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Caught Unawares by Superbugs

The menace of multi-drug resistance

Patients who do not respond well to multiple antibiotics during prolonged illnesses from infectious diseases, such as tuberculosis and typhoid, are not uncommon. Most of us would know at least one person diagnosed with a similar disease which doctors have struggled to cure. The reason for this is simple: the bacteria that cause such infections have become resistant to common antibiotics. In fact, not just bacteria, but several other types of disease-causing microbes including viruses, fungi and parasites have developed resistance to multiple anti-microbial drugs. These are indeed ‘superbugs’ that are extremely difficult to get rid of and are so widespread that they pose a serious threat to humankind. It has been reported that antibiotic resistance kills at least 23,000 people each year in the US alone, recording over $20 billion in medical expenses. This number would be much higher if one considers deaths due to other conditions that would have been complicated by antibiotic-resistant infections.
Evolution of multi-drug resistance
The first antibiotic, Penicillin, was discovered in 1928, and since then many such drugs have been developed. These drugs have the potential to kill bacteria, or at least stop them from multiplying through varied mechanisms that involve disrupting essential structures or biological processes within the bacteria. However, with increasing prevalence of drug-resistant bacteria, one is left wondering about the cause for this resistance. How could bacteria turn resistant to the very antibiotics that were developed to cure it? The answer is deep-rooted in evolution. Bacteria have evolved many mechanisms that confer resistance to antibiotics. The basis for these mechanisms lies in the changes that occur in the bacterial DNA which in turn leads to decreased uptake and/or inactivation and/or efflux of antibiotics, creating an argument for real-time evolution and against the theory of creationism.
In a given population, due to genetic variability, a few bacteria could develop resistance to specific antibiotics. However, it is through the process of Natural Selection, first proposed by Charles Darwin, that these antibiotic-resistant bacteria soon predominate and overtake the others (Figure 1).

Figure 1: Natural Selection of antibiotic resistant bacteria

For instance, a bacterial infection that consists of a mixture of bacteria susceptible (majority) and resistant (minority) to an antibiotic, say X is treated with X. This puts selection pressure on the bacterial population leading to the survival of the ‘fittest’ or ‘antibiotic X-resistant’ bacteria. These bacteria can then rapidly multiply asexually, leading to the entire bacterial population becoming resistant to antibiotic X. Some bacteria can also transfer the DNA responsible for antibiotic resistance to other types of bacteria by employing a form of sexual reproduction known as horizontal gene transfer.

If bacteria resistant to antibiotic X are exposed to another antibiotic, say Y, a small sub-population could potentially develop resistance against Y as well due to the additional selection pressure. Exposure to multiple antibiotics leads to the creation of ‘superbugs’ that are resistant to many different antibiotics. This dramatic evolution in bacterial populations over a short period of time is primarily because natural selection occurs on a generational basis. Thus, the smaller the generation time (or life cycle) of an organism (for example, many types of bacteria divide every 20 minutes, effectively doubling their population), faster would be the rate of evolution. Selection pressure of antibiotics that acts on several generations of bacteria can therefore rapidly result in ‘selection’ of all antibiotic-resistant bacterial progenies.
Perils of improper antibiotic use
Prescription drug abuse – overuse and misuse of antibiotics – is increasing across populations. It has been reported that 40 million people in the US alone use antibiotics each year and only 13 million actually need them. As the symptoms of viral and bacterial infections are quite similar, physicians often prescribe antibiotics for viral infections even though antibiotics are NOT effective in combating viral infections. Improper or delayed diagnosis can therefore greatly accelerate this problem – it has been stated that diagnostic delays are responsible for 490,000 adults and children developing multidrug-resistant tuberculosis every year. Apart from doctors prescribing wrong medications, some over-cautious patients also demand antibiotic prescriptions from their physicians.
This problem is compounded in countries like India where antibiotics are (however illegally) sold over the counter. Studies have shown that in 2015, 30% of the outpatient antibiotics prescribed were unnecessary, 50% of which were prescribed for treating acute respiratory viral infections. With rampant misuse of antibiotics especially when there isn’t enough bacterial infection to kill, a patient might develop an antibiotic-resistant bacterial strain which then spreads to other people through infectious routes even though they do NOT use antibiotics, wreaking havoc with public health. A broad-spectrum antibiotic that kills disease-causing bacteria also ends up killing good bacteria that inhabit the gut, causing gastrointestinal side effects that every pill-popper can relate to.
Apart from humans, animals are also developing antimicrobial resistance. It is unfortunately a common practice to routinely inject farm animals with antibiotics, rather than following stringent sanitation and hygiene procedures to avoid infections in the first place. As a result, farm animals also carry antibiotic-resistant bacterial strains, which infect humans directly, or indirectly through animal products of these infected animals. When such animals defecate, the environment (including soil and water) also gets contaminated, in turn contaminating crop plants and spreading antibiotic-resistant bacteria to humans that consume these plants.
The number of people succumbing to drug-resistant infections is steadily on the rise due to the massive spread of superbugs. Ironically, hospitals are home to many such infections, complicating treatments of other diseases. Moreover, individuals carrying antibiotic-resistant bacterial strains in their body, could be carriers of these microbes without displaying symptoms of any disease. Since such carriers or potentially infectious individuals travel across continents, no place on this planet is safe anymore from antimicrobial resistance. Take for example, the recent case of tourists of Nordic origin who travelled to the Canary islands and spread an antibiotic-resistant bugcausing pneumonia, meningitis and blood infections to many others at local clinics and hospitals.
Combating the superbug threat
The scientific community and pharmaceutical industry at large are trying to combat the worrying threat of multidrug resistance. New assays are being developed to aide faster differential diagnosis and decision-making for antibiotic therapies. A recent study claims that using a combination of antibiotics that target the same cellular processes in bacteria would be more effective and also selective, affecting fewer kinds of bacteria. Various studies on this subject have also been conducted at Shoolini University in Solan, Himachal Pradesh, India. Set up in 2009, it ranks among the top 5 in the country for its achievements in innovation and publication of quality papers. The key focus of this university is on high-impact research. Their research efforts in this domain could go a long way in addressing this overwhelming concern.
The rate at which new anti-microbial drugs are being developed is way slower than the evolution of microbes, countering the effectiveness of the drugs. The process of drug discovery is lengthy, cumbersome, yet essential, as it includes fundamental research, pre-clinical studies, clinical trial and regulatory approvals that could span decades. Given that not many new drugs have been developed in the past 20 years, it is only a matter of time before microbes evolve to conquer and throw us back into the pre-antibiotic era. In fact, the World Health Organization (WHO) has confirmed that the world is swiftly running out of antibiotics.
Given the present situation of multidrug resistance, each and every one of us has a responsibility towards our own health and that of others in the community. It would behoove us to be aware and cognizant of this growing concern that threatens our ability to treat even the most common infections. Physicians need to be careful when prescribing antibiotics and determining their dosage and regimen. Nations need to re-think their investment in research and development of new antimicrobial drugs, vaccines and diagnostic tools as well as their environmental initiatives on safe water, sanitation and hygienic practices in hospitals and animal farms. We as a global community face this fundamental threat to human health and its associated economic and social repercussions, and therefore, awareness and immediate action is needed to contain the spread of superbugs.
-Written for Shoolini University by Dr. Avani Shukla, Molecular Neurobiology,
  International Max Planck Research School, Germany

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