antibiotic uses in animal husbandry & meat value chains...

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ANTIBIOTIC USES IN ANIMAL HUSBANDRY & MEAT VALUE CHAINS

HEALTH SAFETY ANIMAL HEALTH

Dossiers

Hélène CHARDONHubert BRUGERE

Centre d’Information des Viandes Tour Mattei

207, rue de Bercy 75012 PARIS

Translation: Lara Andahazy-Colo [email protected]

Layout: [email protected]

Published in April 2014Translated into English in February 2015


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FOREWORD

The Centre d’Information des Viandes (CIV) dossiers on health safety and animal health aim to make more easily accessible the full range of technical, regulatory and scientific data on livestock health and the control of health safety for beef, sheep meat, horse meat, pork and offal products. In this Dossier, CIV covers the current uses of antibiotics in livestock in France.

The fortuitous discovery of penicillin by Sir Alexander Fleming in 1928 followed by the search for new antibiotics and their use in human and veterinary medicine was a major scientific breakthrough in the 20th century. It allowed many infectious diseases of bacterial origin—scourges for humankind and livestock—to be fought.

During the 1950s, changes in society and in agricultural and industrial systems led to increasingly wide—sometimes even excessive—use of antibiotics among both people and animals alike. The problems with this use appeared very early: starting in the 1960s, incidences of bacterial resistance were described in the context of infectious outbreaks in hospitals (Klebsiella pneumoniae, Escherichia coli), as was the possible transmission of multidrug-resistant bacteria between animals and people (Salmonella enterica) [2, 8].* At this point, discussions began on the rational use of antibiotics in people and animals [18]. However, given their therapeutic interest, antibiotic use continued to grow exponentially worldwide until the end of the 1990s.

The first European recommendations on rational use of antibiotics with the aim of fighting the emergence of bacterial resistance were issued in 1998 at the Copenhagen conference. Currently in France, two plans to fight antibiotic resistance in human and veterinary medicine have respectively been launched for the periods 2011-2016 and 2012-2017.

This CIV Dossier provides answers to the most common questions on how antibiotics are currently used with farm animals in France. Part One presents these uses based on scientific publications and reports by official institutions and bodies. Part Two covers the possible risks of these uses for animal health and human health. Finally, Part Three presents the many measures taken by various stakeholders to encourage appropriate use in animal husbandry.

This Informative Dossier was written by Hélène CHARDON and Hubert BRUGERE. Hélène CHARDON is a veterinarian and head of health safety and animal health projects at CIV; Hubert BRUGERE is a research professor in food safety and industry at the École Nationale Vétérinaire de Toulouse.

We would like to thank the following people for their careful reading of this dossier: Jean-Yves MADEC, research director and head of the antibiotic resistance and bacterial virulence unit at ANSES (laboratory in Lyon), Claude PETIT, research professor in pharmacology-toxicology at the École Nationale Vétérinaire de Toulouse, Jacqueline BASTIEN and Gérard BOSQUET, members of the Société Nationale des Groupements Techniques Vétérinaires’s drug board. Pierre-Michel ROSNER Director of CIV

* The numbers between square brackets correspond to the bibliographic references listed on page 32.

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CONTENTS

Part One: Why and How Antibiotics Are Used in Animal Husbandry 8

1. What Is an ‘Antibiotic’? 8 2. Different Families of Antibiotics 8

3. Uses and Interests of Antibiotics in Animal Husbandry 9

4. Changes in Antibiotic Consumption in Animal Husbandry 11

4.1. Exposure Data for All Species Combined 12 4.2. Exposure Data (ALEA) by Animal Species 12

Part Two: Possible Risks to Animal and Human Health of Antibiotic Use in Animal Husbandry 16

1. The Development of Antibiotic Resistance in Bacteria of Animal Origin 16

1.1. Definition and Associated Mechanisms 16 1.2. Risk of Therapeutic Dead Ends 18 1.3. The Transfer of Resistances Between

Animals and People 19

2. Antibiotic Residues in Meat, Offal and Milk 19

3. Release of Antibiotics in the Environment (Water and Soil) 22

Part Three: Measures Taken to Encourage Appropriate Use of Antibiotics in Animal Husbandry 24

1. Measures for Controlled Use of Antibiotics 24 1.1. Pharmaceutical Industry 24 1.2. Livestock Veterinarians 25 1.3. Value Chain Professionals 26 1.4. Public Authorities 26 1.5. Risk Assessors 28

2. Measures Regarding the Surveillance of Antibiotic Resistance 28

3. Research and Development Outlook in France and Europe 29

3.1. Diagnostic Methods 29 3.2. Range of Antibiotics Available

for Livestock 29 3.3. Alternative Treatments 29 3.4. Improved Knowledge of Resistance

Mechanisms 29

Appendices

Bibliography 32Glossary 33Acronyms 34Useful Links 34


PART ONE

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PartOne



WHY AND HOW ANTIBIOTICS ARE USED IN ANIMAL HUSBANDRY

1. What Is an ‘Antibiotic’?

From the Greek anti meaning ‘against’ and bios meaning ‘life’, antibiotics

are natural substances produced by microscopic mushrooms, bacteria and much less often plants, and sometimes synthetic substances able to:

either destroy bacteria, in which case we speak of ‘bactericidal antibiotics’;

or inhibit the growth of bacteria, in which case we speak of ‘bacteristatic antibiotics’.

All antibiotics are bacteristatic in low doses and bactericidal in higher doses; the gap between their bacteristatic and bactericidal concentration is what allows them to be classified in one or the other group. In addition, their nature can vary according to the strain of bacteria involved. Antibiotics are therefore drugs that can effectively fight bacterial infections. In veterinary medicine, they are used for example to treat mastitis in cows or certain respiratory or digestive infections in calves. In people as in animals, antibiotics have no effect on viruses.

2. Different Families of Antibiotics

Antibiotics have specific effects on bacteria by blocking one of the essential stages in their survival or reproduction. For instance, some antibiotics inhibit the formation of the bacteria’s protective envelopes (membrane or cell wall), others disrupt certain chemical reactions

WHAT ARE BACTERIA?

Bacteria are single-celled living organisms approximately the size of a micron. They are omnipresent in our surroundings and, in people as in animals, they live on the surface of the skin and mucous mem-branes and in intestines (1014 in the human digestive tract). Some bacteria are naturally present in the body and even provide protection against other so-called pathogenic bacteria able to harm human and animal health [10].

Note: Some of the elements shown here, such as the flagellum used for locomotion, are not present in all bacteria.

Sidebar No. 1

capsule

� agellum

bacterial chromosome

plasmids

cell wall

pili

plasma membrane

cytoplasm

ribosomes

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necessary for the bacteria to live, and finally others prevent their genes* from being translated into proteins. Families of antibiotics are defined based on their structure and method of action (see Figure No. 1 and Table No. 1, following page).

The active principles used in veterinary medicine belong to the same families as those in human medicine but are fewer in number.

Consequently, the antibiotic’s action on a species of bacteria depends on the presence of the target within the bacterial cell or the capacity to access this target. For each antibiotic, a spectrum of antibacterial activity is thus defined. For instance, beta-lactams have no effect on mycoplasmas as these bacteria do not have a cell wall. In addition to its mode of action, the effect of an antibiotic—whether bacteristatic or bactericidal—depends on its concentration at the target [1].

Today, some antibiotics such as 3rd

and 4th generation cephalosporins (C3G and C4G) and fluoroquinolones are called ‘critical’ antibiotics because they offer the only treatment for certain infectious diseases in people. European recommendations state that these antibiotics should be reserved for second-line curative treatment and not used as a preventive treatment (see below). They have been available to veterinary medicine for approximately 15 years.

3. Uses and Interests of Antibiotics in Animal Husbandry

Like all living creatures, animals can catch diseases that need to be prevented or cured. Animal health control ensures not only the economic performance of a herd (quantity production of good quality meat or dairy, simpler animal husbandry) but also animal wellbeing. Only animals in good health can be slaughtered so that the meat sold on the market carries no risk for consumers’ health (see below). For these reasons, veterinary drugs are administered to livestock if necessary, in particular antibiotics.

In 2001, the World Health Organization (WHO) estimated

that at least 50% of antibiotics produced worldwide were destined for livestock and pets [20]. In animal husbandry, antibiotics can be administered in three ways to treat bacterial infections [1]:

Therapeutic (or curative) use: animals are clinically ill, and the goal is to cure them and keep them from dying. Curative treatment also has the effect of lessening animal suffering and restoring their production (milk and meat).

Metaphylactic use: in a livestock operation with large numbers of animals, if a very contagious illness breaks out and a sufficiently large number of elements all point to bacteria, all animals may be treated simultaneously to ensure greater treatment effectiveness whether

* Underlined words can be found in the glossary on page 33.

How Antibiotics Act on Bacteria

Figure No. 1

inhibit the synthesis of the plasma membrane

inhibit the synthesis of DNA

inhibit the synthesis of the bacteria’s cell wall

other mechanisms

inhibit protein synthesis

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PartOne



or not each individual animal is clinically ill at the time. Metaphylaxis is generally implemented once

10% to 15% of the animals in the group are ill. We also speak of mass treatment.

Preventive treatment (prophylaxis): animals are not clinically ill but have been exposed

Main Antibiotic Families Used in Veterinary

Medicine

Sub-Families of Antibiotics Modes of Action

Examples of Active Ingredients Used

in Veterinary Medicine

Beta-Lactams Penicillins Cephalosporins

Inhibit synthesis of the cell wall, in particular the synthesis of peptidoglycan, which affects the rigidity

of the structure and the shape of the bacteria. This considerably weakens the outer envelope. The bacteria

become very sensitive to external stresses (osmotic pressure, temperature, mechanical stress) triggering cell

lyses.

penicillins G, M and Acephalosporins

(1st, 2nd, 3rd, and 4th generation*)

Polymyxins /Disrupt the structure of the plasma membrane, by entering the outer phospholipids, which weakens its

integrity. Permeability is no longer ensured. Metabolites and ions exit the cell, killing the bacteria.

colistin polymyxin B

Aminoglycosides /

Inhibit protein synthesis by acting on ribosomes and thereby by blocking their protein synthesis action. This prevents the formation of new proteins, and

thereby bacteria reproduction, and even, in the case of aminoglycosides, triggers their destruction by causing

abnormal proteins to be synthesized.

gentamicin apramycin

Macrolides & Similar

MacrolidesLincosamides Pleuromutilins

erythromycin spiramycin

clindamycin tiamulin

Cyclines / chlortetracyclinedoxycycline

Phenicols / florfenicolthiamphenicol

Quinolones Quinolones Fluoroquinolones

Disrupt DNA structure by attaching to the major regulatory enzymes: topoisomerase and DNA gyrase.

flumequineenrofloxacin

marbofloxacin

Sulfonamides /Competitively inhibit synthesis of base pairs of DNA.

Sulfonamides are structural analogies of folic acid, an intermediary in their synthesis. Blocking this stops

bacterial growth.

sulfadiazinesulfadimethoxine

sulfamethoxazole + trimethoprim

* For some antibiotics, different generations are defined based on their characteristics, their spectrum of activity, and the date they were first marketed. The more recent the generation, the more effective the antibiotic.

Note: There are other antibiotics used in veterinary medicine that belong to other families not described above. This is the case for bacitracin and rifamycin, for example.

Classification of the Main Veterinary Antibiotics

Table No. 1

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to a risk factor (weaning, transport, etc.) and are highly likely to develop an illness in the very short term. Preventive treatment can prevent the expression of an illness. For example, it is used: with piglets during weaning,

as this period is conducive to diarrhoea;

with dairy cows during dry-off, a period conducive to mammary infections; and

with calves during grouping, a period conducive to respiratory issues and diarrhoea.

Despite the obvious practical interest in the field of certain prophylactic treatments, their use must be rational to avoid the selection of resistant bacteria (see Part Two).

4. Changes in Antibiotic Consumption

In France, antibiotic sales are monitored based on declarations

by drug-producing laboratories that hold marketing authorizations (MAs). These data are compared with the turnover numbers declared by laboratories selling veterinary drugs and data from epidemiological investigations. The Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES, the French agency for food, environmental and occupational health safety) and the Agence Nationale du Médicament Vétérinaire (ANMV, the French agency for veterinary drugs) have monitored all this data since 1999 and translate them into various indicators:

Indicators used to evaluate the correlation between antibiotic sales and antibiotic resistance.

Exposure indicators that cover therapeutic activity using antibiotics. According to ANSES, these indicators are to be favoured to monitor overall changes in the use of veterinary

drugs over time and attempt to measure the effects of actions set up on the national level. The Animal Level of Exposure to Antimicrobials (ALEA) is seen as the most reliable exposure indicator because it takes into account data on treatment (dose, duration) and potential users (mass of the potentially consumable animal population rather than the number of animals). Treatments administered to animals are adapted to their weight and expressed in kg of weight. Thus, an ALEA of 1 means that for a given species, the weight treated corresponds exactly to the total weight of the population. An ALEA of 0.326 for cattle in 2012 means that 32.6% of the total mass of cattle was treated in 2012.

The overall tonnage of antibiotics sold in 2012—782 T—is the lowest recorded since sales began to be tracked in 1999 (down 14.0% compared to 2011, down 33.3% over the past five years, and down 41.2% since 1999) [6]. However,

ANTIBIOTICS AND GROWTH FACTORS

We know that using antibiotics as feed additives—that is to say administered in low doses in the animal’s feed—can prevent certain bacterial infections, and modify the composition of the intestinal microflora triggering better assimilation of nutrients by animals and increasing the rate of growth by a few percentage points [17].

However, since 2006, the use of antibiotics to improve the growth and performance of animals

of all species has been formally prohibited in the European Union (Directive 96/22/EC as amended by Directives 2003/74/EC and 2008/97/EC). This use is still, however, authorized in North and South America and Asia.

Note: The use of growth promoters is, let us recall, formally prohibited in Europe. This ban concerns natural steroid hor-mones (progestagens, oestrogens, androgens) as well as any other substance with anabolic or growth-promoting effects (stilbenes, thyreostatics, somatotropins, beta-agonists) [9].

Sidebar No. 2

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PartOne



while a drop in the quantities of antibiotics sold is crucial, this does not necessarily mean that exposure to antibiotics has fallen. Indeed, this drop corresponds—at least in part—to an abandoning of lengthy treatments with older molecules and their replacement by shorter treatments using more recent molecules. Active at lower dose, these latest generation antibiotics require the administration of smaller quantities, but we should remember that some are of critical importance in human medicine (see above).

4.1. EXPOSURE DATA FOR ALL SPECIES COMBINED

According to ANSES, the level of exposure to antibiotics (ALEA) for all species—both livestock and pets—and all administration methods combined, rose by 26.3% between 1999 and 2007, then fell by 20.0% between 2007 and 2012 (most

recent data available). Between 2011 and 2012, exposure dropped by 6.2%. This level of exposure, the lowest recorded since 2000, is almost equivalent to that in 1999 (the year the surveillance plan was launched) (see Figure No. 2).

All species and administration methods combined, from 1999 to 2012 the animal level of exposure doubled for fluoroquinolones and increased by a factor of 2.5 for C3Gs and C4Gs. However, a levelling off in exposure has been seen in recent years—over the past three years for cephalosporins and the past five years for fluoroquinolones [6].

4.2. EXPOSURE DATA (ALEA) BY LIVESTOCK SPECIES

Rabbits, poultry, pigs (see Figure No. 3) and butcher calves are the species most exposed to antibiotics. This can be explained by the fact that these animals

are reared in groups and inside buildings, which means that infectious pressure is greater than it is for animals raised in individual stalls or open air. Among other things, young animals are naturally weaker than adult animals.

From 1999 to 2012, exposure among pigs fell by 20.8%, with a drop in exposure of 36.8% between 2007 and 2012, and of 10.1% between 2011 and 2012 [6].

In 2012, exposure among sheep, goats and horses was on par with the average overall exposure level for all species combined [6].

Between 1999 and 2012, exposure to antibiotics among cattle—for all categories of animals (calves and large cattle) and all types of livestock operations (dairy, suckler, mixed)—rose by 22.6%. A drop of 4.1% can, however, be seen between 2010 and 2012 (see Figure

ALEA, All Species Combined [6]

Figure No. 2

medicinal pre-mixes (ALEA = 0.102)

powders and oral solutions (ALEA = 0.297)

other oral forms (ALEA = 0.007)

injections (ALEA = 0.187)

Total ALEA = 0.592

17 %

32 %

50 %

1 %0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

1999

2003

2007

2000

2004

2008

2001

2005

2009

2011

2002

2006

2010

2012

ALEA

medicinal pre-mixes (ALEA = 0.102) powders and oral solutions (ALEA = 0.297) other oral forms (ALEA = 0.007) injections (ALEA = 0.187)

Total ALEA = 0.592

17 %

32 %

50 %

1 %

Changes in ALEA from 1999 to 2012 ALEA in 2012, by Pharmaceutical Form

13


No. 4, following page). While the drop in exposure is less marked among cattle than among other livestock, one should note that their ALEA remains among the lowest (see Table No. 2).

Current data do not allow for a precise determination of the relative share of different categories of cattle. Nevertheless, ANSES has produced

an estimate of the average number of oral treatments administered to butcher calves. The average number of these treatments is estimated at 4.47 per calf in 2012, or a clear drop compared to 2010 when it was 6.39 [6].

Regarding critical antibiotics (fluoroquinolone and C3G/C4G), evolutions and exposure levels vary

according to species and family of molecules [6]: Among cattle, all categories

combined, despite an increase between 2008 and 2012 in exposure to C3G/C4G (up 36.3%) and to fluoroquinolones (up 13.1%), we can note a levelling off over the 2011-2012 period: a slight increase for C3G/C4G (up 3.5%) and

Tonnage versus ALEA [6]

Figure No. 3

Consumption (in tonnage) Exposure in ALEA

ALEA = weight of animals treated(number of animals) x (weight of adult animals or weight at slaughter)

ALEA in 2011-2012, by Species of Animal [6]

Table No. 2

SpeciesCattle

of which calves

Domestic Carnivores Horses Fish Rabbits Sheep

& Goats Pigs Poultry Other Total

ALEA in 2011

0.323.41 0.69 0.60 0.43 3.76 0.69 1.05 1.27 0.03 0.62

ALEA in 2012

0.3263.156 0.685 0.391 0.217 2.887 0.691 0.991 1.177 0.508 0.592


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PartOne

a drop for fluoroquinolones (down 3.3%).

Among pigs, following the voluntary restriction of the use of C3G/C4G (see Part Three), exposure dropped sharply between 2010 and 2012 (down 62.1%). Between 2008 and 2012, exposure to C3G/C4G dropped by 49.2%. When it comes to fluoroquinolones, exposure dropped between 2008 and 2012 (down 24.7%) despite a rise between 2011 and 2012 (up 11.3%).

Among poultry, exposure to fluoroquinolones rose by 62.9% between 2005 and 2011 but dropped by 8.8% between 2011 and 2012.

Change in the ALEA Among Cattle [6]

Figure No. 4

0.4

0.35

0.3

0.25

0.2

0.15

0.1

0.05

0

1999

2003

2007

2000

2004

2008

2001

2005

2009

2011

2002

2006

2010

2012

ALEA

MONITORING ANTIBIOTICS IN FRANCE AND EUROPE

In France, ANSES-ANMV began monitoring the sale of veterinary antibiotics in 1999 based on the recom-mendations of the guidelines in the OIE’s Terrestrial Animal Health Code 2012, Chapter 6.8, ‘Monitoring of the quantities and usage patterns of antimicrobials agents used in food producing animals’.

In Europe, France is taking part in the European Sur-veillance of Veterinary Antimicrobial Consumption (ESVAC) project launched by the European Medicines Agency (EMA). The aim is to collect harmonized data on antibiotic sales in all European Union countries.

An assessment of real use among the main species that consume antibiotics (poultry, pigs, calves, cattle, sheep, goats, fish and pets) will be conducted secondarily.

Calculated per animal and not in absolute tonnage, the latest available data (2011) show that France ranks 9th in the sale of antibiotics for livestock, behind Cyprus, Italy, Spain, Germany, Hungary, Belgium, Portugal and Poland, but ahead of the United Kingdom and Austria, for example. Thus, France shows an 11% drop compared to 2010 [13].

Sidebar No. 3


PART TWO

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PartTwo



POSSIBLE RISKS TO ANIMAL AND HUMAN HEALTH OF ANTIBIOTIC USE IN ANIMAL HUSBANDRY

Despite the major interest to be found in using antibiotics in animal husbandry to fight infectious bacterial diseases, vigilance is still necessary given the risks for animal health and public health.

1. The Development of Antibiotic Resistance in Bacteria of Animal Origin

Seen for many years as a problem for hospital medicine, we now know that long-known resistance to antibiotics—or antibiotic resistance—is also a concern in veterinary medicine (see Figure No. 5). Indeed, people and animals share the same environment (bacteria, viruses, etc.) and the same antibiotics, so their health is in fact one and the same (‘one health’, see Sidebar No. 4).

1.1. DEFINITION AND ASSOCIATED MECHANISMS

In this document, we speak of antibiotic resistance when certain bacteria are neither killed nor inhibited by the doses of antibiotics administered. Bacteria, living on or in their human or animal hosts, can indeed become resistant to an antibiotic treatment and, consequently, make the treatment of their host ineffective.

1.1.1. How Do Bacteria Become Resistant?

Any antibiotic use triggers a selection effect for resistant bacteria and creates pressure conducive to their growth: these bacteria will survive, reproduce and become preponderant [11].

Today, certain families of antibiotics are already no longer effective against certain species of bacteria. This resistance phenomenon can be:

Natural: Some bacteria are inherently resistant to certain antibiotics. This may be because the antibiotic does not have access to its

Antibiotic Resistance, an Old and Well-Known Phenomenon [11]

Figure No. 5

1940 1950 1960 1970 1980 1990 2000 2010

pre- antibiotic

era

penicillin

penicillin

CLINICAL USES

IDENTIFICATION OF RESISTANT BACTERIA

tetracyclines

tetracyclinesfluoroquinolones vancomycin

vancomycin fluoroquinolones

penicillin resistance in Staphylococcus aureus (WHO, 2007)

1928 discovery

of penicillin

1943 introduction of penicillin

1950 59% of hospital strains are penicillin resistant

1990 penicillin resistance exceeds

95% in most hospitals

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target in the bacterium or because the target is not present. This is the case, for example, with mycoplasmas that do not have cell walls, which makes them unresponsive to beta-lactams (see above) [1].

Acquired: The increase in the rate of resistant bacteria closely correlates to a misuse of antibiotics such as inappropriate treatment, treatment stopped too early or dosed too low, or even an over-consumption of antibiotics [7]. This resistance is regularly described in environments such as hospitals where antibiotics are frequently used.

A bacterium may become resistant either through natural chromosome mutations or following the exchange, among bacteria, of genetic material

carrying genes that are resistant to antibiotics.

Over time a species of bacteria may develop its resistance capacity. For example, resistance to C3G among Escherichia coli isolated from people remained stable from 2002 to 2005 (approximately 2.0%) but then rose (8.6% in 2010) [19].

In addition, we see the emergence of multi-resistance, that is to say the development of bacteria resistant to several families of antibiotics. They are called multi-resistant bacteria (MRB). For a few bacteria, multi-resistance can involve nearly all antibiotics, in which case we speak of highly resistant bacteria (HRB), or all antibiotics, in which case we speak of totally resistant bacteria [7].

The increase in multi-drug resistant bacteria is therefore directly linked to the ‘genetic arsenal’ that these bacteria have to acquire and trade resistance genes through mobile genetic elements such as plasmids, transposons and integrons. There are three main known mechanisms for the horizontal transfer between donor and recipient bacteria of the same species or different species or genera (see Figure No. 6, following page):

Transformation: the uptake, by a recipient bacterium, of a fragment of naked DNA from another bacterium following the lyses of the latter.

Transduction: the transfer of a fragment of DNA from one bacterium to another through the intermediary of a viral vector (bacteriophage, see below).

Conjugation: the transfer of a fragment of DNA from a donor bacterium to a recipient bacterium in the form of a plasmid in the vast majority of cases. This is the most efficient mechanism (the fastest transfer of large quantities of genetic information) and therefore the one most often involved in the spread of antibiotic resistance [11].

For the horizontal transfer of genetic material to be effective and for the recipient bacteria to become resistant, several stages are needed [11]:

DNA, the vehicle for genetic information, must be transferred

THE ‘ONE HEALTH’ CONCEPT

Recent epidemics (H1N1 influenza, SARS, chikungunya, etc.) highlight the growing globalization of health risks and the importance of the human-animal-ecosystem interface in the evolution and emergence of pathogens. Defined in 2008, the ‘one health’ concept aims to take into account the links between human health, animal health, and environment management. The synergy will allow for improvements in health care for the 20th century; it will also speed up discoveries in biomedical research, improve

the effectiveness of public health measures by rapidly growing the foundations of scientific knowledge, and improve medical training and clinical care.

Concretely, this will happen through a strengthened partnership and coordination between the FAO, WHO and OIE, and by the establishment of expertise networks, a warning system, an international portal on health safety and animal and plant health, a animal health emergency management center, etc.

Sidebar No. 4

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PartTwo



from the donor bacterium to the recipient bacterium (see above);

the DNA sequence must enter either the genome (chromosome) or an autonomously replicating structure (plasmid); and

the genes provided by this DNA fragment must then be capable of expressing themselves in the recipient cell.

1.1.2. For a Bacterium, What Are the Main Antibiotic Resistance Strategies?

The main strategies are (see Figure No. 7):

Avoidance/evasion: modification and/or protection of the bacteria that prevents the antibiotic from attaching to: either the bacterial cell wall that

is the source of impermeability; this is the case with resistance to certain beta-lactams or tetracyclines;

or its internal target; this is the case for streptococci whose acquisition of an enzyme, methylase, changes the structure of the ribosome thus reducing its affinity for macrolides (see above).

Attack: modification and/or degradation of the administered antibiotic by bacterial enzymes, inactivating the antibiotic. This is the case for beta-lactams and in particular extended-spectrum beta-lactamases (ESBLs), enzymes produced by enterobacteria that

specifically attack antibiotics in the beta-lactam family, including C3G and C4G for ESBLs.

Elimination: the accelerated ejection of the antibiotic to outside the cell by molecular pumps so that enough of the antibiotic no longer reaches its target within the bacterium. This is the case for the expulsion, via efflux, of tetracyclines or fluoroquinolones by E. coli [11].

A given species of bacteria may utilize several strategies to resist a given family of antibiotics.

1.2. RISK OF THERAPEUTIC DEAD ENDS

Since the 1990s, the number of new antibiotics placed on the market has dropped for scientific and economic reasons.

The easiest antibiotics to perfect are already being sold and the few new molecules tend to be reserved for the most severe cases, shrinking by as much the size of the market for drug companies [7]. In addition, the development of a new molecule currently takes an average of ten years, and this is

Acquisition of Antibiotic Resistance Genes [11]

Figure No. 6

resistancegene(s)

gene(s) entering the chromosome or plasmids

resistancegene(s)

plasmid

bacteriophage

receptor bacterium

donor bacterium

disrupted bacteria

infected bacterium

combination

transduction

transformation

19


a real hindrance to innovation in antibiotic therapies in a complex regulatory environment. Finally, the drug industry’s lower profits from antibiotic development compared to drugs targeting chronic illnesses may lower investments in this area.

Without new antibiotics to treat bacteria resistant to the antibiotics already in use, there is a non-negligible risk of reaching a therapeutic dead end. This is a serious threat to the health of animals unable to be treated, and also a serious public health threat because of both a drop in the production of animal-based foods and the risk of transmission of antibiotic resistant bacteria to people. For example, methicillin-resistant Staphylococcus aureus

(MRSA) are often multi-resistant. These germs therefore raise significant therapeutic problems in both veterinary and human medicine (see Sidebar No. 5).

1.3. THE TRANSFER OF RESISTANCES BETWEEN ANIMALS AND PEOPLE

See following page.

2. Antibiotic Residues in Meat, Offal and Milk

Administering a drug to an animal may leave residues of this substance and its metabolites in the foods the animal produces such as meat, offal and milk. The risks associated with these residues from the use of veterinary drugs in livestock are known because they are assessed in the market authorization application and easily controlled by use in accordance with administration instructions.

All veterinary drugs systematically undergo a series of toxicological studies on different animal species to determine the highest dose of

Main Antibiotic Resistance Strategies in Bacteria

Figure No. 7

modification or protection of the target impermeability

enzymatic inactivation

active efflux

cytoplasm

resistance strategies

avoidance evasion elimination antibioticattack

ANTIBIOTIC RESISTANCE: A FEW NUMBERS FROM EUROPE

According to the European Medicines Agency (EMA) and the European Centre for Disease Prevention and Control (ECDC), the consequences of the development of antibiotic resistance for people are estimated [12]:

in terms of public health, at 25,000 deaths per year due to infec-tion with one of the five most common multi-resistant bacteria (MRBs); and

in economic terms, at 1.5 billion euros in direct medical costs (illness, death), indirect medical costs (the development of associated ailments), and lost productivity.

Sidebar No. 5

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PartTwo



Research director and head of the antibiotic resistance and bacterial virulence unit at ANSES (laboratory in Lyon), member of the Scientific Board of the French National Observatory for Epidemiology of Bacterial Resistance to Antimicrobials (ONERBA), and chairman of the antibiogram committee veterinary group.

Is it possible for antibiotic resistant bacteria to pass from animals to people and from people to animals? If so, how does this happen?

Yes, such transmission happens. It is effectively possible in both directions, from animals to people and also from people to animals. Some methods of transmission are well-known, such as through food. When a food is contaminated by bacteria such as salmonella or campylobacter, whoever eats the food may be infected. If this bacteria is antibiotic resistant, then antibiotic resistant bacteria are transmitted to people. Another example is professional exposure. For example, pig farmers are at higher risk than the general population of being infected by methicillin-resistant Staphylococcus aureus (MRSA) from their pigs. Finally, we can mention examples of reverse transmission, from people to animals. For example, we have found strains of hospital MRSA causing infec-tions in dogs and cattle. Currently, food and direct contact (livestock professionals, animal owners) are the two recognized paths of transmission of antibio-tic resistant bacteria between animals and people.

Is this transmission frequent? How is it measured/tracked?

No, according to current knowledge, the transmis-sion from animals to people (and from people to animals) is probably not very frequent. The two paths of transmission cited above are in fact limited. Food-born resistant salmonella infections are rare, and therefore the risk to people is very moderate. This can, however, depend on the country’s hygiene level. Similarly, professional exposure concerns only

a small proportion of the general population. One should remember that most antibiotic resistance among humans is the result of human treatments, and that most antibiotic resistance among animals is the result of animal treatments.

It is relatively easy to measure these flows when one can count the number of cases of infection by animal resistant bacteria in people. Measurement becomes more complex when it is not necessarily the bacterium itself that is transmitted, but only the genes it contains. In this case, the ways of detecting transmission are not only a matter for medicine but also cutting-edge molecular techniques. Gene flows are much more difficult to measure than bacterium flows. In the future, better knowledge of gene flows could reveal that animal-people and people-animal exchanges are more frequent than we think.

Is research being done?

Yes, many research programs are underway. They seek, for example, better knowledge of antibiotic resistance mechanisms among people and among animals. They aim to better understand the flows of resistance genes between the bacteria in these host populations. Lines of research are also exa-mining the role of the environment in spreading antibiotic resistance (water, soil, livestock manure, hospital waste, etc.). It is important to understand how antibiotic resistance (the bacteria and/or genes) circulate between these different compartments. Finally, there are research programs to identify new therapeutic possibilities (vaccines, new antibiotics, etc.) and new diagnostic methods that are more rapid and more precise.

Three questions for Dr. Jean-Yves MADEC

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this substance (ingested regularly and over the long term) with no harmful effect on the most sensitive animal species: chronic toxicity, effects on reproduction, carcinogenic, mutagenic or microbiological effects, etc. Allergic risks in particular are studied in these studies as some antibiotics—particularly penicillins, sulfonamides and fluoroquinolones—may cause allergic reactions.

After each of these tests, a no-effect dose (NED) is determined. The lowest NED is selected and then extrapolated to people to calculate the acceptable daily intake (ADI). This ADI is obtained by applying a safety factor (SF) of at least 100:

a first factor of 10: assuming that people are 10 times more sensitive than the most sensitive animal species; and

a second factor of 10: assuming that within the human population, some individuals will be 10 times more sensitive than the average.

For antibiotics in specific, the residues contained in meat, offal and milk must not allow for the selection of possible bacteria resistant to these antibiotics in the consumers’ digestive flora. In addition to toxicological studies, specific microbiological studies are done to evaluate the activity of antibiotic residues on more than 100 species of bacteria representative of human digestive flora. A microbiological ADI is calculated in this way. The microbiological ADI, always much

lower than toxicological ADI, is what is used for antibacterials [9].

The maximum residue limit (MRL) in meat, offal and milk for a given substance is determined based on the ADI utilized and the level of consumers’ exposure following consumption of these foods (see Figure No. 8). The fictitious quantities taken into account in these models are higher than the quantities normally consumed. The scenario covers maximal exposure to danger so as to not under-estimate the risk, which is never—by definition—zero. MRLs are proposed by European scientific boards (the EMA or the European Food Safety Authority (EFSA)). They are then set by the European Commission and published in regulations.

MRLs are then utilized by drug producers to set the wait time between the last administration of a given drug and slaughter or milking. This time specifies the period during which the food produced by an animal receiving treatment cannot be sold for human consumption. This period is calculated taking into account the animal’s metabolism and the method of administration and composition of the drug. In order to avoid all risk, the wait times utilized are increased in relation to scientific modelling (by 30% on average). For antibiotics, these measures minimize the risk of any selection of antibiotic resistant bacteria in consumers [9].

The wait time is indicated on the drug fact sheet based on dosages

ADI, MLR and Wait Time

Figure No. 8

veterinary drug veterinary antibiotic

ADI (µg/kg/d)

NED retained (mg/kg/d)

MRL (µg/kg or ppb)

time to slaughter/treatment (d)

microbiological NED (mg/kg/d)toxicological NED (mg/kg/d)

toxicological ADI (mg/kg/d)

MRL (µg/kg or ppb)

time to slaughter/treatment (d)


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set in order to allow veterinarians and farmers to utilize the drug rationally. Meat and offal from an animal during the waiting period cannot enter the distribution circuit for human consumption. Compliance with the wait time does not mean a total absence of residues in the food, but the absence of residues over the regulatory threshold, the MRL, which ensures consumer safety.

3. Release of Antibiotics in the Environment (Water and Soil)

Animals treated with antibiotics may excrete their faeces and urine

in their initial form or in the form of one or more metabolites. Drug residues can therefore be released into nature. The MA application for all drugs—for human or veterinary use alike—accordingly contains an environmental safety assessment. This study includes an assessment of predicted environmental concentration (PEC) and ecotoxicological studies of the impact of the possible residues on representative animal and plant organisms. When the risk is deemed unacceptable or too difficult to evaluate, the MA may be refused.

In 2011, the results of a national survey of the presence of drug

residues in waters destined for human consumption (raw and treated water) were published. It seems that a limited number of veterinary drugs, of which certain antibiotics such as danofloxacin (a fluoroquinolone) and tylosin (a macrolide), are detected in the water and that they are usually present at very low concentrations or only detected as traces [3].

Given the little data available, scientif ic investigations are underway on the toxicity of antibiotic residues in soil and water and, in particular, on their capacity there to select antibiotic resistant bacteria.


PART THREE

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MEASURES TAKEN TO ENCOURAGE APPROPRIATE USE OF ANTIBIOTICS IN ANIMAL HUSBANDRY

All measures implemented in livestock operations, along the lines of the EcoAntibio 2017 plan, have the twofold aim of conserving a therapeutic arsenal to fight bacterial illnesses while also making it possible to lower antibiotic resistance among bacteria in animals.

1. Measures for Controlled Use of Antibiotics

1.1. PHARMACEUTICAL INDUSTRY

European regulations (Directive 2001/82/EC and Regulation EU 712/2012) require any antibiotic for veterinary use to be assessed for quality, innocuousness to the users, consumers (see Part Two), environment and animals for which it is destined, and effectiveness [1]. A market authorization is issued if the scientific study concludes that the benefits of its use are greater than the risks involved (see Figure No. 9). Among other things, the Agence Nationale du Médicament Vétérinaire (ANMV) monitors antibiotics after they have been brought to market in regard to their production (verification of good production practices, quality control), marketing (verification of advertising), and undesirable effects (pharmacovigilance).

Monitoring and Control of the Use of Veterinary Antibiotics

Figure No. 9

Veterinarian

Pharmaceutical Industry

Veterinarian, Pharmacist

Veterinarian, Farmer

PRODUCTION, EXPLOITATION & WHOLESALE DISTRIBUTION (production and sale records)

PRESCRIPTION (script)

DELIVERY (script)

ADMINISTRATION (livestock records)

Pharmacy Inspectors

Fraud Control Offi

cers Veterinary Service A

gents

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1.2. LIVESTOCK VETERINARIANS

1.2.1. Initial and Continuing Education

In the course of their training, all veterinary students follow several years of study in pharmacology allowing them prescribe and administer veterinary drugs as well as alert the ANMV of and report to the ANMV on any undesirable effects in animals following drug therapy (pharmacovigilance, see below).

Among other things, the veterinary profession is regulated. Under the supervision of the Ordre National des Vétérinaires (the national order of veterinary doctors), veterinarians must comply with a certain number of ethical principles contained in a Code of Professional Conduct and regulatory measures set down in the Rural Code. For instance, according to Article R242-33-X, veterinarians acquire the scientific information necessary to exercise their profession, take this information into account in fulfilling their mission, and maintain and perfect their knowledge.

In 2012, 90% of veterinarians exercising in animal production were members of the Société Nationale des Groupements Techniques Vétérinaires (SNGTV, the national league of technical veterinary groups). An association that federates departmental and regional technical veterinary groups (TVGs), the SNGTV’s mission is to develop and promote the veterinary skills involved in animal production value chains.

For several years, one of SNGTV’s priorities has been promoting proper antibiotic use and fighting antibiotic resistance. To this end, a number of tools were created:

Factsheets on good practices in antibiotic therapy for each value chain and animal illness, in line with the 6th measure in the EcoAntibio 2017 plan, ‘development of guides to good antibiotic prescription practice with a primary focus on pathologies identified by the working groups’.

Software to track antibiotic therapy within veterinary clinics (prescription/delivery) and livestock operations (use).

Continuing education for veterinarians, echoing the 7th measure in the EcoAntibio 2017 plan, ‘reinforcement of veterinarians’ continuous training’ through annual conventions, publications, and theoretical and practical training.

Mandator y continuing education in the framework of accreditation covering veterinary drugs and antibiotic resistance.

Training modules for veterinarians so that they can in turn train farmers, their clientele. The goal is to raise awareness among the various stakeholders of what is at stake in the fight against antibiotic resistance and help them understand risk factors to better identify and prevent such risks.

Other tools are planned, such as a database of professional veterinary data in conjunction with the Observatoire de Suivi des Prescriptions (prescription monitoring observatory), the general information system of the DGAL (SIGAL), and various veterinary software programs.

1.2.2. Prescription of Veterinary Antibiotics

In compliance with the Law of 29 May 1975, as established in the decree on prescription-delivery dated 24 April 2007, in France, only veterinary doctors are authorized to prescribe veterinary drugs. This decree also allows them to prescribe drugs without having seen the ill animal as long as they provide regular care to the livestock operation, have conducted a health assessment, have set up a care protocol with the farmer, and perform regular follow-up visits. These drugs may be delivered by a veterinarian or a pharmacist on presentation of the veterinary script. In certain specific conditions, groups of farmers may also be authorized to deliver certain veterinary drugs for preventive purposes that are listed in their livestock health program such as anti-parasite drugs or vaccines.

Note: Some drugs, such as antibiotics, may be introduced into food in advance to facilitate their administration to the animals, in which case we speak of medicated feed. These are veterinary drugs in their own right and, as a result, require a prescription. Producers of medicated feed are assimilated with drug companies and therefore subject to the same regulatory obligations (see above).

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Off-label uses, whose regulatory modalities are referred to as the ‘cascade’, are governed by the Public Health Code (L5143-4). It sets out under what conditions a veterinarian may, in exceptional cases, utilize a drug destined for a different animal species, or even a human drug, when there is no specific veterinary drug available on the market to treat the diagnosed illness in the species concerned. This is, for instance, the case in sheep and goat value chains for which the therapeutic arsenal with MA is limited. The wait time for a drug used off-label may not be less than 28 days for meat and 7 days for milk and eggs. This ‘precautionary’ wait time makes it possible to treat these animals while protecting consumers [9].

Veterinary prescriptions are materialized by the script on which is written the name and address of the person holding the animals, the specific identification of the animals treated, the name of the prescribing doctor, the name of specialties (antibiotic or not), the dose, the mode of administration (duration, frequency), and the wait time (even when it is nil). The veterinarian must keep a copy of all prescriptions written for ten years, listing the date on which the drugs were delivered, the quantities delivered, and the drug lot numbers. This ensures optimal traceability of veterinary prescriptions (see Figure No. 9).

1.3. VALUE CHAIN PROFESSIONALS

Antibiotics are administered by the veterinarian and/or farmer.

Farmers must record all veterinary treatments in their livestock registry, including notably information on the script and the dates on which treatment began and ended, and the name of the person administering the antibiotic. Prescriptions are conserved for five years in the livestock records according to the provisions of the decree of 5 June 2000 (see Figure No. 9). Among other things, to meet food chain information (FCI) obligations, livestock farmers must indicate, using a specific form, which animals leaving their operations have received a veterinary drug for which the ‘meat’ wait time is not over. As a reminder, ill animals and animals during the wait time cannot be sent to the slaughterhouse.

In the cattle value chain, the charter of good animal husbandry practices—a collective, professional and voluntary initiative by farmers—promotes rational and tracked use of veterinary drugs, including antibiotics. To date, more than 110,000 farmers with large suckler and dairy cattle adhere to this charter.

In the pig value chain, a panel of livestock operations was identified and has been surveyed regularly since 2011. This panel makes it possible to measure the quantities and uses by physiological stage. This work is intended to continue in order to obtain a lasting shift in antibiotic use. This monitoring will enable us to compare uses across countries and identify the best

levers of action to lower antibiotic use.

Among other things, since 2011, the pig industry has on its own initiative placed a moratorium on the use of 3rd and 4th generation cephalosporins, resulting in a sharp drop in exposure levels (see Part Two).

In the veal industry, a survey was begun in 2013 on early metaphylaxis strategies (see above) for respiratory problems in livestock operations and alternative solutions.

In addition, a project in partnership with ANSES was launched on antibiotic use on a panel of representative livestock operations and on antibiotic resistance. The aim is to estimate antibiotic use, identify utilization conditions and variability between livestock operations, and estimate the antibiotic resistance of the main digestive bacteria (E. coli). The ultimate goal is to explore the link between use and resistance in the veal industry.

Results are expected at the end of 2014 from both these projects; levers for action will then be identified to lower antibiotic use in this value chain and fight the development of antibiotic resistance.

1.4. PUBLIC AUTHORITIES

1.4.1. Plan EcoAntibio 2017

The national plan to lower the risk of antibiotic resistance in veterinary medicine for 2012-2017 provides

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for the cautious and rational use of antibiotics as manifest by:

Quantitative targets: a 25% reduction in antibiotic use in veterinary medicine over five years. Only the appropriate quantities strictly needed by animals may be prescribed and administered.

Qualitative targets: special effort to reduce the use of antibiotics that are of critical importance in veterinary medicine, notably fluoroquinolones and C3G/C4G.

This 2012-2017 plan is organized into five priorities and 40 measures:

Priority 1: Promote best practices and raise awareness among the stakeholders involved.Promote go o d hygiene and cleanliness practices in animal husbandry to limit the risk of infection, improve health monitoring measures, raise awareness of the risks involved with antibiotic resistance among veterinarians, farmers and technicians and train them in this, etc.

Priority 2: Develop alternatives to antibiotic use by fostering experimentation and research.Promote vaccination, favour recourse to older antibiotics, study alternative treatments, etc.

Priority 3: Reinforce the regulation of commercial practices and prescribing rules.Include health education messages in instruction manuals, strengthen control of advertising, adapt packaging to the quantities delivered, etc.

Priority 4: Improve the system for monitoring antibiotic use and antibiotic resistance and assess the impact of the measures taken.

Priority 5: Promote the same approach on the European and international scale.

This plan involves all stakeholders: farmers in the various value chains, veterinarians and pharmacists, scientists and risk assessors, the drug industry, the public authorities, and the general public [15].

1.4.2. DGAL Inspections

The Direction Générale de l’Alimentation (DGAL, the French general directorate for food) currently carries out inspections, the main purpose of which is to identify anomalies, non-compliance and even fraud. The inspection plan is based on targeted or suspected sampling, that is to say samples are taken based on predetermined targeting criteria. These plans notably cover chemical residues in the meat from butcher animals and concern, among other things, veterinary drug residues including antibiotics [9].

Given the targeting of samples in inspection plans, the level of compliance since 2008 for antibiotic residues in meat from butcher animals must be viewed as very satisfactory (see Table No. 3).

1.4.3. National Drug Residue Plan

The national drug residue plan (PNRM, Plan national sur les résidus de medicaments) including antibiotic

DGAL Inspections for Antibiotics in Meat from Butcher Animals

Table No. 3

Year 2008 2009 2010 2011 2012

Number of Samples Tested 9,879 9,964 9,613 9,680 9,354

Compliance Rate 99.7% 99.7% 99.8% 99.6% 99.7%

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residues, was published on 30 May 2011. It follows on from the work done in France’s national environmental health plan for 2004-2008 (PNSE1) and is part of the PNSE2 (2009-2013). This plan will prioritize the various molecules and metabolites for which work must be done between 2010 and 2015 [14]. It is made up of 3 lines:

Assessment of environmental and health risks: acquire the scientific and technical knowledge on the presence, future and effects of these drugs on the environment and human health.

Environmental and health risk management: control and lessen the release of drug residues in the environment.

Strengthen and structure research: launch calls for research projects and collective scientific expertise on priority target subjects.

1.5. RISK ASSESSORS (ANSES)

1.5.1. Monitoring of Antibiotic Sales: see Part One (pages 11-14)

1.5.2. Monitoring of Veterinary Pharmacovigilance

Since 2002, surveillance of veterinary drugs, including antibiotics, has been set up in France by ANSES. Its goal is to detect as rapidly as possible any developing signals from the declarations of practicing veterinarians, including unexpected undesirable effects or expected effects whose frequency or severity was unexpected. This surveillance

makes it possible to then determine appropriate measures that may, if needed, extend to suspension of the MA for the drug in question.

The 2012 report shows a regular increase in the number of declarations. In more than 90% of cases, these declarations were made by practicing veterinarians and animal owners; in 8% of cases by livestock farmers. The 2012 results (the most recent data available) are on the whole comparable to those from 2011 [5]:

the vast majority of undesirable effects concern domestic carnivores (82%), followed by cattle (9%) and other species (2% per species);

all species of animals combined, external anti-parasite drugs account for 33% of declarations; and

among cattle, the undesirable effects declared are most often linked to vaccines (32%), internal anti-parasite drugs (26%) and antibiotics (24%). 84% of declared cases are qualified as serious.

The data thus collected can, depending to the case, lead to the dissemination of information, changes in MA, or even revised regulations.

2. Measures Regarding the Surveillance of Antibiotic Resistance

European regulations (Directive 2003/99/EC) mandates the surveillance

of zoonoses and zoonotic agents (salmonella, E. coli, etc.). This takes the form of setting up surveillance programs to measure the effects of anti-zoonosis policies and supervise antibiotic use. The information exchange within Europe must make it possible to obtain exhaustive and comparable data. The member-States transmit their reports to the European Commission and the EFSA publishes a yearly summary.

The surveillance of antibiotic resistant bacteria of animal origin also makes it possible to collect a full set of data to describe trends, detect new elements at the origin of a warning, document the level of resistance of various bacterial species, and finally study the emergence of new antibiotic-resistant serotypes. In France, various structures will handle this [1].

The ‘Salmonella’ Network: salmonella are one of the main causes of food-born illness from foods of animal origin. These bacteria are therefore specifically monitored. The Salmonella Network collects strains of salmonella of non-human origin (isolated in food, the environment or on livestock operations) to determine the serotype and study its sensitivity to antibiotics.

The Résapath Network: created for cattle, it was extended to pig and poultry value chains in 2001, and then to an increasingly large number of animal species, notably horses, sheep and goats, in 2007. It collects

29


information from antibiograms from 94 departments. These data are also compared to the data from 16 surveillance networks looking at bacterial resistance among people in cities and hospital settings, as part of the Observatoire National de l’Épidémiologie de la Résistance Bactérienne aux Antibiotiques (ONERBA, national observatory of the epidemiology of bacterial resistance to antibiotics). This integration allows for constant pooling of the human and animal data obtained, which is particularly important when efforts to reduce resistance levels must necessarily be combined.

After a slow and regular increase in the amount of data collected between 2009 and 2011, the year 2012 saw a sharp uptick, all animal species combined, following the hiring of a new laboratory for antibiograms from the horse value chain (see Figure No. 10).

In 2012, antibiograms were usually done for cases of mastitis in cattle, digestive illnesses in calves, sheep and goats, digestive and respiratory illnesses in pigs, and f inally reproduction issues in horses [16].

According to the latest data available, the main bacterium isolated in the 31,211 antibiograms coming from 64 laboratories is Escherichia coli. It accounts for 70% of strains in poultry, 50% in cattle and pigs, 25% to 35% among small ruminants, rabbits and cats. The regular increase, for all animal species combined, of

resistance to C3G and C3G in E. coli is ongoing. It has risen sharply in calves since 2010 and in horses since 2011. However, we can see a downward trend in resistance to fluoroquinolones in E. coli for most animal species (with a levelling off among cattle).

Multi-resistance in E. coli is common in most value chains, especially for strains resistant to C3G/C4G. This phenomenon is more marked among cattle, horses and dogs. Methicillin-resistant Staphylococcus aureus (MRSA) is rarely found in samples of infectious origin in production animals: it is almost nonexistent in cattle, and infrequent but present in dogs and cats. Among horses, testing is being done [16].

In Europe, EMA centralizes all data as part of the ESVAC project (see Sidebar No. 3, page 14).

3. Research and Development Outlook in France and Europe

National and international expertise and research projects on antibiotic use and the development of antibiotic resistance are underway. The lines of work notably address improving diagnostic methods, broadening the panel of antibiotics, and treatment alternatives.

3.1. DIAGNOSTIC METHODS

Clinical diagnosis, post-mortem diagnosis , epidemiological

Number of Antibiograms per Value Chain [17]

Figure No. 10

25,000

30,000

35,000

20,000

15,000

10,000

5,000

0

2005

2006

2007

2008

2009

2010

2011

2012

fish rabbits poultry pigs other horses cats dogs goats sheep cattle

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screening, and the search for the agents responsible for animal diseases are crucial elements to prescribe the appropriate treatment. Tools exist and should be developed in practice:

rapid screening tests to determine the viral, bacterial, or parasitic origin of certain illnesses such as, for instance, certain respiratory problems in cattle and certain digestive problems in calves; and

improved antibiograms (see above), with in particular Measure 11 of the EcoAntibio plan, ‘encouragement of laboratories carrying out antibiograms to use methods validated for veterinary medicine and to develop inter-laboratory networks’.

3.2. RANGE OF ANTIBIOTICS AVAILABLE FOR LIVESTOCK

To overcome the market’s lack of innovation in the field of antibiotics, several possible paths are currently being envisaged:

In Europe, the Innovative Medicines Initiative began a research program in 2012 to develop new antibiotics, ‘New Drugs 4 Bad Bugs’ (ND4BB); this 223 million euro program targets the clinical development of antibiotics for priority resistant bacteria. This funding should make it possible to finalize the development of new

molecules underway, but may not necessarily cover the search for new molecules [7].

Rehabilitation of older antibiotics that are no longer used or fabricated (see above).

Public/private partnerships to develop new antibiotics.

Regulatory changes: current MA procedures are lengthy (10 years on average) and costly.

Market exclusivity for new molecules that fill a true public health need.

3.3. ALTERNATIVE TREATMENTS

Research is studying potential supplements and alternatives to antibiotics [7]:

Improving infection prevention strategies: new vaccines or developing new antibacterial materials.

Developing promising new peptide-based antibiotics, bacteriocins.

Treating bacterial infections with bacteriophages; this is called phage therapy. Bacteriophages are viruses that have the unique characteristic of only infecting bacteria because the have the capacity to recognize, infect and

destroy a bacterium, releasing new phages. The phages are characterized by a very high degree of specificity as each phage infects only a given sub-group within a species of bacteria. They therefore only attack the targeted bacterial populations, unlike antibiotics that always have a broader spectrum of activity. Reflections are underway in Europe to envisage a specific regulatory framework for phage therapy and conduct clinical trials and fundamental research on the biology of phages and their effects on organisms and the ecosystem.

Lines of fundamental research need to be explored, such as new molecules produced by still little-known marine micro-organisms, medicinal plants and/or plant extracts, probiotics, etc.

3.4. IMPROVED KNOWLEDGE OF RESISTANCE MECHANISMS

ANSES is pursuing many lines of prospective research to better understand the strategies bacteria use to resist antibiotics. Teams of epidemiologists are attempting to define risk factors in the emergence of illnesses, whether linked to animal husbandry practices, building configuration, administration of prophylactic treatments, environmental factors, human factors, etc. For their part, bacteriologists are developing techniques to detect and describe pathogens [4].

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In order to preserve the effectiveness of antibiotics and stop the development of antibiotic resistance in bacteria of animal or human origin, appropriate use of antibiotics is crucial in animals and people equally.

In the space of a few years, the awareness and mobilization of many animal health and public heath stakeholders has made it possible to identify and carry out actions to fight antibiotic resistance and preserve the considerable medical progress made during the 20th century. In the cattle, sheep, horse and pig livestock value chains, notable progress has also been achieved since antibiotic sales have begun to be tracked by both the tonnage of antibiotics sold and by animal exposure levels.

However, aware of the risks involved in poor use of antibiotics among production animals, professionals are continuing their efforts to improve and reduce their use and attain the targets set out in the EcoAntibio 2017 Plan.

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APPENDICES



BIBLIOGRAPHY

1. AFSSA, 2006. Usage vétérinaire des antibiotiques, résistance bactérienne et conséquences pour la santé humaine.

2. Anderson E.S., 1968. Drug resistance in Salmonella Typhimurium and its implications. Br Med J. 3: 333-339.

3. ANSES, 2011. Campagne nationale d’occurrence des résidus de médicaments dans les eaux destinées à la consommation humaine.

4. ANSES, 2013. Les résistances aux insecticides, antiparasitaires, antibiotiques… Comprendre où en est la recherche. Les Cahiers de la Recherche.

5. ANSES, 2013. Pharmacovigilance vétérinaire. Le système français de pharmacovigilance et les principaux événements en 2012 en matière d’effets indésirables.

6. ANSES, 2013. Suivi des ventes de médicaments vétérinaires contenant des antibiotiques en France en 2012.

7. Centre d’analyse stratégique, 2012. Les bactéries résistantes aux antibiotiques. Note d’analyse n° 299.

8. Chabbert Y.A., Le Minor L., 1966. Transmission de la résistance à plusieurs antibiotiques chez les Entero-bacteriaceae. II Bactériologie générale de la résistance (suite)-Rôle clinique. Presse Méd. 74: 2479-2484.

9. CIV, 2009. Résidus et contaminants chimiques des viandes : les connaître et les maîtriser. Cahier Sécurité des Aliments.

10. CIV, 2012. Micro-organismes et parasites des viandes : les connaître pour les maîtriser, de l’éleveur au consommateur. Cahier Sécurité des Aliments.

11. Doublet B. et al., 2012. Le concept « One Health » en antibiorésistance et les flux de gènes. Innovations

Agronomiques. 24: 79-90 & www7.tours.inra.fr/Pole_Sante_Animale/publications/liste_des_publications/publiccations_2012

12. ECDC & EMA, 2009. The bacterial challenge: Time to react.

13. ESVAC, 2013. Sales of veterinary antimicrobial agents in 19 European Union / European Economic Area countries in 2011.

14. French Ministries of Health, the Ecology, Agriculture, Higher Education and Research, 2011. Plan national sur les résidus de médicaments dans les eaux.

15. French Ministry of Agriculture, 2011. Plan national de réduction des risques d’antibiorésistance en médecine vétérinaire.

16. Résapath, 2013. Réseau d’épidémiosurveillance de l’antibiorésistance des bactéries pathogènes animales – Bilan 2012.

17. Sanders P., 2005. L’antibiorésistance en médecine vétérinaire : enjeux de santé publique et de santé animale. Bull. Acad. Vét. France. Tome 158: 137-143.

18. Swann M., 1969. Report of the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medecine. London, UK Her Majesty’s Stationary Office.

19. Trystram G. et al., 2012. Réseau européen de surveillance de la résistance bactérienne aux antibiotiques (EARS Net) : résultats 2001-2010 pour la France et place en Europe. BEH InVS. 42-43: 477-479.

20. WHO, 2001. WHO Global Strategy for Containment of Antimicrobial Resistance.

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GLOSSARY

Antibiogram: a laboratory test that can assess bacteria’s sensitivity to various antibiotics.

Calf: male or female cattle from birth to the age of 8 months.

DNA (deoxyribonucleic acid): molecule composed of two strands twisted in a double helix, each made up of a series of nucleotides. Carrier of genetic information, DNA is responsible for the growth and functioning of living organisms.

Dose: a set quantity of a substance to administer.

Gene: a unit of heredity that corresponds to a region of DNA controlling a specific characteristic. A given gene governs synthesis of a single protein or a single ribonucleic acid (RNA) and in this way conditions the transmission or manifestation of a given hereditary characteristic.

Grouping: the grouping together of animals from different livestock operations based on the animals’ physiological and economic criteria.

Innocuousness (of food): a characteristic of something that presents no danger to the consumer’s health.

Integron: a genetic element found exclusively in bacteria, and mainly in Gram-negative bacteria. It forms a natural system to capture, express and spread genes that can allow bacteria to respond to environmental stresses. It is notably involved in the multi-resistance of bacteria to antibiotics.

Ion: an electrically charged particle made up of an atom or a group of atoms having gained or lost one or more electrons.

Metabolite: a molecule resulting from biochemical transformations of a substance that is produced within the cell or the organism.

Mutation (genetic): the modification of the genetic information of a cell or a virus.

Peptidoglycan: a component of the cell wall of Gram-positive bacteria and to a lesser extent Gram-negative bacteria; it provides them with mechanical and physical protection.

Phospholipid: a crucial element of cell membranes, separating the interior of the cell from the outside surroundings.

Plasmid: a fragment of DNA, usually circular, that can be found in the cytoplasm of bacteria. Bacteria plasmids can carry genes that are resistant to antibiotics, antiseptics or heavy metals enabling their adaptation in hostile environments.

Post-Mortem: after death, relating to an autopsy.

Probiotic: a living micro-organism (bacteria or yeast) that, added as a supplement to certain food products such as fermented milk products or cereals, is said to have a beneficial effect on the consumer’s health.

Ribosome: present in the cytoplasm of cells, its function is to synthesize proteins by decoding the information contained in messenger RNA.

Serotype: a sub-set of a microbial species grouped together on the basis of shared antigenic properties.

Transposon: a DNA sequence capable of moving and inserting itself in one or anther spot in the genome.

Zoonosis: an infectious or parasitic disease naturally transmissible from people to animals and from animals to people

34

APPENDICES



ACRONYMS

ADI: Acceptable Daily Intake

ALEA: Animal Level of Exposure to Antimicrobials

ANMV: Agence Nationale du Médicament Vétérinaire (the French agency for veterinary drugs)

ANSES: Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (the French agency for food, environmental and occupational health safety)

C3G/C4G: 3rd/4th generation cephalosporin

DGAL: Direction Générale de l’Alimentation (French general directorate for food)

DNA: Deoxyribonucleic Acid

ECDC: European Centre for Disease Prevention and Control

EFSA: European Food Safety Authority

EMA: European Medicines Agency

ESBL: Extended-Spectrum Beta-Lactamase

ESVAC: European Surveillance of Veterinary Antimicrobial Consumption

FAO: Food and Agriculture Organization

MA: Market Authorization

MRL: Maximum Residue Limit

MRSA: Methicillin-Resistant Staphylococcus Aureus (‘golden staph’)

NED: No-Effect Dose

OIE: World Organisation for Animal Health, formerly the Office International des Epizooties

SF: Safety Factor

SNGTV: Société Nationale des Groupements Techniques Vétérinaires (national league of technical veterinary groups)

WHO: World Health Organization

ANSES: Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travailwww.anses.fr

CIV: Centre d’Information des Viandeswww.civ-viande.org

EFSA: European Food Safety Authoritywww.efsa.europa.eu

European Commission: European Commission – Directorate-General for Health and

Consumers (DG SANCO) http://ec.europa.eu/index_en.htm

French Ministry of Agriculturehttp://agriculture.gouv.fr

OIE: World Organisation for Animal Healthhttp://www.oie.int/en

WHO: World Health Organizationwww.who.int/en

USEFUL LINKS

https://www.anses.fr

www.civ-viande.org

www.efsa.europa.eu

ec.europa.eu/index_fr.htm

agriculture.gouv.fr

www.oie.int/en

http://www.who.int/en

Hélène CHARDON

The Centre d’Information des Viandes is a non-profit association under the French Law of 1901. Its mission is to contribute, on a scientific basis, to knowledge and the debates on societal issues related to livestock and meat value chains (beef, veal, lamb, pork, horse meat and offal products). It pays particular attention to issues of health safety, animal health and well-being, human nutrition and food, and environmental and societal impacts.

On these subjects, CIV produces expert information based on monitoring and analyzing technical, scientific and social trends, and on collaboration with public, private and civil society stakeholders that have been recognized for the rigor of their approaches. This information is destined for professional or well-informed audiences interested in or concerned by the societal impacts of meat production and consumption.

In this way, CIV publishes scientific documents, keeps an up-to-date website serving as a documentary resource centre, runs discussions, and takes part in conferences, congresses and scientific events.

Created in 1987 at the joint initiative of INTERBEV (the French national inter-branch association for cattle and meat) and a public establishment, FranceAgriMer, CIV conducts its activities under the patronage of a Scientific Steering Board.

For more information visit www.civ-viande.org

antibiotic uses in animal husbandry & meat value chains...

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