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.
Superbugs
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 Test 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.
