Introduction to protecting antibacterials

Antibacterials are essential drugs for treating bacterial infections. They have brought great benefits to humans and domestic animals by enabling the treatment of diseases that previously caused significant morbidity and mortality.

Unfortunately antibacterials have become victims of their own success and their increasing usage has encouraged the development of antibacterial resistance. Although the use of antibacterials does not in itself induce antibacterial resistance, exposure to antibacterials favours the survival of organisms carrying resistance genes.

At the same time as antibacterials have become less effective as a result of the development of antibacterial resistance, there has been a reduced rate of development of new drugs. These two factors mean that we need to PROTECT the effectiveness of the antibacterials we have through responsible use and stewardship.

Antimicrobial resistance has become a significant public health issue and because the antibacterials used in human medicine are, in many cases, the same as or closely related to antibacterials used in veterinary medicine, the suggestion has been made that emerging resistance to antibacterials in human pathogens is associated with the overuse and misuse of antibacterials in veterinary medicine.

Until now interest in the veterinary use of antibacterials has concentrated on their use in farm animals and on resistant bacteria entering the food chain. However there is now increasing interest in the use of antibacterials in companion animals, both because of the importance of companion animals in human health and because of the recognition of resistant bacteria in companion animal practice.

It is difficult to assess the impact of the veterinary use of antibacterials on antibacterial resistance in human medicine, because of both the paucity of evidence and the complexity of antimicrobial resistance as a biological phenomenon. It now seems most likely that resistance in human pathogens is more closely associated with patterns of antibacterial use by the medical profession. However there is little doubt that many of the same antimicrobial substances are used in both humans and animals and that bacteria, including those carrying antimicrobial resistance, can be transferred between domestic animals and humans. The World Veterinary Association (WVA) has described antimicrobial resistance as a truly global 'one health' issue, and both the American Veterinary Medical Association and the Federation of Veterinarians in Europe have stated that the responsible and judicious use of antimicrobials is in the best interests of both animal health and human health.

While in many parts of the world protozoal diseases are a significant cause of morbidity and mortality, and they are relevant to the discussion of antimicrobial resistance, in the UK and the rest of Europe the emphasis is primarily on bacterial disease.

In the UK all veterinary antibacterials are prescription-only medicines (POM-V), therefore the responsibility for and control of antibacterial use rests with the prescribing veterinary surgeon. The Royal College of Veterinary Surgeons (RCVS) has stated that 'The development and spread of antimicrobial resistance is a global public health problem that is affected by both human and animal use of these medicinal products. Veterinary surgeons must be seen to ensure that when using antimicrobials they do so responsibly, and be accountable for the choices made in such use.'

It is vitally important that the veterinary profession embraces the responsible use of antibacterials in order to:

  • Minimize selection of resistant veterinary pathogens, and therefore safeguard animal health
  • Minimize possible transfer of resistance to human pathogens
  • Retain the right to prescribe certain antibacterials that are important in human medicine, e.g. the fluoroquinolones and third-generation cephalosporins

Antimicrobial resistance – a public health issue

The World Health Organization (WHO) has stated that antimicrobial resistance is a global public health problem. In the European Union (EU) 25,000 people die each year as a result of infection with multidrug-resistant bacteria, at an estimated cost to healthcare systems of €1.5 billion per year. It is estimated that 5–12% of hospital patients acquire an infection during their stay, and each year an estimated 400,000 people are infected with a resistant strain of bacteria. Although the occurrence of meticillin-resistant Staphylococcus aureus (MRSA) shows a decrease in some European countries, one third of countries are still reporting that, of all invasive S. aureus infections, more than 25% involve MRSA. At the same time, resistance is increasing in Europe in some bacteria, especially Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae, in which new resistant mechanisms are emerging and new drugs are currently not in sight.

WHO – Frequently asked questions on antimicrobial resistance:

A recent study determined the excess number of deaths, bed-days and hospital costs associated with bloodstream infections (BSI) caused by MRSA and E. coli resistant to third-generation cephalosporins (G3CREC) in 31 countries in Europe. The study found that the excess mortality associated with BSI due to MRSA and G3CREC is significant, especially in the UK which had the highest and second highest excess mortality rates, respectively. Long hospital stays imposed a considerable burden on healthcare systems, leading to €62 million excess costs in Europe in 2007 (de Kraker et al., 2011).

A meta-analysis of studies looking at mortality associated with S. aureus infections found that rates of infection have increased during the past two decades, with reported mortality rates of 15–60%. Resistance to meticillin among S. aureus isolates is a growing problem: 52.3% of nosocomial infections in patients in the intensive care unit (ICU) are due to meticillin-resistant S. aureus (MRSA). This represents a 37% increase in the incidence of MRSA infections from 1994 to 1998. Community-acquired MRSA infections are also now seen as an emerging problem (Cosgrove et al. 2003).

Critically important antibacterials

There is significant overlap between the classes of antibacterials, and often the actual compounds, used in companion animal veterinary medicine and in human medicine. The World Health Organization (WHO) has developed a list of antimicrobial agents used in human medicine, classified by importance. No antimicrobials in use were considered unimportant and three categories were defined: critically important, highly important and important. Antimicrobials were assigned to these categories on the basis of two criteria:

  1. The drug is the sole therapy or one of few alternatives to treat serious human disease.
  2. The drug is used to treat disease caused by organisms that may be transmitted via non-human sources, or diseases caused by organisms that may acquire resistance genes from non-human sources.

Antimicrobial drugs that met both these criteria were classified as critically important while those that met only one of the criteria were classified as highly important. The current list can be accessed at: http://www.who.int/foodsafety/foodborne_disease/CIA_2nd_rev_2009.pdf

The World Organization for Animal Health (OIE) has produced a similar list of the antimicrobials considered important in veterinary medicine, which used the same classification although the criteria used were slightly different:

  • Criterion 1 was met when a majority of the respondents (more than 50%) identified the importance of the antimicrobial class in their response to the questionnaire
  • Criterion 2 was met when compounds within the class were identified as essential against specific infections and there was a lack of sufficient therapeutic alternatives.

Although these lists have been compiled in different ways there is significant overlap, with many antibacterials considered critically important in human medicine also being considered critically important in veterinary medicine.

Control of antibacterial drugs

Since the 1990s, when antimicrobial resistance was recognized to be a serious threat to public health, there have been various initiatives to reduce its impact. In November 2011 the European Commission (EC) announced their latest action plan.

In the UK the Department of Health has an Antimicrobial Resistance Strategy and Action Plan which involves recommendations for the prudent use of antimicrobials in domestic animals as well as humans. In this plan the Veterinary Medicines Directorate is responsible for promoting the prudent and optimal use of antimicrobials in animals.

In order to maximize the efficacy of an antibacterial product, a veterinary surgeon should follow the manufacturer’s recommendations for dose and duration of treatment as detailed in the Summary of Product Characteristics.

Where there is no suitable authorized veterinary medicinal product in the UK for a condition in a particular species, a veterinary surgeon may, in particular to avoid unacceptable suffering, treat the animal in accordance with the 'Cascade'.

The Royal College of Veterinary Surgeons’ Code of Professional Conduct states that 'A decision to use a medicine which is not authorised for the condition in the species being treated where one is available should not be taken lightly or without justification.' They go on to state that where a veterinary surgeon prescribes a medicine under the cascade they are required to obtain consent from the owner for 'off-licence use'.

For drugs that are not authorized for the particular use in the particular species, the information provided with the product may not be adequate. In this case the veterinary surgeon is responsible for providing the owner with information regarding potential side effects, for example by the provision of one of the BSAVA Client Information Leaflets.

Adverse reactions
Adverse reactions are harmful and unintended reactions to a medicine when it is administered to an animal at its recommended dose and route of administration. Adverse reactions are normally considered in respect of the individual animal under treatment. They include toxicity and treatment failure, which must be considered in the context of the individual animal and in relation to concurrent treatment or pre-existing conditions. In the case of an antibacterial agent this includes treatment failures that occur despite culture and sensitivity results indicating that an appropriate antibacterial class has been used, or where a particular antibacterial product is authorized for the specific condition and species, and where the clinician’s experience suggests that a positive response should have occurred.

Reports should be made to the Veterinary Medicines Directorate (VMD) using the Suspected Adverse Reaction Surveillance Scheme (SARSS) forms. These forms are available to download here.

EU Action Plan against antimicrobial resistance

This is online at http://europa.eu/rapid/pressReleasesAction.do?reference=IP/11/1359

The Action Plan covers seven areas:

  1. Making sure antimicrobials are used appropriately both in humans and animals
  2. Preventing microbial infections and their spread
  3. Developing new effective antimicrobials or alternatives for treatment
  4. Co-operating with international partners to contain the risks of AMR
  5. Improving monitoring and surveillance in human and animal medicine
  6. Research and Innovation
  7. Communication, Education and Training

The proposal also sets out 12 concrete actions to:

  1. Improve awareness raising on the appropriate use of antimicrobials
  2. Strengthen EU law on veterinary medicines and on medicated feed
  3. Introduce recommendations for prudent use of antimicrobials in veterinary medicine, including follow-up reports
  4. Strengthen infection prevention and control in hospitals, clinics, etc.
  5. Introduce legal tools to tighten prevention and control of infections in animals in the new EU Animal Health Law
  6. Promote unprecedented collaboration to bring new antimicrobials to patients
  7. Promote efforts to analyse the need for new antibiotics in veterinary medicine
  8. Develop and/or strengthen multilateral and bilateral commitments for the prevention and control of AMR
  9. Strengthen surveillance systems on AMR and antimicrobial consumption in human medicines
  10. Strengthen surveillance systems on AMR and antimicrobial consumption in animal medicines
  11. Reinforce and co-ordinate research
  12. Improve communication on AMR to the public.
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