There is increasing awareness amongst public health officials in Canada about the emerging threat of antibiotic resistance, a threat which if left unchecked could see the end of many of the effective treatments for common bacterial infections which we have become used to in the modern world.
Reports of resistance to common antibiotic drugs in humans and animals are growing across the world. Antibiotic use in livestock agriculture is controversial, and many activist groups have accused the industry of creating unnecessary risks to human health, particularly through the use of antibiotics as growth promoters. Antibiotic resistant salmonellae, campylobacter, E. coli, and enterococci strains found in humans have been shown to have originated from livestock. However, groups such as the Beef Cattle Research Council claim that the link between antimicrobial use in cattle and resistance in human medicine is difficult to prove or disprove.
Strictly speaking, the term “antibiotic” should only refer to those drugs intended to destroy bacteria, however it is often used interchangeably with “antimicrobial”, a term which can include anti-protozoals such as ionophores which are used to control coccidiosis. Alcohol and soap can also be called antimicrobial or indeed anything which can destroy micro-organisms. Antimicrobial and antibiotic substances exist in nature, where they are often produced by microbes in order to gain a competitive advantage over other competing species. Antimicrobials work by blocking or disrupting specific structures or metabolic processes.
The risks of over use
It is estimated that 80% of all antibiotic use globally is for animals. The Canadian Animal Health Institute (CAHI) estimates that Canadian animals receive 1,600 metric tons of antibiotics annually, representing three quarters of the total consumption of antibiotics within the country.
The most recent data for Canada indicates that, per head, the dairy sector is the heaviest user of antibiotics, followed by beef, then poultry. However, per metric ton of meat produced, poultry is by far the heaviest user.
Some intensive beef operations rely on antibiotics to maintain growth and feed efficiency. Within the dairy sector they are vital for mastitis control during a cow’s dry period; however, lactating dairy cows are unlikely to receive heavy doses of antibiotics in order to avoid residues in milk.
Calf rearing is a sector for which there appears to be a significant risk of antibiotic resistance developing; this is due to a number of factors, and there also appears to be evidence from a number of countries that antibiotic resistance has a greater propensity to develop in younger animals compared with adults. The milk from cows treated for mastitis with antibiotics cannot be sold for human consumption for a specified withdrawal period; often this milk is fed to calves or pigs, exacerbating the problem of resistance in calves.
In the intensive poultry sector, where thousands of birds are kept in the same building, the treatment of an individual sick bird is impractical or uneconomical, thus preventative treatments may involve mass medication with antibiotics. Resistant bacteria may be passed to humans through direct contact, through food or through other means. Fluoroquinolone resistant campylobacter and salmonellae have been associated with treatment failure in human patients, and these strains have been shown to originate from poultry. Bacteria found in the digestive tract of animals can contaminate carcasses, and lead to illness in humans, which may not respond to antibiotic treatments.
Raising resistant bacteria
Antibiotic resistance exists within nature, with resistant bacteria found within soil; however, the human use of antibiotics leads to selection of bacteria with resistant DNA (see Figure 1).
Antibiotic resistant organisms are able to survive treatment, and these reproduce leading to the development of resistant populations. Resistance to a particular antimicrobial may also develop in non-target microbes, and form a reservoir of resistance within nature. Low doses of antibiotics often leads to a situation where more of the resistant organisms survive, and resistance often develops faster than when higher doses are used.
Resistance to antibiotics may develop in normally susceptible organisms by two methods, mutation or by the transfer of resistance coding genes. There are four specific mechanisms leading to the development of resistance.
Firstly, some microbes produce drug inactivating enzymes. Resistance to choloramphenicol is thought to be due to the target organisms acquiring genes to produce bacterial enzymes that react with the antibiotic molecule, which prevents it from binding to the target organism.
Some antibiotics such as trimethoprin work on susceptible enzymes within the target organism. Resistance can be caused by mutations which lead to the bacteria producing less susceptible enzymes. There may be reduced affinity of the antibiotic for the target organism, due to mutations in the bacterial ribosomes, onto which antibiotics bind. Target organisms can also become impermeable due to mutations causing the loss of proteins which carry the antibiotic across the bacterial cell wall.
It has been known since the 1950s that feeding low doses of antibiotics to animals leads to increased weight gain, and the practice has become widespread in some countries. In 1974 it was found that drug resistant bacteria came to dominate the intestines of chickens with oxytetracycline added to their feed, and that within six months of the introduction of this feed, people living and working on the farm also carried oxytetracycline resistant bacteria. It was also found however, that six months after the feed was discontinued, workers on the farm no longer carried the resistant bacteria. This research led to a ban on the use of oxtetracyclines as growth promoters within Europe.
Contaminated water and soil also play in role in preserving and spreading antibiotic resistant bacteria. Antibiotics have been detected in waste water from livestock farms, and this can lead to increased antibiotic resistance in aquatic systems and the natural environment. Another mechanism for spreading resistance may be that of antibiotic residues in meat and milk which could lead to the development of resistant bacteria within human population, and the breakdown of efficacy of antibiotics in human medicine.
The problem of antibiotic resistance has been described as a classic example of the “tragedy of the commons”—with the private benefits of antibiotic use for growth promotion contributing to a very public cost in terms of resistance. There is considerable political pressure to legislate to restrict the use of antibiotics in livestock farming. In the EU the routine use of antibiotics for pigs and poultry was banned in 2006, with growing pressure for stronger legislation in many countries including Canada and the US.
In 2011 the CAHI—a body that represents the manufacturers of veterinary drugs—called for the phasing out of the use of medically important antimicrobials for growth promotion, and that these products should only be used under the supervision of a veterinarian. In October 2014, Health Canada published a Federal Framework for tackling the problem of antimicrobial resistance, which is likely to lead to significant implications for the use of antibiotics and other antimicrobials within the Canadian livestock sector. Key action points include strengthening regulations governing the use of veterinary medicines within the livestock sector, and encouraging practices which lead to a reduction in the use of antibiotics.
In 2013, the US department of Health and Human Services identified four key actions to reduce the threat from antibiotic resistance. The actions are preventing infections, tracking the spread of resistant bacteria, improving the use of current antibiotics, and measures to develop new antibiotics.
Prevention and practices
Some simple measures may prevent infections which will help to slow the development of antimicrobial resistance. Professor John Prescott of the University of Guelph has suggested that increased hand washing on farms, and improved infection control practices including the quarantining of sick animals will help. These should be coupled with increased use of vaccinations, improved animal husbandry practices and hygienic conditions.
The increased availability of effective and affordable animal vaccines against major infections could help. In Norway the introduction of salmon vaccines led to a 99% reduction in the use of antibiotics in salmon farming between 1987 and 2007, whilst at the same time salmon production grew by 142%.
Lower stocking densities, and better nutrition and management, can also contribute to improved animal health and a reduced need for antibiotics. A study of Swiss veal calf production found that large groups, the external purchase of calves, the feeding of milk bi-products, and the administration of antimicrobials through feed on arrival on the farm all contributed to increased risk of resistance at the farm level.
Tracking resistant bacteria and understanding the extent of resistance in bacterial populations and where it has derived from is vital; thus surveillance is seen as being the key to understanding and tackling this problem. Many countries carry out research on the epidemiology of resistant bacteria, and the Canadian Bacterial Surveillance Network is a network of clinical laboratories, which provide data and bacterial isolates for further study and analysis. The Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) is an initiative of the Public Health Agency of Canada, Health Canada, the Canadian Food Inspection Agency and provincial partners. Monitoring resistance within the food chain is a key component of the program. CIPARS is modelled on similar surveillance programs in the US and Denmark.
The more prudent use of antibiotics in livestock will slow down the development of resistance. Long term low doses of antibiotics are more likely to lead to the development of resistance than higher short term doses. A low dose means that bacterial growth continues, but puts selective pressure in favour of resistant strains.
The efficacy of an antibiotic depends on the target organism which it is being used against. Inappropriate use, particularly against viral infections will only develop resistance within non target organisms. Not following the instructions on the label, or ending a course of treatment early leads to resistant bacteria surviving. If a prescription designed to kill 99.9% of the population of bacteria is ended early, then only half may be killed. Those bacteria that do survive are likely to be the antibiotic resistant ones.
Promoting the development of new antibiotics, and developing new diagnostic tests for resistant bacteria is another important part of the strategy. Rotating different products and classes of antimicrobial will reduce the selection pressure for resistant strains. There are a number of different classes of antibiotics with varying uses across human and veterinary medicine; these include the sulphonamides, pennicillins and cephalosporins, aminoglycosides, tetracyclines and macrolides. Few new antibiotics are being developed as the costs of developing, testing and licensing a new antibiotic run into the billions. Measures to encourage research and commercialization of new antimicrobial products should be part of the solution. Diagnostic tests for resistant organisms will aid surveillance, and encouraging the more targeted use of existing antimicrobials.
Proper treatment of waste water from livestock units can lead to a reduction of up to 90% of the antibiotics present, and reduce the development of resistant bacteria in the natural environment.
There is no magic solution to this problem, and simply banning the use of antimicrobials in animals is not a workable solution. It is better to take a more integrated approach, leading to more prudent and judicious use of these important medicines. As professor Prescott has pointed out: this involves everyone—farmers, veterinarians, doctors, patients, the pharmaceutical industry and the general public.