Antibiotic Resistance: Challenges and Solutions

RUHS Journal of Health Sciences, Volume 2 Number 3, July -September 2017
Reveiw Article
Antibiotic Resistance: Challenges and Solutions
Kishore Mangan, R S Khedar2
'Consultant, Critical Care, 2Director, Internal Medicine and Critical Care, Eternal Hospital, Jazpur.

ABSTRACT
Antibiotics have played a pivotal role in modern
healthcare. They have been instrumental in treatment and prevention of infections in various clinical settings, but effectiveness of antibiotics is decreasing which is largely because of development of antibiotic resistance. The
development of generations of antibiotic -resistant microbes and their widespread distribution in microbes
throughout the environment is because of many years of unremitting selection pressure from human and animal applications of antibiotics. This is a manmade situation, and with the help of natural processes, superimposed on nature.'
Until recently, the effects of antimicrobial resistance were not felt much as there has been a continuous stream of newer antibiotics. However, over the past 2 decades, there has been dearth of new antibiotics from pharmaceutical
companies leading to inability to fight these MDR organisms.2 This marked increase in antimicrobial resistance among common bacterial pathogens is now
threatening this therapeutic accomplishment,
jeopardizing the successful outcomes of critically ill patients and is cause of severe infections, complications,
longer hospital stays and increased mortality.' In fact, the
World Health Organization has named antibiotic
resistance as one of the three most important public health threats of the 21st century.4
ANTIBIOTIC RESISTANCE
Antibiotic resistance refers to changes in bacteria that reduce or eliminate an antibiotic's ability to destroy it.' Drug resistance happens to almost every antimicrobial drug, not just antibiotics, and almost all pathogens and parasites, not just bacteria.' Evidence from various published data from around the world indicates an overall

decline in antibiotic effectiveness: resistance to all types of antibiotics, including last resort, is rising.'
The U.S. Centers for Disease Control and Prevention (CDC) estimates that at least 23,000 deaths and more than 2 million infections are because of antibiotic resistance each year in the United States. Total economic costs are also huge with estimated direct cost of $20 billion and additional productivity losses of $35 billion.' Similarly in Europe, an estimated 25,000 deaths are attributable to
antibiotic -resistant infections, costing 1.5 billion
annually in direct and indirect costs! UK government review recently estimated that deaths from Antimicrobial resistance could rise from approximately 70,000 to around 10 million yearly by the year 2050.9 Estimates indicate that more than 56,000 neonates die each year from resistance -attributable neonatal sepsis deaths caused by bacteria resistant to first -line antibiotics in India
alone.19
MECHANISM OF RESISTANCE
Antimicrobial resistance has been there since ages and it is because of the interaction between organisms and their environment. Since most antimicrobial compounds have been developed from natural molecules, the bacteria have evolved mechanisms to overcome their action in order to survive (Figure 1).
Thus, these bacteria are often considered to be
"intrinsically" resistant to one or more antimicrobials.4 However, in clinical settings, we are typically referring to the expression of "acquired resistance" in a bacterial
population that was originally susceptible to the
antimicrobial compound as the main focus of the problem. But this is a complex problem which will be described in following section.

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Biochemical aspects

Modification of Antibiotic molecule
Prevention to reach target

Chemical alteration
Destruction
Reduced Permeability
Efflux Pumps

Changes or Bypass target site

Target protection
Modification of target site

Genetic aspects

Mutations
Horizontal gene transfer

Transformation Transduction

Conjugation

Figure 1: Mechanism of resistance

GENETIC BASIS OF ANTIMICROBIAL RESISTANCE
Bacteria have a remarkable genetic plasticity that allows them to respond to a wide array of environmental threats. Bacteria with genes providing antibiotic resistance are found naturally in microbial populations: they can arise de novo because of random mutations in a bacterium or as a method of surviving antibiotics produced by competing bacteria.'
From an evolutionary perspective, bacteria use two major genetic strategies for survival against the antibiotics, a) spontaneously during bacterial DNA replication orb) the acquisition of new genes by DNA transfer from other bacteria or uptake of exogenous DNA.4
Mutational resistance Spontaneous mutation is one of the key mechanism bacteria use to survive stress conditions. In this scenario, in the presence of antibiotic drug, some of the bacterial cells derived from a susceptible population develop

mutations in genes that affect the activity of the drug, resulting in preserved cell survival. Once a resistant mutant emerges and the antibiotic drug eliminates the
susceptible population and the resistant bacteria
predominate. 12
In general, mutations resulting in antimicrobial resistance
alter the antibiotic action via one of the following
mechanisms,
a) target modification, b) decreased uptake of drug, c) activation of efflux mechanisms, or
d) enzymatic modulations in important metabolic
pathways.
Thus, resistance arising due to acquired mutational
changes is diverse and varies in complexity.'
Horizontal gene transfer (HGT)
Acquisition of foreign DNA material through HGT is one of the most important drivers of bacterial evolution and it is frequently responsible for the development of

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RUHS Journal of Health Sciences, Volume 2 Number 3, July -September 2017

antimicrobial resistance. Furthermore, this genetic exchange has been implicated in the dissemination of
resistance to many frequently used antibiotics.4
Classically, bacteria acquire external genetic material through three main strategies, a) Transformation (transfer of free DNA from dead
bacteria), b) Transduction (transfer of DNAby viral delivery) and, c) Conjugation (transfer of plasmid from a resistant
bacteria).13
Transformation is perhaps the simplest type of HGT. Some bacteria such as Streptococcus pneumoniae and Neisseria gonorrhoeae, appeared to be capable of uptake, integration, and functional expression of naked fragments of extracellular DNA, but only a handful of them develop clinically relevant resistance.' The mobilization or transfer of Antibiotic resistant genes by bacteriophages has been documented for various bacterial species. The transferable DNA sequences range from chromosomal DNA to mobile genetic elements such as plasmids, transposons and genomic islands 4''4
Conjugation is a very efficient method of gene transfer that involves cell -to -cell contact. It uses mobile genetic elements (MGEs) as vehicles to share valuable genetic information, although direct transfer from chromosome to chromosome has also been well characterized. The most important MGEs are plasmids and transposons, both of
which play a crucial role in the development and dissemination of antimicrobial resistance among
clinically relevant organisms. Not uncommonly, many plasmids contain more than one resistance gene. Thus, plasmid acquisition itself can in many cases confer resistance to multiple antibacterial agents.4
BIOCHEMICAL BASIS OF ANTIMICROBIAL
RESISTANCE
Antibiotic resistance mechanisms can be categorized
according to the biochemical route involved in resistance 4'15
1) modifications of the antibiotic molecule, 2) prevention to reach the antibiotic target and 3) changes and/or bypass of target sites
1. Modifications of the Antibiotic Molecule
Bacteria replace or modify antibiotic molecule by producing enzymes that inactivate the drug by adding specific chemical moieties to the compound or that
destroy the molecule itself.

A. Chemical alterations of the antibiotic
The production of enzymes that degrade or modifies the antimicrobial molecule is a well-known mechanism of acquired antibiotic resistance in both gram -negative and gram -positive bacteria. The resulting effect is often related to steric hindrance that decreases the avidity of the drug for its target, which, in turn, is reflected in higher bacterial MICs. Many types of modifying enzymes have been described, include acetylation (aminoglycosides,
chloramphenicol, streptogramins), adenylation
(aminoglycosides, lincosamides), and phosphorylation (aminoglycosides, chloramphenicol). 4
B. Destruction of the antibiotic molecule-One of the
earliest and classical recognized mechanism of
destruction of antibiotic molecule was by the discovery of 0- lactamases. After penicillin became widely available, soon it was realized that, penicillin -resistance is clinically relevant and the mechanism of resistance was found to be
a plasmid-encoded penicillinase that was readily
transmitted.' These enzymes destroy the amide bond of the f3-lactam ring, rendering the f3-lactam antimicrobial ineffective. In order to overcome this problem, new f3lactam compounds with wider spectrum of activity and less susceptibility to penicillinases (such as ampicillin) were manufactured. However, during the 1960s a new plasmid-encoded 13-lactamase capable of hydrolyzing ampicillin was found among gram -negatives (known as TEM-1). From then on, newer generations of 13-lactams has been developed, but has systematically been followed by the rapid appearance of enzymes capable of destroying
them (e.g. Extended spectrum (3-lactamase and
Carbapenemase), in a process that is a prime example of antibiotic -driven adaptive bacterial evolution. 4'16
New Delhi metallo-f3-lactamase (NDM-1) is a recently identified broad spectrum carbapenemase with ability to, inactivate all P-lactams except aztreonam. However, most
of the NDM-1-producers also produce aztreonam hydrolysing-f3-lactamases thereby making these
pathogens absolutely resistant to all 13-lactams.17Another worrying concern is the ability of b1aNDM gene to be
readily transmissible among different types of gram negative organisms, spreading to many countries in a short span of time and becoming one of the most feared resistance determinants in several parts of the world. Particularly in the Indian subcontinent (i.e. India and Pakistan), the blaNDMgene is not only extensively

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RUHS Journal of Health Sciences, Volume 2 Number 3, July -September 2017

disseminated among nosocomial pathogens, but it is
frequently found in community -associated isolates. 4
2. Decreased Antibiotic Penetration and Efflux
A. Reduced permeability-Many antibiotics have
intracellular bacterial targets or, in case of gram -negative bacteria, targets are located in the cytoplasmic membrane. Therefore, the compound must penetrate the outer and cytoplasmic membrane in order to exert its antimicrobial effect. Bacteria have developed mechanisms to decrease the uptake of the antimicrobial molecule. This mechanism
is particularly important in gram -negative bacteria,
limiting the influx of substances from the external milieu.
Alterations of porins could be achieved by 3 general processes,
I) a replacement in the type ofporins expressed, ii) alteration in the level ofporin expression, and
iii) impairment of the porin function. Importantly, changes in permeability through any of these
mechanisms frequently result in low-level resistance and are often associated with other mechanisms of resistance, such as increased expression of efflux pumps.
Example of porn -mediated resistance is the aberrant production of OprD in Ps. aeruginosa, which is normally
used for the uptake ofbasic amino acids and antibiotics. 4
B. Efflux Pumps- The efflux pumps are the membrane proteins that export the antibiotics out of the cell and keep its intracellular concentrations at low levels. They not only provide intrinsic resistance to the bacteria but also when overexpressed, efflux pumps can also confer high levels of resistance to previously clinically useful antibiotics. This mechanism of resistance affects a wide range of antimicrobial classes including protein synthesis inhibitors, fluoroquinolones,13-lactams, carbapenems and polymyxins. The genes encoding efflux pumps can be
located in MGEs or in the chromosome."
3. Changes in Target Sites
Most antibiotics specifically bind to their targets with high affinity, thus preventing the normal activity of the target.
So interfering with these target site results in
antimicrobial resistance. To achieve this, bacteria have evolved different mechanisms, including protection of the target and modifications of the target site that result in decreased affinity for the antibiotic molecule.

A. Target protection-Although some of the genetic determinants coding for proteins that mediate target
protection have been found in the bacterial chromosome, most of the clinically relevant genes involved in this mechanism of resistance are carried by MGEs. Examples of drugs affected by this mechanism include tetracycline (Tet[M] and Tet[O]), fluoroquinolones (Qnr) and fusidic acid (FusB and FusC).
B. Modification of the target site-Introducing
modifications to the target site is a common mechanisms of antibiotic resistance in bacterial pathogens affecting almost all families of antimicrobial compounds. These target changes may consist of:
a) point mutations in the genes encoding the target site, b) enzymatic alterations of the binding site (e.g. addition
of methyl groups), and/or
c) replacement or bypass of the original target. 4
TRENDS IN ANTIBIOTIC RESISTANCE Antibiotic -resistant bacteria, including methicillinresistant Staphylococcus aureus (MRSA), extended -
spectrum beta-lactamase (ESBL) producers, and
carbapenem-resistant Enterobacteriaceae, are increasing in prevalence worldwide, resulting in infections that are difficult and expensive to treat.
Escherichia coli: In five of the six WHO regions, some countries reported E. coli resistance of more than 50
percent to fluoroquinolones and third -generation
cephalosporins." In India, From 2008 to 2013, E. coli resistance to third generation cephalosporins increased from 70% to 83%, and fluoroquinolone resistance increased from 78% to 85%. Resistance to carbapenems in E. coli isolates increased from 10% in 2008, to 13% in
2013.'9
Klebsiella pneumoniae resistance rates to third -
generation cephalosporins are above 30 percent in most WHO member countries and exceed 60 percent in some
regions!' In India, amongst Klebsiella pneumoniae isolates, third -generation cephalosporin resistance decreased from 90% to 80%, and fluoroquinolone resistance increased from 57% to 73%. Carbapenem
resistance among K pneumoniae jumped from just 2% in 2002 to 52% in 2009 in one tertiary -care hospital in New
MRSA resistance rates exceed 20 percent in all WHO

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RUHS Journal of Health Sciences, Volume 2 Number 3, July -September 2017

regions and are above 80 percent in some regions.18 In India, a large private laboratory network reported a steep increase in MRSA, from 29 % in 2009 to 47 % in 2014 of S. aureus isolates.'
High levels of resistance have been reported in N. gonorrhoeae isolates (beta-lactamase producers),
Salmonella Typhi isolates (fluoroquinolones),
Enterococcus faecium isolates (11% were vancomycin
resistant).19
E. coli and Klebsiella spp. carrying NDM-1 now account
for the majority of carbapenem resistance in some
countries. From their original detection in 2008, NDM-1carrying Enterobacteriaceae have been identified in more than 70 countries in all regions."
REASONS FOR INCREASE IN ANTIMICROBIAL RESISTANCE
Following are the reasons for increase in antimicrobial resistance (Figure 2).

Antibiotic quality issue

Increasing Global
consumption

Environmental factors

Inappropriate Human use

Health system factors

Excessive use in Agriculture

Figure 2 : Reasons for increase in Antimicrobial resistance
1. GLOBAL CONSUMPTION
Antibiotic use is a major driver of resistance and demand for antibiotics continues to rise and thus the antibiotic
resistance." Between 2000 and 2010, total global
antibiotic consumption grew by more than 30 percent, from approximately 50 billion to 70 billion standard units, based on data from 71 countries. Although per capita

consumption is still generally higher in high -income countries, the greatest increase in antibiotic use between 2000 and 2010 was in Lower to Middle Income countries (LMIC), where use continues to rise. In 2010, India was the world's largest consumer of antibiotics for human health at 12.9 x 109 units (10.7 units per person). The next largest consumers were China at 10.0 x109 units(7.5 units per person) and the US at 6.8 x109 units (22.0 units per person). 76 % of the overall increase in global antibiotic consumption between 2000 and 2010 was attributable to BRICS countries.21 Worldwide, increases were also significant for two "last -resort" antibiotic classes : carbapenems (approximately 40 percent) and polymyxins (13 percent). The growth in retail carbapenem sales was particularly steep in India, Pakistan, and Egypt.'
2. HUMAN USE OFANTIBIOTICS
An estimated 80 percent of all antibiotics are used in the
community, where prescribing and purchasing of
antibiotics without prescription are common, especially in
LMICs. In many countries at all economic levels, clinicians have incentives to overuse antibiotics.' In
hospital settings, the confluence of patients with serious medical conditions, interconnectedness of hospitals through mobile patient populations, and high density of antibiotic use make antibiotic use disproportionately important.
Another issue with antibiotic consumption is
inappropriate antibiotic use. It is estimated that from 20 to
50 percent of total antibiotic use is inappropriate.' "Inappropriate" can mean use of antibiotics when no
health benefit is possible, such as to treat upper respiratory
tract infections caused by viruses or malaria or acute diarrhoeas, this may occur because of an absence of clinical training and guidelines on antibiotic treatment
available to physicians, or because of a lack of diagnostics and trained personnel to conduct testing and identify the cause and susceptibility ofthe infection.
It also comprises of suboptimal use of antibiotics for
responsive conditions, such as the choice of drugs with an unnecessarily broad spectrum, an incorrect dosage or
duration, or poor patient adherence to the prescribed treatment.' In addition, more than 50% of patients worldwide fail to take their medications properly. Either overuse or underuse of antibiotics can also result in
serious antimicrobial resistance.22

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3. HEALTH SYSTEM FACTORS
Health system factors are also at fault. Infection control in hospitals is poorly monitored and could be improved. Inadequate national commitment to a comprehensive and coordinated response and ill-defined accountability with respect to antimicrobial use and resistance is an issue to be considered. Weak surveillance and regulatory system is also an important determinant of antimicrobial
resistance. Samples are generally tested only when patients fail to respond to common treatments!' Other structural and behavioral drivers include education,
access to insurance, antibiotic costs, and patient demand. Over-the-counter access to antibiotics is a problem, but regulations to restrict access have to be balanced against the need to maintain access for the significant proportion of the population that lacks access to doctors. Indeed, lack of access to effective and affordable antibiotics still kills more children in countries like India than does drug
resistance. Use of wide range of fixed -dose
combinations in the market, often without scientific or medical merit or evaluation.19
4. ANTIBIOTICS IN AGRICULTURE
Of all antibiotics sold in the United States, approximately 80% are sold for use in animal
agriculture. Global antibiotic consumption in livestock was conservatively estimated at 63,200 tons in 2010,
accounting for nearly two-thirds of the estimated 100,000 tons of antibiotics produced annually
worldwide. By 2030, consumption is projected to rise by two-thirds, to 105,600 tons.'
Antibiotics have three roles in animal production: to treat individual animals with bacterial infections, to prevent infections, and to promote growth. The third role, growth promotion, has no counterpart in human antibiotic use. It accounts for the majority of use in animals and is the focus of most legal and regulatory efforts to reduce antibiotic consumption in livestock and poultry. Growth promotion is accomplished with ultra
low doses of antibiotics mixed with feed by the
manufacturer or the farmer.'
There is growing evidence that antibiotic resistance in humans is promoted by the widespread use of this non therapeutic antibiotics in animals. Resistant bacteria are transmitted to humans through direct contact with
animals, by exposure to animal manure, through

consumption of undercooked meat, and through contact with uncooked meat or surfaces meat has touched. 24
5. ENVIRONMENTAL FACTORS Despite the widespread nature of antimicrobial resistance, limited focus has been placed on the role of
environmental factors in propagating resistance. There
are only few studies that examine the role of the
environment, specifically water, sanitation and hygiene factors that contribute to the development of resistant pathogens. Antibiotics result in contamination of various aspects of the environment and this can result in the introduction of resistance genes and resistant bacteria into the human food chain and clinical environments. These factors are often interlinked with gene transfer
going in both directions, perpetuating the cycle of Antimicrobial resistance. There is however scope for both innovative and traditional environmental public health approaches, including the provision and
enforcement of adequate standards and guidelines, basic
food safety, secondary treatment of water and
wastewater/waste products, basic sanitation and hygiene practices, to eliminate or reduce the problem. 25
6. ANTIBIOTIC QUALITY ISSUES
Substandard manufacturing Poorly manufactured drugs may enter the market because of insufficient quality control and a lack of necessary microbiological technologies for testing.
Even antibiotics that were manufactured to
specifications may degrade before they reach consumers because of hot climates, bottlenecks and delays in supply chains, poor storage conditions, and weak distribution systems.'
Counterfeit drugs
Counterfeit medicines may enter the market as a result of crime, corruption, and consumers' reliance on informal drug sellers. It has been estimated that sales of falsified medicines are worth more than $75 billion. The WHO and FDA have estimated that up to 10 percent of drugs worldwide- perhaps even 30 percent in some low- and
middle -income countries (LMICs)-may be
counterfeit. In Africa and Asia, up to 60 percent of
antimicrobials may be falsified, a number that increased 10 -fold in the decade from 2002 to 2012.7
Experts have recommended stiffer punishments for

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counterfeit drug producers and stricter enforcement of current laws. Developing better, simpler, and more accessible testing methods for substandard drugs could bolster both surveillance and control efforts.'
EXTENDING ANTIBIOTIC EFFECTIVENESS
Global Antibiotic Resistance Partnership (GARP) has put emphasis on six strategies will contribute to slowing resistance and maintaining the effectiveness of current drugs' (Figure 3).

Ensure political commitment

Reduce the need for antibiotics
Improve hospital infection control and
antibiotic stewardship

Educate and inform health professionals, policy makers ,and
the public

Reduce antibiotic use in agriculture

Change incentives that encourage
antibiotic overuse and misuse

Figure 3: Strategies to extend antibiotic effectiveness

1. Reduce the need for antibiotics.
The most attractive strategy is to reduce the need for antibiotics by reducing the burden of infectious diseases requiring antibiotics. This can be achieved by improving vaccination coverage, improving access to clean water and sewerage systems, and ensuring a safe and healthful
food supply.
2. Improve hospital infection control and antibiotic stewardship.
Infections can spread within hospitals. Hand washing with soap or using alcohol disinfectant between patients and good environmental cleaning are necessary but not sufficient to prevent the spread of infections. Other hospital -based interventions to improve antibiotic use
include antibiotic stewardship programs and

surveillance of resistance and hospital -acquired
infections to guide clinical and policy decision making.'
3. Change incentives that encourage antibiotic
overuse and misuse
Economic incentives can encourage the overuse of antibiotics all along the supply chain-in hospitals and communities and in agriculture. Doctors may benefit from prescribing a particular drug or more expensive drugs. Hospitals may also rely on antibiotics to treat infections that could be prevented with improved
infection control.'
4. Reduce antibiotic use in agriculture.
Eliminating antibiotic use for growth promotion and minimizing use for disease prophylaxis need not jeopardize animal or human health. Documenting levels and patterns of antibiotic use in agriculture will provide a sound basis for reviewing and strengthening laws and regulations. Incentivizing the rational use of antibiotics
is important in the veterinary field as well. 7
5. Educate and inform health professionals, policy makers ,and the public.
Education and guidelines for healthcare professionals, engagement with policymakers, and national awareness campaigns for the public will begin changing the norms
in antibiotic use and promote conservation. The educational component of antibiotic stewardship programs is often conducted at the hospital level, but guidance on antibiotic prescribing, antibiotic
stewardship, and infection control can be incorporated into both undergraduate and postgraduate medical programs to instill appropriate prescriber practices early on.
6. Ensure political commitment.
Generating local interest and pressure by healthcare professionals and the public and undertaking a thorough situation analysis are necessary to build political commitment and cooperation for combating antibiotic resistance. Thereafter, politicians need to allocate time, money, and resources to designing and implementing strategies to promote the rational use of antibiotics. In addition, government can convene academics and stakeholders from other government sectors to create locally relevant, evidence -based policies. Examples of such political efforts include the Jaipur Declaration on Antimicrobial Resistance, in which WHO Southeast

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Asia member states committed to developing
multisectoral national alliances to develop national
antibiotic policies.'
GLOBAL AND NATIONAL COMMITMENTS
In May 2015, the World Health Assembly endorsed the Global Action Plan on Antimicrobial Resistance, which calls on all countries to adopt national strategies within two years." In the United States, the National Action Plan for combating antibiotic -resistant bacteria stresses the need to slow the spread of antibiotic resistance through stewardship at all levels. The European Union has taken a
similar stance. Southeast Asian WHO countries committed to addressing the issue in the Jaipur
Declaration.'
Government of India released national treatment
guidelines for antimicrobial use in infectious diseases in
2016. Recently realizing the need to contain
Antimicrobial resistance, Government of India made its National Action Plan on Antimicrobial Resistance which outlines the priorities and interventions planned to be implemented over 2017 - 2021 to tackle the public health
challenge of Antimicrobial resistance in India. The National Centre for Disease Control (NCDC) has been appointed as the focal point for implementation and
coordination of the Antimicrobial resistance programme. The National action plan has objectives of enhancing
awareness, strengthening surveillance, improving
rational use of antibiotics, reducing infections, promoting
research and to provide leadership on antimicrobial resistance with collaborations.'
SURVEILLANCE SYSTEMS
Many countries have at least partial surveillance systems in place to report and track antibiotic resistance trends. The Indian Council of Medical Research began setting up the Anti -Microbial Resistance Surveillance Network in 2011. Its seven nodes will focus on (i) diarrhea (e.g., Shigella, Vibrio cholerae), (ii) enteric fever (e.g., Salmonella Typhi, S. Paratyphi), (iii) sepsis caused by Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae), (iv) other Gram-negative organisms (e.g., P seudomonas aeruginosa, Acinetobacter baumannii), (v) Gram-positive bacteria (e.g., MRSA and VRE), (vi)
fungal infections (e.g., Candida spp.), and (vii)
respiratory pathogens (e.g., Streptococcus pneumoniae). Each node will focus on certain set of organisms. Medical colleges across the country will act as regional centers. 19

Antibiotic resistance data in India are also collected as a part of CDDEP's Resistance Map (www.resistancemap.org),
which represents invasive isolates from blood and
cerebrospinal fluid. Resistance Map tracks the following pathogens: E. coli, K pneumoniae, A. baumannii, S. aureus, P aeruginosa, Enterobacter spp., Salmonella Typhi, Salmonella Paratyphi, and Enterococcus spp.'
NEW ANTIBIOTICS AND OTHER INTERVENTIONS
There has been dearth of new antibiotic research and development. Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Many scientific solutions have been suggested like finding new screening strategies to identify novel antibiotic scaffolds and to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction." As of December 2014, at least 37 new antibiotics, developed by mainly small companies, were in the development pipeline for approval in the United States. Eight of these were in phase 3 trials. In 2015, teixobactin, an antibiotic belonging to a new class, was discovered through the novel growth of uncultured organisms in a laboratory at Northwestern University. Also some older antibiotics that had been largely phased out have been returned to use to treat multi drug resistant infections, colistin being the
most prominent one.
Also, for at least some antibiotics, resistance levels decrease with declining use, conserving and even
recovering some antibiotic effectiveness. In some high income countries, where antibiotic stewardship has taken hold and public health is good, antibiotic resistance levels have stabilized or declined. The availability of rapid diagnostics for the healthcare provider would greatly enhance the ability to prescribe more appropriately. A test
to distinguish a viral from a bacterial infection, for example, one based on procalcitonin levels, should decrease unnecessary antimicrobial use. More rapid susceptibility tests would aid the initial selection of an
antibiotic.'
Alternative and complementary approaches to infection control and treatment, such as improved diagnostic tools, new vaccines, and bacteriophages, will also help maintain the effectiveness of current and emerging antibiotics. Global antibiotic stewardship in the broadest sense should make it possible not only to conserve the current

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effectiveness of existing antibiotics, but even to reclaim some of effectiveness that has been lost.'
CONCLUSION
The importance and value of antibiotics cannot be
overestimated; we are totally dependent on them for the treatment of infectious diseases, but rise in antibiotic resistance in bacteria has lead to therapeutic failure. With the advent of Multi -drug resistant and Pan -drug resistant organisms, antibiotic resistance has become a major public health problem. Factors leading to this problem include increased use and misuse of antibiotics,
lack of education and awareness among public and healthcare providers, poor public health infrastructure, widespread antibiotic use in animal farming, and the
unregulated sale of cheap antibiotics.
Urgent priorities need to be implemented like improving infection prevention and control practices, optimizing
prescribing (through antimicrobial stewardship),
improving professional education, training and public engagement, developing new drugs, treatments and diagnostics, better access to and use of surveillance data, better identification and prioritization of research needs and strengthened international collaboration.
A complete understanding of the mechanisms by which bacteria become resistant to antibiotics is of paramount importance to design novel strategies to counter the resistance threat. Otherwise preantibiotic era awaits our future.
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Corresponding Author
Dr Kishore Mangal, Consultant Critical Care, 3A, Jagatpura Road, Near Jawahar Circle, Jagatpura, Jaipur.

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