Deadly infections are no longer a horror of the past. By the 2050s, antimicrobial resistance will lead to 10 million deaths annually – more than cancer.
“Antimicrobial resistance, or bacterial resistance to antibiotics, can be compared to climate change, because it is a global phenomenon that affects everyone,” says Annamari Heikinheimo, Doctor of Veterinary Medicine.
Heikinheimo is investigating antimicrobial resistance. In her work, Heikinheimo focuses on human, animal and environmental health, a chain of closely connected links. This approach, known as One Health, is also used by the World Health Organization in its fight against antimicrobial resistance.
In addition to ordinary people – parents of small children, pet owners and agricultural producers – the use of antibiotics and their reduced efficacy is also troubling to the researchers in the field and decision-makers alike.
Why are antibiotics no longer effective?
Negligent use of antibiotics makes antimicrobial resistance a problem. In India, for example, antibiotics are sold over the counter. This contributes to the spread of super bacteria by those who travel in Asia. Humans or animals may be asymptomatic carriers of bacteria that are resistant to antibiotics. Problems will arise when antibiotics no longer effectively treat human or animal infections caused by resistant bacteria.
To many micro-organisms, antimicrobial compound production is an age-old tool in the fight over habitat and acclimatisation to different environments. The exploitation of these compounds, or antibiotics, by man was begun only after penicillin produced by fungi was discovered and turned into a manufactured product.
“Penicillin has already lost its efficacy in many regions, and several other drugs are heading in the same direction,” says Heikinheimo.
The carbapenem class of antibiotics, critical to humans, is losing its efficacy as genes that code the enzymes capable of splitting these antibiotics, or carbapenemase genes, are transmitted between bacterial strains and species. According to the National Institute for Health and Welfare (link in Finnish only), bacterial strains producing carbapenemases have caused widespread epidemics all over the world. They can be categorised as extensively drug resistant (XDR) strains that can only be combated with one or two types of antibiotics currently in use. Bacteria resistant to carbapenems can be found also in Finland, but to a much smaller extent than in, for example, the countries of Southern Europe.
Physicians and veterinarians at the forefront
Farms are the largest consumer of antibiotics in the world. In Finland, the use of antibiotics as feed additive was stopped already in 1996. However, in the United States and many other countries agricultural producers were able, for a long time, to add antibiotics to feed without prescriptions by veterinarians. Legislation in the United States allowed feed companies to routinely add antibiotics to feed for animal growth promotion. This practice changed at the beginning of 2017 when the implementation of amended guidance given by the U.S. Food and Drug Administration was completed: the use of all medically significant antibiotics, or antibiotics used in humans, requires prescription or authorisation by a veterinarian. The goal is to stop using such antibiotics in animal growth promotion and to combat antimicrobial resistance.
In Finland, the use of antibiotics as feed additive was stopped already in 1996.
Consumer attitudes in the United States are also changing – in a survey carried out by Cargill, a beef producer, 54% of consumers said they prefer buying beef that is raised without antibiotics. However, only 35% were willing to pay more for it.
Sometimes even a simple procedure can have a significant impact on the use of antibiotics; in Great Britain, officials stepped in by targeting physicians who prescribed antibiotics the most with a letter campaign that reduced the total consumption of prescribed antibiotics by several percentage points. Reductions in antibiotic use in animals have also been achieved, with a reduction of 9% in total sales of antibiotics used in animals in 2015. This was made possible by veterinarians and agricultural producers joining forces against antimicrobial resistance.
According to speculation, resistant bacterial strains have been introduced to Finnish animal farms by, among other things, imported breeding animals. In Finland too, the genesis and selection of resistant bacterial strains is caused by the treatment of animals.
In Finnish food, there are fewer bacteria resistant to antibiotics as compared to many other countries. The extent to which resistant bacteria are transmitted by food imports is not well known, since the control of imported materials and goods is primarily carried out outside Finnish borders. On the other hand, the European Food Safety Authority considers heat treatments and good working hygiene as ways to reduce the risk of bacterial contamination through food.
Pets too consume antibiotics
Bacteria resistant to antibiotics are also transmitted in direct human-animal contact. The recommendations on antibiotic therapies for pets given by Evira, the Finnish Food Safety Authority, are clear: laboratory samples should be collected to verify bacterial infection diagnoses, and antibiotic treatment must be avoided when not necessary for treating certain infections.
“Antimicrobial resistance in companion and hobby animals has been completely sidelined in the EU's international monitoring programme, even though their situation is alarming,” says Merja Rantala, Doctor of Veterinary Medicine and specialist in infectious animal diseases.
Antimicrobial resistance in companion and hobby animals has been completely sidelined in the EU's international monitoring programme.
A research group led by Rantala is monitoring bacteria resistant to antibiotics in pets. The group is following resistance development over time and conducts research in the field of molecular epidemiology, or the charting of bacterial strains and their genome. Rantala is also a member of a group that gives recommendations on antimicrobial drugs in Finland.
“This helps us find out whether the reason underlying the spread of antimicrobial resistance is bacterial clones, or the offspring of a few bacterial types, or whether that spread is related to gene transfer between bacteria,” says Rantala.
For the first time, Rantala’s group identified carbapenem-resistant bacteria, or the NDM E. coli bacteria that produce carbapenemases, in two Finnish dogs.
“The finding was a surprise, since carbapenem use in animals is prohibited in Finland,” Rantala muses.
Earlier, only two cases of the NDM E. coli strain were known in the world: in the United States and Algeria. According to Rantala, there are some global signs of carbapenemase-producing bacteria becoming increasingly common both in pets and farm animals.
On the other hand, ESBL E. coli bacteria resistant to several antibiotics are prevalent in horses and dogs. E. coli causes, among other diseases, urinary tract infections. As much as 20% of E. coli strains causing urinary tract infections in dogs and cats are resistant to the two antibiotics most commonly used for their treatment. In practice, the drug of choice may be ineffective in one in five patients.
Do farm animals need antibiotics?
The use of antibiotics in farm animals and related antimicrobial resistance is monitored closely by EU member states. The situation is different outside the EU where some countries lack the resources required for monitoring and combating antimicrobial resistance.
In Finland and other Nordic countries, the use of antibiotics in animal treatment is relatively rare when compared to other European countries. This is due to health programmes carried out by production lines, a good state of affairs as regards veterinary diseases and production hygiene, as well as local legislation.
Modern animal farming is possible with moderate antimicrobial medication.
The Animal Health ETT association does concrete work in preventing veterinary diseases. In Finland, the situation has been kept in check, but according to the recently published report by Evira, Animal Diseases in Finland 2016, there is more cause for concern.
Antimicrobial resistance was, however, less prevalent in bacteria extracted from Finnish farm animals than the average in the EU (link only in Finnish). No antibiotics are used in Finnish chicken farming, and little also in other poultry farming.
“Modern animal farming is possible with moderate antimicrobial medication. Finnish industrially farmed chicken, raised completely without antibiotics, are living proof of that,” notes Heikinheimo.
According to Heikinheimo, examples of healthy animals with very little antibiotic use can also be found in Finnish pig and cattle farming. It all comes down to basics – healthy animals, sufficiently roomy livestock units and good farm hygiene. In Finland, the treatment of individual animals is favoured instead of mass medication.
Colistin is an antibiotic drug that is used as the drug of last resort in treating serious bacterial infections in humans. In Europe, colistin is also widely used in medicating farm animals. As regards colistin use, Finland makes a favourable impression, since the drug is not used at all in animal farming. Bacterial resistance to colistin is on the rise – what does that mean?
“Observations of increasing colistin resistance is a new concern. This characteristic has been seen in both human and animal bacteria. If it turns out that transferable colistin resistance spreads quickly, it threatens to undo the viability of the last antibiotic drug effective in treating multiresistant bacteria,” says Rantala.
Indeed, the European Medicines Agency has recommended reducing the use of colistin in European farm animals – with a radical aim of reducing its use by 65% in three or four years.
Salmonella, a common occurrence elsewhere in Europe, has been kept in check in Finnish farm animals, with a prevalence of less than one per cent. In 2015 and 2016, only a few of the salmonella strains extracted from farm animals have been resistant to one or more antimicrobial drug.
“In addition to using antibiotics as little as possible in animal farming, the goal is to keep the need for these drugs low,” says Heikinheimo.
Rantala and Heikinheimo agree that there are situations in animal farming when the use of antibiotics is necessary, even in Finland. Roughly one in five milk cows require antimicrobial treatment for mastitis – in such cases every animal is medicated individually. Infections spread, for example, in calf-rearing units where animals are brought in from several farms. When infectious diseases break out in such conditions, mass medication is often required.
“Even in Finland, bacteria have had the opportunity to develop resistance to the most commonly used antibiotics. Our arsenal of antibiotics effective in the treatment of farm animals is relatively sparse,” notes Rantala.
Even though the antimicrobial resistance of bacteria transmitted between humans and animals, or zoonotic bacteria, has remained on a generally reasonable level, some resistant pathogens have reached Finland as well. These include ESBL bacteria in poultry and MRSA bacteria in pigs. Heikinheimo is currently leading a research project that investigates the potential transmission of ESBL bacteria from hens to chicks through the egg. The same project, funded by the Academy of Finland, is investigating the use of novel treatment methods, such as phage therapy, in MRSA carrier state prevention in pigs.
Antibiotics are environmental waste
Where do all the antibiotic drugs in the world end up after our bodies have used them or when we discard unused drugs? What role does the pharmaceutical industry have to play? Antimicrobial residues found in crops, soil and water were considered a global concern by the UN General Assembly in 2016.
Pharmaceutical companies have outsourced most of their antibiotic production to India in order to avoid the stringent waste regulations in Europe and North America, and to profit from the significantly lower production costs. Large-scale antibiotic emissions into the environment caused by untreated waste water lead to the development of bacteria resistant to antimicrobial drugs. Antibiotics are emitted into waste water all around the globe also in urine and faeces. In waste water and at sewage treatment plants, human bacteria come together and interact with bacteria originating in the environment, which makes for ideal surroundings for gene transfer and the spread of resistance between bacteria. Professor Marko Virta is participating in the StARE project implemented in cooperation between eight European countries, that investigates antimicrobial resistance and antibiotics found in sewage treatment plants.
“Sewage treatment plants have been designed to filter nitrogen, phosphorus and organic carbon, not antibiotics. Finnish plants are, however, extremely good, in addition to which antibiotic residues are not as big of a problem as in some other European countries,” says Virta.
Virta has also studied the impact on human health of manure fertiliser from farm animals medicated with antibiotics. According to Virta, antibiotic levels are low in Finland, and even though antimicrobial resistance genes occur in manure, they disappear rather quickly from fields after fertilisation. In the spring, they can no longer be found.
Is all hope lost? What does science say?
According to some, the most significant benefits of antibiotics have already been reaped, and we are currently engaged in warding off the inevitable.
But there are glimmers of hope too, as Marko Virta thinks: the Netherlands, for example, has followed the Nordic countries in keeping antimicrobial resistance in check. Responsible use of antibiotics, including the reduction of antibiotics use in animals, was begun in the Netherlands a few years ago. Measures taken have swiftly led to change for the better.
Rantala presses for more research and the development of treatment practices. Comparative research on how different practices actually work is needed.
“I trust that when push comes to shove, researchers will discover new ways of preventing and treating infections, such as vaccines and other innovations. As a researcher, I cannot run for the hills to wait for super bacteria to strike. Is less more in the use of antibiotics? Answers are urgently needed,” states Rantala.
Methods for preventing the spread of antimicrobial resistance are also needed. Groundbreaking work on developing hospital and treatment hygiene has been carried out at the Veterinary Teaching Hospital. This includes identifying “at risk” patients and screening for resistant bacteria.
“Nature has provided us with research situations in the form of epidemics caused by resistant bacteria. These cases have given us valuable lessons in the epidemiology of resistant bacteria and how programmes for the prevention of antimicrobial resistance should be structured,” says Rantala.
According to Rantala, the fight against antimicrobial resistance is made harder by lack of resources – for instance, the lack of political will to promote the prevention of antimicrobial resistance by giving more funds for research and the development of novel modes of treatment. Farms must be supported in infection prevention and health care programmes. The price of meat and other animal-based food should reflect the need for little medication. Additionally, more funds should be directed towards veterinary specialist education.
Virta agrees that investment in research has been negligible. National resources should be maintained and ready to be used in the event of epidemics.
“The fight against antimicrobial resistance cannot be fought alone in isolation from the rest of the world. When faced with a serious global threat, international cooperation and contacts are essential,” says Virta.
University Lecturer, DVM Annamari Heikinheimo, Faculty of Veterinary Medicine and the Finnish Food Safety Authority Evira
DVM, specialist in infectious animal diseases Merja Rantala, Faculty of Veterinary Medicine
Professor Marko Virta, Faculty of Biological and Environmental Sciences
Related dissertations in year 2017
Johanna Muurinen: Antibiotic resistance in agroecosystems
Annika Ciragan: Structural studies of potential new-generation antibiotic targets and the use of one of them, TonB as a model protein in protein engineering
Pauliina Kärpänoja: Antimicrobial resistance in the major respiratory tract pathogens - methods and epidemiology
Andreas Helfenstein: Fighting Bugs by Numbers: Bioinformatics Tools for Antimicrobial Drug Discovery