The modern age of antibiotics began with Sir Alexander Fleming’s discovery of penicillin in 1928. Since then, antibiotics have revolutionized modern medicine and saved millions of lives. Antibiotics were first given in the 1940s to treat serious infections. Penicillin was successful in controlling bacterial infections among soldiers in World War II. However, penicillin resistance soon became a major clinical problem, so by the 1950s many of the advances of the previous decade were eclipsed. In response, new beta-lactam antibiotics were discovered, developed and established confidence in their use. However, the first case of methicillin-resistant Staphylococcus aureus (MRSA) was soon detected in the UK in 1962 and the USA in 1968.
In the end, resistance was seen in almost all antibiotics developed in bacteria. Vancomycin was used in clinical practice in 1972 for the treatment of methicillin resistance in S. aureus and coagulase-negative staphylococci. The development of resistance to vancomycin was so difficult to induce that it was believed to be unlikely to occur in a clinical setting. Unfortunately, cases of vancomycin resistance in coagulase-negative staphylococci were reported in 1979 and 1983. From the late 1960s to the early 1980s, the pharmaceutical industry developed many new antibiotics to solve the problem of resistance, but after that, studies slowed down and fewer new drugs were introduced. As a result, in 2015, years after the first patients were treated with antibiotics, bacterial infections again became a threat.
Causes of antibiotic resistance: Overuse
In early 1945, Sir Alexander Fleming had given the first alarm about antibiotic overuse, saying that “the public will demand [antibiotics]… then the era of abuse will begin…”.
The overuse of antibiotics is clearly driving the evolution of resistance. Epidemiological studies have shown a direct relationship between antibiotic consumption and the emergence and spread of resistant bacterial strains.
In bacteria, genes can be inherited from their ancestors or derived from different bacteria with mobile genetic elements such as plasmids. This horizontal gene transfer (HGT) allows the transfer of antibiotic resistance between different bacterial species. Resistance can also occur spontaneously through mutation. Antibiotics eliminate drug-resistant competitors and reveal resistant bacteria as a result of natural selection.
Despite warnings about overuse, antibiotics are overprescribed around the world. In many countries, the use of antibiotics is unregulated and available without a prescription. This lack of regulation ensures easy access to abundant and inexpensive antibiotics and leads to their overuse. The ability to purchase such products online has made antibiotics accessible in countries where antibiotic use is regulated.
Causes of antibiotic resistance: Misuse
Incorrectly prescribed antibiotics contribute to the emergence of resistant bacteria. Studies have shown that the course of treatment, the choice of antibiotic, or the duration of antibiotic therapy are incorrect in 30% to 50% of cases. In addition, 30% to 60% of antibiotics prescribed in intensive care units were found to be unnecessary, inappropriate, or below the required level. Misused antibiotics provide a controversial treatment and expose patients to potential complications of antibiotic therapy. Antibiotic concentrations below the lethal and therapeutic levels can promote genetic changes such as gene expression, horizontal gene transfer, and mutation, enabling bacteria to develop antibiotic resistance. While antibiotic-induced changes in gene expression may increase the pathogenicity, increased mutation and horizontal gene transfer increase antibiotic resistance and spread. Low levels of antibiotics have been shown to contribute to subspecies diversity in organisms such as Pseudomonas aeruginosa.
In a study conducted in England, it was determined that at least 20% of antibiotic prescriptions in primary care are inappropriate. In response to this threat, the UK government has aimed to reduce inappropriate antibiotic prescribing by 50% by 2020.
How does antibiotic resistance spread? Agriculture impact
In both developed and developing countries, antibiotics are widely used as growth supplements in livestock. An estimated 80% of antibiotics sold in the US are used in animals, specifically to promote growth and prevent infection. It is said that with the use of antimicrobial substances in animal husbandry, the general health of animals improves, more yield and higher quality products are obtained.
The transmission of resistant bacteria to humans by livestock was first recorded more than 35 years ago. A high rate of antibiotic resistance was found in the intestinal flora of both livestock and farmers. Recently, it has been shown that resistant bacteria in farm animals reach consumers through meat products using molecular detection methods. This happens as follows:
1) the use of antibiotics in livestock animals kills or suppresses non-resistant bacteria, allowing antibiotic-resistant bacteria to grow;
2) resistant bacteria are transmitted to humans through the food supply;
3) these bacteria can cause infections in humans that can have adverse health effects.
Agricultural use of antibiotics also affects the environmental microbiome. Up to 90% of antibiotics given to animals are excreted in urine and faeces, then dispersed by manure, ground and surface waters.
Antibacterial products sold for hygienic or cleaning purposes can also contribute to this problem. Because they can limit the development of immunity to environmental antigens in both children and adults. As a result, the versatility of the immune system may be compromised. Disease and death rates are likely to increase due to infections that would not normally cause disease.
Why aren’t new antibiotics discovered?
The development of new antibiotics by the pharmaceutical industry as an effective strategy to combat resistant bacteria in the past has almost stalled due to economic and regulatory barriers. Of the 18 largest pharmaceutical companies, 15 have left the field of antibiotics. Antibiotic research in academia slowed down as a result of funding cuts due to the economic crisis.
Antibiotic development is no longer considered an economically wise investment for the pharmaceutical industry. Antibiotics are used for relatively short periods of time. Therefore, antibiotics; are not as profitable as drugs that treat chronic conditions such as diabetes, psychiatric disorders, asthma or gastroesophageal reflux. An analysis by the Office of Health Economics in London showed that the net worth of a new antibiotic is about $50 million, while the approximate value of a drug used to treat a neuromuscular disease is $1 billion. Because drugs for chronic conditions are more profitable, pharmaceutical companies prefer to invest in them.
Microbiologists and infectious disease experts have recommended restrictions on the use of antibiotics. After a new antibiotic is marketed, doctors instead of prescribing it immediately, reserve the new agent for the worst cases only for fear of increasing drug resistance and continue to prescribe older agents with comparable efficacy. For this reason, new antibiotics are often considered “last-line” drugs to combat serious illnesses. This practice leads to reduced use of new antibiotics and reduced return on investment.
On the other hand, when new antibiotics are used, the emergence of resistance is almost inevitable. Because bacterial evolution is uncertain, the timeline for resistance development is unpredictable. For this reason, a manufacturer that spends a large amount of money on antibiotic development is concerned that its earnings will be cut prematurely when resistance develops to the antibiotic it produces.
Antibiotic crisis at the door
The World Economic Forum (WEF), in its report on global risks, has arguably cited antibiotic-resistant bacteria as the biggest risk.
We live in a constantly mutating bacterial world. After billions of years of evolution, microbes have developed antibiotics against every biochemical target that can be attacked — and therefore, of necessity, they have also developed resistance mechanisms to protect all these biochemical targets.
Widespread antibiotic resistance has been discovered among bacteria discovered in underground caverns that have been geologically isolated from the planet’s surface for 4 million years. Remarkably, resistance was found in these bacteria even to synthetic antibiotics that were not available in the world until the 20th century.
These results underscore a critical fact: there is already antibiotic resistance in nature to drugs we haven’t invented yet. So what are the main implications of these findings?
First, the use of antibiotics results in the natural selection of pre-existing populations of resistant bacteria.
Second, it is not just “inappropriate” antibiotic use that causes resistant bacteria to be selected. Whether properly prescribed or not, the rate at which resistance spreads is dependent upon bacterial exposure to antibiotics.
Thus, even if all inappropriate antibiotic use is eliminated, antibiotic-resistant infections will still occur (albeit at a lower frequency).
As a conclusion
Antibiotics not only saved the lives of patients, but also played an important role in making great advances in medicine and surgery. It has successfully prevented infections that may occur in patients who have undergone chemotherapy treatment, have undergone complex operations such as heart surgery, and have chronic diseases such as diabetes and kidney disease.
Antibiotics have been very effective in the treatment of bacterial infections, helping to prolong life expectancy. In 1920, the average life expectancy of people in the USA was 56.4 years, while the average life expectancy in the USA today is about 80 years. Antibiotics have similar beneficial effects worldwide. There are developing countries where sanitation and hygiene are still weak. In these countries, antibiotics reduce morbidity and mortality from foodborne and other poverty-related infections.
However, we are on the edge of an abyss in the fight against infection with antibiotics. Today, approximately 700,000 deaths occur annually due to antibiotic resistance. It has also made treating numerous infections more difficult, including pneumonia, tuberculosis, and gonorrhea. If we don’t figure out how to stop bacteria from developing resistance to antibiotics, it’s estimated that preventable diseases could cause 10 million deaths a year by 2050.
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Ventola, C. Lee. “The antibiotic resistance crisis: part 1: causes and threats.” Pharmacy and therapeutics 40.4 (2015): 277.
Davies, Sally C. “Reducing inappropriate prescribing of antibiotics in English primary care: evidence and outlook.” Journal of Antimicrobial Chemotherapy 73.4 (2018): 833–834.