Ongoing explosion of Antimicrobial Resistance

Winning the Battle but Losing the War?

Why in news -

After 2010, when British journal Lancet has named an enzyme as NDM-1, the antimicrobial

resistance in India has become an issue of international importance. Time and again widely

debated across the world

In September 2016- United Nations held a high level meeting to tackle antimicrobial

resistance and pledges to fight drug-resistant superbugs.

It is only the fourth time where general assembly has held a high-level meeting for a health

issue (previously-it was for HIV, non-communicable diseases such as heart disease and

diabetes and the Ebola).

What is antimicrobial resistance?

Antimicrobial resistance happens when microorganisms (such as bacteria, viruses, fungi

and parasites) evolve or change when they are exposed to antimicrobial agents(such as

antibiotics, antivirals, antifungals, antimalarials, and antihelminthics) and develop

resistance mechanisms to it.

As a result, the medicines become ineffective and infections persist in the body, increasing

the risk of spread to others

Microorganisms that develop antimicrobial resistance are sometimes called as multi drug

resistant microbes or superbugs

Antimicrobials in Brief - Antibiotics, Antivirals, Antifungals, Antiprotozoal.

Antibiotics

are a type of antimicrobial drug used in the treatment and prevention of bacterial infections. Antibiotics are also known as antibacterials.

They may either kill (bactericidal) or inhibit the growth of bacteria (bacteriostatic). A limited number

of antibiotics also possess antiprotozoal activity (anti parasitic) but antibiotics are not effective

against viruses.

Mode of action- by inhibiting cell wall synthesis, inhibiting enzymes, interfering with cell wall

permeability, interfering with protein & DNA synthesis etc

Broad Classification-

1. Narrow-spectrum antibiotics- antibiotics that target only specific kinds of bacteria, such

as gram-negative or gram-positive .

2. Broad-Spectrum Antibiotics- antibiotics that are used to treat wide range of bacterial

infections.

Use-

a) Medical use- To treat or prevent bacterial infections and sometimes protozoan infections. It is used as

an empiric therapy when the responsible pathogen is not known and as a definite therapy when the

responsible pathogen is known.

Antibiotics may be given as a preventive measure (prophylactic) in patients with weakened immune

system.

Thus they played a pivotal role in achieving major advances in medicine and surgery

b) Agriculture- antibiotics are widely used as growth supplements in livestock to improve the overall

health of the animals, producing larger yields and a higher-quality product. An estimated 80% of

antibiotics sold in the U.S. are used in animals, primarily to promote growth and to prevent infection

Antivirals-

Antivirals are a class of antimicrobials used specifically for treating viral infections.

For example-Flu, Herpes, HIV etc

Mode of action - Antiviral drugs do not destroy their target pathogen; instead they inhibit their

development.

Antifungals-

Antifungals are a class of antimicrobials used to treat fungal infections.

For example-ring worm, Athletes foot etc

Mode of Action- Antifungals work by exploiting differences between mammalian and fungal cells to kill

/inhibit the fungal organism with fewer adverse effects to the host. Since, fungal and human cells are similar at the biological level many antifungal drugs cause side-effects.

Antiprotozoals-

Antiprotozoal are a class of antimicrobials used to treat infections caused by protozoans.

For example-malaria, amoebiasis etc

Mode of action-by interfering with metabolic processes; by interfering with reproduction and larval

physiology and by interfering with neuromuscular physiology of parasites.

Antihelminthics-

Are a group of antiparasitic drugs mainly used to treat parasitic worms (helminths) without causing

significant damage to the host. They are also called as vermicides and used to treat infected animals

Why is antimicrobial resistance a global concern?

1. New resistance mechanisms are emerging and spreading globally, threatening our

ability to treat common infectious diseases, resulting in prolonged illness, disability,

and death.

i.

2. Without effective antimicrobials for prevention and treatment of infections, medical

procedures such as organ transplantation, diabetes management and major surgeries

(for example, hip replacements or caesarean sections) become very risky.

3. Antimicrobial resistance increases the cost of health care with lengthier stays in

hospitals and more intensive care required.

4. Antimicrobial resistance is putting the positives of the Millennium Development Goals

at risk and endangers achievement of the Sustainable Development Goals.

Causes of antimicrobial resistance- multiple factors

1. Inappropriate use of antibiotics –The prime reason for resistance to antibiotics is their

misuse. As underlined by the European Centre for Disease Prevention and Control (ECDC)

they are three main types of misuse:

a) The unnecessary prescription of antibiotics for viral infections.

b) Frequent prescription of broad-spectrum antibiotics , instead of better targeted

antibiotic, through more accurate diagnosis

c) Patient failure to adhere to regimens for prescribed antibiotics.

2. Indiscriminate use of antibiotics in agriculture and veterinary practice

a) Antibiotic-resistance genes are used in genetically modified crops as "markers" The

genes are inserted into the plant in early stages of development for some specific

purpose .These antibiotic-resistance marker will be taken up by the potentially

recipient bacteria before being integrated into the bacterial genome, and the

resistance genes are then expressed

b) Antibiotics are also sprayed onto fruit trees to prevent and treat infection. Traces of

antibiotics that remain after the initial spraying may lead to emergence of resistant

strains of bacteria.

c) The use of antibiotics in feed supplements given to farm animals to promote animal

growth and to prevent infections (rather than cure infections).

3. Insufficient research and development

a) Pharmaceutical industries do not consider Antibiotic development as an

economically wise investment as antibiotics are used for relatively short duration.

b) Antibiotics are not as profitable as drugs that treat chronic conditions, such as

diabetes, asthma, psychiatric disorders.

c) Fast development of resistant strains also making antibiotic ineffective soon

4. Regulatory approvals-

Difficulties in pursuing regulatory approval include:

a) Redtapism, no clear rules and regulations

b) differences in clinical trial requirements among countries,

c) changes in regulatory and licensing rules.

Even for those companies that are optimistic about the discovery of new antibiotics,

obtaining regulatory sanction is often an obstacle.

Mechanism behind resistance

Several mechanisms have evolved in bacteria which make them resistant to antibiotic. They

are-

1. By chemically modifying the antibiotic- A specific enzyme modifies the antibiotic in a

way that it loses its activity.

For Example- The antibiotic streptomycin is chemically modified so that it will no

longer attach to the ribosome to block protein synthesis

2. Efflux pumps or By physical removal of antibiotic from the cell –efflux pumps are high

affinity reverse transport systems located in the membrane that transport the antibiotic

out of the cell.

For Example - Mechanism of resistance to Tetracycline.

3. By modifying the target site- so that it is not recognized by the antibiotic.

For Example - Mechanism of resistance to sulfonamides.

4. By enzymatic inactivation of the antibiotic. An enzyme is produced that degrades the

antibiotic, thereby inactivating it.

For Example- The Penicillinases are a class of beta-lactamase enzymes that slice the

beta lactam ring of the penicillin molecule.

The Acquisition and Spread of Antibiotic Resistance in Bacteria-

1. Natural (Inherent )resistance. Bacteria may be inherently resistant to a particular

antibiotic.

For example- An organism may lack the target site of the antibiotic molecule ,so that no

binding of antibiotic takes place.

2. Acquired resistance. It can be either modification of existing genetic material or the

acquisition of new genetic material from a different source.

Two processes- Vertical gene transfer & horizontal gene transfer.

Vertical gene transfer

Mutation means sudden change or modification in the genetic structure

of the bacteria. One in every 108- 109 bacteria in an infection will develop resistance

through this process.

Although mutation is a very rare event, but the very fast growth rate of bacteria doesn't

take long before resistance is developed in a population.

Once the resistance genes are developed, they are transferred straightly to all the

bacteria's progeny during DNA replication. This is known as vertical evolution Or

vertical gene transfer

Horizontal gene transfer

Horizontal gene transfer (HGT) is a process in which genetic material contained in small

packets of DNA can be transferred between individual bacteria of the same species or

even between diverse species.

There are at least three possible mechanisms of HGT-Transduction, Transformation

and conjugation.

a) Transduction - takes place when bacteria-specific viruses called bacteriophages

transfer DNA between two closely related bacteria.

b) Transformation –takes place where parts of DNA are taken up by the bacteria

from the external environment. This DNA is normally present in the external

environment due to the death and lysis of another bacterium.

c) Conjugation- takes place when there is direct cell to cell contact between two

bacteria (which need not be closely related) and transfer of small pieces of DNA

called plasmids takes place. This is believed to be the main mechanism of HGT.

For these reasons bacterial adaptation (resistance to antibiotic) to the antibiotic environment

seems to take place very fast in evolutionary time-Therefore Bacteria evolve fast

Spread of antibiotic resistance to humans-

Can bacteria lose their resistance capacity?

Yes, antibiotic resistance traits can be lost, but this reverse process occurs more slowly. If

the selective pressure that is applied by the presence of an antibiotic on the bacterial

population is removed, they can potentially go back to a population of bacteria that

responds to antibiotics

Combating antibiotic resistance

Need for coordinated action-Antimicrobial resistance is a complex problem that affects all

sections of the society and is driven by many interconnected factors. Single, isolated

interventions have limited impact.

This include-

Better hygiene -preventing infections from happening in the first place .

To have access to clean water

Infection control in health-care facilities.

Vaccination- to reduce the need for antibiotics.

To have national action plans on AMR

Greater innovation and investment are required in research and development of new

antimicrobial medicines, vaccines, and diagnostic tools

How to tackle resistance- Contribution from all stakeholders

People can help tackle resistance by:

using antibiotics only when prescribed by a doctor

completing the full antibiotic course, even if they feel better

Not sharing antibiotics with others or using leftover prescriptions.

Large scale public health education and awareness regarding the use and

importance antibiotics

Stopping the use of antibiotics as growth-promoters in farm animals.

Health workers and pharmacists can help tackle resistance by:

enhancing infection prevention and control

Prescribing and dispensing antibiotics only when they are truly needed as

determined by antibiotic sensitivity testing, when possible.

Prescribing and dispensing the right antibiotics to treat the illness.

Ban on over- the counter sale of antibiotics

Compliance with rules and regulations

Policymakers can help tackle resistance by:

Having national plans and guidelines on antimicrobial resistance

strengthening resistance tracking and laboratory capacity;

Regulating and promoting appropriate use of medicines.

increase spending on innovation and infrastructure

Industry can help tackle resistance by

promoting innovation and research and development of new tools

Promoting Cooperation and Information Sharing Among all Stakeholders.

Common Antimicrobial Resistant strains-

Resistance in Bacteria

Resistance in Staphlylococcus aureus-a main cause of severe infections in health care facilities and in community is widespread. It is estimated that People with MRSA(methicillin

resistant Staphylococcus aureus) are 64% more likely to die than people with a non-resistant form of the

infection

Resistance in Klebsiella pneumoniae – K. pneumoniae is a main cause of hospital-acquired infections such

as bloodstream infections, pneumonia, and infections in newborns and intensive-care unit patients.

Resistance in E. coli to one of the most widely prefered fluoroquinolone antibiotics for the treatment

of urinary tract infections is very widespread.

Colistin is the last resort treatment for life-threatening infections caused by Enterobacteriaceae which

are resistant to Carbapenems. Resistance to Colistin has recently been detected making treatment of

such infections very difficult or untreatable

Resistance in viruses

Resistance to HIV, Hepatitis, Influenza antivirals are problematic, and even multi-drug resistant strains have

evolved

Resistance in fungi

Multidrug resistance in fungi is increasing because of the widespread use of antifungal drugs to treat infections

in immune-compromised individuals.

For example-Candidiasis infection

Resistance in parasites

Drug resistant malaria and Leishmaniasis has become a great concern

New Delhi metallo-beta-lactamase-1(NDM-1)

What is NDM-1?

NDM-1 stands for New Delhi Metallo-beta-lactamase-1.It is an enzyme that

makes bacteria resistant to a broad range of antibiotics (particularly for beta-lactam

antibiotics). What are β-lactam antibiotics (beta-lactam antibiotics) - are a class of broad-

spectrum antibiotics, that contain a β-lactam ring in their molecular structures.

For Example-penicillin derivatives, Carbapenems etc

How they Act- Most β-lactam antibiotics work by inhibiting cell wall synthesis in the

bacteria and are the most widely used group of antibiotic

Why (NDM-1) was in news?

In 2010 a study by a multi-national team was published in a journal The Lancet Infectious

Diseases which reported cases in India. The authors concluded that the new resistance

mechanism "clearly arose in India. (But the journal authority later apologized for using the

name of New Delhi to describe a pathogen was an error")

NDM-1 was first described by Yong et al in 2009. In 2008,it was first detected in

a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin .It was later

detected in India, Pakistan, UK, US, Canada, Japan etc

The most common bacteria that make this enzyme are of Gram-negative type such

as Escherichia coli and Klebsiella pneumoniae.

Why is NDM-1 dangerous?

The World Health Organisation (WHO) – NDM-1 could be ushering in the dooms day

scenario of a world without antibiotics."

The NDM-1 gene causes bacteria to produce an enzyme called a carbapenemase.

Carbapenemase makes nearly every antibiotic ineffective including Carbapenems.

Note- Carbapenems are one of the most powerful antibiotics. They are used as a last line of treatment for

many bacterial infections, such as E. coli and Klebsiella pneumoniae carbapenemase (KPC).

Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because

infections caused by them are difficult to treat.

NDM-1 raises fears that diseases in the future will not respond to antibiotics. If NDM-1

passes over into other bacteria, secondary diseases will emerge spreading across the

world which might lead to a health crisis.

How does NDM-1 spread?

The DNA code for NDM-1 can jump from one bacteria strain to another through a process

known as horizontal gene transfer (HGT).

In 2010, scientists were aware that some strains of bacteria, such as E. coli and Klebsiella

pneumoniae (KPC), carry the NDM-1 gene. It has since been found that horizontal gene

transfer (HGT) is possible between KPC and NDM-1.

Has NDM-1 already spread?

The gene is widespread in India and Pakistan, especially in hospitals where the climate

encourages its persistence year round. It has been found in the hospitals and also in

drinking water.

NDM-1 has surfaced in countries around the world including the United States, Japan,

Australia, and the United Kingdom.

Can NDM-1 be treated?

At the moment, the only way to combat the spread of NDM-1 is through quickly

identifying, isolating infected patients, disinfecting hospital equipment, following hand-

hygiene procedures and surveillance in hospitals.

So far, patients with NDM-1-related infections have been treated on a case-by-case basis,

with a combination of medications, but there is no effective treatments are available for

many of the infections caused by NDM-1. Some strains of bacteria are totally resistant to

virtually all kinds of antibiotic.

Initiatives taken by India with respect to AMR

1. In 12th Five Year Plan -A National Programme for Containment of AMR has also been

initiated with the following objectives:-

To generate awareness among healthcare providers and in the people regarding rational

use of antibiotics.

To establish a laboratory based surveillance system.

To strengthen infection control guidelines and practices and

To promote rational use of antibiotics.

2. The National Policy for Containment of Antimicrobial Resistance –released in

2011.However, little was done to implement the policy and the recommendations were

considered to be difficult to implement and there was no clear action plan.

Key points-

a) Proposed Actions to monitor Sale of Antibiotics

Schedule H of the drug and cosmetics act contains a list of drugs which are required to be

dispensed on the prescriptions of a registered medical practitioner.

A separate schedule as Schedule H1 may be introduced under the Drugs and Cosmetics

Rules to regulate sale of antibiotics exclusively

A provision could be incorporated for spot suspensions /cancellation of the sale licence for

contravention of the provision of Schedule H1.

Drug Inspectors may conduct surprise raids at the chemist shops to ensure that the

provision of the Drugs and Cosmetics Rules especially in respect of Schedule H1 are strictly

complied by the licensees.

A system of colour coding of third generation antibiotics

The drug testing laboratories in the country should be strengthened in terms of

infrastructure, number and also training of drug inspectors.

Incentives should be given to pharmacies for not selling antibiotics without prescription

and appropriate regulation for the same should be formulated.

b) Set up an Antibiotic Management Team (AMT) -This is a Multi disciplinary team with

experts in Infectious diseases, Internal medicine, Clinical microbiology etc

The functions of the AMT is to develop the hospital antimicrobial policy

c) Establishment of inter-sectoral coordination committee comprising Central Council for

Scientific and Industrial Research (CSIR), Ministry of Health and Family Welfare, Ministry

of Agriculture, Indian Council for Agricultural Research ,Department of Animal Husbandry

(FSSAI)etc.

To review available data regarding the use of antimicrobials.

Generation of data by undertaking studies on the use of antimicrobials as Animal Growth-

Promoters.

Specify the antibiotics for use in Livestock etc

3. Chennai declaration-

A Roadmap to Tackle the Challenges of Antimicrobial Resistance -For the first time, medical

societies in India came together and organised a symposium in Chennai to discuss the problem

of antimicrobial resistance and possible solutions.

International experts were invited to explain how developed countries were trying to tackle

antimicrobial resistance.

The Chennai Declaration called for urgent initiatives to formulate an effective national policy to

control the rising antimicrobial resistance, which include ban on over-the-counter sale of

antibiotics, and also to make changes in the medical education curriculum to include training in

antibiotic usage and infection control.

4. National Anti-Microbial Resistance Research and Surveillance Network (AMRRSN)- to

enable compilation of national data of AMR at different levels of Health Care has been set up

by the Indian Council of Medical Research (ICMR in order to strengthen the surveillance of

antimicrobial resistance (AMR) in the country as Information regarding usage of antibiotics in

India is not being centrally collected.

5. The Drugs and Cosmetic Rule, 1945 were amended in 2013 to include a new Schedule

H1.

The Drugs coming under Schedule H1 are required to be sold in the country with the following

conditions:-

a) The supply of a drug mentioned in Schedule H1 shall be recorded in a separate register at

the time of the supply containing the name and address of the prescriber, the name of the

patient, the name of the drug and the quantity supplied and such records shall be

maintained for three years and be open for inspection.

b) The drug specified in Schedule H1 shall be labeled with the symbol Rx which shall be in red

and clearly displayed on the left top corner of the label, and shall also be labeled with drug

warning.

6. National Treatment Guidelines for Antimicrobial Use in Infectious Diseases- for rationalizing the

use of antimicrobials in the health care facilities in the country. It is emphasized that

antimicrobials should be prescribed only when they are necessary in treatment following a clear

diagnosis

7. 2016 February, the Union Health Minister launched a multimedia campaign called "Medicines

with the Red Line" to create awareness on the rational use of medicines which carry a red line

on their strip. This was the first mass campaign by the government that accepted the public

health crisis and attempted to address the issue

World Health Organisations Initiatives

WHO is providing technical assistance in helping countries to develop their national action plans,

and strengthen their health and surveillance systems so that they can prevent and manage

antimicrobial resistance better.

One Health approach by WHO, working effectively with the World Organisation for Animal Health

(OIE) and FAO - To encourage best practices to avoid the emergence and spread of antibacterial

resistance, including optimal use of antibiotics in both humans and animals.

A global action plan on antimicrobial resistance was adopted by Member States at the Sixty-eighth

World Health Assembly and supported by the governing bodies of FAO and OIE The objective of the

global action plan is to make sure, as long as possible, continuity of successful treatment and

prevention of infectious diseases with effective and safe medicines that are quality-assured, used in

a responsible way, and available to all who need them.

A high-level meeting on antimicrobial resistance was held at the United Nations General Assembly

was held in September 2016 to accelerate global commitments and boost national multi-sectoral

efforts to combat antimicrobial resistance

Summary

The discovery of antibiotics was a boon in modern medicine. They have been able to stop

the growth or kill many different kinds of microorganisms. However, bacteria have proven

to be much more innovative and adaptive than we anticipated and have started to develop

resistance to antibiotics at an ever increasing pace.

Bad practices and mismanagement have only worsened the situation. We could soon

return to a state of medical health that was as grim as that which occurred prior to

antibiotic use. However, with more research, awareness & education of the public, and well

thought out regulations, the problems can be controlled and managed better

How to approach for the Civil Services Examination

Prelims- Current affairs, general science(biology).

GS Paper II- Health related aspect (public health and safety. Welfare etc).

Practice Questions-

In Prelims-

Which of the following statement is /are correct

a) Resistance to antimicrobials are only seen in bacteria and viruses and not in fungi and

parasites

b) Antimicrobial resistance can occur naturally irrespective of the presence of antibacterial

agents.

c) Antibiotic resistance in bacteria is a reversible phenomena.

d) Antibiotics have antiprotozoal and antiviral property.

In Mains-

Essay-

a) Post antibiotic era -Catastrophic threat to human health and safety

b) Antibiotic resistance in 21st century-winning the battle but losing the war

GS paper II-

a) Abuse in the use of antibacterial drugs in several settings is the driving force

behind the increase of antibacterial resistance. Critically discuss?

b) The health threats posed by antimicrobial resistance need to be tackled urgently, in

a coordinated manner and in many different ways. Discuss?

c) The initiatives taken by India to combat the threat of superbugs is very minimal

considering the harm it can cause to public health and safety. Critically analyse?