Antimicrobial resistance is an all-time serious problem and clinicians, veterinarians and livestock owners are often held responsible for its emergence and spread. In the presentation, bigger players of this dogma have been revealed.

1. Who is responsible for Emerging
Antimicrobial Drug Resistance: Antibiotic
Use in Veterinary Practice or Someone Else?
“AMR is mandatory for life on Earth”
Without AMR Bacteria can’t survive in the environment loaded
with antimicrobials, and without survival of bacteria (first in food
chain) no life is possible on the Earth.
Bhoj R Singh
Pri. Scientist & Act. Head of Epidemiology
Indian Veterinary Research Institute, Izatnagar-243122, India

2. Deaths due to AMR
• Worldwide, each year about 700,000 people die from antimicrobial-resistant infections and this mortality has
been projected to reach 10 million per annum by 2050 (O'Neill, 2014).
• AMR causes 25 000 deaths annually in the European Union alone
(http://www.euro.who.int/__data/assets/pdf_file/0005/348224/Fact-sheet-SDG-AMR-FINAL-07-09-2017.pdf).
• The crude infectious disease mortality rate in India is more than 400 per 100,000 persons and at least 23,000
deaths in adults and 58,000 neonatal deaths per year are caused AMR bacteria.
(http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001974)
Deaths attributable to AMR every year by 2050
https://www.nature.com/articles/nmicrobiol2016187/figures/1

3. Antimicrobial use in human and livestock
• Globally about 35 billion doses of antibiotics (3500-5000 tons) are used for
therapy and disease prevention in human medicine, and about 50000 tons
for treatment and growth promotion in livestock and agriculture sector.
• Globally, about 20% of antimicrobials are used in humans and 80% in
livestock, but in India? Scenario is much different.
Use in Humans
Use in livestock
Indian livestock population is the
biggest in the world. Use of antibiotics
in livestock in India is much less than
anywhere else and even less than that
used in humans in India.

4. Human versus animal: Antimicrobial use in India
Antimicrobials are used as per body mass for therapy
Source: togetherabx.com/8.php
Humans Animals
Individual treatment Usually mass treatment
Human units (2012) 1.22 billion
By mass Human: Livestock::1:1.89*
Livestock units (2012) 1.24 billion by number & 2.3
billion by mass index
Antibiotics used
6.5 billion defined daily doses
= 2 billion grams= 2000 tons
~1500 tons
Ratio of antibiotic uses
Penicillin and cephalosporin use
2000 1
Quinolones and Fluoroquinolones
99000 1
Tetracyclines
0.4 0.6
Carbapenems and 4th Generation cephalosporin
1 0
31% of total antimicrobials used in livestock are ionophores that is non-antibiotics
*In US Human: Livestock::1:3.5; most commonly used antibiotics in livestock tetra & fluoroquinolones.

5. Use of Non-antibiotic antimicrobials
• Biocides/ Disinfectants and antiseptics
• Non-antibiotic, antimicrobial (NAAM) chemicals are used in much
larger quantities than antibiotics, resulting in high residual levels of
NAAM chemicals in the wider environment. For example, triclosan
(TCS), a common biocidal agent used in over 2000 kinds of products
such as toothpaste and hand washing liquids. In US alone, 1.1 ×
105 to 4.2 × 105 kg of TCS are discharged from wastewater
treatment plants (WWTPs) every year (Dann and Hontela, 2011).
• Consumption of Liquid detergents in 2008 in India was 7339
(KiloLitres~ Tons) with share of Dettol (4.8% Chloroxylenol, 84%),
Savlon (4% chlorhexidine gluconate ,13%) and Suthol (Cetrimide,
Chlorhexidine Gluconate, Neem, Turmeric, Marigold and Aloe vera,
3%). (Karania, 2012; https://www.slideshare.net/DhirKarania/dettol-marketing).
• In year 2000, worldwide production of Chloroxylenol (used as
4.8%) was estimated at 30,000 tonnes.

6. Who is responsible for emergence and
spread of AMR?
• Two fighting cats & a Monkey ?????
• Vets & Medicos WHO?
FAO?/ OIE?
Administrators/ Governments?
Pharma companies?
Consumers?
Or
All cats and Monkeys!!!!

7. Causes of Emergence of AMR
Popular beliefs propagated by WHO and FAO and
different Health Agencies & AMR Experts
• Overuse/misuse/underuse/disuse of antibiotics by
humans and the routine use of antibiotics to grow food
animals.
• Exposure of bacteria to antimicrobials. Antibiotic
exposure of bacteria in irrational/ inappropriate/ sub-
therapeutic doses.
• Where from antibiotic exposure come to Bacteria?
– Human consumption for therapeutic and preventive
purposes.
– Veterinary use for therapeutic and preventive purposes.
– Use in food production system: Animals, birds, fish,
agriculture.
– Hospital and laboratory wastes containing antimicrobials.

8. Causes of Emergence of AMR
New Dimensions
• Sanitizers: Though claims 99.99% effective in killing of germs, microbiologist in Ontario showed that just
46%-60% of bacteria were killed on the hands after use of hand sanitizers
(https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm378393.htm).
• The antiseptics and disinfectants as 10% povidone iodine, 4% chlorhexidine gluconate solution, 4.8%
chloroxylenol dettol, 2% lysol, 2% glutaraldehyde, 1% sodium hypochlorite solution, 2% liquid phenol,
chlorophenol can induce resistance gene in the microbes to be propagated to the hospital environment
(Ghosh et al., 2016; http://ijbamr.com/pdf/September%202016%20640-648.pdf.pdf)
• Biocides: Exposure to low concentrations of a variety of biocides and dyes resulted in the appearance of
resistant mutants," (SGM). "The number of efflux pumps in the bacteria increased. Because the efflux
pumps can also rid the cell of some antibiotics, pathogenic bacteria with more pumps are a threat to
patients as they could be more resistant to treatment. (Society for General Microbiology. Disinfectants Can Make
Bacteria Resistant To Treatment. ScienceDaily, 6 October 2008. www.sciencedaily.com/releases/2008/10/081005203059.htm).
• Induced MDR: Triclosan induces heritable multi-drug resistance in E. coli. The oxidative stress induced by
TCS caused mutations in fabI, frdD, marR, acrR and soxR. Mutations led to resistance by up-regulating
beta-lactamase and multi-drug efflux pump (Lu eta l., 2018; https://doi.org/10.1016/j.envint.2018.06.004).
• Chlorhexidine Induces VanA-Type Vancomycin Resistance Genes in Enterococci (Bhardwaj et al., 2016;
http://aac.asm.org/content/60/4/2209.full.pdf+html).
• Chlorinated phenols (chlorophenols) induces the mexAB-oprM-mediated antibiotic-resistant phenotype
(Muller et al., 2015; https://academic.oup.com/femsle/article/362/21/fnv172/1804557). mexAB efflux pump activation is
responsible for pan drug resistance in Pseudomonas aeruginosa even against herbal drugs (Vadhana et al.,
2017; www.researchgate.net/publication/320166069_Molecular_Studies_on_Resistance_against
_Carvacrol_in_Escherichia_coli_Pseudomonas_aeruginosa

9. Emergence of AMR due to Pharma companies
Contamination of environment (soil, water and air)
– Pharmaceutical waste from antibiotic producing pharmaceuticals polluting water bodies and soil to make natural
resources the breeding grounds for AMR bacteria. (https://www.theguardian.com/sustainable-business/2016/oct/25/antibiotic-waste-pollution-
india-china-rivers-big-pharma-superbugs-resistance), https://metamag.org/2018/02/01/era-of-life-saving-antibiotics-could-be-over-if-pharmaceutical-waste-not-tackled/,
https://www.statnews.com/2016/10/14/superbugs-antibiotic-resistance-india-china/.
– Indian and Chinese drug makers routinely release untreated waste fluid containing active ingredients into
surrounding soil and waterways. (https://www.statnews.com/2016/10/14/superbugs-antibiotic-resistance-india-china/).
– Reducing antibiotic-laden pollution from pharmaceutical manufacturing plants is a relatively easy, affordable part
of the solution. However, in India releasing all noxious wastes in to Ganges, its tributaries and other sacred rivers
is much more easier and cheaper using bribes.
• Pharma pollution an 'ignored' cause of antibiotic resistance (https://www.in-
pharmatechnologist.com/Article/2016/08/24/Pharma-pollution-an-ignored-cause-of-antibiotic-resistance).
• Pharma pollution: Shut the back door on superbugs. https://epha.org/pharma-pollution-shut-the-back-door-on-superbugs/
• DRUG RESISTANCE THROUGH THE BACK DOOR; http://epha.org/wp-content/uploads/2016/08/DRUG-RESISTANCE-THROUGH-
THE-BACK-DOOR_WEB.pdf.
• India Has Become a 'Hot Spot' of Antimicrobial Resistance. Large environmental contaminations, including
those leading to resistant organisms, have repeatedly been identified around bulk drug manufacturing plants
in India and China. "Particular bulk drug manufacturing plants in Hyderabad, South India, have been shown to
dump waste into their surroundings or fail to treat manufacturing discharges appropriately, resulting in the
contamination of rivers and lakes. (https://articles.mercola.com/sites/articles/archive/2017/05/30/antibiotic-resistance-accelerating-
near-pharmaceutical-factories.aspx).
• How Big Pharma’s industrial waste is fuelling the rise in superbugs worldwide? (Davies, 2015;
https://www.thebureauinvestigates.com/stories/2016-09-15/how-big-pharmas-industrial-waste-is-fuelling-the-rise-in-superbugs-worldwide).
• Occurrence and Abundance of Antibiotics and Resistance Genes in Rivers, Canal and near Drug Formulation
Facilities (Khan et al., 2013; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696045/).
• Pharma effluents promoting drug resistance. (Rohit, 2017; https://www.thehindu.com/sci-tech/health/pharma-effluents-
promoting-drug-resistance/article18516694.ece)

10. Source:
January 24
2018,
By Madlen
Davies , Sam
Loewenberg
https://www.t
hebureauinves
tigates.com/st
ories/2018-01-
24/big-
pharma-fails-
to-disclose-
waste-leaked-
from-factories

11. Role of Government and Regulators
• Sub-therapeutic exposure of microbes to antimicrobials
comes from the foul-play of administrators and
pharmaceutical companies in India, as:
• Misuse of antibiotics as preservative: Use of
Enrofloxacin as preservative in FMD Vaccine in India,
https://www.researchgate.net/publication/267705649_Testing_of_FMD_Vaccine_intended_to_
be_used_under_FMD-CP_of_Govt_of_India_at_CCS_NIAH_Baghpat_UP_India?_sg=-_mO-
HUl7fFptskNyZRmPrw-GZeBC7R5XZSIWMai00AO42QOqc9-
s6V4avawDLzVBDrKx9pSGmfCN1Nvk7LvHnCWwi20voqR1h4Dy0RG.xcSIPCtBcnwQecaXuz14vFbi
aWtDpOEj_F0TO6sXdhcalaZotay9K2Kh2-xF4DixVGRVN23qnEGvRGQLrpfOKw.
• Therapeutic use of sub-standard (NSQD) and fake
antibiotics in therapy.
• Therapeutic use of non-approved antibiotics in
therapy.

12. Therapeutic use of sub-standard (NSQD)
antibiotics in therapy
• Multibillion dollar business of Substandard and spurious
Antibiotics for therapeutic use.
– India is the leader.
(https://www.researchgate.net/publication/317715214_Why_India_Failed_to_Penalize_those_Responsible_for_the
_Circulation_of_Substandard_Medicines_and_Vaccines_while_China_Succeeded?_sg=-_mO-HUl7fFptskNyZRmPrw-
GZeBC7R5XZSIWMai00AO42QOqc9-
s6V4avawDLzVBDrKx9pSGmfCN1Nvk7LvHnCWwi20voqR1h4Dy0RG.xcSIPCtBcnwQecaXuz14vFbiaWtDpOEj_F0TO6sX
dhcalaZotay9K2Kh2-xF4DixVGRVN23qnEGvRGQLrpfOKw).
• As per CENTRAL DRUGS STANDARD CONTROL ORGANIZATION
(CDSCO), India, about 6.3-10.64% drugs were substandard
(NSQD) and up to 0.47% were fake, in 2010 in India.
(http://www.cdsco.nic.in/writereaddata/REPORT_BOOK_13-7-10.pdf).
• Estimated business of antibiotics in India in 2009 was Rs.
64.14 billion (Ganguly, 2011), in 2016, India consumed
antibiotics worth more than Rs. 150 billion (Dutta PTJ, 2017)

13. Not
Approved
FDCs, 75,
64%
Approved
FDCs, 43,
36%
All antibiotic FDC formulations
Not
Approved
FDCs, 20,
38%
Approved
FDCs, 33,
62%
Antibiotic FDC formulations by
MNCs
Not approved Antibiotic uses in India
Not
Approved
FDCs, 55,
85%
Approved
FDCs, 10,
15%
Antibiotic FDC formulations by
Indian firms
No one is behind, neither Indian nor
MNCs in flooding the Indian market
with “not-approved” antibiotics. Care
takers (chaukidaars) and policy makers
are sleeping, corrupt regulators are
minting money.

14. 41
79
43
75
85
3031
51
38
50
73
26
0
10
20
30
40
50
60
70
80
90
2013 2014 2015 2016 2017 2018
Number of NSQ antibiotics and producers in India from
2013 to May 2018 as per http://www.cdsco.nic.in, about
1% lots are sampled
NSQ Antibiotics reported NSQ Antibiotic Producers

15. 2506
2754
2059
2467
2319 2432
3146
3785
3937
2903
0
500
1000
1500
2000
2500
3000
3500
4000
4500
2007-08 2008-09 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15 2015-16 2016-17
Total NSQ & Fake drugs for Veterinary use in India
As per RTI (CDSCO/R/2018/50068) from CDCSO
About 5% of total medicine samples intended for use in livestock were detected NSQ & Fake over
last 10 years in India.
Action: All Pharma companies engaged in the business of NSQ & Fake drugs are still engaged in business evident
by the fact that year after year products of the same firms are found NSQ or fake.

16. How India is Fighting to beat AMR?
• In 2012, India’s medical societies adopted the Chennai Declaration, a set of national recommendations to
promote antibiotic stewardship. Banning or restricting the use of antibiotics as growth promoters in animal
livestock.
• Only one quarter line about Pharma companies in 2017 document of Chennai Declaration: Develop national
framework for surveillance of antibiotic residues and contaminants in environment including waste from farms,
factories (pharmaceutical industry, making animal feed, processing meat, dairy, fish), veterinary and human
health care settings.
• The NCDC is also drafting a National Infection Control Policy, which is in the final phases of preparation.
• Union Health Ministry has finalised “National Action Plan on Antimicrobial Resistance”. Ministers and
representatives of eleven ministries signed “Delhi Declaration” to combat Antibiotic resistance.
http://www.business-standard.com/content/b2b-pharma/health-ministry-finalises-action-plan-to-combat-
antimicrobial-resistance-117042000371_1.html, but unfortunately there are no funds allocated for
it//economictimes.indiatimes.com/articleshow/63108265.cms?utm_source=contentofinterest&utm_medium=tex
t&utm_campaign=cppst
• Kerala- the first Indian State to announce implementation of National Antibiotic policy (Jan 2018).
• The Indian Council of Medical Research (ICMR) has established the Antimicrobial Resistance Surveillance Network
(AMRSN) to monitor AMR at six reference laboratories in four tertiary care medical institutions, on six pathogenic
groups (i) diarrhoeagenic bacterial organisms, (ii) enteric fever pathogens, (iii) Enterobacteriaceae causing sepsis,
(iv) Gram negative non-fermenters, (v) Gram positives including MRSA, and (vi) fungal infections.
• Formulation of Inter-sectorial coordination committee on AMR (ICC-AMR).
• Formulation of Core Working group on AMR (CWG-AMR) under chairmanship of Director NCDC.
• Formulation of Technical advisory group on AMR (TAG-AMR) chairmanship of Director General of Health services.
• An amendment in the Drugs and Cosmetics Rules 1945 sets a timeframe for which animals treated with
antibiotics should be kept out of human food chain for 28 days. The amendment is inserted in the rule 97 of the
Drugs and Cosmetics Rules (2012).
• The Food Safety and Standards Authority of India is yet to come up with final standards of antibiotic residues in
chicken and other livestock products.

17. Scenario of AMR in Livestock versus Human
(a limited data base, about 5000 isolates from clinical sample)
62.7
44.7
32.4
20.6
57.9
23.6
19.9
7.3
24.4
78.6
31.2
13.0
25.8
21.5
7.4
17.2
3.4
22.3
71.3
40.3
17.6
27.5 28.2
14.2
16.9
7.8
23.2
64.4
50.2
29.2
26.5
51.0
21.1
23.7
12.4
35.0
67.4 66.8
20.5
29.2
54.1
12.5
7.8
4.3
10.2
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0 Human n=325
Wild life n=484
Domestic animals n=2004
Dogs & Cats n=468
Poultry birds n=262
%Resistant
1. Why resistance to Carbapenems,
tigecycline and cefepime in isolates of
animal origin, none of these is used in
livestock?
2. Why resistance in bacteria from wild
life?
3. Why bacteria causing disease in
poultry were more often sensitive?
4. Who is Responsible for AMR?

18. Comparison of resistance pattern of Human (Delhi
area)and Livestock (Bareilly area) bacteria in North India
Source: ICAR-Indian Veterinary Research Institute for Livestock 2018, WHO 2009.
59
71
35
41
61
85
50
57
65
77
0
10
20
30
40
50
60
70
80
90
Ampicillin Cephalexin Ciprofloxacin Cotrimoxazole Nalidixic acid
Resistance (%) in bacteria isolated from livestock clinical cases, Bareilly
Resistance(%) in bacteria isolated from humans AMRSN, Delhi

19. Source for Human data: http://www.dbtindia.nic.in/wp-content/uploads/ScopingreportonAntimicrobialresistanceinIndia.pdf
13.4 13.3
28.2
11.5
56.6
46.8
16.2
56.6
41.8
0.0
10.0
20.0
30.0
40.0
50.0
60.0
E. coli K. pneumoniae P. aeruginosa
Animals-Indian Veterinary
Research Institute, 2018
Humans, Gandra et al., 2016
Humans, ICMR 2015
Percentresistant
Carbapenem resistance (%) in bacteria of human and animal

20. Resistance pattern of E. coli, Salmonella, Brucella
and ESKAPE pathogens from livestock
83.65
40.35
10.86
64.27
55.40
10.25
76.54
53.99
19.59
50.00
15.22
11.11
21.67
25.00
5.36
0
10
20
30
40
50
60
70
80
90
MDR ESBL CR
E. coli (746) from healthy
E. coli (722) from sick
ESKAPE Bacteria (439) from sick animals
Brucella (46) from sick animals
Salmonella (60) from sick animals
MDR, multi-drug-resistance; ESBL, extended spectrum β-lactmase producers; CR, carbapenem resistant

21. 1.59 1.96
0.00
6.90
3.62
1.09 0.700.00
3.92
0.00
12.07
8.70
12.02
3.52
0.00
37.25
68.97
65.94
54.64
57.04
6.35
58.82
13.04
34.48
44.93
41.53
20.42
0.00
11.76
26.09
65.52
23.91
19.13
7.75
0
10
20
30
40
50
60
70
80
2012 2013 2014 2015 2016 2017 2018
Tigecycline
Meropenem
Imepenem
Moxalactam
Piperacillin
Aztreonam
Cefipime
Percentpositive
Resistance trends of E. coli isolates (722) from
diseased animals/ bird for antibiotics therapeutically
not used in Livestock

22. 88.16
53.95
3.95
88.64
56.82
18.18
94.20
49.15
18.77
81.91
64.89
25.53
61.26
54.00
8.72
81.29
30.67
4.60
71.57
73.53
0.00
0
10
20
30
40
50
60
70
80
90
100
MDR ESBL CR
E. coli from Healthy Human
(76)
E. coli from Human patients
(44)
E. coli from Healthy dogs (293)
E. coli from sick dogs (94)
E. coli from sick domestic
animals (413)
E. coli (326) healthy poultry
birds
E. coli (102) from sick birds
%Resistant AMR patterns of Escherichia coli from different sources

23. 63.16
2.63
3.95
17.11
0.00
1.32
56.58
55.2654.55
13.64 13.64
15.91
13.64
4.55
50.00
22.73
78.16
13.31
16.04
21.16
2.05 1.02
60.41 60.75
65.96
19.15
23.40
31.91
4.26 3.19
74.47
34.04
28.33
5.57
7.75
9.44
10.65
2.18
45.04
18.89
4.29 4.60 4.91
8.28
2.45
0.00
34.66
5.52
13.73
0.00 0.00
1.96
5.88
0.00
57.84
7.84
0
10
20
30
40
50
60
70
80
90
Aztreonam Imepenem Meropenem Moxalactam Colistin Tigecycline Piperacillin Cefipime
E. coli from Healthy Human (76)
E. coli from Human patients (44)
E. coli from Healthy dogs (293)
E. coli from sick dogs (94)
E. coli from sick domestic animals (413)
E. coli (326) healthy poultry birds
E. coli (102) from sick birds
AMR patterns of Escherichia coli from different sources for antibiotics
rarely or not used therapeutically in Livestock
%Resistant

24. 51.32
67.11
17.11
46.05
60.53
43.42
36.84
72.3772.70
76.45
21.84
53.58
65.19
53.58
43.34
88.7487.42
4.91
10.43
59.51
65.64
13.50
4.29
92.02
14.71
7.84
9.80
54.90
49.02
12.75
28.43
83.33
0
10
20
30
40
50
60
70
80
90
100
E. coli from Healthy Human (76)
E. coli from Human patients (44)
E. coli from Healthy dogs (293)
E. coli from sick dogs (94)
E. coli from sick domestic animals
(413)
AMR patterns of Escherichia
coli from different sources for
antibiotics commonly used in
Livestock therapeutics
%Resistant

25. 1.71
2.05
2.39
2.05
0.73
0.00
1.47
2.70
0.00
0.50
1.00
1.50
2.00
2.50
3.00
Ajowan oil Carvacrol Cinnamon oil Thyme oil
E. coli from Healthy Human (76)
E. coli from Human patients (44)
E. coli from Healthy dogs (293)
E. coli from sick dogs (94)
E. coli from sick domestic animals (413)
E. coli (326) healthy poultry birds
Herbal antimicrobial resistance patterns of Escherichia coli from different
sources
%Resistant