Antibiotic%20Use%20-%20David%20Burch

jderekarmstrong

Antibiotic%20Use%20-%20David%20Burch

Antibiotic use and antibiotic resistance – its potential impact on the cattle industry

Introduction

‘The times they are a changin’ (Bob Dylan, 1964) sums up what is going on the antibiotic front, in the

UK, EU and even USA at the moment. The human medical side are facing many issues regarding

antimicrobial resistance (AMR), particularly on the hospital and care-home side but this is also rolling

out into the general community. In some cases, they have reached the end of the road regarding

antibiotic therapy and are now resorting to using compounds for example such as colistin, which had

previously been discarded on safety grounds but have continued to be used in veterinary medicines.

There has been little development of new antibiotic products in the last 30 years by the

pharmaceutical industry, so that most compounds are generic and outside the UK and EU have been

readily available and off-prescription and there have been a lack of controls and monitoring

regarding use and the development of antimicrobial resistance. Globalisation of travel and food

supplies has increased the chances of the spread of AMR.

So going forward, Governments, the United Nations and their institutions are moving forward to try

to improve the situation and looking at ways of preserving the antibiotics that we still do have so

they can be effectively used for as long as possible. This involves not only the medical side locally but

also globally and agriculture has been identified as a potential contributor to the problem on a global

and local basis. Substantial quantities of antibiotics are used in agriculture. Bacteria that may be

resistant can easily be transmitted to humans working with animals such as farmers, vets and

slaughter-house workers and to a lesser extent to consumers of meat, milk, cheese and eggs.

Zoonotic infections such as salmonellosis and campylobacteriosis are well recorded examples of

bacterial transfer and these may be resistant to key antibiotics used in man to treat infections. So

although agriculture probably plays a lesser role, it is involved and as such must play a part in the

solution.

UK Government strategy – O’Neill Report (2016)

The UK Government is keen to increase the monitoring of the use of antibiotics in agriculture. For

several years they have worked with the pharmaceutical industry to record the sales of antibiotics

on a yearly basis. This gives a good overview but does not break down use by animal species.

Knowledge of this use can then be compared with antimicrobial resistance found in bacteria from

that animal species or food products and this can be monitored and recommendations regarding the

future use/restrictions of the products can be made, particularly if they have an impact on human

therapy. The Government has been incredibly active in pushing this forward not only in the UK but

also Globally, culminating in the O’Neill report in May 2016.

The O’Neill report described 3 main steps to go forward in agriculture:

“First, 10-year targets to reduce unnecessary antibiotic use in agriculture, introduced in 2018 with

milestones to support progress consistent with countries’ economic development. For this to

succeed, governments must support and speed up current efforts, including those of the World

Organisation for Animal Health (OIE) and others, to measure antibiotic use and farming practices.

Second, restrictions on certain types of highly critical antibiotics. Too many antibiotics that are now

last-line drugs for humans are being used in agriculture; action should be taken on this urgently by

an international panel.

Third, we must improve transparency from food producers on the antibiotics used to raise the meat

that we eat, to enable consumers to make more informed purchase decisions.”

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The O’Neill report points highlight the direction the Government wants to go in the UK. They want

farm industries to monitor usage ideally by 2018. They want to set targets for reduction of usage by

2018, which will be implemented over a 10 year period, to allow for adoption of improved farming

practices. He is advocating the restrictions of the CIAs, for example, 3 rd and 4 th generation

cephalosporins, fluoroquinolones and more recently colistin. Regarding food producers, the larger

companies and supermarkets are already taking action on this front.

So far, in the UK the poultry meat industry (broilers, turkeys and ducks) has been successfully

recording their use over the last 3 years and made major changes to their management and

production systems to try to reduce routine use of antimicrobials and critically important antibiotics

(CIAs). This information is publicly released and also to VMD and falls of 44% in usage have been

recorded. The egg industry, which is under a much wider ownership, is also starting to make

progress. The pig industry has been recording usage for the last 2 years and has introduced a new

system to try to collate the data centrally in April 2016 and it is hoped that will be implemented next

year. They have seen falls of 10% in 2015 but as high users of antibiotics, have some way to go. The

cattle industry can be divided into two major groups such as dairy and beef production and each has

their own antibiotic usage patterns and issues. A coordinated recording system and approach needs

to be developed by both categories. The dairy industry appears to be very cognisant of the issues

already.

The Responsible Use of Medicines in Agriculture Alliance (RUMA) has been charged with the

responsibility of setting antibiotic usage targets in 2017 by species, closely working with species

representatives from their respective industries.

Classification of Antibiotics – WHO, EMA

A number of bodies have tried to classify antibiotics according to their importance in human

medicine and the risk of resistance transfer from animals to man. The World Health Organisation

(WHO) has been taken by many authorities as the lead but the European Medicines Agency (EMA)

has also come up with a list which varies somewhat from WHO, which is more of a Global use list

and some may consider over-restrictive in EU terms (see Table 1).

The WHO classification based on the following selective criteria: –

Criterion 1: An antimicrobial agent which is the sole, or one of limited available therapy to treat

serious human disease

Criterion 2: Antimicrobial agent is used to treat diseases caused by either: 1. organisms that may be

transmitted to humans from non-human sources or 2. Human diseases caused by organisms that

may acquire resistance genes from non-human sources.

Critically important antimicrobials (CIAs) – both criteria;

Highly important antimicrobials (HIAs) – single criterion;

Important antimicrobials (IAs) – neither criterion.

The EMA is based on the following selective criteria: –

Category 1 – Antimicrobials used in veterinary medicine where the risk to public health is currently

estimated low or limited;

Category 2 - Antimicrobials used in veterinary medicine where the risk to public health is currently

estimated higher;

Category 3 – Antimicrobials currently not approved for use in veterinary medicine.

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Table 1. Comparison of categorisation of antimicrobial families by EMA (2014) and WHO (2011)

Antimicrobial family EMA WHO

Public health - risk low Category 1

Macrolides 1 CIA

Penicillins (natural)

1 CIA

(Penicillin G and V)

Penicillins (narrow spectrum, 1 HIA

beta-lactamase resistant,

(cloxacillin, oxacillin)

Rifamycin 1 CIA

Tetracyclines 1 HIA

Public health - risk higher Category 2

Cephalosporins 3G & 4G 2 CIA

Fluoroquinolones

2 CIA

Quinolones

Polymixins (colistin) 2 CIA

Aminoglycosides 2 CIA

Penicillins

2 CIA

Aminopenicillins (ampicillin,

amoxicillin)

+ beta-lactamase inhibitors

combinations

(Amoxicillin/clavulanic acid)

Not approved as vet medicines Category 3

Carbapenems 3 CIA

Cephalosporins 5G 3 -

Cyclic esters (fosfomycin) 3 CIA

Glycopeptides (vancomycin) 3 CIA

Glycylcyclines (tigecycline) 3 CIA

Monobactams (aztreonam) 3 CIA

Oxazolidinones (linezolid) 3 CIA

Penicillins

3 CIA

Carboxy and ureido-penicillins +

betalactamase inhibitor

combinations

Sulfones 3 HIA

Tuberculosis drugs 3 CIA

Key: CIA – Critically important antimicrobials – both criteria; HIA – Highly important antimicrobials –

single criterion; IA – neither criterion.

There are some variations between the two classifications mainly the macrolides and natural

penicillins are classified as Category 1 by EMA and CIAs by WHO. Tetracyclines are Category 1 by

EMA but HIA by WHO. Category 3 antibiotics are not approved for veterinary use and certainly not in

food-producing animals, as maximum residue limits (MRLs) have not been set. Other families of

antibiotics are under review by the EMA in 2017 and this list might change.

The shared Category 2/CIA list is the 3 rd and 4 th generation cephalosporins, fluoroquinolones,

polymixins (colistin) and currently aminopenicillins (amoxicillin) alone and with beta-lactamase

inhibitors, such as clavulanic acid. Penicillins and cephalosporins as a group are under review by EMA

and may be further sub-divided. Currently, 1 st and 2 nd generation cephalosporins are considered as

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HIAs by WHO, which may be important for various mastitis products. A BCVA own classification and

list will be introduced in due course.

EU legislation – likely changes/impact

Currently two pieces of legislation are going through the EU procedure, one relating to medicated

feeds and the other veterinary products. The main changes which are already appearing in EMA

guidelines are the use of antibiotics preventively. The routine preventive use will be replaced by

metaphylaxis i.e. when a few animals are showing signs of disease before treatment is started on the

whole group. Treatment will remain as normal. This could have an impact on the way dry cow

therapy is perceived as well as routine medication of calves is used.

Currently, the European Parliament is advocating the use of the WHO classification but this needs to

be confirmed when the legislation is finalised, possibly towards the end of 2017. The effects of Brexit

are unsure at this stage but as the UK has been a major driving force in this whole procedure, it is

unlikely to be too dissimilar.

Conclusions that might be relevant for the cattle industry

Regarding the dairy industry there will be the need to set up the monitoring of antimicrobial use on

a herd basis and targets for use will have to be set and agreed by RUMA. It is advisable to have your

own classification and list of antimicrobials ideally using the EMA and WHO classification but dividing

products into three categories, if possible, to allow for further flexibility in use. The Critical list

should include the 3 rd and 4 th generation cephalosporins, fluoroquinolones and colistin. These should

be reserved use and the veterinarian should be able to justify their use under responsible use

guidance, based on bacterial isolation and sensitivity testing. This would refer to mastitis control as

well as injectable and topical treatments.

Regarding calf rearing for dairy replacements or beef production, the list will need to apply as well as

the methods of administration. Routine prophylaxis will not be permitted and metaphylaxis will

need to be justified based on bacterial isolation and sensitivity testing.

Changes are coming and all livestock industries will be involved. Government have warned that if

targets are not introduced by species sectors, then they will set them.

Working with the producer, via assurance scheme monitoring, health plan utilisation and following

examples of husbandry improvements and antibiotic usage evaluation and reduction have been

demonstrated by Bristol University and may act as a model for the industry.

DGSB 8/12/16

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