June 19, 2015

Antimicrobial Resistance — A Major Global Health Risk

AFP/Scanpix
South Korean soldiers wear facemasks as they march after a ceremony marking the 60th anniversary of Korean Memorial Day at the National Cemetery in Seoul on June 6, 2015.
South Korean soldiers wear facemasks as they march after a ceremony marking the 60th anniversary of Korean Memorial Day at the National Cemetery in Seoul on June 6, 2015.

Infectious diseases are one of the leading causes of death in the world. Even though the situation is more dire in developing countries, serious problems occur even in the developed world, as globalisation and open borders allow infectious agents to travel with people, animals, food and goods and to move freely from one continent or country to another with no regard for state boundaries or distance. Today’s high-tech healthcare should be able to save the life of every person suffering from an infectious disease but, in reality, the infection process is not only influenced by a human organism and its biological features, but also by epidemiological, social and economic factors that can make it uncontainable, which is why infectious diseases pose a great threat to every country and society.

One of the main reasons why the infection process becomes uncontrollable and makes the treatment complicated, if not impossible, is the pathogens’ increasing resistance to pharmaceuticals. For the patient, this means prolonged ailments, time-consuming and more expensive treatment, extended absence from work and a decrease in income; it also imposes a great additional burden on healthcare institutions and the system as a whole. For instance, antimicrobial resistance causes 4,000,000 cases of disease and 25,000 deaths in European Union countries, which in turn creates additional healthcare costs and €1.5 billion euros worth of lost productivity; and more than 2,000,000 cases, 23,000 deaths and $20 billion in additional costs in the United States.

What is Antimicrobial Resistance?

Antimicrobial resistance is the insusceptibility of pathogenic microorganisms (bacteria, viruses, fungi, parasites) to the effect of antimicrobial drugs. A disease-causing microorganism is resistant if it has developed insensitivity to one or several antimicrobial drugs. Resistant pathogens stay alive in a human organism despite the patient’s use of doctor-prescribed medication.
Antimicrobial drugs are medical substances or compounds that inhibit the reproduction of pathogens or destroy them.
Antimicrobial medications are classified as: (a) antibacterial—most of these are antibiotics; (b) antiviral; (c) antifungal; and (d) antiprotozoal.
Antimicrobial resistance is far from being a modern phenomenon. Its development in living nature was foreseen by the creator of the theory of evolution, Charles Darwin—in order to survive, living organisms must adapt and protect themselves against harmful factors by developing resistance. Pathogenic microbes have indeed adapted, by developing resistance against other malicious microorganisms and drugs that kill them, namely antibiotics. Penicillin, a widely known antibiotic, is actually a compound produced by a fungus in order to protect itself from the harmful bacteria that share its living environment. Due to a factor that has been influencing the process for decades—imprudent and excessive use of antibiotics—evolution continues, as confirmed by the increasing development of antimicrobial resistance in pathogens on one hand and the emergence of new highly infectious pathogens on the other.
Resistance develops in pathogens wherever antimicrobial drugs, especially antibiotics, are used—in human, animal and bird organisms, and also in external environments where the drugs or their degradation products are expelled. Consequently, the issue of antimicrobial resistance does not belong only to the field of human medicine, but is equally relevant in veterinary medicine, animal husbandry and environmental protection.

Dawn of the Age of Antibiotics and Antibiotic Resistance

While many pathogens of dangerous diseases were discovered in the second half of the 19th century, it took another 50 years to bring about the age of their powerful adversaries—antibiotics. The age of antibiotics was heralded by Alexander Fleming, who discovered penicillin in 1928. During the Second World War, this “miracle cure” saved the lives of hundreds of thousands of Allied soldiers. New antibiotics such as tetracycline, erythromycin, methicillin and gentamicin were added to the list, but it was penicillin that ushered in the rather sinister age of antimicrobial resistance: the first case of penicillin resistance was identified in 1940 and involved the microbe Staphylococcus aureus, or golden staph—a generally harmless microbe colonising human skin, which can become highly pathogenic and cause malignant pneumonia, toxic shock syndrome and other major diseases.
This was only the beginning, as microbes—pressured by new antibiotics—made a natural choice in their own favour by using the mutation process to become antibiotic-resistant mutant microbes, which defied one or two antibiotics at first and often eventually became completely uncontrollable by antibiotics.
The line of causality is quite clear: the antibiotic tetracycline came into medical use in 1950 and its resistance in Shigella was detected in 1959; methicillin was introduced in 1960 and resistant Staphylococci were discovered in 1962; gentamicin came into use in 1967 and its resistance in Enterococci was detected in 1979; vancomycin was introduced in 1972 and Enterococci developed resistance to it in 1988; levofloxacin came along in 1996 and its resistance in Pneumococci was discovered in the same year. One recent example of fast resistance development comes from 2010, when ceftaroline came into medical use and had caused Staphylococci to become insensitive to it by the following year. One example of long-term development of drug resistance involves Pneumococci—after penicillin was introduced in 1943, pneumococcal infections could be productively treated until 1965, when Pneumococci finally developed penicillin resistance.
For the patient suffering from an infectious disease, drug resistance meant that the outlook was bleak. There was a time when even doctors did not know its cause and blamed it on “bad and ineffective drugs”.
Golden staph has been considered the epitome of drug resistance for years—having emerged as the winner after running the gauntlet of many antibiotics, it has become insusceptible to previously highly effective antibiotics like penicillin, linezolid, vancomycin and ceftaroline. Golden staph is famous for its resistance to methicillin, as a result of which it is known as Methicillin-resistant Staphylococcus aureus, or MRSA. Due to drug resistance, this almost uncontainable microbe has assumed a life of its own by spreading quickly at any given opportunity and causing irreparable damage to those infected.

Antibiotic Resistance is Highly Dangerous to an Infected Person

Antibiotic resistance has been called one of the greatest threats to modern medicine, as it remains without a definite cure. The number of different pathogenic bacteria with decreased or lost sensitivity to antibiotics has risen in the past few decades. A pathogenic bacterium continues its unrestricted destruction in an infected patient’s organism because it has developed partial or full resistance to the antibiotics used for treatment.
These antibiotic-resistant bacteria are dangerous because they can spread in hospitals and social welfare institutions as well as families, and transfer to people who are in contact with an infected person like other patients, family members, visitors or fellow workers and students. The bacterium may therefore not develop antibiotic resistance in the organism of an infected person, but a person may become infected through contact with other patients. Antibiotic-resistant bacteria that are transferred via droplet-aerosols or direct or everyday contact are most easily spread this way.
It is wrong to believe that a patient becomes resistant to a certain antibiotic during treatment. What becomes antibiotic resistant is the pathogenic bacterium that is damaging the patient’s organism.
If a pathogenic bacterium has developed resistance to many antibiotics, it becomes a multidrug-resistant (or MDR) bacterium, which makes treatment complicated and often futile. Such cases may result in serious complications or even death.

Why do Bacteria Develop Resistance to Antibiotics?

Widespread, imprudent and unreasonable use of antibiotics in both human and veterinary medicine facilitates the development of drug resistance in pathogenic bacteria. Each time a patient uses the antibiotic prescribed to them, the susceptible bacteria are killed, while stronger bacteria survive and continue multiplying, because they retain their ability to neutralise the effect of antibiotics.
The main factor that promotes the development of drug-resistant bacteria is the repeated, improper, indiscriminate and irrational use of antibiotics. Antibiotics must be used to treat a laboratory-confirmed bacterial infection, and the fact that they are not effective in the case of viral infections should always be kept in mind.
The main principle is to detect the pathogen that causes the infection, using laboratory tests to determine whether it is a bacterium, virus, pathogenic fungus or parasite; only then is the correct drug to use decided upon. In cases where the cause is unclear, using antibiotics is a stab in the dark, which is conducive to the significant development of long-known antibiotic resistance. The development of antibiotic resistance in unconfirmed cases is also furthered by the prescription of antibiotics with a view to preventing complications of bacterial origin or as a prophylactic—an unknown cause means that we do not know what to prevent, either.

How do Bacteria Develop a Resistance to Antibiotics?

Antibiotic resistance develops when antibiotics affect the life functions of bacteria so that their susceptibility to antibiotics is weakened or eliminated. As a result, bacteria will survive and continue to reproduce.
Antibiotic resistance in bacteria can develop in several ways: (a) a bacterium is capable of neutralising the active substance in antibiotics before it starts damaging it; (b) bacteria can exchange genes that encode resistance with one another—susceptible bacteria receive resistance-conferring genes from bacteria that are insensitive to antibiotics; (c) bacteria may alter the antibiotic’s target site so that it does not affect its function; (d) some bacteria are able to quickly remove the antibiotic from the cell or to pump it out; (e) by mutation; and (f) by acquiring antibiotic-resistant plasmids (DNA fragments that encode resistance) from resistant bacteria.

Sources of Antimicrobial-resistant Pathogens

The sources of antimicrobial-resistant pathogens are: people receiving inpatient or outpatient care; healthcare professionals—chronic carriers of microorganisms; visitors to patients of healthcare institutions; people who have received medical treatment in countries other than their own; travellers who have contracted a disease abroad; and farm animals, birds and pets.

Spread of Resistant Pathogens

Antimicrobial-resistant—specifically antibiotic-resistant—pathogens are transferred in the same way as other disease-causing agents: via droplets and aerosols, everyday contact, blood, sexual transmission, vectors, and animals and birds.
The spread of antimicrobial-resistant pathogens is furthered by the imprudent use of antimicrobial drugs (mainly antibiotics), the transfer of resistant genes within and between pathogen species, and the international spread of resistant pathogens. (For example, these could be brought into Estonia by Estonian residents who have received medical treatment abroad, foreigners being treated in Estonia, and travellers who have contracted a disease abroad.)
Refugees from developing countries may bringantimicrobial-resistant microorganisms to receiving European countries. The state of these people’s health is often unknown and an antimicrobial-resistant pathogen unfamiliar to Europe reveals itself only after they become ill. How long and to what extent refugee microbe carriers have spread resistant pathogens in the local community will remain unknown for now. The consequences of this will become clear only when the pathogens causing diseases in locals stop reacting to treatment. Moreover, determining the origin of foreign pathogens is costly, as their genotype has to be identified. At the same time, at least 30% of people in each population are carriers of some kind of asymptomatic potential disease-causing agents, at least 2% of whom carry antibiotic-resistant pathogens.
Antimicrobial-resistant pathogens may also spread from a hospital or other healthcare institution to the local population via a former patient or a healthcare professional or visitor infected at such an institution.
It is very dangerous to transfer patients with antimicrobial resistance to welfare institutions, retirement homes, medical institutions for the chronically ill, children’s institutions, other closed collectives and families that include immuno-compromised members.

Resistant Bacteria Spread from Animals and Birds to Humans

Antibiotic-resistant bacteria are transferred from animals and birds to humans through food of animal origin and via direct contact with animals and birds or their excrement and excretions. For instance, Campylobacteria colonise the digestive tract of chickens without causing much damage, and humans can contract them by eating chicken meat that has not been properly heat-treated.
In several countries where broiler chickens have been fed antibiotics, Campylobacteria showing drug resistance to these antibiotics have been discovered in humans. Since antibiotic-resistant bacteria occur in the organisms of farm animals and birds in the same way as they do in people who take antibiotics and can easily transfer to people, the treatment of patients with bacterial infection places great importance on determining the origin of the drug-resistant bacteria, which requires cooperation between doctors of human and veterinary medicine.

Antibiotics are Also Given to Farm Animals and Pets

Antibiotics are used in farm animals, birds and pets for three reasons: to treat infectious diseases, to avoid infections during a certain growth period, and to promote growth (antibiotics are banned from use for growth promotion within the European Union). In the first two cases, antibiotics are administered to animals or birds in large quantities during a short period of treatment, and in the third case, in small quantities over a longer period of time. Since in each case antibiotics are administered to a large number of animals or birds, the chances of the emergence of antibiotic-resistant bacteria are high. Antibiotic-resistant bacteria developed in the organisms of animals and birds could transfer to the human population through people who keep and take care of them.

Antibiotic-resistant Bacteria are Also Transferred Through Food

Many pathogenic bacteria colonise the digestive tract of humans, animals and birds. For instance, a large number of farm animals, especially those raised for human consumption, carry Salmonella, Campylobacteria and pathogenic Escherichia coli, all of which are dangerous to humans. On the other hand, humans also carry pathogenic bacteria such as Shigella and Salmonella. These bacteria may come into contact with food via food producers and animal keepers. Since these and other pathogens can be antibiotic-resistant, these bacteria may transfer to food—and from there to the human organism, infecting people.

Soaps, Cleaning Agents and Probiotics Do Not Influence the Development of Drug Resistance

Hygiene requirements play a big role in avoiding the spread of infectious diseases among the population—washing hands and cleaning everyday items and work surfaces is of the utmost importance. There are no data to support claims that antibacterial soaps and other washing and cleaning substances influence the development of drug resistance in pathogens.
Probiotics are microorganisms that have a positive effect on an organism’s function and a person’s health, which can also in certain conditions inhibit the proliferation of pathogens in an organism. There is no information on whether they influence drug resistance.

Antibiotic-resistant Bacteria Develop Mainly in Hospitals and Welfare Institutions

In Europe and other parts of the world, drug-resistant microbes develop and spread mainly in hospitals, with welfare institutions, outpatient treatment centres and care facilities for the chronically ill or the elderly not far behind. Approximately 70% of microbes that cause hospital infections today are resistant to at least one antimicrobial drug. Why do new drug-resistant pathogens develop in hospitals and welfare institutions? There are several interlinked reasons, and this is why infections related to healthcare services are easier to prevent than to control later on.

  1. The immune system of people who end up in hospitals has been weakened by a prolonged or sudden illness. In this type of patient, the sedentary so-called normal flora bacteria (present in every human) in their organisms can become pathogenic, which brings about the development of a new infectious process unconnected to the main illness. This risk group also includes people with age-associated immunodeficiency like small children and the elderly.
  2. Hospitals conduct many large- and small-scale surgical and other procedures that involve penetrating the skin and mucous membrane, and indwelling catheters are inserted in organs and cannulas in blood vessels. Even the slightest deviation from hygiene or safety requirements during surgery or an invasive procedure creates an opportunity for pathogens to enter the patient’s organism. This is one reason why hospital infections mostly occur in surgical and intensive care departments.
  3. A person admitted to hospital carries pathogens that colonise their living environment.
  4. Healthcare professionals bring pathogens from their living environments to hospitals or welfare institutions, or may treat patients while being ill themselves.
  5. Visitors can bring pathogens to hospitals or welfare institutions not only during epidemic periods of influenza, for example, but also on a daily basis.
  6. The spread of antimicrobial resistance has no restrictions—in cases of intensive international communication, drug-resistant microbes enter countries with tourists who need treatment abroad, natives who have received medical care abroad and travellers or patients who go abroad specifically to be treated there, especially those who travel to receive surgery. Countries thus face drug-resistant non-native pathogens. Travellers can also bring drug-resistant viruses to the country via the same mechanism. For instance, during the 2007–8 influenza season in several EU member states, including Estonia, resistance to the medication Oseltamivir was detected in those A/H1N1/-influenza viruses that had caused illness in patients who were not treated with Oseltamivir.
  7. It has been discovered that in the working environment of large hospitals, where a large number of potentially disease-causing or indeed pathogenic microorganisms are circulating between patients, personnel and equipment, bacteria can exchange genes that encode drug resistance, as a result of which antibiotic-resistant bacteria may begin to inhabit the organism of a patient who has not previously been treated with this antibiotic.
  8. It has been noted that even the doctors who prescribe antimicrobial treatment to patients are not without blame: antibiotic treatment is prescribed for cases in which the disease-causing microorganism has not been laboratory-confirmed. This means that it is not known whether it is a bacterial, viral, parasitic or other infection and therefore (a) prescribing antibiotics for acute respiratory viral infections when there is no risk of bacterial complications is very common; and (b) when empirically prescribed antibiotic treatment turns out to be necessary, it is not known whether or not the patient has antibiotic-resistant microbes and, as a result, the prescribed treatment may not show any positive results. The main problem therefore lies in the excessive and incorrect use of antibiotics.

Doctors do not provide patients with sufficient information on the rules for taking antibiotics and the need to complete the treatment (many patients are known to quit antimicrobial treatment after the first signs of improvement), or the risks and negative results of incorrect use of antibiotics and drug resistance.

Antimicrobial Resistance is Also a Problem in Agriculture, Veterinary Medicine and Environmental Protection

Most antibiotics used in veterinary medicine are similar to or the same as those used in treating humans. Pathogens causing infectious diseases in animals can also develop drug resistance. Drug-resistant pathogens found in farm animals and pets can transfer to humans.
In addition, antibiotics have been used in agriculture as feed additives to prevent animal and plant diseases and for growth promotion. Antibiotic-resistant genes are also removed from genetically modified plant cells. Most EU countries have now stopped using antibiotics for these purposes, because the underlying threat to human health has been clearly confirmed.
After circulating in the organisms of infected people, and bacteria-carrying humans, animals and birds, drug-resistant pathogens are finally expelled via excrement, excretions and wastewater to the external environment—soil, bodies of water, and ground and drinking water. From there, entering a human organism is only a matter of an opportune moment or the laws of nature. The occurrence and proliferation of antibiotic-resistant pathogens in the external environment are generally acknowledged risks to human health.

Antibiotic Resistance in Human Medicine

Antibiotic resistance in human medicine also describes the situation in veterinary medicine and its spread in the external environment, because the main purpose of society is to protect human health. Estonia does not have a monitoring system for antibiotic resistance that includes these three areas.
In the EU, the European Centre for Disease Prevention and Control has organised a monitoring programme in the field of human medicine that involves observing antibiotic resistance on the basis of determining resistance to major antibiotics in seven indicator pathogens causing bacterial diseases. For instance, in Estonia, the incidence in 2013 and 2014 of resistance to aminoglycocides (a group that includes, among others, the antibiotics gentamycin, amikacin, streptomycin and kanamycin) in indicator bacteria detected in patients was as follows:

  • Escherichia coli 7.6% and 4.7% (the EU average for 2013 was 9.9%, with the highest rate in Bulgaria at 32.1%)
  • Klebsiella pneumoniae 9.9% and 17.9% (2013 EU average 24.5%; highest in Slovakia, 64.0%)
  • Pseudomonas aeruginosa 9.5% and 4.8% (2013 EU average 15.9%; highest in Romania, 51.2%)
  • Enterococcus faecalis 20.0% and 38.1% (2013 EU average 30.9%; highest in Latvia, 61.1%).

The penicillin resistance of the main causative agent of pneumonia Streptococcus pneumoniae was 1.3% in 2013, with no resistance detected in 2014 (the highest figures for 2013 were Poland with 32.2% and Cyprus with 40.0%)
The incidence of dangerous methicillin-resistant Staphylococcus aureus was 3.5% and 3.1% respectively (2013 EU average 18%; highest 64.5% in Romania and 40.3% in Greece).
The general incidence of antimicrobial resistance in Estonia is therefore relatively low. As a whole, pathogens’ antibiotic resistance is greater in southern and eastern European countries and lower in northern and western European countries.
According to the 2013 data, Estonia had problems with 46.4% resistance of Escherichia coli to aminopenicillins; 26.7% resistance of Klebsiella pneumoniae to fluorokinolones and 23.3% resistance to third-generation cephalosporins; and 25.0% resistance of Pseudomonas aeruginosa to fluorokinolones. The downside of these data is the fact that the number of test samples was relatively small and they only describe the situation in hospitals (forms of resistance can differ even within hospital boundaries) and there is no information about the spreading frequency of antimicrobial resistance in first-level medical care and the population.
The consumption of antibiotics within the population is also significant. According to 2012 data, the rate in Estonia was 11.6 prescribed daily doses per 1,000 residents per day, which is a reasonable figure. The EU average was 21.5 prescribed daily doses per 1,000 residents per day, while in Greece the number was as high as 31.9 prescribed daily doses.

Controlling the Spread of Antimicrobial Resistance is a Problem Shared By Europe and the World

The monitoring and prevention of antimicrobial resistance in the EU began in 1999. In January that year, the European Commission formed the European Antimicrobial Resistance Surveillance Network for epidemiological monitoring and control of antimicrobial resistance, one of the most important priorities of which was to coordinate methods of antimicrobial resistance prevention in its member states. The European Council adopted the resolution “A Strategy against the Microbial Threat” in June 1999, and six months later, the “Council Conclusions on Future Actions in the Framework of the Strategy against Antimicrobial Resistance”. These documents served as a basis for the 2001 European Council Recommendation on the prudent use of antimicrobial agents in human medicine. This recommendation serves its purpose despite the spread of antimicrobial resistance having become considerably more serious in recent years and changes in the prevention strategy.
In November 2011, the European Commission issued a thorough action plan against the increasing threats from antimicrobial resistance, which includes 12 actions to combat the spread of antimicrobial resistance in the EU. In February 2015, the European Centre for Disease Prevention and Control and the European Food Safety Authority published a joint report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2013. The European Commission has cooperated with the European Federation of Pharmaceutical Industries and Associations in the field of developing and producing new antibiotics.
EU members’ main principles on the prevention and treatment of antimicrobial resistance are:

  • to organise multisectoral monitoring, data collection and analysis with regard to antimicrobial-resistant pathogens and the use of antimicrobial drugs
  • all antimicrobial drugs must be dispensed on the basis of a prescription
  • to compile and implement a strategy for the prudent use of antimicrobial drugs and to control the spread of antimicrobial resistance
  • to devise national instructions and principles for the prudent use of antimicrobial drugs and a system for assessing their implementation
  • to improve preventive measures against the spread of communicable diseases by reducing the use of antimicrobial drugs, improving immunisation plans, promoting hygiene, preventing and stopping the spread of hospital and communal infections and following the infection control standards set for medical and welfare institutions
  • to inform the general public and patients and raise their awareness of questions of antimicrobial resistance
  • to intensify antimicrobial resistance training for healthcare professionals
  • to promote research on antimicrobial resistance and develop reliable and highly sensitive rapid diagnostic tests for the early detection of infectious diseases and to start justified antibiotic treatment
  • to found and name a national intersectoral institution to exchange relevant information and coordinate joint activities, as well as to implement the national strategy for controlling the spread of antimicrobial resistance.

Most EU member states have used these principles to devise their own national strategy and action plans for the prevention and control of the spread of antimicrobial resistance, and have implemented them.
Since antimicrobial resistance is a global health risk, the World Health Organization coordinates the compilation and implementation of measures dealing with its prevention and control. This is handled at the highest level by the World Health Assembly, the 68th of which (in May 2015) issued two important documents: the fulfilment of the resolution “Containment of Antimicrobial Resistance” adopted at the previous Assembly and a new “Global Action Plan to Tackle Antimicrobial Resistance”. Unfortunately, good action plans tend not to be implemented, mainly due to lack of political will and support.

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