Antimicrobial resistance new

A Threat to Public Health
Presenter
Dr. Gaurav Rajawat
Junior Resident
Moderator
Dr. Meenakshi Kalhan
Professor
PT. B.D.SHARMA, PGIMS, ROHTAK

CONTENTS
 Overview
 Global concern
 Antimicrobial Resistance: Mechanism
 Antimicrobial Resistance: Causes
 New Delhi Metallo-Beta-Lactamase-1(NDM-1)/Super bug
 Initiatives taken by India: AMR Surveillance, National
AMR policy

Antimicrobial resistance (AMR)
is the ability of a microbe to
resist the effects of medication
previously used to treat them.
DEFINITION
This broader term also covers antibiotic resistance, which
applies to bacteria and antibiotics.

NO
Antimicrobial resistance (AMR) is a property of the
microbe, not of a person or other organisms infected
by a microbe.

 There are definitepolicies/guidelines for appropriate
use of antimicrobials at national level in specific
national health programmes being run in the country
e.g. RNTCP, National AIDS Control Programme, etc.
 But for other diseases of public health importance like
enteric fever, diarrhoeal disease, respiratory infections,
etc individual hospitals are following their own
antimicrobial policies and hospital infection control
guidelines.
 To monitor antimicrobial resistance it is necessary to
have regulations for use and misuse of antibiotics in
the country.

The Centers for Disease Control and Prevention (CDC)
estimates more than two million people are infected
with antibiotic-resistant organisms, resulting in
approximately 23,000 deaths annually in the United
States, costing $20-$35 billion annually.
In Europe, an estimated 25,000 deaths are attributable
to antibiotic-resistant infections, costing €1.5 billion
annually.
In India, it is estimated that 58,000 neonatal sepsis
deaths are attributable to drug resistant Infections.
Center for Disease Dynamics, Economics & Policy, 2015.

Three agents of greatest concern
associated with both hospital- and
community acquired infections.
 E-coli
 Klebsiella pneumoniae
 Staphylococcus aureus
WHO 2014, reported E. coli
resistance of more than 50 %
ﬂuoroquinolones and 3rd gen.
cephalosporins.
K.pneumoniae resistance rates to 3rd
generation cephalosporins exceed 30-
60%.
MRSA resistance rates exceed 20-
80%.
Percentage of Staphylococcus aureus
isolates that are methicillin resistant
(MRSA), by country (2011-14)

 Between 2000 and 2010, total global antibiotic
consumption grew by more than 30 percent, from
approximately 50 billion to 70 billion standard units.
 In most countries, about 20 percent of antibiotics are
used in hospitals and other healthcare facilities, and
80 percent are used in the community, either
prescribed by healthcare providers or purchased
directly by consumers or caregivers without
prescription.

 The countries consuming the
most antibiotics overall in 2010
were India, 13 billion SU; China,
10 billion SU; and the United
States, 7 billion SU.
 However, in per capita terms
among these countries, the
United States led in 2010 with 22
SU per person, compared with 11
SU in India and 7 SU in China.
ANTIBIOTIC CONSUMPTION:
WORLD

TOTAL ANTIBIOTIC CONSUMPTION IN
SELECTED COUNTRIES, 2000 AND 2010
WHO study, 2011 showed that 53% of Indians were taking
antibiotics without a prescription.

Mechanism Antibiotic Resistance
Intrinsic (Natural) Acquired
Genetic Methods
Chromosomal Methods
Mutations
Extra chromosomal Methods
Plasmids

Bacteria resist the effects of antibiotics by using the
following genetic strategies, with thousands of variations:
 Producing destructive enzymes to neutralize antibiotics.
 Modifying antimicrobial targets, by mutation, so that
drugs cannot recognize them.
 Removing antimicrobial agents by pumping them out
(efﬂux).
 Preventing antibiotics from entering by creating a
“bioﬁlm” or otherwise reducing permeability.
 Creating by passes that allow bacteria to function
without the enzymes targeted by antibiotics.
Source: Penesyan et al. (2015)

 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
Yes
Mira PM, Crona K, Greene D, Meza JC, Sturmfels B, Barlow M (2015) Rational Design of Antibiotic Treatment
Plans: A Treatment Strategy for Managing Evolution and Reversing Resistance. PLoSONE 10(5): e0122283.
doi:10.1371/journal.pone.0122283

1. Inappropriate use & misuse of
antibiotics
2. Indiscriminate use of antibiotics
in agriculture and veterinary
practice
3. Insufficient research and
development

Three main types of misuse as underlined by the
European Centre for Disease Prevention and Control
(ECDC) :
 The unnecessary prescription of antibiotics for viral
infections.
 Frequent prescription of “broad-spectrum antibiotics”,
instead of better targeted antibiotic.
 Patient failure to adhere to regimens for prescribed
antibiotics.

Practical Guide to ANTIMICROBIAL STEWARDSHIP in hospitals.pdf
2015

 No drug needed e.g. unnecessary & ineffective
antimicrobials or antidiarrhoeals given instead of Oral
Rehydration Solution.
 Unsafe drugs e.g. Analgin (Dipyrone) banned in most
developed countries, but is used in many developing
countries.
 Under use of available effective drugs e.g. ORS not used
effectively.

 Ineffective drugs & drugs with doubtful efficacy e.g.
unnecessary excessive use of tonics & multivitamin
preparations.
 Incorrect use of drugs e.g. overuse of Injections
 Many viral infection (sore throat, sinusitis, conjunctivitis
etc ) does not need antibiotics for treatment.

 Antibiotic-resistance genes are
used in genetically modified crops.
 Antibiotics are also sprayed onto
fruit trees to prevent and treat
infection.
 The use of antibiotics in feed
supplements given to farm animals
to promote animal growth and to
prevent infections (rather than
cure infections).
An estimated 80 percent of all antibiotics consumed in
the United States are used in food animals (U. S. FDA

The use of the antibiotic avoparcin as a growth promoter
in food animals in Europe resulted in the development
and amplification of Vancomycin Resistant Enterococci
(VRE) and subsequent colonization in human intestine.
Enerofloxacin was approved for use in food production
animals in many countries. The use of this antibiotic in
food animals has resulted in the development of
ciprofloxacin-resistant strains of Salmonella spp. and
Campylobacter spp.
The use of animal feed supplements with the antibiotic
tylosin has led to the development of erythromycin-
resistant streptococci and staphylococci.
European Union (EU) has banned the use of animal growth promoting
antibiotics (tylosin, spiramycin, bacitracin and virginiamycin)

 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. Two-thirds of the increase is due to increase
in the number of animals, and the remaining one third is
due to the shift from extensive to intensive farming .

Antibiotic Consumption In Livestock,
Top Ten Countries 2010–2030 (projected
for 2030)

 Non-therapeutic uses of antibiotics common in poultry
production. However, currently there is no regulatory
provision regarding the use of antibiotics in livestock.
 The prescribed tolerance limit (mg/Kg) of antibiotics use
shall not exceed for sea foods including shrimps, prawns
or any other variety of fish and fishery products (The
Prevention of Food Adulteration Rules, 1995-part XVIII)
a) Tetracycline (0.1) mg/Kg
b) Oxytetracycline (0.1) mg/Kg
c) Trimethoprim (0.05) mg/Kg
d) Oxolinic acid (0.3) mg/Kg

 Industry uses larges volumes of
detergents and disinfectants - including
quaternary ammonium compounds
(QACs) - known together as biocides
 Nearly all domestic cleaning products
and shampoos also contain QACs.
 They wash out in large volumes with
the waste water from factories and
homes.
 QAC resistance genes are significant
because they are often located with
antibiotic resistance genes on the same
piece of DNA, so exposure to one will co-
select for the other.

 Pharmaceutical industries do not consider antibiotic
development as an economically wise investment as
antibiotics are used for relatively short duration.
 Antibiotics are not as profitable as drugs that treat
chronic conditions, such as diabetes, asthma, psychiatric
disorders.
 Fast development of resistant strains also making
antibiotic ineffective soon

4. Regulatory approvals–
 Red tapism, no clear rules and
regulations
 Differences in clinical trial
requirements among countries
 Changes in regulatory and
licensing rules.

 New Delhi Metallo-beta-lactamase 1 (NDM-1) is a
genetic element with multiple resistance genes that can
be harbored by and transmitted between Gram-negative
bacteria.
 NDM-1 was first described by Yong et al in 2009.
http://aac.asm.org/content/53/12/5046.full?view=long&pmid=19770275

 It was first identiﬁed in a Swedish patient returning
from New Delhi, India, in 2008.
 The infection was unsuccessfully treated in a New Delhi
hospital and after the patient's repatriation to Sweden, a
carbapenem-resistant Klebsiella pneumoniae strain
bearing the novel gene was identified.
 The authors concluded that the new resistance
mechanism "clearly arose in India, but there are few
data arising from India to suggest how widespread it is

 In Aug,2010 a study by a
multi-national team was
published in a journal ’The
Lancet Infectious
Diseases’ which reported
many NDM-1 resistance
cases in India.
 The authors concluded
that India should be
avoided for elective and
cosmetic surgeries because
of NDM-1 bacterial strain

This reported 37 cases isolates with NDM-1 in the United Kingdom, 44
in Chennai, 26 in Haryana, and 73 in various other sites in Pakistan
and India.
An environmental point prevalence study conducted between 26
September and 10 October 2010 found bacteria with the NDM-1 gene in
drinking water and seepage samples in New Delhi. (Johnson and Woodford
2013)

 On 12 January 2011, the editor of The Lancet, Richard Horton,
apologized and acknowledged that naming a superbug after New
Delhi was an "error".“
 Following this, Ajai R. Singh, editor of Mens Sana Monographs,
demanded that such 'geographic names giving' be abandoned and
replaced by 'scientific name giving'.
 He proposed changing NDM-1 to PCM (plasmid-encoding
carbapenem-resistant metallo-beta-lactamase)
Furthermore name is not changed yet and follows the naming of most
genes of this type.
• VIM: Veronna imipenemase in Italy
• GIM: Germany imipenemase
• DIM: Dutch imipenemase

 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.

 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.
 Patients with NDM-1-related infections have been treated
with a combination of medications, but there is no
effective treatments are available for many of the
infections caused by NDM-1.

 Better hygiene -preventing infections from happening
in the first place.
 To have access to safe 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.

1. 12th Five Year Plan- Containment of AMR
2. The National Policy for Containment of Antimicrobial
Resistance
3. National Anti-Microbial Resistance Research and
Surveillance Network (AMRRSN)
4. Jaipur declaration (a WHO initiative)
5. Chennai declaration
6. The Drugs and Cosmetic Rule, 1945 were amended in
2013 to include a new Schedule H1.
7. National Treatment Guidelines for Antimicrobial Use in
Infectious Diseases

8. 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

A National Programme for containment of AMR has
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

Released in 2011 & yet to be implemented
 Key points-
a) Proposed Actions to monitor Sale of Antibiotics
b) Set up an Antibiotic Management Team (AMT)
c) Establishment of inter-sectoral coordination
committee
d) Reducing antibiotic selection pressures by
appropriate control measures
e) Promotion of discovery of newer and effective
antimicrobials based on current knowledge of
resistance mechanisms

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 license for contravention of the
provision of Schedule H1

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.
 Central Council for Scientific and Industrial
Research
 Ministry of Health and Family Welfare,
 Indian Council for Agricultural Research
 Department of Animal Husbandry .

 The Indian Council of Medical Research began
setting up the Anti-Microbial Resistance
Surveillance Network in 2011.
 When complete, its focus will be on:
1. Diarrhea (e.g.,Shigella, Vibrio cholerae)
2. Enteric fever (e.g., Salmonella Typhi , S. Paratyphi)
3. Sepsis caused by Enterobacteriacea (e.g., E-coli, Klebsiella
pneumoniae)
4. Gram-negative organisms (e.g., Pseudomonas aeruginosa,
Acinetobacter baumannii)
5. Gram-positive bacteria (e.g.,MRSA and VRE)
6. Fungal infections (e.g., Candida spp.), and
7. Respiratory pathogens (e.g., Streptococcus pneumoniae).

1. Identification of the pathogens / diseases of public
health importance for surveillance- Extended Spectrum-
lactamases [ESBLs] and Metallo -lactamases [MBLs], NDM-1,
MRSA & VRE
2. Creating a network of AST laboratories- In the first phase,
the following three central Govt. Hospital in Delhi will be
included for AMR surveillance.
a) Sucheta Kriplani Hospital (SKH) & Lady Hardinge Medical College
(LHMC), New Delhi
b) Dr Ram Manohar Lohia (RML) Hospital, New Delhi
c) Vardhman Mahavir Medical College (VMMC) and Safdarjung Hospital,
New Delhi

3. Standardize methodology for microbial identification and
AST- Laboratories should be having expertise to do MRSA, ESBL
and Carbapenemase (Modified Hodge test / Imipenem + EDTA E
test) testing.
4. AST Data analysis - WHONET 5 for AST data reporting and
analysis
5. Dissemination of AMR data- The AMR data generated by the
respective network laboratories should be sent to the coordinating
center, regularly on a quarterly basis.
6. Development of National Repository of Bacterial strains /
cultures - Institute of Microbial technology (IMTECH),
Chandigarh has the requisite infrastructure and expertise to do the
same.

 A one day sensitization workshop for the senior
microbiologists of the network laboratories.
 2-3 days training workshop for junior microbiologist/
data reporting personnel on various aspects of AST
specially quality control and data analysis/
transmission.
 Followed by regular monitoring and review meetings
once in 6/12 months

 New and simple surveillance tools with the capability to
detect AMR at the lowest capable health centre should
be developed and its ability to track the infection should
be established.
 All surveillance activities should be linked with
epidemiological studies particularly surveillance around
relevant vaccination programs.
 A National Health Policy Unit should be entrusted with
analysis of the surveillance data and provide advisory
for framing of policies for use of antibiotics according to
region, nation or hotspots.

 The drug testing laboratories in the country should be
strengthened in terms of infrastructure, number and
also training of drug inspectors.
 The supply of a drug mentioned in Schedule H1 shall be
recorded in a separate register at the time of the supply.
 It contains 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.

 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.
 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.

 Incentives should be given to pharmacies for not
selling antibiotics without prescription and
appropriate regulation for the same should be
formulated.
 Appropriate steps will be taken to curtail the
availability of fixed dose combination of antibiotics
in the market, by and large combinations should be
discouraged except for naturally interactive ones
like Cotrimoxazole, Amoxyclave, etc.

 Two of the best known national campaigns took place in
France and Belgium.
 In France, which once had the highest rate of antibiotic
consumption in Europe, the government launched an
awareness campaign called “Antibiotics are not
automatic” in 2001, as a part of a program to preserve
antibiotic effectiveness.
 This campaign achieved a reduction in antibiotic
prescribing of 27 percent over ﬁve years in all regions of
the country, with the greatest decline, 36 percent, in
children 6 to 15 years of age.
 Belgium, the Belgian Antibiotic Policy Coordination
Committee established a national media campaign in
2000 that succeeded in reducing antibiotic prescribing
by 36 percent over seven years.

 Drug division of Haryana has worked for promotion
of rational use of Medicines during the 2012-2013
Activities-
a. Prescription audits
b. Trainings and workshops on rational drug use
c. Publication of material on rational drug use
3. Audit of drug stores
4. Setting up Centralized Medicine Testing Unit.

 Incomplete format of Prescriptions- In 58% prescriptions,
all drugs were written in generic names. In 27% of
prescriptions a mix of generic and brand naming of drugs
were used.
 Polypharmacy- It was found that the number of drugs
prescribed per encounter in hospital was 3.4 and higher
than the WHO recommended values of 1.6-1.8
 Treatment was incomplete in respect of dosage form,
strength, frequency and duration of the treatment.

 No mention of drug strength - In 71% prescriptions, none
of the drugs that were prescribed mentioned the
strength.
 Overuse of analgesics and antibiotics-
54 % prescriptions were having antibiotics as compared to
the WHO standard of 15-25%. While, 57% of the
prescriptions were having analgesics.

• Using antibiotics, prescribed by a doctor
• Completing the full antibiotic course, even if they feel better
• Not sharing antibiotics with others or using leftover
prescriptions.
• Public health education and awareness
• Stopping the use of antibiotics as growth-promoters in farm
animals.
People
• Enhancing infection prevention and control
• Prescribing and dispensing antibiotics only when they are
truly needed, after 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
Health workers and pharmacists
How to tackle resistance- Contribution from all
stakeholders

• 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
Policymakers
• Promoting innovation and research and development of
new tools
• Promoting Cooperation and Information Sharing Among
all Stakeholders.
Industry
Cont..

 National policy for containment of antimicrobial resistance
India 2011.Pdf
 Global action plan on antimicrobial resistance 2015.pdf
 Center for Disease Dynamics, Economics & Policy, 2015.pdf
 HSHRC Annual Report 2012-13.pdf

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