Overuse and misuse of antibiotics have long been believed to fuel antimicrobial resistance (AMR), but new research shows that simply lowering consumption is not enough. Poor sanitation, corruption and low public health spending have a bigger role in pushing up drug-resistant infections in low- and middle-income countries, including India.

1. Unusual causes of the emergence of the
Antimicrobial drug resistance
BR Singh
Pri. Scientist Head
R Karthikeyan & A. Yadav
Division of Epidemiology
Indian Veterinary Research Institute, Izatnagar-243122, India
Bhoj R Singh

2. Causes of 2.68 million deaths during the neonatal period in 2015, worldwide; 40100 dies
due to sepsis. (https://www.who.int/en/news-room/fact-sheets/detail/congenital-anomalies)
Surge In Antibiotics Is A Boon For Superbugs
https://www.npr.org/sections/goatsandsoda/2018/03/26/597014559/s
urge-in-antibiotics-is-a-boon-for-superbugs
Bhoj R Singh

3. 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 annul by 2050 (O'Neill, 2014). The crude infectious disease mortality rate in
India is more than 400 per 100,000 persons (0.4%) 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)
• NEW ZEALAND: Surge in the spread of superbug, doctors warn urgency to address life threatening problem.
https://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=12129249
10 million deaths attributable to AMR every year by 2050 globally and 2 million may be in India
alone. https://www.nature.com/articles/nmicrobiol2016187/figures/1
Bhoj R Singh

4. Why no or rarely any new antibiotic introduced in last one decade?
• A 2017 estimate puts the
cost of developing an
antibiotic at around US$1.5
billion (Towse, A. et al. 2017.
Health Policy 121, 1025–
1030). Meanwhile, industry
analysts estimate that the
average revenue generated
from an antibiotic’s sale is
roughly $46 million per year.
“That’s tiny and nowhere
near the amount needed to
justify the
investment,” because life of
the antibiotic is not much.
• Wockahrdt could introduce a
new (a derivative of flocaxin,
Levonadifloxacin) antibiotic
in Indian market after 15
years in January 2020). Bhoj R Singh

5. Global antibiotic consumption by country income classification
(India is the largest consumer of antibiotics)
(Klein et al, 2018,
http://www.pnas.org/content/pnas/early/2018/03/20/1717295115.full.pdf)
Bhoj R Singh

6. Antimicrobial use: Human versus 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. New
Estimates are >100 000 tonnes of antibiotic uses in livestock (OIE, 2019)
• Globally, about 10% of antimicrobials are used in humans and 90% in
livestock, but in India?
Use in Humans
Use in livestock
Van Boeckel et al. (2015) predicted 312% growth
in antibiotic use in poultry in India by 2030.
Bhoj R Singh

7. 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? Not in India.
Human units (2012) 1.22 billion
By mass, in India Human: Livestock::1:1.89*
*In US Human: Livestock::1:3.5
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
Global Antimicrobial uses in livestock (OIE, 2019)
Antimicrobial groups African countries Americas Asia Europe
Penicillin and cephalosporin use 5.6% 9.6% 17.4% 20.5%
Quinolones and Fluoroquinolones ~11.7% 3.5% 1.9% 2.6%
Tetracyclines 31.7% 40.8% 31.2% 41.2%
Macrolides 8.8% 5.8% 11.8% 8.1%
31% of total antimicrobials used in livestock are ionophores that is non-antibiotics
Bhoj R Singh

8. Importance of Antibiotics in economy
• Antibiotics constitute 12% of the Indian
pharma market.
• India's antibiotics market = Rs 16,000 Crore,
30-40% is of injectable antibiotics.
• The Pharma sector contributed around 1.72
per cent to the country's GDP.
• Livestock sector contributes 4.11% GDP and
25.6% of total Agriculture GDP.
Bhoj R Singh

9. Causes of Emergence of AMR
Popular beliefs
• Misuse and Overuse of antibiotics by humans and the
routine use of antibiotics to grow faster the food animals
are key causes.
• Exposure of bacteria to antimicrobials. Antibiotic
exposure of bacteria in irrational/ inappropriate/ sub-
therapeutic doses.
• Where from antibiotic exposure come to Bacteria?
Use of antibiotics (irrespective of proper or improper use)
– 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.
Bhoj R Singh

10. New Dimensions in emergence of AMR
• Overuse and misuse of antibiotics have long been believed to fuel
antimicrobial resistance (AMR), but new research shows that simply
lowering consumption is not enough. Poor sanitation, corruption and low
public health spending have a bigger role in pushing up drug-resistant
infections in low- and middle-income countries, including India.
• 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).
• Loads of hand sanitizers in India are of Non-standard quality (>20 batches in
2020).
• 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)
Bhoj R Singh

11. New Dimensions
• 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
Bhoj R Singh

12. 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 disinfectants 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 was
estimated at 30,000 tonnes.
Bhoj R Singh

13. Role of Government and Regulators in
Emergence and Spread of AMR
• 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_t
o_be_used_under_FMD-CP_of_Govt_of_India_at_CCS_NIAH_Baghpat_UP_India?.
• Therapeutic use of sub-standard (NSQD) and fake
antibiotics in therapy.
• Therapeutic use of non-approved antibiotics in
therapy.
• Pharmaceutical waste disposal in to environment.
Bhoj R Singh

14. 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/
Bhoj R Singh

15. Pharma pollution
• 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)
Bhoj R Singh

16. 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
Bhoj R Singh

17. Indian drug companies try to gut antibiotic
pollution controls
• In January 2020, the Indian government published a draft bill to introduce
its first limits on the concentration of 121 common antibiotics that can be
discharged into rivers and the surrounding environment. The bill came
after several investigations by the Bureau and Changing Markets and
campaigning by the Centre for Science and Environment in New Delhi and
the Stockholm International Water Institute.
• The Indian Drug Manufacturers Association (IDMA) has lobbied both the
Ministry of Environment, Forests and Climate Change and the Central
Pollution Control Board. In a letter to the ministry, the association claimed
that if the proposed environmental measures go ahead, the industry
would face “untold miseries from litigations and harassment by the
activist and regulator alike”.
(https://www.thebureauinvestigates.com/stories/2020-03-31/indian-drug-
companies-try-to-gut-antibiotic-pollution-controls).
• Being the most Pharma friendly Nation (https://azad-
azadindia.blogspot.com/2021/01/india-worlds-most-corporate-
pharma.html), the bill is dumped now.
Bhoj R Singh

18. 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)
Bhoj R Singh

19. 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 in Indian Market
Not
Approved
FDCs, 55,
85%
Approved
FDCs, 10,
15%
Antibiotic FDC formulations by Indian
firms
No one is behind, neither Indian
pharmas nor MNCs in flooding the
Indian market with “not-approved”
antibiotics. Care takers (Chaukidaars)
and policy makers are sleeping, &
corrupt regulators are minting money.Bhoj R Singh

20. Bhoj R Singh
41
79
43
75
85
73
118
97
31
51
38
50
73
63
89
78
0
20
40
60
80
100
120
140
2013 2014 2015 2016 2017 2018 2019 2020
Number of NSQ antibiotics and producers in India
from 2013 to December 2020 (CDSCO, India)
https://cdsco.gov.in/opencms/opencms/en/Notifications/Alerts/
Only ~ 1% lots are sampled for testing, reality may be 100 times more serious
NSQ antimicrobial bactches
NSQ antimicrobial producers

21. 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 doing business evident by the fact
that year after year products of the same firms are found NSQ or fake.
Bhoj R Singh

22. Bhoj R Singh