Antibiotics: The resistance issue

Antibiotics: The resistance issue

This Industry Alert from Animal Pharm Reports gives an up-to-date and accurate account of the four-decade antibiotic resistance debate. Written by Dr Kevin Woodward, Schering-Plough Animal Health, this report brings together a balanced view from across the animal health industry.

It begins by addressing the uses of antibiotics in both human health and animals. It then addresses the issue of resistance and how it actually occurs. Studies including findings from the Swann Report are also analysed.

Having addressed both therapeutic and sub-therapeutic uses of antibiotics, this report then focusses on antibiotic growth promoters. It examines the effects that bans of antibiotic growth promoters have had on animal health product sales.

To provide a complete overview, this report suggests a practical way forward. Clear, practical guidelines are given for both the veterinary and medical professions on how to adopt the 'prudent use' approach.

PUBLISHED: JULY 1999
PAGES: 88
REF: SR185E
PRICE: £190/$399/¥46,000

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CONTENTS
LIST OF TABLES
EXECUTIVE SUMMARY
ABBREVIATIONS

CHAPTER 1 THE USES AND REGULATION OF ANTIBIOTICS IN ANIMALS AND HUMANS
1.1 Introduction
1.2 Use of antibiotics in animal health
1.2.1 Therapeutic use of antibiotics
1.2.1.1 Cats and dogs
1.2.1.2 Cattle
1.2.1.3 Sheep
1.2.1.4 Pigs
1.2.1.5 Horses
1.2.1.6 Poultry
1.2.1.7 Fish
1.2.2 Administration of therapeutic antibiotics to animals
1.2.3 Growth promotion with antibiotics
1.3 Regulation of antibiotic use in animals
1.3.1 Therapeutic antibiotics
1.3.2 Antibiotic growth promoters
1.4 Sales of antibiotics in veterinary medicine

CHAPTER 2 ANTIMICROBIAL RESISTANCE
2.1 Mechanisms of resistance
2.1.1 Acquisition of resistance
2.1.2 Expression of resistance
2.1.3 Why antibiotic resistance occurs
2.2 Implications of resistance
2.3 The Swann Report
2.3.1 Recommendations of the Swann Report

CHAPTER 3 THE RESISTANCE CONTROVERY
3.1 Resistance in human pathogens
3.1.1 Nosocomial infections
3.1.1.1 Staphylococcus aureus
3.1.1.2 Enterococci species
3.1.1.3 Streptococcus pneumoniae
3.1.1.4 Listeria monocytogenes
3.1.1.5 Haemophilus influenzae
3.1.2 Food-borne pathogens
3.1.3 Major human disease pathogens
3.2 Resistance in zoonotic pathogens
3.2.1 Salmonella species
3.2.2 Escherichia coli
3.2.3 Campylobacter species
3.2.4 Other bacteria
3.3 Fluoroquinolones
3.4 Concluding remarks

CHAPTER 4 ANTIBIOTIC GROWTH PROMOTERS
4.1 Background
4.2 The current situation
4.2.1 The UK House of Lords Report
4.2.2 The EU ban on growth promoters
4.3 Scientific evidence for the induction of antibiotic resistance
4.3.1 The Heidelberg Appeal Nederland Foundation
4.3.2 The precautionary principle
4.4 The US approach
4.5 Effect of the EU ban on antibiotic growth promoters

CHAPTER 5 THE WAY AHEAD
5.1 Introduction
5.2 Prudent use of antibiotics
5.2.1 Prudent use in human medicine
5.2.2 Prudent use in veterinary medicine
5.2.3 Education in prudent use of antibiotics
5.3 Surveillance of antibiotic resistance in veterinary medicine

REFERENCES AND FURTHER READING

LIST OF TABLES
Table 1.1 Important antibiotics currently used in animal medicine
Table 1.2 Current status of antibiotic growth promoters in the EU
Table 1.3 Five new active antibiotics introduced into veterinary medicine since the late 1980's
Table 1.4 Total sales of antibiotics in the EU (tonnes), 1997
Table 2.1 Bacterial pathogens of humans and the diseases that they cause
Table 4.1 Use of antibiotic growth promoters in the EU, 1997
Table 4.2 Reductions in consumption and by-products in pigs due to the use of antibiotic growth promoters

EXECUTIVE SUMMARY
Antibiotics are widely used in veterinary medicine for the treatment and control of bacterial diseases. Their uses and modes of employment parallel those in human medicine. Antibiotics used in veterinary medicine generally belong to the same classes as those used in human medicine, such as the penicillins, cephalosporins, macrolides, tetracyclines and fluoroquinolones. They are used in all types of animals - including food-producing and companion animals, to treat diseases - many of which are potentially life threatening if left untreated.

In most developed countries, including the Member States of the European Union (EU), veterinary medicinal products are tightly regulated from both the point of view of initial authorisation and (for those used in food-producing animals) the limits and controls on their residues in food of animal origin.

Antibiotics are also widely used in animals for growth promotion purposes - they are referred to as antibiotic growth promoters or, occasionally, feed additive antibiotics. They are given in feed at low, subtherapeutic levels. In the EU, as in most countries, these too are subject to rigorous regulatory controls.

A major concern over the use of antibiotics in animals, as well as in humans, is the induction of resistance. That is, the ability of bacteria to resist the therapeutic effects of antibiotics. At its most extreme, this would render antibiotics useless when dealing with animal or human pathogens. This would be bad enough in otherwise healthy animals or humans, however it is potentially disastrous in those with reduced immune competence. This includes transplant patients given immunosuppressive drugs to combat tissue rejection, cancer patients given antineoplastic drugs which are themselves immunosuppressive, and patients suffering from immunodeficiency diseases such as acquired immune deficiency syndrome (AIDS) in humans and feline leukaemia virus (FeLV) in cats. There is also concern that organisms that are pathogenic in both animals and humans (zoonotic) will acquire resistance through veterinary treatment in animals causing any ensuing disease in humans to be difficult to treat. Examples include diseases caused by salmonella, campylobacter and Escherichia coli.

There are a number of mechanisms by which bacteria can become resistant to the effects of antibiotics, including mutations and the acquisition of resistance genes. Similarly, there are a number of ways in which this resistance can be expressed, such as the production of enzymes which deactivate the antibiotic or bacterial activity, which either reduces the amount of antibiotics entering or increases the amount leaving the cell. There is adequate evidence to demonstrate that antibiotic resistance is increasing in both human and animal pathogens.

Antibiotic use increases the selection pressures for the development of resistant bacteria. There have long been concerns that selection pressure is maximised when bacteria are exposed to subtherapeutic concentrations of antibiotics, as this allows the survival and proliferation of resistant organisms. Hence, the current focus on the microbiological safety of antibiotic growth promoters.

However, other factors can contribute to the origins of resistance, including the use of inappropriate antibiotics for a particular disease, the use of antibiotics for diseases caused by viruses and failure to comply with product recommendations and labelling advice.

Antibiotic resistance to human pathogens is becoming a major problem in some areas. Examples include nosocomial infections, ie those that arise in the hospital environment. This has become a critical issue with methicillin-resistant Staphylococcus aureus (MRSA). There is also concern over resistance in major human pathogens, for example Mycobacterium tuberculosis, the causative organism of tuberculosis, and Neisseria gonorrhoeae, the causative organism of gonorrhoea which are both now widely resistant to the effects of antibiotics. Of even more concern is that many organisms are showing multidrug resistance. As a result, some antibiotics are now considered as being the last line of defence for use when bacteria have become resistant to other substances.

There is evidence to suggest that resistance in human pathogens generally arises from the use, or rather from the misuse, of antibiotics in human medicine. For example, with tuberculosis, failure to complete courses of antibiotic treatment is common, thus favouring the emergence of resistance.

Antibiotics are often prescribed for inappropriate conditions, such as sore throats caused by viruses, and so increasing the selection pressures. It is likely that there is much overuse of antibiotics in human medicine.

In veterinary medicine, the emergence of antibiotic resistance is evident in a number of areas and resistance in some zoonotic pathogens such as Salmonellae is probably due to the therapeutic use of antibiotics. Again, the emergence of resistant organisms is probably favoured by the misuse of antibiotics, including inadequate dosing, failure to complete treatment courses and the use of antibiotics or specific antibiotics where another drug, or even none at all, would have been more appropriate.

However, there is little or no evidence to suggest that this has caused problems in zoonotic disease in humans. Many zoonotic organisms, like salmonella and campylobacter, cause enteric disease and this is not generally treated with antibiotics. It is only when the infection spreads to distant organs and tissues, such as the lung or brain, that antibiotic therapy is called for, and this is relatively rare.

The major problem here is not so much antibiotic resistance but the fact that the infection arises in the first place. Such infections follow the contamination of carcasses at abattoirs and cross-contamination in domestic refrigerators. The solution to this type of problem lies in better industrial and domestic hygiene and improved education on issues such as food storage and cooking practices.

There is little evidence to suggest that antibiotic growth promoters have contributed to the emergence of resistant organisms. Nevertheless, the EU - largely responding to political pressure, particularly from Sweden - has provisionally banned several antibiotic growth promoters. Two others antibiotic growth promoters, carbadox and olaquindox, have been banned because of concerns over mutagenicity and carcinogenicity. This leaves only three antibiotic growth promoters for use in the EU. These are now also at risk as a scientific committee within the European Commission (EC) has recommended that all growth-promoting uses of antibiotics be banned.

However, there are strategies that can be adopted to reduce the potential risks in both human and veterinary medicine, and these have some obvious similarities. The major approach is to develop principles of prudent use. These include:

Stopping unnecessary prescribing
Shortening unnecessarily long dosing periods
Avoiding unnecessary repeat prescriptions
Avoiding broad-spectrum antibiotics
Better and faster diagnosis
Educating the public and health professionals on what treatment is appropriate and what their expectations should be

Specifically, for veterinary medicine, the following should be included in any prudent use programme:
Accurate and rapid diagnosis combined with knowledge of the drug's pharmacokinetics
Appropriate prescribing (ie not for viral disease)
Determine the origins of infection (and remove if possible)
Careful dose selection
Careful monitoring of the effectiveness of treatment
Integrated disease management to reduce overall levels of infections
Regular assessment of disease levels
Investigation of cases of recurrence
Education of farmers to ensure treatment compliance

Where possible, national surveillance programmes are needed to monitor the prevalence of antibiotic resistance. Ideally, these should include all pathogens of interest. However, this is not feasible due to practical and cost considerations. As a consequence, for veterinary medicine, emphasis should be given to zoonotic pathogens. The results of such exercises will not only indicate where problems might be developing, it will also allow alternative therapeutic and husbandry strategies to be developed.