieveveehouderij. De meerderheid van de stammen die zijngevonden bij voedselproducerende dieren behoort tot hetsequentie type 398. Op basis van tijdgerelateerde,geograsche, epidemiologische en genetische associatiesis er voldoende bewijs voor een oorzakelijk verband tussenhumane klinische isolaten en isolaten vanvoedselproducerende dieren. Direct contact met levendedieren is de belangrijkste transmissieroute vanvoedselproducerende dieren naar de mens. Degedenticeerde risicogroepen zijn mensen die wonen owerken op varkens- o kalverhouderijen, dierenartsen en

werknemers in het slachthuis. Ongeveer 30% van devarkens- en kalverhouders in Nederland is drager vanv-MRSA; het risico op dragerschap neemt toe naarmate deintensiteit en de duur van het contact met de dierentoeneemt. Overdracht van persoon naar persoon is


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beperkt; dit verkleint het risico op secundaire verspreidingen limiteert uitbraken in het ziekenhuis. Er zijn geenaanwijzingen dat de aanwezigheid van v-MRSA op vleeseen risico vormt voor de volksgezondheid o voor mensenwerkzaam in de vleesverwerkende industrie.V-MRSA veroorzaakt vooral huid- en wekedeleninecties,maar kan ook invasieve inecties veroorzaken. In deagelopen jaren werden jaarlijks ongeveer honderdv-MRSA-inecties gemeld; dit is ongeveer 10-15% van hettotale aantal MRSA-inecties. De in de literatuurgerapporteerde klinische gevallen van v-MRSA betrofenmensen uit beroepsgroepen in direct contact met dieren,patinten met andere onderliggende ziekten, oudere

patinten en patinten die een operatie haddenondergaan. V-MRSA is resistent tegen meerdere klassenantibiotica, waardoor de behandelopties beperkt zijn. Deziektelast en de -kosten (COI) van MRSA zijn nietgekwanticeerd, maar zijn waarschijnlijk toegenomen metde opkomst van de v-MRSA-inecties. Er zijn geenaanwijzingen dat de individuele ziektelast van v-MRSAverschilt van die van hospital-acquired MRSA (HA-MRSA).MRSA-patinten blijken psychische problemen te ervarenals gevolg van stigmatisering en isolatie. Risicoperceptie isniet onderzocht.Momenteel zijn er, buiten de gezondheidszorg, geen

specieke bestrijdingsmaatregelen gericht op v-MRSA,met uitzondering van de algemene maatregelen in deveehouderij om het gebruik van antibiotica teverminderen. Tot de potentile bestrijdingsmaatregelen inde primaire productiesector behoren aankoop van dierenvan MRSA-negatieve bedrijven, restrictie gebruik vanantibiotica en grondige reiniging en ontsmeing; hetefect van deze maatregelen is echter nog nietgekwanticeerd. Opties voor preventieve maatregelen omblootstelling van proessionals aan levende dieren en hunomgeving te verminderen zijn aanpassingen in dierlijkeproductiesystemen en het gebruik van persoonlijkebeschermingsmiddelen. Persoonlijke

beschermingsmiddelen zijn theoretisch efectie, maar alsdeze niet goed worden toegepast, kunnen deze het risicoop besmeing juist verhogen.Er zijn geen risk assessments beschikbaar voor v-MRSA;voor beantwoording van het merendeel van de risico-gerichte vragen kan analytisch epidemiologisch onderzoekin combinatie met microbile typering volstaan.

ESBL-producerende bacterin

Breedspectrum bta-lactamasen (Engels: extended-spectrum beta-lactamases, ESBLs) zijn enzymen dieGram-negatieve bacterin resistent maken tegen

bta-lactam antibiotica en geremd worden door bta-lactamase remmers. ESBLs zijn een belangrijke oorzaakvan het mislukken van initile cealosporinebehandelingenvan inecties veroorzaakt door ESBL-producerendebacterin.

Sinds het begin van deze eeuw is het aantal ESBL-producerende bacterin toegenomen onder zowelhumane als veterinaire (met name pluimvee) isolaten.CTX-M is op dit moment het meest voorkomendeESBL-type onder mensen. ESBL-genen bevinden zich opplasmiden die kunnen worden overgedragen tussenbacteriesoorten. Deze plasmiden bevaen dikwijls ookandere antimicrobile resistentiegenen, waardoor debacterin resistent zijn tegen meerdere klassen antibiotica.Op basis van tijdgerelateerde, genetische enepidemiologische associaties is er voldoende bewijs voorhet bestaan van een relatie tussen plasmiden en de hieropgelegen ESBL-genen in humane klinische isolaten en

isolaten van pluimvee; het bewijs is momenteel echter nogte beperkt om te concluderen dat er een causaal verbandis. Recente gegevens suggereren dat zowel voedsel alsdirect contact een rol spelen bij de overdracht vanuitvoedselproducerende dieren naar de mens. Uit pilot-onderzoek is gebleken dat ecaal dragerschap onderNederlandse vleeskuikenhouders veelvuldig voorkomt (zesvan de achien onderzochte personen positie). Het isonduidelijk o de aanwezigheid van ESBL-producerendebacterin op vlees een risico vormt voor devolksgezondheid o voor mensen werkzaam in devleesverwerkende industrie.

In ziekenhuizen worden uitgebreide en bewerkelijkebestrijdingsmaatregelen genomen om de verspreiding vanESBL-producerende bacterin te voorkomen.Behandelingsopties met alternatieve antibiotica zijnbeperkt; deze zijn vaak duurder en kunnenziekenhuisopname vereisen. In 2009 werden naarschaing 5400 urineweginecties bij patinten in dehuisartsenpraktijk veroorzaakt door ESBL-producerendeE. coli. Bovendien werden er in datzelde jaar naar schaing500 invasieve inecties veroorzaakt door ESBL-producerende bacterin. De huidige kennis overrisicoactoren voor dragerschap en inectie is beperkt.Gedenticeerde risicoactoren zijn eerdere opname in

gezondheidszorginstellingen, het gebruik van antibiotica,reizen naar hoogendemische landen en de aanwezigheidvan ESBL-positieve gezinsleden. De ziektelast en -kostenzijn nog niet gekwanticeerd, maar zijn waarschijnlijkaanzienlijk en zullen toenemen. De sociale gevolgen enrisicoperceptie zijn niet onderzocht.Het besluit van de Nederlandse dierenartsen om testoppen met het gebruik van cealosporines bij pluimvee isde enige bestrijdingsmaatregel die momenteel wordttoegepast. Andere potentile maatregelen in de primaireproductie zijn restrictie gebruik van antibiotica engrondige reiniging en ontsmeing van stallen; het efect

van deze maatregelen is echter nog onduidelijk. Eentijdelijke stop op het gebruik van cealosporines bijpluimvee in Canada bleek efectie te zijn voor hetverminderen van de prevalentie van ESBL-producerendebacterin op pluimveevlees. Het uitvoeren van een


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antimicrobile risk assessment (AMR-RA) zou van nut zijnbij de aanpak van de ESBL-problematiek.

Aanbevelingen

Op basis van de verzamelde inormatie, worden devolgende aanbevelingen gedaan: monitoring van humane resistentie die geassocieerd

wordt met het reservoir van voedselproducerendedieren door middel van verjning van de bestaandehumane surveillancesystemen;

uitwerking van nationale onderzoeksagendas om degeconstateerde kennislacunes met betrekking totantimicrobile resistentie in te vullen en het betrekken

van risicobeoordelaars daarbij; uitvoering van een risicoschaing (risk assessment)

met betrekking tot ESBL-producerende bacterin invoedselproducerende dieren.


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Risk prole on antimicrobial resistance transmissible rom ood animals to humans |

Conens1 Introduction 11

1.1. Aim o the project ABRES-vet-med and questions addressed 111.2 Risk management ramework 121.3 Glossary 13

2 Description of the microbiological hazards 172.1 Nature o the problem 17

2.2 Direct hazards o antimicrobial resistance 202.3 Indirect hazards o antimicrobial resistance 202.4 Example agents 222.5 Antimicrobial usage and resistance in human health care 22

2.5.1 Importance o the drugs or human medicine 222.5.2 Usage 242.5.3 Resistance 27

2.6 Adverse health consequences in humans 302.6.1 Mechanisms leading to inectious disease 312.6.2 Populations at risk 322.6.3 Type and severity o adverse health consequences 34

2.7 Magnitude o the problem 35

2.7.1 Disease burden 352.7.2 Economic consequences 382.7.3 Social consequences and risk perception 39

3 Antimicrobial usage and resistance in (food-producing) animals and the environment 41

3.1 Usage in ood animals 413.2 Resistance in ood animals 46

3.2.1 Campylobacter 483.2.2 MRSA 523.2.3 ESBL-producing bacteria 57

3.3 Resistance in oods o animal origin 583.4 Other reservoirs o resistance 60

3.4.1 The environment 60

3.4.2 Additional reservoirs 63

4 Transmission of antimicrobial resistance to humans 654.1 Associations between antimicrobial resistance in ood animals and humans 654.2 Transmission routes 69

4.2.1 Transmission through direct contact with ood animals 694.2.2 Transmission through oods o animal origin 714.2.3 Transmission through the environment 72

4.3 Relative contribution o the ood animal reservoir to resistance in humans 76

5 Future hazards 77


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6 Possibilities for intervention 796.1 Current control measures in the ood animal production branche 796.2 Further possibilities or control 80

7 Risk assessment 83

8 Answers to the questions and recommendations 89

References 93

Appendices 115List o abbreviations 115Classes o antimicrobials used in human and veterinary medicine 117


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In ood animal production, antimicrobial drugs are widelyused and antimicrobial resistance is increasing. This hasraised concerns about the transmission o antimicrobialresistance rom ood animals to humans and theconsequences or health care and public health. TheMinistry o Agriculture, Nature and Food quality (LNV, nowEL&I) has commissioned the project ABRES-vet-med todevelop a risk prole on this problem, which is presentedin this report.In this chapter the aim o the project and questionsaddressed in the risk prole are described in section 1.1.The risk prole is part o the risk management ramework,

which is described in section 1.2. Antimicrobial resistanceterms used in this risk prole are listed in section 1.3.

1.1 Aim of he projec ABRES-ve-med

and quesions addressed

The aim o the ABRES-vet-med project is to develop a riskprole (this document) with respect to the transmission of

antimicrobial resistance from food animals to humans and the

consequences for health care and public health. This risk prole

is aimed to inorm risk managers as a rst step in the riskmanagement process.

Based on the inormation presented in the risk prole, theollowing questions will be addressed:

1. What are the adverse efects o antimicrobial resistanceto human health care and public health and what is themagnitude o these efects?

2. How strong is the evidence o an association betweenantimicrobial resistance in ood animals and resistancein humans?

3. Through which routes does transmission occur?4. To what extent does antimicrobial resistance in ood

animals contribute to resistance in humans?5. What are the options or intervention and what is their

presumed efectiveness?6. Which uture hazards can be anticipated?

This risk prole describes the state o the art inantimicrobial resistance at the interace o ood animalproduction and human healthcare and public health. Itdescribes the nature o the resistance problem,antimicrobial use, development o resistance, adversehealth consequences or humans, and the magnitude othe impact on society (chapter 2), antimicrobial use,development o resistance, and presence o antimicrobialresistance in ood and ood animals and other reservoirs(chapter 3), associations and transmission routes (chapter4), anticipated uture hazards (chapter 5), possibilities or

intervention with emphasis on prevention o transmissionrom ood animals to humans (chapter 6), and riskassessment (chapter 7). The inormation primarilydescribes the Dutch situation; international data will begiven when relevant.

1Inroducion


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Given the broad scope o this risk prole, theabovementioned topics will be illustrated by means othree relevant examples o antimicrobial resistancehazards (section 2.4). In the concluding chapter 8, theabove mentioned questions will be answered or the threeexample hazards and recommendations will be given.

1.2 Risk managemen framework

Risk analysis provides risk managers and risk assessorswith objective methods and transparent procedures toassess, manage and communicate public health risk issues

like antimicrobial resistance. Several steps can beidentied in the risk analysis process (Figure 1); thedevelopment o a risk prole is part o the preliminary riskmanagement activities. The ramework o the riskmanagement process or antimicrobial resistance isspecied below and is based on (Codex, 2007) and (Codex,2009).

1. Preliminary risk management activities

a. Identication of risk managersThe Dutch Ministry o EL&I is responsible or policymaking with respect to reduction o the transmission o

antimicrobial resistance rom ood animals to thehuman population. The ministry is thereore identiedas the main risk manager.

b. Identication of a public health issueThe health hazard o antimicrobial resistance is thedevelopment o resistance in a pathogenic bacterium, aswell as the development o a resistance determinantthat may be passed to other bacteria that arepathogenic (Vose et al., 2001b). Use o antimicrobials inood animals may result in reduced susceptibility ohuman pathogenic bacteria to one or severalantimicrobial drugs. Humans exposed to thesepathogens may all ill and, as a consequence o the

reduced therapeutic value o the antimicrobials used,may sufer rom prolonged illness and/or a higher risk odeath.

c. Risk proleThe risk prole (this document) reviews relevantinormation with respect to spread o antimicrobialresistance rom ood animals to the human populationand the consequences or human health. Theinormation is reviewed in a structured way and ollowsa risk based approach. The objectives o the risk proleare to support urther risk management activities byinorming the risk manager on the context o the

problem, data gaps, the easibility o a risk assessment,and potential management options and priorities.Based on the outcomes o a risk prole, the riskmanager may decide the ollowing actions: no action,initiation o a risk assessment or, in case o an urgent

public health concern, immediate (provisional) action(Codex, 2007).

d. Risk assessment policyA risk assessment policy should be established anddocumented by the risk manager in close collaborationwith the risk assessors beore carrying out a riskassessment. The risk assessment policy aims to protectthe scientic integrity o the assessment and ofersguidance with respect to possible sources o subjectivitye.g. uncertainties, choice o data sources, data gaps,value judgments, policy choices, etcetera (Codex, 2007).

e. Commissioning of a risk assessment and consideration of theprocess and the results

Risk assessments are commissioned by the risk managerand carried out by the risk assessors. Based on the riskprole a choice is made or an antimicrobial-resistantbacterium - antimicrobial use - specied transmissionroute combination to be assessed and a provisional listo risk management options to be evaluated (Codex,2009). It is also possible to commission a comparativeexposure assessment in which the aribution o variouspathways can be compared. The results o theassessment should be presented by the risk assessors ina clear and transparent way in order to be properlyunderstood by the risk manager. Special aention

should thereore be given to the strengths andlimitations o the assessment: assumptions, uncertainty,variability in data and data sources and their inuenceon the outcomes (Codex, 2007).

2. Identication and selection of risk management

options

The risk manager has to consider all possible riskmanagement options identied in the risk prole andselect a suitable option or combination o options orpractical implementation taking into account allevaluation inormation obtained rom the risk proleand risk assessment. The selection o options should be

based on their ability to reduce the risk posed byantimicrobial resistance transmied rom ood animalsto the human population to an appropriate level,possible efects on animal health, advantages/disadvantages, and practical easibility (Codex, 2007;Codex, 2009).

3. Implementation of risk management options

Implementation o risk management options includethe actual realization o the options and verication thatthey are implemented as intended. Several stakeholdergroups may be involved (authorities, armers,

veterinarians, pharmaceutical industry, ood industry,health care, consumers, patients, etcetera). To ensuretransparency, decisions on management risk optionsshould be communicated by the risk managers to allstakeholders involved. Minimum measures that should


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be implemented are prudent use guidelines and generalon-arm and ood hygiene principles (Codex, 2007).

4. Monitoring and review

Monitoring and review activities are essential parts othe risk management process. Monitoring is thecontinuous gathering, analysing and interpreting o datarelated to the use o antimicrobials, antimicrobialresistance development in selected bacteria,surveillance o clinical disease related to antimicrobial-resistant agents, etcetera. (Codex, 2009). This is aniterative process, as monitoring is essential beore,

during and aer implementation o the riskmanagement options, to establish a baseline, tocompare the efectiveness o new risk managementactivities and to support the risk manager on decisionso urther steps to be taken. Review activities measurethe efectiveness, appropriateness and implementationo the selected risk management options and may leadto a change in risk management activities. Riskmanagement options should be reviewed regularly orwhenever new relevant inormation becomes available(Codex, 2007).

1.3 Glossary

Acquired resistance: the resistance that is acquired either by mutation or by the uptake o exogenous genes byhorizontal transer rom other bacterial strains (EFSA, 2008b).

Activated sludge: a semi-liquid mass o aerated precipitated sewage containing micro-organisms which isadded to untreated sewage to reduce organic pollution. Sludge o treated sewage can beused as ertilizer.

Antibiotic: see antimicrobial (drug).

Antimicrobial resistance riskassessment (AMR-RA):

a scientic tool to qualitatively or quantitatively evaluate the health risk resulting romexposure to resistant bacteria or resistance genes (Codex, 2009).

Antimicrobial resistance: the capacity o bacteria to survive exposure to a dened concentration o an antimicrobial(EFSA, 2008b).

Antimicrobial (drug): any substance o natural, semi-synthetic, or synthetic origin that kills or inhibits thegrowth o micro-organisms by interacting with a specic target at in vivo concentrations(FAO/OIE/WHO, 2008), also reerred to as antibiotic. In this risk prole, the termantimicrobial/antibiotic will be limited to antibacterial drugs that are used or therapeuticor preventive use in ood animals and/or humans, unless otherwise stated.

Aquaculture: the cultivation o aquatic organisms (as sh or shellsh) especially or ood.Bactericidal antibiotics: antibiotics that kill bacteria (Wikipedia)Bacteriophage: a virus that lyses bacteria (Dorlands medical).

Bacteriostatic antibiotics: antibiotics that limit the growth o bacteria by interering with bacterial proteinproduction, DNA replication, or other aspects o bacterial cellular metabolism (Wikipedia)

Carrier: an individual who harbors the specic organisms o a disease without maniest symptomsand is capable o transmiing the inection (Dorlands medical).

Figure Risk analysis ramework (FAO/WHO, ).

Risk management

Preliminary risk management activities Identication and selection of options Implementation of options Monitoring and review

Risk communication

Risk assessment

Hazard identication Exposure assessment

Hazard characterization

Risk characterization


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Clinical resistance: inections having a low probability o clinically responding to treatment, even i maximum

doses o a given antimicrobial are administered (EUCAST, 2000 and Acar and Rstel, 2003in EFSA, 2008b).

Colonization: the oundation and growth o a new group o microorganisms on a host (Dorlandsmedical)

Commensal bacteria: bacteria that live on or within another organism without causing injury to their host(Dorlands medical).

Conjugation: a orm o sexual reproduction in which nuclear material is exchanged during thetemporary usion o two cells (conjugants), (Dorlands medical).

Co-resistance: two or more diferent resistance genes that are physically linked e.g because they arecontained in larger genetic elements such as integrons, transposons or plasmids (EFSA,2008b).

Co-selection: concurrent selection o genetic traits that are linked, e.g. virulence and resistance genes.

Cost o illness: ramework to calculate the cost o illness or society (Kemmeren et al., 2006).Cross contamination(o ood): the transer o micro-organisms rom one ood to another.Cross resistance: resistance to either several antimicrobials within one class due to a similar mode o action

and/or a similar target, or resistance to antimicrobials in unrelated classes due to lessspecic mechanisms o resistance such as eux pumps or overlap in bacterial targets(EFSA, 2008b).

Dened Animal Daily Dose(ADD):

the assumed maintenance dose per day or a drug or its main indication in a specicanimal species.

Dened Daily Doses (DDD): the assumed average maintenance dose per day or a drug used or its main indication inadults (WHO, 2009).

Direct (health) hazard: hazard that directly afects human health (e.g. resistant zoonotic pathogens).Direct health care costs(DHC):

all costs that are directly connected to prevention, diagnostics, therapy, revalidation andthe care o patients, (Kemmeren et al., 2006).

Direct non-health care costs(DNHC):

costs that patients make due to disease (e.g. time and travel costs), (Kemmeren et al.,2006).

Disability Adjusted Lie Year(DALY):

one lost year o healthy lie (WHO, measure o disease burden).

(Disease) susceptibility: diminished immunity to a disease, especially an inection (Dorlands medical).Euent: the outow o water rom a (waste water) treatment plant.Empiric treatment: the initial treatment o an inection prior to the denitive diagnosis on the causative agent

and its antimicrobial resistance (Wikipedia).Exposure assessment: second step in AMR-RA; identies the pathways o exposure and aims to estimate the

requency and amount o the (antimicrobial resistance) hazard to which humans areexposed (Codex, 2007).

Fomite: an object that is not in itsel harmul, but is able to harbor pathogenic microorganisms andthus may serve as an agent o transmission o an inection (Dorlands medical)

Fresh produce: arm-produced goods, especially vegetables and ruit, that are in the same state in storesas when they were harvested.

Gram-negative: losing the stain or decolorized by alcohol in Grams method o staining, a primarycharacteristic o bacteria having a cell wall composed o a thin layer o peptidoglycancovered by an outer membrane o lipoprotein and lipopolysaccharide (Dorlands medical).

Gram-positive: retaining the stain or resisting decolorization by alcohol in Grams method o staining, aprimary characteristic o bacteria whose cell wall is composed o a thick layer opeptidoglycan with aached teichoic acids (Dorlands medical).

Growth promotor: any medicine that destroys or inhibits bacteria and is administered at a low,subtherapeutic dose (website ao).

Habitat: the area or environment where an organism or ecological community normally lives oroccurs.Hazard characterization: third step in AMR-RA; aims to determine the probability o disease as a consequense o

exposure to the (antimicrobial resistance) hazard (Codex, 2007).Hazard identication: First step in AMR-RA; aims to identiy the (antimicrobial resistance) hazard (Codex, 2007).


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Hazard: a biological, chemical or physical agent with the potential to cause an adverse health efect

(Codex, 2007).Horizontal gene transer: exchange o genetic material between two microorganisms; no new microorganism is

created (hp://www.tus.edu/med/apua/Miscellaneous/Glossary.html).Immunocompromised: having the immune response aenuated (Dorlands medical).Indirect (health) hazard: hazard that indirectly afects human health (e.g. resistance genes).Indirect health care costs(IHC):

the uture savings on health care that arise as a secondary consequence o the illness ortreatment, (Kemmeren et al., 2006).

Indirect non-health carecosts (INHC):

the value o production lost to society due to disease, (Kemmeren et al., 2006).

Inection: invasion and multiplication o microorganisms or parasites in body tissues; it may beclinically inapparent (subclinical inection) or remain localized (Dorlands medical).

Integrons: a two component gene capture and dissemination system, initially discovered in relation

to antibiotic resistance, and which is ound in plasmids, chromosomes and transposons(Wikipedia).

LOS: length o stay, the number o days a patient stays in a hospital or other health care acilityMicroaerophilic: requiring oxygen or growth but at lower concentration than is present in the atmosphere

(Dorlands medical).Microbiological resistance: toleration o higher concentrations o an antimicrobial than phenotypically related

bacteria o the original or wild type strain (Acar and Rstel, 2003 in EFSA, 2008b).Minimum inhibitoryconcentration (MIC):

the lowest concentration o an antimicrobial that will inhibit visible growth o thebacterium aer overnight incubation (Wikipedia).

Mobile genetic elements: segments o DNA that can move around within the genome, e.g. plasmids andtransposons (Wikipedia).

Multidrug-resistance (MDR): resistance to multiple classes o antimicrobial drugs . Note: the number o classes is notstandardized (EFSA, 2008b).

Mutation: changes in the DNA sequence o a cells genome (Wikipedia).Non-wild type: microorganism with acquired or mutational resistance to a specied antimicrobial drug

(Kahlmeter et al., 2003).Nosocomial inection: an inection not present or incubating prior to admiance to a hospital, but occurring a

ew days aer admiance; the term is usually used to reer to patient disease, but hospitalpersonnel may also acquire nosocomial inection (Dorlands medical)

Opportunistic pathogen: a microorganism that does not ordinarily cause disease but that, under certaincircumstances (e.g., impaired immune responses resulting rom other disease or drugtreatment), becomes pathogenic (Dorlands medical).

Outpatients: a patient who comes to the hospital, clinic, or dispensary or diagnosis and/or treatmentbut does not occupy a bed (Dorlands medical)

Pan-drug resistance: resistance to all available classes o antimicrobial drugs

Pathogenicity island: part o the genome that contains one or more virulence actors and can be transerred byhorizontal gene transer.

Phagetherapy: the therapeutic use o bacteriophages to treat bacterial inections (Wikipedia).Plasmid: an extrachromosomal sel-replicating structure ound in bacterial cells that carries genes

or a variety o unctions not essential or cell growth (Dorlands medical).Public health risk: a unction o the probability o an adverse health efect and the severity o that efect in a

human population, as a consequence o a hazard (Codex, 2007).Reservoir (host): an alternate or passive host or carrier that harbors pathogenic organisms or parasites,

without injury to itsel, and serves as a source rom which other individuals can be inected(Dorlands medical).

Risk analysis: a process consisting o three components: risk assessment, risk management and riskcommunication (Codex, 2007).

Risk assessment: a scientically based process consisting o the ollowing steps: (i) hazard identication, (ii)hazard characterization, (iii) exposure assessment, and (iv) risk characterization (Codex,2007).

Risk characterization: ourth step in AMR-RA; integrates the results o the preceding steps and aims to generatean overall estimate o the health risk (Codex, 2007).


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Risk communication: the interactive exchange o inormation and opinions throughout the risk analysis process

concerning risk, risk-related actors and risk perceptions, among risk assessors, riskmanagers, consumers, industry, the academic community and other interested parties,including the explanation o risk assessment ndings and the basis o risk managementdecisions (Codex, 2007).

Risk management: the process, distinct rom risk assessment, o weighing policy alternatives, in consultationwith all interested parties, considering risk assessment and other actors relevant or thehealth protection o human beings and or the promotion o air trade practices, and, ineeded, selecting appropriate prevention and control options (Codex, 2007).

Risk perception: the subjective judgment that people make about the characteristics and severity o a risk(Wikipedia)

Risk prole: the description o the public health issue and its context (Codex, 2007).Scheduled processing: to separate positive and negative ocks or slaughter, ollowed by reezing or chemical

decontamination o the meat o the positive ocks (Wagenaar et al., 2006).Selective pressure: the intensity o selection acting on a population o bacteria e.g. as a result o antimicrobial

use. Its efectiveness is measured in terms o survival and reproduction, and consequentlyin change in the requency o alleles in a population (adapted rom FAO: hp://www.ao.org/docrep/003/x3910e/X3910E22.htm).

SOS response: the synthesis o a whole set o DNA repair, recombination and replication proteins inbacteria containing severely damaged DNA (Biotechnology glossary FAO website: hp://www.ao.org/docrep/003/x3910e/X3910E22.htm).

Transduction: a method o genetic recombination in bacteria, in which DNA rom a lysed bacterium istranserred to another bacterium by bacteriophage, thereby changing the geneticconstitution o the second organism (Dorlands medical medical).

Transormation: the exchange o genetic material between strains o bacteria by the transer o a ragmento naked DNA rom a donor cell to a recipient cell, ollowed by recombination in therecipient chromosome (Dorlands medical medical).

Transposon: a small mobile genetic (DNA) element that can move around within the genome or toother genomes within the same cell, usually by copying itsel to a second site butsometimes by splicing itsel out o its original site and inserting in a new location(Dorlands medical medical).

Vertical gene transer: the transer o genes rom a bacterium to its ofspring.Virulence: the relative capacity o a bacterium to cause damage in a host (Casadevall and Piroski,

1999)Waste water treatmentplant:

a acility where waste water is processed to improve its chemical and biologicalcomposition to a point that it can saely be released to the environment.

Wild type: microorganism without acquired or mutational resistance to a specied antimicrobial drug(Kahlmeter et al., 2003).

Years Lost due to Disability(YLD):

total number o years that patients have spent with disease in a human population(Havelaar, 2007).

Years o Lie Lost (YLL): the total number o years lost due to premature death in a human population (Havelaar,2007).

Zoonosis: disease transmied between vertebrate animals and man under natural conditions (Vander Giessen et al., 2010)


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This chapter ocusses on the specic microbiological

aspects o the health hazards studied in this risk prole.These hazards were identied in section 1.2 as thedevelopment o resistant bacteria and their resistancegenes originating in ood animal production that directlyor indirectly may cause adverse health efects in humans.Section 2.1 provides background inormation onantimicrobials and antimicrobial resistance. Sections2.2-2.4 describe the direct and indirect health hazards oantimicrobial resistance and the selection o three agentso concern that are used as examples throughout this riskprole.

2.1 Naure of he problem

Definitions of antimicrobials and antimicrobial resistance

Antimicrobials or antimicrobial agents are dened as:

Any substance o natural, semi-synthetic, or synthetic

origin that kills or inhibits the growth o micro-organismsby interacting with a specic target at in vivoconcentrations (FAO/WHO/OIE, 2008).

This very broad denition includes antibacterial, antiviral,antiungal, and antiparasitic agents. In this risk prole, theterm antimicrobial is limited to antibacterial drugs (alsonamed antibiotics) that are used or therapeutic orprophylactic use in ood animals and/or humans to treator prevent bacterial inections. Antimicrobials disturb vitalprocesses o bacteria resulting in either growth inhibition(bacteriostatic antibiotics) or killing the bacteria

(bacteriocidal antibiotics).

Antimicrobial resistance is generally dened as:The capacity o bacteria to survive exposure to a denedconcentration o an antimicrobial (EFSA, 2008b).

2

Descripionof he micro-

biologicalhazards


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When bacterial populations are exposed to antimicrobials(selective pressure), resistant bacteria will have a selectiveadvantage over the susceptible ones and the resistantraction in the population will increase. As a consequenceo resistance, antimicrobial drugs become less efective orinefective or treatment o bacterial inections.

Origin and development of antimicrobials

The majority o antimicrobials that are used or therapeutic

or prophylactic use in ood animals and humans have an

environmental origin. The production o antimicrobials by

ungi and bacteria is a natural phenomenon in

environmental microbial populations, e.g. soil, where many

microorganisms have to compete or suitable niches(Martnez, 2008). For example, penicillin, the rst

antimicrobial that was discovered and used therapeutically,

is produced by the ungus Penicillium chrysogenum. Most

antimicrobials currently used or therapeutic goals are

produced semi-synthetically or ully synthetically.

Nowadays there are hundreds o therapeutic antimicrobials,

which are subdivided into several classes and subclasses

based on their chemical structure (Appendix).

Mechanisms of antibiotic action

There are ve main categories o the mechanisms o

antibiotic action (Tenover, 2006): intererence with cell wall synthesis inhibition o protein synthesis intererence with DNA/RNA synthesis inhibition o metabolic pathways disruption o bacterial membrane structures

Emergence of resistance

Antimicrobial resistance mechanisms arise through

mutation o bacterial genes. In bacteria, mutations occur

spontaneously with a mutation rate o approximately 10-10

per base pair and per generation (Drake, 1999). When

bacteria are stressed, e.g. when exposed to antimicrobials,

mutation rates increase as a result o an activated bacterial

stress response system, the SOS response. This may result

in resistant mutants that are beer adapted to the

worsened conditions, which potentially speeds up

antimicrobial resistance (Galhardo et al., 2007).

Mechanisms of antimicrobial resistance

Four main mechanisms o antimicrobial resistance can bedistinguished (EFSA, 2008b; Tenover, 2006): target alteration, e.g. production o cell walls that have

no or altered binding sites production o enzymes that inactivate or degrade the

antimicrobial drug permeability changes, by either limited access by altered

porins (transmembrane proteins) or by eux pumpsthat pump out the antimicrobial drug

alternative metabolic pathways

Measurement of resistance

Antimicrobial resistance o a bacterium is generallydetermined in vitro and based on its survival to a denedconcentration o an antimicrobial. Resistance is usuallyexpressed as the minimum inhibitory concentration (MIC),i.e. the lowest concentration o an antimicrobial that willinhibit visible growth o the bacterium. Threshold valuesor breakpoints are used to dene whether a bacterium issusceptible or resistant to an antimicrobial; thesethresholds depend on the objective o the investigation(see resistance terminology below).

Resistance terminology

Depending on the objective o the investigation, thereare two denitions o resistance: clinical and

microbiological resistance. Clinical resistance means that

the MIC o an antimicrobial or the bacterium is

associated with a high likelihood o therapeutic ailure o

treatment with this drug (EFSA, 2008b). Microbiological

resistance means that the MIC o the antimicrobial is

higher than expected or wild type strains (EFSA, 2008b).

In this report, resistance means microbiological

resistance unless otherwise stated.

There are several denitions o resistance in use that reer

to the origin o the resistance, e.g. acquired resistance

(resistance acquired by mutation or horizontal transer),anthropogenic resistance (resistance as the result o

human activities) and natural resistance (or intrinsic or

autochthonous resistance), which reers to resistance that

is present in wild type strains in nature that makes these

bacteria insensitive to the antimicrobial.

Bacteria that are resistant to one antimicrobial o a certainclass, usually are resistant to all other antimicrobials in thesame class due to a similar mode o action and/or a similartarget. This is reerred to as cross-resistance. Crossresistance may also occur in unrelated classes e.g. due toless specic mechanisms o resistance such as enhancedeux pumps or overlap in bacterial targets. Co-resistance

means that resistance genes are physically linked togethere.g. when they are situated on the same plasmid. As aconsequence selection or one resistance gene will alsoselect or the resistance genes that are linked to it. Finally,multidrug resistance (MDR) means that a bacterial strain isresistant to diferent classes o antimicrobials.

Spread of antimicrobial resistance

Spread o antimicrobial resistance rom animals tohumans may take place by transmission o antimicrobial-resistant bacteria or by transer o antimicrobial resistancegenes. Antimicrobial-resistant bacteria that are

transmied rom animals to humans and potentially causedisease in humans, i.e. resistant zoonotic bacteria, pose adirect hazard (see also 2.2). Transmission o antimicrobial-resistant bacteria may occur via direct contact, ood orenvironmental routes, which are discussed in more detail


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in chapter 4. Bacteria o ood-producing animals that donot cause disease in humans, but potentially transer theirresistance genes to pathogenic bacteria o humans, i.e.horizontal gene transer, pose an indirect hazard (see alsosection 2.3). Mechanisms o horizontal gene transer aredescribed below.

Mechanisms of gene transfer

Transer o resistance genes may occur through verticalgene transer or horizontal gene transer. Vertical genetranser is the transer o genes rom a bacterium to itsofspring. Horizontal gene transer is the exchange o

genetic material rom a donor bacterium to a recipientbacterium that is not its ofspring. There are threemechanisms or horizontal gene transer: conjugation,transduction and transormation (see also Figure 2).With these processes, genetic material is moved between

bacteria by either a temporary linkage between a donorand recipient bacterium (conjugation), by bacteriophages(transduction) or by uptake o ree DNA (transormation).Conjugation is the most commonly reported antimicrobialgene transer mechanism and may occur between bacteriao diferent species or genera (EFSA, 2008b). Duringconjugation, mobile genetic elements e.g. plasmids ortransposons, can be transerred. Integrons are genecapture systems that can be ound in plasmids,chromosomes and transposons and play an important rolein the dissemination o genetically linked antimicrobialresistance by the capture, mobilization, and expression o

resistance genes (Kovalevskaya, 2002). Published genetranser rates during conjugation were ound to varywidely (Hunter et al., 2008). Besides increased mutationrates, the SOS response also promotes horizontal genetranser (Beaber et al., 2004).

Figure Horizontal gene transer between bacteria (rom: Furuya and Lowy, )

Release of DNA

Antibiotic-resistance geneDonor cell

a Bacterial transformation

b Bacterial transduction

c Bacterial conjugation

Recipient cell

Release of phage

Phage-infected donor cell Recipient cell

Transposon Donor cell Recipient cell

Copyright 2006 Nature Pulbishing GroupNature Reviews | Microbiology


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Persistence of antimicrobial resistance in bacterial

populations

Acquisition o antimicrobial resistance may result in areduced biological tness o the bacterium (Andersson,2003). As a result, resistant bacteria may be outcompetedby susceptible bacteria in environments where antibioticselection pressure is absent. However, several studies haveshown that aer removal o the selective pressure, i.e.aer withdrawal o the use o the antimicrobial,antimicrobial resistance may persist or many yearsthough oen at a lower level (Srum et al., 2006). This canbe explained by several mechanisms (Andersson, 2003)and (Zhang et al., 2006): compensatory mutations no-cost or low cost o resistance enhanced tness (Luo et al., 2005) genetic linkage to other resistances (i.e. co-resistance) gene silencing (Enne et al., 2006) plasmid addiction systems (Woodord et al., 2009) besides these mechanisms, the epidemiological eatures

(e.g. transmissibility, survival in the environment) arealso o importance or persistence o antimicrobial-resistant bacteria (Garcia-Migura et al., 2007)

Virulence and antimicrobial resistance

The virulence o a bacterium is its relative capacity to causedamage in a host (Casadevall and Piroski, 1999). Virulence

actors are actors related to invasiveness, inectiousness

or toxigenicity o the bacterium. Virulence is oen encoded

by several genes, which are requently ound on mobile

genetic elements or pathogenicity islands that can be

transerred by horizontal gene transer. Genes determining

virulence and antimicrobial resistance genes can be

genetically linked in a bacterium, e.g. on mobile genetic

elements. As a consequence co-selection may take place,

i.e. selection pressure induced by antimicrobials may select

or more virulent bacteria. Fortunately, examples o

enhanced virulence o antimicrobial-resistant bacteria, e.g.

increased disease maniestation and colonization in

community acquired MRSA (Diep and Oo, 2008), are rare.

In absence o antimicrobial drug use, antimicrobialresistance may still inuence the virulence o a bacterium.For example, genes that have a unction in virulence aswell as antimicrobial resistance have been described(Quinn et al., 2007). The complex relationship betweenvirulence, transmissibility, and antimicrobial resistance isdiscussed at length by (Martnez and Baquero, 2002).

2.2 Direc hazards of animicrobial

resisance

Antimicrobial-resistant bacteria that are transmied romvertebrate animals to humans under natural conditionsand potentially cause disease in humans (zoonoses), pose

a direct hazard or human health. Antimicrobial resistancemay reduce the ecacy o initial empirical treatment othe zoonosis and limit the choice o treatment aerdiagnosis. Resistant strains o (oodborne) zoonoticbacteria may cause a longer duration o illness, moreinvasive illness, higher mortality, and increased risk ohospitalization than susceptible strains (Mlbak, 2005).

Antimicrobial resistance in zoonotic bacteria

In the Netherlands, several bacterial zoonoses may occurand varying levels o antimicrobial resistance have beenound in the causative agents (overview, see Table 1). Themajority o these zoonoses are linked to reservoirs in

animal husbandry; the main exposure sources are oodproducts o animal origin.Surveillance programs on the prevalence o antimicrobialresistance are perormed or the zoonotic agentsSalmonella spp., Campylobacterspp. and STEC O157(MARAN-2008) and an extensive research program orlivestock-associated MRSA has been carried out in theNetherlands (Wagenaar and Van de Giessen, 2009). It isincreasingly reported that part o the human urinary tractinections caused by commensal E. coli may also originaterom the ood animal reservoir (Jakobsen et al., 2010;Johnson et al., 2007), but conclusive evidence is lacking.

2.3 Indirec hazards of animicrobial

resisance

Use o antimicrobials in ood animals will promote thedevelopment o antimicrobial resistance in bothpathogenic and commensal bacteria (Varga et al., 2009).Resistance genes carried on mobile genetic elements maybe transerred to the human ora by horizontal genetranser during transit or colonization o the human body(EFSA, 2008b; Hunter et al., 2008). Consequently thehuman ora may become resistant, including bacteria that

are potentially harmul to humans, e.g. nosocomialpathogens (Donskey, 2004). These resistance genesthereby pose an indirect hazard.

Transfer of antimicrobial resistance genes from animals

to humans

Horizontal gene transer has been responsible or the

dissemination o numerous antimicrobial-resistance genes

among various bacterial species (Barlow, 2009). In

particular the gastrointestinal tract is an important

hot-spot or horizontal inter- and intra-species gene

transer. Major residents o the mammalian

gastrointestinal tract, e.g. Enterococcus spp. and Escherichiacoli, possess a wide spectrum o mobile genetic elements

and have been shown to be potent donors and receivers o

antimicrobial resistance genes, e.g. glycopeptide resistance

in Enterococcus spp. and beta-lactam resistance in E. coli.


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Table Overview o the main bacterial zoonoses in the Netherlands (Valkenburgh S, ; website ziekdoordier) and their

antimicrobial resistanceZoonose Agent Animal reservoirs Average number of

human cases/yr

Antimicrobial resistance

Botulism Clostridium

botulinum

Mammals, birds, sh,

environment

Rare; intoxication --

Brucellosis Brucella spp. Cale, goats, sheep,

dogs

Rare; travel or import

related

Reduced susceptibility to

riampicin and

sulamethoxazole-

trimethoprim ound,

susceptible to most antibiotics

or treatment

Campylobacteriosis Campylobacter

spp.

Mammals and birds;

especially poultry

, symptomatic

cases in the general

population, lab

conrmed cases

Increasing resistance to

ciprooxacin + multidrug

resistance. Erythromycin

resistance in imported

products

Cat-scratch disease Bartonella

henselae

Cats - estimated

cases

--

Leptospirosis Leptospira spp. Rats, mice, cale $ reported cases

Listeriosis Listeria

monocytogenes

Cale, goats, sheep

(note: common in

environment)

reported cases Most isolates susceptible, slow

increase o resistance . In NL

resistance to

sulamethoxazole ound.

Lyme disease Borrelia

burgdorferi

Tick borne; deer

rodents, cale, sheep,

dogs

, cases with

erythema migrans in

No scientic evidence or

acquired antimicrobial

resistance LA-MRSA Staphylococcus

aureus

Cale, pig, poultry,

horses

symptomatic cases Resistant to ciprooxacin,

beta-lactams, tetracycline,

erythromycin, lincomycin,

gentamicin, kanamycin,

doxycycline, tobramycin, and

clindamycin ,

Psiacosis Chlamydophila

psiaci

Birds, incl. poultry - cases year

(underestimate)

--

Q-ever Coxiella burnei Cale, goats, sheep cases, more than

cases in the

epidemic

--

Salmonellosis Salmonella spp. Mammals, birds,

reptiles, amphibians;

especially poultry, pigs

,-,

symptomatic cases in

the general population,

lab conrmed

cases

Increasing levels + multidrug

resistance. Quinolone

resistance related to travel and

imported products

STEC* Escherichia coli Cale, sheep cases o

gastroenteritis, at

GP, HUS

Rare

Tuberculosis Mycobacterium

bovis

Cale $ Rare; reported cases

in Multi and extensive drug

resistance

-- = no inormation ound on acquired resistance; * Shiga toxin-producing Escherichia coli; # Livestock-associated methicillin-resistantStaphylococcus aureus; $ ocial ree status in animal husbandry; (Van Pelt et al., a); (Erkens, ), (Turkmani et al., ); (MARAN-); (Conter et al., ); (Huneld and Brade, ); (Van Loo et al., ); (Van Duijkeren et al., ); (Havelaar

et al., )


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Transer o antimicrobial resistance genes rom animals tohumans (i.e. rom donor bacteria o animal origin andrecipient bacteria rom human origin) has been shown invitro and in vivo (De Niederhusern et al., 2004; Lester etal., 2006). The association o antimicrobial resistancebetween (ood-producing) animals and humans is morecomplex or indirect hazards than direct hazards, but theultimate impact on health may be many times greater(Mevius, 2009), see also section 4.1.

2.4 Example agens

Based on urgency, data availability and host-pathogencharacteristics, two direct hazards and one indirect hazardwere selected to serve as examples throughout this riskprole. The selected agents are: quinolone-resistant Campylobacterjejuni (direct hazard) LA-MRSA (direct hazard) ESBL-producing bacteria (indirect hazards)

For the ESBL-producing bacteria and genes, ocus will beon ESBL-producing Escherichia coli and Salmonella spp. inanimal husbandry and ESBL-producing E. coli and Klebsiellaspp. in human health. The general characteristics o the

two bacteria and the beta-lactam inactivating enzymes arebriey described below.

Quinolone-resistantCampylobacterjejuni

Campylobacterjejuni is a Gram-negative, microaerophilic,

motile, spiral-shaped bacterium. Its natural habitat is the

intestinal tract o mammals and birds. Campylobacteriosis is

the most common zoonosis in the Netherlands. The last

decade, a strong increase in quinolone resistance in

Campylobacterisolates o poultry and o human inections was

observed and is ound to be directly related to the use o the

uoroquinolone enrooxacin in poultry (Endtz et al., 1991).

Livestock-associated MRSA (LA-MRSA)

Staphylococcus aureus is a Gram-positive, acultativeanaerobe, non-motile, coc-shaped bacterium that appearsas grape-like clusters under the microscope. Its naturalhabitat is the skin, nasal cavity and oroarynx o mammalsand birds. Meticillin-resistant S. aureus (MRSA) are resistantto all beta-lactam antibiotics and to various other classeso antimicrobial drugs, which makes inections with thisbacterium more and more dicult to treat. Livestock-associated MRSA (LA-MRSA) was discovered in 2005 in theNetherlands and is now widespread among pigs and vealcalves (Wagenaar and Van de Giessen, 2009).

Extended-spectrum beta-lactamase (ESBL) producing

bacteria

Beta-lactamases are enzymes produced by Gram-negative

bacteria that cleave the amide bond in the beta-lactam ring,

rendering the bacteria resistant to beta-lactam

antimicrobials. Extended-spectrum beta-lactamases

(ESBLs) are beta-lactamases capable o inactivating

penicillins, cephalosporins and aztreonam and are inhibited

by beta-lactamase inhibitors (Paterson and Bonomo, 2005).

Several types o ESBLs can be distinguished, e.g. SHV-,

TEM-, and CTX-M beta-lactamases. The CTX-M type is

currently the most predominant type and comprises more

than 80 enzymes (hp://www.lahey.org/studies/). ESBL-

encoding genes are usually located on plasmids that oen

also carry other antimicrobial resistance genes, rendering

the bacteria resistant to multiple antimicrobials and making

co-selection likely. Both clonal spread and transer o

mobile genetic elements between several Gram-negativebacterial species may occur (Cantn and Coque, 2006). The

number o ESBL-producing Gram-negative bacteria is rising

considerably both in humans and animals (EARRS, 2009;

MARAN-2008).

The example ESBL-producing bacteria in this risk prole(E. coli, Salmonella spp. and Klebsiella spp.) are Gram-negative, acultative anaerobe, rod-shaped bacteria. Theirnatural habitat is the intestinal tract o animals andhumans, but they may also survive or brie or longerperiods in the environment. Salmonellosis is a zoonosis,whereas E. coli and Klebsiella spp. are common non-

pathogenic inhabitants o the gastrointestinal tract thatmay become opportunistic pathogens when the immunesystem is impaired or normal deence barriers arebreached (e.g. surgery, trauma, underlying disease).

2.5 Animicrobial usage and resisance

in human healh care

2.5.1 Importance o the drugs or humanmedicine

Impact on disease burden

Since their introduction, now more than 60 years ago,antimicrobial drugs have substantially reduced the diseaseburden caused by inectious diseases that were previouslywidespread, untreatable and oen atal. Together withimproved hygiene, housing, nutrition and vaccinationprogrammes, they have contributed to a longer andhealthier lie o millions o people (WHO, 2002).

Classification

Drugs are classied according to the the Anatomical

Therapeutic Chemical (ATC) classication system o the WHO

(www.whocc.no). Within this classication, the majority oantibacterial drugs belongs to class J01, the antibacterials or

systemic use. The ATC system also includes the Dened Daily

Dose (DDD), which is a measurement o drug consumption

based on the usual daily dose o each antibiotic in adults


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(see also section 2.5.2). There are several classes o

antibacterial drugs available or human and veterinary

medicine, see also Appendix. This classication is based on

similarities in their molecular structure. Some classes are

solely used in either human or veterinary medicine, but the

majority is used in both.

Critically important antimicrobial drugs

During expert meetings organized by the WHO, a list oantimicrobial drugs that are deemed critically important inthe treatment o human disease was developed (WHO,2007). This list was developed as a risk managementstrategy to determine which antimicrobial drugs should be

banned or should be used only limited in the non-humansector to contain the problem o antimicrobial resistance.The ollowing (sub)classes o antimicrobials were classiedas critically important or human medicine: beta-lactams: penicillins, cephalosporins (third and

ourth generation) and (carba)penems aminoglycosides tetracyclines (tigecycline only) macrolides and ketolides glycopeptides quinolones lipopeptides

oxazolidinones streptogramins ansamycins drugs used solely to treat tuberculosis or other

mycobacterial diseases

A comparable list o critically important antimicrobials orood animal therapy was developed by the OIE (OIE, 2007).

Quinolones

Quinolones are a broad and expanding class oantimicrobials that contain a dual-ring structure withnitrogen, a carbonyl and a carboxyl group in the rst ring

(Figure 3). Quinolones with uorine in the second ring arenamed uoroquinolones. Quinolones can be categorizedin our broad groups: the rst group being the olderquinolones with activity against Gram-negativeenterobacteria and group 2, 3 and 4 the uoroquinoloneswith ever increasing spectrum and an improved activityagainst Gram-positive cocci and anaerobes (Finch, 2003).

Quinolones are bactericidal antimicrobial drugs and theirmechanism o action is the inhibition o bacterial DNAreplication and transcription.The rst quinolones were derived rom aempts to

synthesize the anti-malarial drug chloroquine. Nalidixicacid was the rst quinolone introduced or clinical use in1962, several others quickly ollowed. Some quinoloneshave been withdrawn rom clinical use due to toxicityproblems. Their therapeutic use comprises a wide range o

disorders, e.g. genitourinary tract inections, respiratorydisorders, sinusitis, ocular inections, etcetera. (Finch,2003). Quinolones are classied as critically important orboth human and animal health and should be addressedas the highest priority or the development o riskmanagement strategies with respect to antimicrobialresistance (FAO/WHO/OIE, 2008).

Beta-lactamsBeta-lactams orm a broad class o antimicrobials thatcontain a beta-lactam ring in their molecular structure(Figure 2). This class includes the subclasses penicillins,cephalosporins, monobactams, and carbapenems.

Beta-lactam antibiotics are bactericidal antimicrobial drugs

and their mechanism o action is the inhibition o the

bacterial cell wall synthesis. Penicillin, discovered by

Alexander Fleming in 1928, was the rst antimicrobial drug to

be introduced or large scale treatment. Production o this

antimicrobial drug started during World War II or treatment

o inected war wounds. Soon, derivatives o penicillin were

developed to treat a wider range o inections. Beta-lactam

antibiotics are the most requently used antimicrobial drugs

in hospitals and primary health care (SWAP. NethMap, 2009).

They are used to treat a wide range o inections, e.g. urinary

tract inection, wound inection, sepsis, respiratory

inections, meningitis, etcetera. They are known to be among

the saest antibiotics to be used therapeutically, but

unortunately allergic reactions do occur requently (Finch,

2003). The subclasses penicillins, cephalosporins (third and

ourth generation) and (carba)penems are categorized as

critically important or human health. The penicillins and

third and ourth generation cephalosporins are also classied

as critically important or ood animal medicine (FAO/WHO/OIE, 2008). Moreover, experts dened that the

cephalosporins should be addressed as the highest priority

or the development o risk management strategies with

respect to antimicrobial resistance (FAO/WHO/OIE, 2008).

Figure Essential structure o all quinolone antibiotics: the

blue drawn remainder o R is usually piperazine; i theconnection contains uorine (red), it is a uoroquinolone(Wikipedia, )

R

N

R

R

R

F

OO

HO


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2.5.2 Usage

Collection of consumption data

In the Netherlands, all antimicrobial drugs are prescription-

only medicines delivered to patients by either community

pharmacies, hospital pharmacies or general practitioners

with their own pharmacy, who serve approximately 8.4%

o the Dutch population (Van Batenburg-Eddes et al.,

2002). Sel-medication does occur, but is more prominent

in southern and eastern European countries (Grigoryan etal., 2008). Inormation on the human consumption o

antimicrobial drugs is collected by the Dutch Foundation

on Antibiotic Policy (Stichting Werkgroep Antibiotica

Beleid, SWAB). The data are presented annually in the

yearly NethMap reports which can be downloaded rom

www.swab.nl. Data on the consumption o antimicrobial

drugs in hospitals are obtained rom hospital pharmacies.

Antimicrobial drug use in the community (primary health

care) is obtained rom approximately 90% o all

community pharmacies and is provided by the Foundation

or Pharmaceutical Statistics (Stichting Farmaceutische

Kengetallen, SFK), (Prins et al., 2008).

Measures: DDD and DID

Antimicrobial drug usage is expressed in the standardizedmeasure Dened Daily Dose (DDD). DDD is the assumedaverage maintenance dose per day or a drug used or itsmain indication in adults (WHO, 2009) and is used tocompare drug consumption between diferent countries.To compare usage over time, the usage in primary healthcare is expressed as DDD per 1000 inhabitants per day(DID) and in hospitals as DDD per 100 patient-days and inDDD per 100 admissions (Filius et al., 2005).

Consumption of antimicrobial drugs (Sources: SFK andSWAB)

The overall use o antimicrobial drugs or systemic use inprimary health care in 2008 was 11 DID. In hospitals, theoverall usage o systemic antimicrobial drugs in 2007 was

61 DDD/100 patient-days and 335 DDD/100 admissions. Inprimary health care, the main classes used aretetracyclines (17%, mainly doxycycline) and beta-lactams(39%) o which penicillins with extended spectrum (25% ototal use, mainly amoxicillin) and combinations openicillins with beta-lactamase inhibitors (15%, mainlyco-amoxiclav) are the main subclasses (Figure 5). Inhospitals, the main class is the beta-lactams (62%) owhich combinations o penicillins with beta-lactamase

inhibitors (24%, mainly co-amoxiclav) and cephalosporins(14%) are the main subclasses (Figure 6).

Trends in antimicrobial drug usage (SWAB. NethMap,

200)

From 1999-2008, the overall use o antimicrobial drugs orsystemic use in primary health care gradually increasedrom 10 to 11 DID (Table 2).

From 2003-2007, the overall use o antibiotics or systemicuse in hospitals increased rom 52 to 61 DDD/100 patient-days (Table 3). However, the mean antibiotic use perhospital patient remained constant (333 and 335 DDD/100

admissions in 2003 and 2007 respectively). The ollowingtrends in antibiotic use per (sub)class could be seen: Mean use per patient increased or cephalosporins,

carbapenems, lincosamides, glycopeptides andnitrourantoin.

Mean use per patient remained the same, but due tomore admissions the use per hospital increased orpenicillins with extended spectrum, combinations openicillins, macrolides and uoroquinolones.

Mean use per patient decreased, but due to an increasein admissions the use per hospital remained constantor tetracyclines, beta-lactamase resistant penicillins,

combinations o sulphonamides and trimethoprim andgroup 1 quinolones.

Mean use per patient decreased or trimethoprim andderivatives and aminoglycosides.

Figure Core structure o penicillins () and cephalosporins (). Beta-lactam ring in red (Wikipedia, ).

R1

R2 H

O

O

2

O

OH

SN H

N

R H

O

O

1

O

OH

SN H

N


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Table Data on the use o antibiotics or systemic use (J) in primary care (DDD/ inhabitants-days), and . Source:SFK, table adapted rom (SWAB. NethMap, )

ATC Group* Therapeutic group Year

999

JAA Tetracyclines . .

JCA Penicillins with extended spectrum . .

JCE Beta-lactamase sensitive penicillins . .JCF Beta-lactamase resistant penicillins . .

JCR Penicillins + beta-lactamase-inhibitors . .

JD Cephalosporins . .

JEA Trimethoprim and derivatives . .

JEC Intermediate-acting sulphonamides . .

JEE Sulphonamides + trimethoprim . .

JFA Macrolides . .

JFF Lincosamides . .

JGB Aminoglycosides . .

JMA Fluoroquinolones . .

JMB Other quinolones . .

JXB Polymyxins . .

JXE Nitrouran derivatives . .

JXX Methenamine . .

J Antibiotics or systemic use (total) . .

* From the edition o the Anatomical Therapeutic Chemical (ATC) classication system

Figure Distribution o the use o antibiotics or systemic use in primary health care, Source: SFK, gure obtained rom (SWAB.

NethMap, )

tetracyclines (JA)

penicillins with extended spectrum (JCA)

beta-lactamase-sensitive penicilins (JCE)

beta-lactamase-resistant penicillins (JCF)

penicillins, incl. beta-lactamase inhibitors (JCR)

sulfonamides and trimethoprim (JE)

macrolides, lincosamides (JF)

quinolones (JM)

other antibacterials (JX)

% %

%

%%

%

%

%

%

Figure Distribution o the use o antibiotics or systemic use in hospitals, . Source: SWAB, gure obtained rom (SWAB. NethMap,

)

tetracyclines (JAA)

penicillins with extended spectrum (JCA)

beta-lactamase sensitive penicillins (JCE)

beta-lactamase resistant penicillins (JCF)

combinations of penicillins, incl. beta-lactamase inhibitors (JCR

cephalosporins (JDB-DE)

carbapenems (JDH)

sulfonamides and trimethoprim (JE)

macrolides (JFA)

lincosamides (JFF)

aminoglycosides (JGB)

quinolones (JM)

other antibacterials (JX)

%

%

%

%

%

%

%

%

%

%

%

%

%


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Comparison with usage in other European countries

Inormation on antimicrobial drug consumption in European

memberstates, candidate countries and ree-trade countries

is collected by the European Surveillance o Antimicrobial

Consumption project (ESAC). Usage is expressed in DID. In

2006, the total outpatient use ranged rom 27.91 DID in

France to 9.58 DID in Russia (Figure 7). The Netherlands had

the second lowest score, 10.85 DID (Coenen et al., 2009). In

general, antimicrobial drug usage seems to be higher in

southern European countries (Goossens, 2009).

Quinolones

In the Netherlands, the total use o quinolones in primary

health care increased slightly, rom 0.89 in 1999 to 0.91 DID

in 2008. Ciprooxacin was the most commonly used

uoroquinolone o which the use more than doubled

(Figure 8). In hospitals, the total use o quinolones

increased rom 6.5 in 2003 to 7.6 DID and rom 41.6 to 42.1

DDD/100 admissions in 2007. The use o ciprooxacin

increased, while the use o the other quinolones decreased,or remained relatively low (Figure 9). Within Europe,

quinolone use ranged rom 3.46 DID in Italy to 0.37 DID in

Denmark. The use in the Netherlands was airly low with

0.91 (the h lowest use, Figure 7), (Coenen et al., 2009).

Beta-lactams

The total use o beta-lactams in primary health careincreased rom 3.94 in 1999 to 4.44 DID in 2008. The useo amoxicillin slightly decreased, while the use oco-amoxiclav almost doubled (Figure 10). In hospitals, thetotal use o beta-lactams increased rom 6.5 in 2003 to 7.6DDD/100 patient-days and rom 41.6 to 42.1 DDD/100

admissions in 2007. The use o co-amoxiclav increasedrom 1999-2006, but decreased in 2007 (Figure 11). The useo most other penicillins also decreased in 2007. The useo rst and third generation cephalosporins increased,while second generation cephalosporins stabilized (Fi

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Risk profile on antimicrobial resistance transmissible from food animals to humans