Antibiotic Resistance
THE CAUSES, THREATS AND SOLUTIONS
CONTENTS
Introduction……………………………………………………………………. Page 1
The discovery and development of antibiotics………………………………………..Page 2
The Mechanics ……………………..Page 2
The Development and Acquirement of Resista
Introduction
Over the past five decades, antibiotics have been a necessary weapon in the battle against the diseases and infections that have occurred in our society. Before the beginning of the 20th Century, these infectious diseases accounted for and extremely high morbidity and mortality across the globe. Highlighting this further, the average life expectancy for an infant at birth was 46 years for a male and 48 years for a female. Along with this low life expectancy disease such as smallpox, cholera, pneumonia, tuberculosis and typhus were extremely common and deadly if contracted. Their primary discovery in 1928, with the detection of penicillin by Sir Alexander Fleming, signified the start of a massive change in the public’s healthcare and the start of an era in which antibiotics were available.
This era revolutionised the treatment of both the infectious diseases mentioned earlier and many more, on a global scale. An example of this, which clearly displays the way in which treatment was reformed, is in the US the leading cause for death changed from being communicable diseases (an infectious disease that is transferred from person to person or via a vector) to non communicable diseases ( such as a tumour or a stroke). In addition to this, the average life expectancy at birth increase from 78.8 years and the older population grew from a mere 4% to 13% of the US entire population.
A very important and significant threat, however, to the antibiotic era is antibiotic resistance. Antibiotic resistance is the ability of a species of bacteria and any other species of microorganism to become resistant to the effects of an antibiotic to which they were once sensitive. It can be also referred to as drug resistance. Antibiotic Resistance and the implications it has further a field present us with the growing threat of a worldwide healthcare crisis. This growing resistance already accounts for hundreds of thousands of deaths annually (review on Antimicrobial Resistance 2014), and its predicted growth has caused the World Health Organisation to recognise it as a key threat to us as a human race. This ongoing battle against the resistance to antibiotics has come prevalent due to a wide range of factors, those being of a clinical, community, agricultural, biochemical and physiological mechanisms. Some example of significant resistant pathogens are: Penicillin- Resistant Streptococcus Pneumonia (PRSP), Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE) and Multiple-Drug-Resistant Gram-Negative Bacilli (MDRGNB).
The discovery and development of antibiotics
The first recognised antibiotic was discovered in 1928 by Sir Fleming. Whilst carrying out his research, he noted that it had an inhibiting effect on certain strains of bacteria. Fleming proceeded to culture the Penicillium Notatum and then published some notes on its antibacterial activity. However, it remained virtually unknown until the publication of the report made by E. Chain, H.W Florey and associates in 1940 .The report detailed a the way in which they had been able to isolate penicillin and use it to treat bacterial infections. They had found that the extracts of the fungal species cultured by Fleming had the ability to cure certain fatal infections of both laboratory animals and humans. After this breakthrough, a vast search ensued to acquire other chemical agents with the same antibacterial properties. This investigation produced more than twelve agents which prevent the growth of bacteria, although none had the same, identical properties. Chain and Florey published a academic paper describing the process in which the purification of penicillin can be achieved. With this information now in circulation, the mass production of penicillin G could now be achieved. Their findings were first utilised in the Second World War, but the new drug only came into circulation clinically during 1944. Due to Flemings discovery and the way in which he screened the pathogenic bacteria, less resourced were required than animal testing and so this became used during the mass screenings for the antibiotic producing micro-organisms. Along with this, Alexander Fleming was among the first people to caution humanity and the scientific community about the potential for there to be a resistance to penicillin, if used for a too brief period of treatment. Fleming, Chain and Florey, due to their revolutionising of treatment, were awarded the Nobel Prize for Medicine in 1945.
During the time period in which Fleming was working on his ‘penicillin project’, Gerhard Domagk, a German doctor, made another ground-breaking discovery. He announced that he had discovered a synthetic molecule with antibacterial properties. From this molecule, a series of synthetic antibiotics named sulphonamides (sulfa drugs) were produced. This drug came into clinical use during the 1930s to fight off urinary tract infections and Pneumonia amongst others. These sulfa drugs proved to be not as affective as natural antibiotics but nevertheless are in circulation today. Due to his efforts, Domagk was awarded the Noble Prize in 1939 for the discovery of the synesthetic molecule which lead to the production of a drug he called Prontosil.
The Mechanics and Properties of Antibiotics GLOSSARY
In ideal situations antibiotics are either bacteriostatic, meaning they inhibit bacteria from reproducing without killing them, or bactericidal, meaning they do indeed actively kill them. However, in reality, there is not a clear distinction between the two due to the fact that the categorisation depends on the concentration of the drug and the bacterial species in question. It may seem as though bactericidal may be more beneficial than bacteriostatic. In cases involving meningitis, endocarditis, osteomyelitis and neutropenia, this is true, but there is actually no evidence that bactericidal preforms better in most clinical situations than bacteriostatic.
There are three main classes of mechanisms into which antibiotics fall into. These include Beta-Lactam, Macrolides and (Fluro)Quinolones.
Beta-Lactam
Beta-Lactam antibiotics destroy any bacteria that are encapsulated by a cell wall. They are characterised by their four-membered, nitrogen containing beta-lactam ring at the centre of their structure, which is fundamental to their effectiveness. In order to produce a cell wall, bacteria join molecules together. Beta-Lactam antibiotics target the penicillin-binding proteins- a group of enzymes attached to the cell membrane which are involved in interlinking of a bacterial cell wall. The beta-lactam ring of the antibiotic bonds to the different penicillin-binding proteins, making them useless and unable to involve themselves with cell wall synthesis. Without this support from their cell wall, the osmotic pressure within the cell becomes too great and the cell ruptures. Examples of Beta-Lactams include penicillin and cephalosporin, both of which are used to treat a variety of bacteria infections.
Macrolides
Macrolides work by inhibiting protein synthesis. They bind to the “50s subunit of the ribosomes and inhibit transpeptidation and translocation processes”. Ribosomes are involved in the building of proteins both in human and bacterial cells. Macrolides only block bacterial ribosomes and inhibit them from constructing proteins. This results in an early detachment, meaning that the polypeptide chains are released incomplete. If used in high concentrations, it can be bactericidal, but mostly it is bacteriostatic. An example of a macrolide is Erythromycin, which is most commonly used to treat skin infections and respiratory tract infections.
(Fluro)Quinolones
Quinolones prevent the production of nucleic acid synthesis. They have been observed to bind to the “DNA gyrase-DNA complex” and to disturb a process that leads to the “negative supercoiling of bacterial DNA.”12 This leads to faults in the supercoiling and leave the bacteria without the capacity to multiply and survive. Quinolones include ciprofloxacin and levofloxacin, both of which are used to treat infections such as bronchitis and pneumonia.
In general terms, Antibiotics destroy invading bacteria cells, by affecting the organelles that bacteria cells have and human cells have not got. By doing this, antibiotics leave the human cells virtually untouched and unaffected. An example of an organelle that is lacked by a human cell is a cell wall. Penicillin prevents the production of a cell wall (mentioned earlier), so as there is no cell wall to begin with in a human cell, this does no damage. Another difference is that there is a variation in the structure of a cell membrane and the process of building proteins and copying DNA. Some antibiotics dissolve bacteria cell membranes, others affect the protein building and the DNA copying processes that is unique to bacteria.
The Development and Acquirement of Resistance to Antibiotics
Antibiotics have completely revolutionised the way in which we treat infectious illnesses, and we, as a society, have become reliant on their abilities to tackle the problem of bacterial infections. However, even before penicillin was put into extensive use, some observations were made that suggested to scientists that the bacteria could destroy the antibiotic via enzymatic degradation. This evolutionary process happens in all organisms all over the planet, so it is predictable that bacteria would undergo the same changes. Organisms evolve and adapt to their environment to overcome hurdles that have been presented to them by their current ‘habitat’. Antibiotic resistance, in fact, is a prime example of an organism, in this case bacteria, simply adapting to overcome something that is hindering its survival in a certain environment.
Antibiotic resistance poses a significant threat to the overall success of the treatment of infectious disease. This is due to the fact that resistant organisms are very hard to treat and get under control. They either require a higher and more potent dosage, or simply a different drug. This may seem like an easy alternative, but there becomes a point where there are no alternative drugs left to try. In addition to this, the higher dosages and different drugs are more expensive and could be more toxic to the patient. According to the Centers for Diseases Control and Prevention, more than 2 million people are infected with an antibiotic resistance strain of bacteria, and on top of this more than 23,000 people die every year as a result of these infections.
Resistant strains of infectious diseases come about by a number of factors, of which are overuse, inappropriate prescribing, extensive agricultural use, regulatory barriers, and the production of no new antibiotics. Other factors are bad quality medicines, insufficient hospital policies when it comes to infection control, poverty, lack of resources to prevent antibiotics and the further spreading of resistant organisms via overpopulation and unhygienic living conditions.
Resistance can also occur from natural resistance in certain strains of bacteria, which has been present before antibiotics were discovered, genetics mutations in microbes, ‘selection pressure from antibiotic use that provides a competitive advantage for mutated strands’ and finally a species of bacteria acquiring the resistance from another.15 Natural antibiotic resistance may have come before the initial discovery of antibiotics, and may prove difficult to control, but the majority of antibiotic resistances happen in developing countries and have become prevalent due to social, economic and behavioural factors.
Combating ‘Manmade’ Resistance
Misuse by Physicians
“Antibiotic use provides selective pressure favouring resistant bacterial strains” and if used inappropriately, the risk is increased for the spread of antibiotic-resistant bacteria, and in turn they are also placed at a competitive advantage. The relationship between the spread of resistance and the way in which antibiotics are used is far more complex than it seems. The usage found in clinical situations such as hospitals and practices are not able to explain the high density of resistant organisms. Unwarranted and overindulgent use is, however, partially to be held accountable for the rising rates of resistance, most importantly in hospitals across the globe .In addition, the needless prescription of antibiotics seen in nations has also been recorded. This situation is very common when it comes to developing countries and infectious disease like acute infantile diarrhoea and viral respiratory infections. However, misuse of antibiotics is said to be more common amongst the private healthcare sector, with more private health clinics charging higher fees and more private patients demanding more antibiotics. Furthermore, more antibiotics and drugs in general are available on the private side of healthcare as there is more money to fund them.
Misuse by Unskilled Practitioners
In most underdeveloped countries, well educated and practised healthcare professionals are very hard to come by, and the few that are available cannot solitary treat the whole of the population inhabiting the country. The situation is much worse, additionally, when it comes to rural areas. Most healthcare workers have basic training in dealing with minor injuries that have no threat on the patient’s life. The quality of training, qualifications and the training itself will undoubtedly vary from country to country. Lack of all these things leads to lack of knowledge when it comes to the detrimental affects of over prescribing antibiotics. An example highlighting this is pharmaceutical technicians in Thailand prescribed an antibiotic called ‘rifampicin’ for conditions like urethritis and tetracycline. Furthermore, underqualified or unqualified drug dispensers offer alternates to the drugs that they are out of stock in or they refill prescriptions without consulting the person who prescribed it in the first place. In India, traditional healers are commonly known to give out antibiotics, without any qualifications that have educated them about the drug.
In terms of suggested strategies for tackling the inappropriate use of the drugs, several have been suggested. Monitoring systems and antibiotic treatment protocols have been seen to reduce the antibiotic prescription rate and in addition the implementation of a ‘national essential drug list’ can limit the antibiotics available. Unfortunately, however, the use of these strategies does not allow for the maximum and optimum antibiotic use by practitioners in countries that are still developing. This is due to the fact that there is an irregular and unstable antibiotic supply, the availability of the drugs required is varied and comes from unverified sources and finally there are financial shortages that limit the choices that can be made about antibiotics. Another solution is to simply continue to educate medical practitioners. This suggestion should help change the attitude of clinicians. Studies preformed in Cuba and Pakistan recommended that education was, in fact, the single most important tool for combating the issue. Though this strategy has not been effectively put in place by many countries that are still under developed. It is in these countries that both the government and the healthcare professionals can not simply afford the time and have not got the money needed for the continuation of educating the medical professionals. As well as this, medical healthcare workers have little to no access to machines and data that provide them with a more detailed understanding of what is wrong with the patient. This is what is known as objective healthcare information.
Misuse by the Public
In many developing countries, antibiotics can be purchases without a prescription, and the practice does not even have to be legal. Antibiotics can also be readily available from hospitals, pharmacies, drugstores, roadside stalls and vendors, all that is needed to acquire these drugs is to demand them and hand over a sum money. An example of this is in rural Bangladesh, 95% of drugs consumed in 1 month came from local pharmacies, and only 8% were actually prescribed. Moreover due to the limited quantities of antibiotics available, people are encouraged to purchase from illegal and unofficial vendors as the drug is simply not available in the hospital run by the government. The distributors commonly have little to no experience and qualifications that allow them to understand the dosages required, or if the patient even requires the drug to be prescribed. Vendors, found in markets and along public roads, actually try and convince people to buy the drug that they are selling, even if the person is not remotely ill.
Moreover, patients may, to save themselves time, may skip the step of getting a diagnosis by a doctor and go straight to a source which they know stocks the drug. In most cases, unofficial stockists are easier to access and are more readily available than official sources. An example of this is in Nepal, drug outlets are four times more abundant than government hospitals. On top of this, these alternative sources of drugs offer different course lengths of treatment, for example smaller samples of the drug are available to be purchased by the patient. Hospitals require longer courses of the antibiotic, as by purchasing this shorter course, the chance of the infectious disease becoming immune becomes much more likely.