The development of antibiotics in the 1940s led to a revolution in the treatment of infectious diseases. But after more than 60 years of use and misuse, many antibiotics have lost much of their effectiveness as bacteria develop resistance to them. This situation has arisen partly as a result of overuse in clinical medicine, but also as a consequence of the huge quantities of antibiotics used in agriculture, not only to treat infections in animals, but also to increase productivity in the meat industry by promoting animal growth. Antibiotic-resistance is now recognised as a global public health issue and as major food safety problem. Although the EU has taken action to tackle antibiotic resistance, many other countries have not. As demand for cheap meat rises in developing economies, what can the food industry do to help postpone the arrival of a ‘post-antibiotic era’ in medicine?
There is no doubt that the widespread availability of antibiotics since the 1940s has saved the lives of countless people who might otherwise have fallen victim to what are now considered minor bacterial infections. Unfortunately that very availability has also led to decades of what is now considered to be reckless overuse of antibiotics in medicine and in agriculture. The result has been that bacterial pathogens have been continuously exposed to antibiotics for a considerable time and have developed resistance to them. Many antibiotics have become less and less useful as therapeutic agents as resistance in microbial populations has increased. The situation has now reached crisis point as the armoury of effective antimicrobial drugs is depleted and there are worryingly few alternatives in the development pipeline to re-stock it. The World Health Organisation (WHO) now regards antibiotic-resistance as a “global threat”, stating that more than 25,000 people die each year in the EU of infections caused by antibiotic-resistant bacteria.
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The development and spread of resistance
Antibiotic-resistance is not only a threat to public health but has also become an important food safety issue. This has come about largely because of the widespread use of antimicrobial drugs in agriculture. In many countries, notably the USA, it is estimated that more than half of all antibiotics produced are used by agriculture. Much of the demand is for therapeutic drugs used to treat bacterial diseases like mastitis and respiratory and enteric infections in livestock, but antibiotics are also used at sub-therapeutic levels, both to prevent infection and as animal growth promoters. This latter phenomenon was discovered in the USA more than 60 years ago when poultry fed on the by-products of a fermentation process to produce tetracycline were found to gain weight more rapidly than normal. The mechanism responsible for this effect is still not understood, but may have something to do with the suppression of the normal gut microflora allowing greater nutrient uptake by the animal. The discovery led to widespread incorporation of antibiotics into animal feed at sub-therapeutic levels from the 1950s onwards – a practice that was highly successful in increasing productivity and feed efficiency. In the USA, the quantity of antibiotics used as growth promoters rose by a factor of fifty between 1951 and 1978, while therapeutic use in humans and animals increased only tenfold over the same period. Similar patterns were reported in other countries where intensive livestock farming was developing. At the same time, it became apparent that bacterial isolates from animals and humans were rapidly becoming more resistant to commonly used antibiotics. One report published in the UK in 1961 showed that the proportion of E. coli isolates from poultry resistant to tetracycline rose from 3.5% to 63.2% in the four-year period after the antibiotic’s introduction in 1957.
How did the dramatic increase in tetracycline resistance seen in the UK in the late fifties happen so fast? At least part of the answer lies in the mechanisms by which antibiotic resistance arises and then spreads in bacterial populations. Bacterial cells can acquire resistance through a mutation in the DNA of the genome. When the mutated cell is in the presence of an antibiotic to which it carries resistance it has a considerable competitive advantage over susceptible cells, which die out. In this way the resistance gene quickly becomes dominant in the population. But resistance is more often acquired through genes located on plasmids and other mobile DNA fragments passing from one cell to another (horizontal transmission). The two cells need not be of the same species and it is also possible for more than one resistance gene to be transmitted on the same fragment of DNA, since they are often co-located. This means that a bacterial cell can acquire co-resistance to several different antibiotics in a single horizontal transmission event. In this way, multiple-resistance can spread very rapidly through mixed microbial communities, which are able to thrive when the antibiotics concerned are present. In other words, the presence of the antibiotic in the environment selects for resistance genes in the bacterial population.
Concerns for the food industry
The WHO considers that the food supply chain plays an important part in the dissemination of antibiotic-resistant bacteria from animals into the human population. Animal products like raw and cured meats, eggs, unpasteurised dairy products and farmed fish are all potential vehicles for transmission, as is fresh produce contaminated by agricultural animal waste through irrigation or manuring. Furthermore, the global extent of modern food and feed supply chains provides a mechanism for the rapid spread of antibiotic-resistant strains around the world. For the food industry, the development of antibiotic resistance is a particular safety hazard when it occurs in bacterial pathogens that can be transmitted from animals to humans (zoonoses).
Some of the most common agents of foodborne disease are zoonoses, including Salmonella, Campylobacter and verocytotoxigenic E. coli (VTEC). Strains of all these pathogens showing resistance to multiple antibiotics have arisen over the last 30 years and have been involved in serious food poisoning outbreaks. One of the best known examples is Salmonella Typhimurium definitive phage type (DT) 104. S. Typhimurium DT104 isolates are typically resistant to five types of antibiotic: ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. The pathogen was first isolated in the UK in the 1980s and was later discovered to be endemic in cattle, which acted as a reservoir for contamination of meat production. It then spread worldwide with alarming speed during the 1990s and is now common, especially in Europe and North America. S. Typhimurium DT104 has also shown a worrying ability to acquire resistance to other types of antibiotic, including the clinically important fluoroquinolones and cephalosporins.
Other foodborne pathogens of special concern are strains of Campylobacter resistant to the fluoroquinolone antimicrobial drug ciprofloxacin, which is an important therapeutic drug used to treat human infection and is sometimes used in the treatment of gastrointestinal disease. It has emerged that the use of enrofloxacin, another fluoroquinolone, in food animals has resulted in the development of resistance to ciprofloxacin in Campylobacter and in Salmonella. The notably virulent strain of E. coli O104:H4, which caused the major fatal outbreak of infection in Germany in 2011, was resistant to a number of antibiotics, including ampicillin, trimethoprim, cephalosporins and tetracycline. It was also found to possess a plasmid-borne gene for extended-spectrum beta-lactamase (ESBL) production. E. coli strains with the ESBL gene are often resistant to a wide range of important therapeutic antibiotics and infections are notoriously difficult to treat. They are most common in urinary tract infections, but the presence of ESBL in foodborne pathogens is an emerging concern. The best known of all antibiotic resistant bacteria, methicillin-resistant Staphylococcus aureus, or MRSA, has also been turning up occasionally in livestock and foods of animal origin. According to the WHO there is evidence that antibiotic resistance in Salmonella has been “associated with more frequent and longer hospitalisation, longer illness, a higher risk of invasive infection and a twofold increase in the risk of death in the two years after infection.” Infections by resistant Campylobacter strains are also linked to a greater risk of invasive illness.
The most recent surveillance report for antibiotic resistance in zoonotic bacteria was published earlier this year by the European Food Safety Authority (EFSA) and by the European Centre for Disease Control (ECDC). The data presented in the report comes from 26 EU member states and three other countries and was collected in 2010. It shows that antibiotic resistance was common in Salmonella, Campylobacter and E. coli isolates from animals and food samples. Of special concern is the high proportion of isolates, especially from poultry, resistant to ciprofloxacin. Resistance to ciprofloxacin, nalidixic acid and tetracyclines in Campylobacter isolates from meat and animals was found at levels from 21% to 84%.
Current strategies
Considering how long ago the problem of antibiotic resistance was first recognised, governments have been almost glacially slow in addressing it. The first warning was contained in a report produced by a UK government committee in 1969. The Swann Report recommended that antibiotics used in human medicine should not be used as growth promoters and advised that a committee should be set up to review and authorise antibiotic use. These recommendations were eventually followed, but not until almost thirty years later. At the time the report was largely ignored. The use of antibiotic growth promoters continued worldwide until 1986, when the practice was banned in Sweden. As research uncovered more about the dangers of unrestricted antibiotic use in food animals, other countries began to take action, notably Denmark. Measures were also introduced at EU level as concerns grew, and all antibiotic growth promoters were finally withdrawn in 2006. Nevertheless, there is evidence that in some Eastern European countries, antibiotics are still widely available without prescription and could be being used by farmers. Additionally, large quantities of antibiotics continue to be used to prevent and treat diseases in food animals.
The steps taken in the EU have not been replicated elsewhere in the world, even though the WHO also recommends that antibiotic growth promoters be banned or quickly phased out. The USA is one of the biggest meat-producing nations and has yet to ban growth promoters despite prolonged campaigns by consumer groups and others. The Food and Drug Administration (FDA) is the body responsible for regulating antibiotic use, but although it has expressed a wish to see growth promoters phased out, action has been limited. For example, in 2000 the FDA proposed the banning of enrofloxacin use in poultry, but legal challenges delayed the measure until 2005. The US meat industry is a powerful lobby and is reluctant to accept the banning of antibiotic growth promoters for economic reasons. The issue is controversial and has led to the commissioning of a large body of research into the effectiveness or otherwise of banning growth promoters as a means of controlling the development of antibiotic resistance.
Nevertheless there is evidence from countries where bans have been in place for some time. A WHO expert panel has studied the effect of the withdrawal of antibiotic growth promoters from food animals in Denmark on human health, animal health, animal production and the national economy. The panel focused on pig and poultry production and found a significant decrease over 10 years in the prevalence of enterococci resistant to glycopeptide antibiotics previously used as growth promoters. They also found a 50% drop in the use of antibiotics in pig production, both as a result of withdrawing growth promoters and a policy to reduce the use of therapeutic antibiotics by improvements in animal husbandry. Over the same period, pig productivity improved significantly. So it seems that the use of growth promoters can be discontinued and the risk to human health reduced, without long term damage to the economics of food animal production. Similar effects have been reported in Sweden and in Norway, where the fish-farming sector has been very effective in reducing antibiotic use. But in the EU as a whole the prevalence of antibiotic resistant bacteria in food and animals has remained more or less unchanged since growth promoters were withdrawn in 2006. One reason for this may be the persistence of resistance genes in the bacterial population even when the antibiotic concerned is removed from the environment. It may take several more years before the effects become clear.
Reducing antibiotic use
A wide range of policy measures has been developed to tackle the problem of antibiotic resistance in bacteria in the food chain. The elimination of antibiotic growth promoters in food animals is just one of these. Other regulatory measures recommended by WHO include ensuring that antibiotics can only be given to animals when prescribed by a veterinarian, and ensuring that important clinical drugs like fluoroquinolones are only administered to treat animals when their use is fully justified. There are also important steps that can be taken to reduce the need for therapeutic antibiotics in animals, including improving animal health and preventing disease by better biosecurity and vaccination programmes, and by improving on-farm hygiene practices. WHO also points out that there may be economic incentives to prescribe antibiotics inappropriately, which should be eliminated. Finally, better surveillance is needed to determine the real usage of antibiotics in animals and to track the prevalence of resistance in foodborne bacteria. The EFSA surveillance report shows how much useful information can be revealed by this method, but the results suggest significant variation in the effectiveness of surveillance programmes in different countries. There is room for improvement.
It is clear that the development of resistance in bacterial pathogens is a major public health hazard, which threatens to make antibiotics virtually redundant as treatments for infection, with potentially catastrophic results. Whether antibiotic use in food animals is a major factor in this development is a more contentious issue. The evidence suggests not only that it has an important role, but also that antibiotic use in food animals can be cut dramatically without rendering the industry economically unviable. It seems an obvious and important way forward, but given that it is now 43 years since the Swann report was published, it seems unlikely that any solution will be a speedy one.
