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Man v/s Microbes: Antimicrobial Resistance

Posted By HealthcareOnTime Team Posted on 2022-05-05 Man v/s Microbes: Antimicrobial Resistance

The world is not in stasis. Every life is engaged in a perpetual struggle for survival in the limited space and resources available in nature. While the hierarchy of the food chain may appear stationary, each of these species and each individual in these species is continually evolving to maintain its position in the ecosystem. One action of evolution in the predator begets a reactionary adaptation in the prey. If either of them fails in this task, they face a very real risk of falling behind in this evolutionary arms race and getting extinct. Leigh Van Valen named it, the Red Queen Hypothesis. As the Red Queen said to Alice, even to maintain their current position, one needs to keep striving

While the classic relationship of predator and prey come to mind in this respect, another relationship that holds almost equal magnitude in nature is host parasite interaction. With both of these, continuous adaptation to current situation is necessary for survival. Mankind is in the crux of one such struggle- the rapidly increasing problem of antimicrobial resistance. While humans developed antimicrobials to combat infectious agents, these pathogens in turn are adapting to become resistant to our medicines.

Antimicrobial Resistance: Current Predicament
Antimicrobial resistance (AMR) is the ability of microorganism to develop resistance against therapeutic agents, so that these drugs become ineffective against them. Most of the studies have been focused on antibiotic resistant bacteria, however, resistance can also develop in viruses, fungi and parasites. While it is a part of due course of evolution, human misuse of antibiotics has greatly accelerated this process to the extent that there is fear now that certain strains of microorganisms may develop which are resistant to most of the drugs commonly used against them. Currently, this problem is emerging all over the world and many infections like pneumonia, tuberculosis, and gonorrhea are becoming harder to treat. Further, the existing antimicrobials at our disposal are limited and the development of new drugs is a long and arduous process. There is fear that if the situation is not urgently controlled, we may return back to the medical dark ages which was a time before antibiotics.

Multiple varieties of antimicrobials have been developed with different modes of action, such as inhibition of the synthesis of proteins, DNA or RNA, disruption of microbial membrane. Antibiotic resistance against a particular drug is said to occur when a microorganism can grow despite its presence. In such situations, a higher equired to have the same effect. So far, strains resistant against penicillin, tetracycline levofloxacin, gentamicin, methicillin, and quinolones have already been reported in different parts of the world.

Situation in India-Cause and Effect
India carries a large burden of drug resistant pathogens, mainly multidrug resistant tuberculosis. It is estimated that 2 million deaths will occur annually in India by 2050 that will be attributable to Antimicrobial resistance. Since, infectious disease is still among the leading causes of mortality in India, it makes sense that the greatest cause of Antimicrobial resistance development in India is irrational and overuse of antibiotics, of which, India is among the largest consumers. It is estimated that more than 50,000 newborns die from sepsis caused by drug resistant pathogens." The gene called NDM-1 which is among those that confer drug resistance to microbes is believed to originate in India, hence its name-New Delhi Metallo beta-lactamase-1.

Antibiotic over-prescription is fueled by the lack of knowledge regarding its dangers in both the provider and the patient. The availability of antibiotics at pharmacies without a prescription as well as the lack of monitoring antibiotic use in hospitals are driving the spread of resistance in India. Adding to that, is the huge burden of infections caused due to poor sanitation and inadequate healthcare systems. Last December, a case of Klebsiella pneumoniae infection was discovered in Vellore that was both hypervirulent and multidrug resistant.

History: Emergence of antimicrobial resistance
The emergence of antibiotics in the mid-20" century has undoubtedly saved countless lives and have not only been used for therapeutic purposes but also in prophylaxis in agricultural industries and animal husbandry. While we all know that the first antibiotic penicillin was discovered by Alexander Fleming, it was also Fleming who first cautioned against the irresponsible use of antibiotics to fight infections.

The time may come when penicillin can be bought by anyone in the shops. There is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant." -A. Fleming

Drug resistant strains were first discovered in hospitals. A strain of sulphonamide resistant Staphylococcus pyogenes emerged in a military hospital in the 1930s, while other reports of penicillin resistant Staphylococcus aureus were coming up in London civil hospitals by the 1940s. While initially given little regard, further development of resistance in Hemophilus and Neisseira strains in the 1970s against ampicillin began to worry people. The frequency of Antimicrobial resistance was on the rise, fueled by indiscreet antibiotic use, especially in countries where antibiotics were readily available without prescriptions. The problem was exacerbated by poor sanitation and small healthcare budgets at the time. After the 1980s, tuberculosis reemerged as multidrug resistant and Extensively Drug Resistant (XDR), which was further enhanced by the HIV infections.

Today individuals are at risk of succumbing to multidrug resistant infections because all available drugs fail to treat them. Notable global examples include MDR strains of Mycobacterium tuberculosis, Enterococcus faecium, Enterobacter cloacae, Klebsiella pneumoniae, Staphylococcus aureus, Acinetobacter baumannii and Pseudomonas aeruginosa. With tuberculosis, strains have been reported that are resistant to as many as 8 drugs, making them almost incurable. Such cases usually arise in those people who have been inadequately treated for inadequately in the past.

Mechanism of Antimicrobial Resistance
Resistance in microbes develops at the genetic level through mutation. In the presence of antimicrobials, the microbes are under selective pressure, which allows the survival of that particular microbe that has the gene for resistance already present in its genome, while the others perish. When the resistant cell multiplies, it creates a population of resistant microorganism. This is a classic case of natural selection. The genetic material which renders a microbe resistant to a particular drug can also be propagated through horizontal gene transfer by exchange of plasmids, infection by bacteriophages, naked DNA or transposons. Aside from these two cases, resistance can develop in a step-wise progression from low-level to high-level resistance through the accumulation of favorable mutations in the genomes of the microbes. This was seen in the case of resistance developed in N. gonorrhoeae against penicillin and tetracycline.

The level of resistance is found to be strongly correlated with the degree of antibiotic use. Overtime, the microbe may gain resistance against several drugs. Microbes that lead to enhanced morbidity and mortality due to its high level of resistance to the antibiotic classes used for treatment of that infection, such a microbe is called as a superbug, the treatment options against which are limited. These super-infections are associated with extended periods of hospital stay and higher treatment costs. Currently, some of the most serious examples of superbugs are Staphylococcus aureus, Mycobacterium tuberculosis (MTB) and E. coli..

If the resistance is developed against a particular mode of action of an antibiotic class, then all antibiotics under within that class become ineffective. For example, betalactams like Extended-Spectrum Beta-Lactamases (ESBLs), penicillin and cephalosporin act on cell membranes of certain types of bacteria. Resistance against this class of structurally related drugs is brought about by the generation of beta lactamase enzyme in the bacteria which hydrolyzes beta lactams and renders them ineffective .

Management and Control of Antimicrobial resistance
The first major step toward tackling this problem in India was taken in the form of a National Task Force on Antimicrobial resistance Containment in 2010, which was followed by involvement of ICMR on this issue. Recently, the Government has adopted the National Action Plan (NAP) which has laid down priorities in line with the Global Action Plan (GAP) by the WHO.

As per the National Action Plan for Antimicrobial resistance, six strategic priorities have been identified:

  • Improving awareness and understanding of Antimicrobial resistance through effective communication, education, and training
  • Gaining knowledge and evidence of Antimicrobial resistance through surveillance
  • Reducing the incidence of infection
  • Regulating the use of antimicrobial agents as drugs in humans, animals, and food
  • Increasing investments for Antimicrobial resistance research and innovations
  • Strengthening India's leadership on Antimicrobial resistance

Chemical modification of existing drugs has shown some success against the commonly known modes of resistance. For example, many drugs are pumped out of the cell by the microbe. This mechanism can be interrupted by the development and use of inhibitors that will prevent efflux of substances out of the microbial cell. Other strategies include chemical modification of drugs so that they retain their antimicrobial activity while ceasing to be targets of the microbe's resistant activity. Although this only buys us some time and cannot completely reverse Antimicrobial resistance.

Cycling of antibiotics is also proposed to reduce selection pressure on the microorganisms. This also is not a long term solution, since the resistant strains do not disappear from the population.

The most widespread strategy followed today is using drugs in combination to overcome resistance. These drugs are selected to have different modes of action so that even if a microbe is resistant to one drug, it will succumb to the destructive mechanisms of the other drugs used. This has also been successfully used in cancer treatment and against HIV.

Poor regulation of antibiotic use is the biggest hurdle in the control of Antimicrobial resistance. Hence stronger implementation of regulatory mechanisms on the production, sale and use of antibiotics is imperative. No problem can be solved without understanding it first. Laboratories all over the country should be networked to follow uniform protocols and forward data to regional and central agencies for formulating actions to combat Antimicrobial resistance.

Some of the initiatives that have been launched by WHO to address Antimicrobial resistance include:

  • The Global Antimicrobial Resistance Surveillance System (GLASS)- for developing standardized approaches to the collection, analysis and sharing of data related to Antimicrobial resistance
  • Global Antibiotic Research and Development Partnership (GARDP)- GARDP encourages research and development of new treatments, improvement of existing antibiotics and expediting the introduction of new drugs into clinical use, through public-private partnerships.
  • Interagency Coordination Group on Antimicrobial Resistance (ACG). It aims at improving international coordination to ensure effective global action against Antimicrobial resistance.

Diagnostics and Antimicrobial resistance control
The role of early and accurate diagnosis of Antimicrobial resistance in controlling its spread cannot be overstated. Rapid diagnostic tests can be used to guide treatment and reduce the risk of Antimicrobial resistance. Cost effective diagnostics can help tackle Antimicrobial resistance by ensuring that the right test and the correct treatment is made available to the patient as early as possible. Oiten bacterial and viral infections are clinically indistinguishable and cannot be managed appropriately without the aid of diagnostic tests. These tests can also reduce the number of antibiotic prescriptions, hence reducing drug consumption overall. With differential diagnoses, it can assist in the appropriate shift from broad spectrum antibiotics to narrow spectrum for specific infections.

The most common reason that diagnostic tests are not always implemented before a prescription is that diagnostic tests are more costly while antibiotics are cheaper. However, the development and spread of Antimicrobial resistance warrants another look at this mindset. The idea that adding diagnostic tests to the antibiotic pathway can make much difference in the effort against Antimicrobial resistance.

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