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Antibiotic Resistance: An Imperative To Stop Indiscriminate
Use And New Hope To Tackle Resistant Bacteria

Recent analyses and studies have generated hope towards protecting mankind from antibiotic resistance
which is fast becoming a global threat.


 

The discovery of antibiotics in mid 1900s was a significant milestone in the history of medicine as it was a miracle therapeutic for many bacterial infections and bacteria-causing diseases. Antibiotics were once termed as a “wonder drug” and now antibiotics are indispensable in both basic healthcare and advanced medical care and technology as they have really changed the world by protecting lives and being an essential part of treating various medical conditions as well as assisting in critical surgical procedures.

Resistance to antibiotics is growing at a fast pace

Antibiotics are medicines which are naturally produced by microorganisms and they stop or kill bacteria from growing. It is of critical importance because bacterial infections have plagued mankind throughout time. However, the “resistant” bacteria develop defences that protect them against the effects of antibiotics when previously they were killed by them. These resistant bacteria then are able to withstand any attacks by antibiotics and consequently if these bacteria are disease-causing, the standard treatments stop working for that disease, persisting the infections which can then easily spread to others. Thus, the “magical” antibiotics have unfortunately started to fail or started becoming ineffective and this is posing immense threat to the healthcare system worldwide. The number of resistant bacteria already cause more than 500,000 deaths every year and are eroding the efficiency of antibiotics for prevention and cure by being a silent killer by residing in almost 60% of the world’s populations in some form. Realistically and factually speaking, antibiotic resistance threatens our ability to cure many diseases like tuberculosis, pneumonia and carry out advances in surgeries, treatment of cancer etc. It is estimated that approximately 50 million people will die from antibiotic resistant infections by 2050 and the day might actually come when antibiotics can no longer be used for treating critical infections the way they are being used now. This issue of antibiotic resistance is now an important health topic which needs to be addressed with a sense of urgency for a better future and the medical and scientific community and the governments worldwide are taking steps toward achieving this goal.

WHO Survey: The ‘post-antibiotic era’?

The World Health Organization (WHO) has declared antibiotic resistance a high priority and serious health issue through its Global Antimicrobial Resistance Surveillance System (GLASS) which was launched in Oct 2015. This system collects, analyses and shares data on antibiotic resistance worldwide. As of 2017, 52 countries (25 high-income, 20 middle-income and seven low-income countries) have enrolled in GLASS. It’s first report1 contains information on antibiotic resistance levels provided by 22 countries (one-half million participants enrolled in the survey) showing growth at an alarming rate – overall a huge 62 to 82 percent resistance. This initiative by WHO aims to create awareness and coordinate between different nations to tackle this serious problem at a global level.

We could have prevented antibiotic resistance and still can

How did we reach this phase of humanity where antibiotic resistance has turned into a global threat? The answer to that is quite simple: we have extremely overused and misused antibiotics. The doctors have overly prescribed antibiotics to any or every patient in the past many decades. Also, in many countries, especially the developing countries of Asia and Africa, antibiotics are available over-the-counter at the local pharmacist and can be purchased without even requiring a doctor’s prescription. It is estimated that 50 percent of the time, antibiotics are prescribed for virus-causing infection where they basically do no good because the virus will still complete its life span (generally between 3-10 days), whether antibiotics are taken or not. In fact, it’s just wrong and a mystery for many as to how exactly antibiotics (which target bacteria) will have any effect on viruses! All the antibiotics could do is ‘maybe’relieve some symptoms associated with the viral infection. Even then this continues to be wrong and medically unethical. The correct advice should be that since no treatment is available for most viruses, the infection should just run its course and in the future, these infections should be alternatively prevented by following strict hygiene and keeping one’s environment clean. Furthermore, antibiotics are being routinely used in enhancing agricultural output worldwide and feeding to livestock and food-producing animals (chicken, cow, pig) as growth supplements. Thus, by doing so humans are also put to huge risk of ingesting antibiotic-resistant bacteria which reside in those food or animals causing rigorous transfer of resistant strain bacteria across borders.

This scenario is further complicated by the fact that no new antibiotics have been developed by pharma companies in the past several decades – the last new antibiotic class for gram-negative bacteria was the quinolones developed four decades ago. Thus, as we stand currently, we can’t really be thinking of preventing antibiotic resistance by adding more and different antibiotics as this will only further complicate the resistances and transfer. Many drug companies have pointed out that developing any new drug is firstly very expensive as it’s a long process requiring huge investments and the potential profit from antibiotics is generally very low that they are unable to ‘break even’. This is actually convoluted by the fact that a resistant strain would develop for a new antibiotic somewhere in the world within two years of its launch since no legal framework is in place to curb antibiotic overuse. This doesn’t exactly sound hopeful from a commercial as well as a medical point of view and thus developing new antibiotics is not really the solution for prevention of their resistance.

WHO recommends plan of action2 for preventing antibiotic resistance:

a) Healthcare professionals and workers should be doing a careful detailed assessment before prescribing antibiotics to humans or animals. A Cochrane review of various methods3 aimed at reducing antibiotic abuse in any clinical set up has concluded that the ‘3-day prescription’ method was fairly successful, in which the patient suffering from an infection (which is not bacterial) is conveyed that his/her condition will improve in 3 days, else antibiotics can be taken if symptoms get worse - which they generally don’t since the viral infection has run its course by that time.

b) The general public should be confident to ask questions when they are being prescribed antibiotics and they must take antibiotics only when satisfied that it is absolutely necessary.

They must also complete the prescribed dosage to prevent fast growth of resistant bacterial strains.

c) Agriculturists and livestock breeders should follow a regulated, limited use of antibiotics and do so only where it matters (eg. to treat an infection).

d) Governments should setup and follow national level plans to curb antibiotic use1. Customized frameworks need to be set up for developed countries and middle- and low- income countries relating to their needs.

Now that the damage is done: tackling antibiotic resistance

So that we do not plunge into a new ’post antibiotics’ era and return to the pre-penicillin (first antibiotic to be discovered) era, lot of research is happening in this field loaded with failure and occasional successes. Recent multiple studies show ways to tackle and maybe reverse antibiotic resistance. The first study published in Journal of Antimicrobial Chemotherapy4 shows that when bacteria become resistant, one of the ways which they adopt to restrict antibiotics action is by producing an enzyme (a β-lactamase) which destroys any antibiotic that is trying to get into the cell (for treatment). Thus, ways to inhibit the action of such enzymes could successfully reverse antibiotic resistance. In a second subsequent study from the same team at University of Bristol, UK but in collaboration with University of Oxford published in Molecular Microbiology5, they analysed the effectiveness of two types of inhibitors of such enzymes. These inhibitors (from the bicyclic boronate class) were seen to be very effective on a particular type of antibiotic (aztreonam) such that in the presence of this inhibitor, the antibiotic was able to kill many resistant bacteria. Two of such inhibitors avibactam and vaborbactam – are now undergoing clinical trial and have been able to save a life of a person suffering from untreatable infection. The authors though have succeeded with only a particular type of antibiotic, nevertheless, their work has generated hope in turning back the tide of antibiotic resistance.

In another study published in Scientific Reports6, the researchers at Université de Montréal have devised a novel approach to block the transfer of resistance between bacteria which is one of the ways the antibiotic resistance spreads in hospitals and health units. The genes which are responsible for making the bacteria resistant are coded on plasmids (a small DNA fragment which can replicate independently) and these plasmids transfer between the bacteria, thus spreading the resistant bacteria far and wide. The researchers computationally screened a library of small chemical molecules which would bind to the protein (TraE) that is essential for this plasmid transfer. The inhibitor-binding site is known from the protein’s 3D molecular structure and it was seen that once the potential inhibitors were bound to the protein, the transfer of antibiotic-resistant, gene-carrying plasmids was significantly reduced thus suggesting a potential strategy for restricting and reversing antibiotic resistance. However, for this kind of study the 3D molecular structure of a protein is required which makes it slightly limiting as many proteins are yet to be structurally characterized. Nevertheless, the idea is encouraging and such inhibitors could likely play an important role in everyday health care.

Antibiotic resistance is threatening and undermining several decades of improvements and gains which we have made in human health care and such positive research needs to be further developed and implemented because this is the need of the hour as it will have a huge direct impact on the capability of people to live healthy, full and fruitful lives.

Source:

  1. WHO. Global antimicrobial resistance surveillance system (GLASS) report. http://www.who.int/glass/resources/publications/early-implementation-report/en/. Accessed January 29, 2018.
  2. WHO. How to stop antibiotic resistance? Here's a WHO prescription. http://www.who.int/mediacentre/commentaries/stop-antibiotic-resistance/en/. Accessed February 10, 2018.
  3. Arnold, SR. and Straus, SE. 2005, ‘Interventions to improve antibiotic prescribing practices in ambulatory care’,Cochrane Database Syst Rev. vol. 19, no. 4, CD003539, DOI: 10.1002/14651858.CD003539.pub2
  4. Jiménez-Castellanos, JC. et al. 2017, ‘Envelope proteome changes driven by RamA overproduction in Klebsiella pneumoniae that enhance acquired β-lactam resistance’. Journal of Antimicrobial Chemotherapy, vol. 73, no. 1, pp. 88-94, DOI: 10.1093/jac/dkx345
  5. Calvopiña, K. et al.2017, ‘Structural/mechanistic insights into the efficacy of nonclassical β-lactamase inhibitors against extensively drug resistant Stenotrophomonasmaltophilia clinical isolates’. Molecular Microbiology, vol. 106, no. 3,pp.492-504, DOI: 10.1111/mmi.13831
  6. Casu, B. et al. 2017, ‘Fragment-based screening identifies novel targets for inhibitors of conjugative transfer of antimicrobial resistance by plasmid pKM101’. Scientific Reports, vol. 7, no. 1, pp. 14907, DOI: 10.1038/s41598-017-14953-1

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Vol.1 Issue 2 February 2018

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