Superbugs the deadly monsters.

1. SUPERBUGS
EMERGING THREAT AND WHO IS RESPONSIBLE ?
Credit Seminar
By: KUSHAL GRAKH

2. What is Superbug ?
 When bacteria resist the effects of an antimicrobial agent, it is referred to as
resistant.
 If a bacterial strain is exceedingly resistant to almost every known/antibiotics
available, it is informally called “a superbug” or “a super bacterium”
implying a super fighter against antimicrobial agents (Reinhardt, 2010).

3. Mechanism of resistance

4. Rise of Superbugs
 AMR - existed ten thousand years before modern man
discovery of medicines.
 A 1000 year-old mummies- Inca Empire –resistant
bacteria from gut.
 DNA found in 30, 000-year-old permafrost sediments
from Bering - contain genes that encode resistance to a
wide range of antibiotics (Balamurugan et al 2018).

5. Superbugs – Emerging Threat
 The effective treatment of infections and diseases- under threat.
 Infections by superbugs claims 700,000 lives annually around the world.
 Every year- 23,000 deaths in America (CDC 2018), 25,000 in Europe and 80,000 deaths
in China -antibiotic-resistant infections.
 300 million premature deaths are expected over the next 35 years due to AMR
worldwide (WHO 2018).
(Review on Antimicrobial Resistance, December 2014, Antimicrobial Resistance: Tackling a Crisis for the
Health and Wealth of Nations)

6.  Superbugs would make medical procedures such as organ transplants, surgery
and chemotherapy impossible.
 The rise in super bugs causing Ventilator-Associated Pneumonia (VAP) - major
cause of mortality despite recent advances in management (Quereshi et al 2015).
 Post-antibiotic era-minor injuries - lethal
 Once curable diseases - untreatable.
 If not addressed -expected loss - US$100 trillion (globally), lowering projected
GDP by 2 to 3.5 percent.
 Due to global spread - serious and highly contagious illnesses such as gonorrhoea
and pneumonia, may soon become incurable.
(Review on Antimicrobial Resistance, December 2014, Antimicrobial Resistance: Tackling a Crisis for the
Health and Wealth of Nations)
Emerging Threat……

7. Nightmare superbugs
 In Nevada (USA) woman in her 70s was hospitalized (August 2016) after returning from an
extended trip to India.
 Infected with multidrug-resistant Klebsiella pneumoniae resistant to 26 antibiotics.
 Died in September from multiple organ failure and sepsis.
 Klebsiella pneumoniae was found in patients at Christian Medical College (CMC), Vellore
after they were admitted for sepsis.
 At CMC, Vellore- 31 per cent patients treated for sepsis in the hospital become infected by
a strain of Klebsiella pneumoniae - both resistant to antibiotics and hypervirulent.

9. India
Every section of the population is at risk.
 More than 23,000 adults die annually due to AMR.
 Newborns are particularly vulnerable to AMR
because- immune systems are fragile, leaving little
time for doctors to find a drug that works.
 More than 58,000 Indian babies died in 2013 as a
result of AMR - a serious setback to progress in
reducing Indian infant mortality rates.

14. Resistance trends- India
During the period from 2008-2014 in India
 MRSA – from 29% to 47%
 Cabapenam resistant E. coli- from 10 to 13%.
 Flouroquinolones resistant Salmonella isolates from 8% to 28%.
 Kebsiella pneumoniae- pneumonia, meningitis, bloodstream infections and urinary tract
infections - 29% to 57%.
 V. cholerae O1 resistant to ampicillin, furazolidone, ciprofloxacin, and tetracycline.
Source: The State of Worlds Antibiotics, 2015 Center for Disease Dynamics, Economics and Policy (CDDEP)
National action Plan –AMR 2017

16. Who is responsible?

17. Inappropriate use in humans
Over-prescription/Overuse
 In the 76 countries studied consumption increased from 21.2 billion in 2000 to 34.8 billion in
2015.
 Global consumption - set to rise by 67% between 2010-2030.
 In the BRICS countries(Brazil, Russia, India, China, and South Africa)- the estimated increase –
99% - up to seven times projected population growth.
 India-largest consumer of antibiotics for human health. (Laxminarayan et al 2016)
 Patient with preconceived ideas and demand quick relief
 Fear of losing customers - Doctors compelled to give antibiotics
(Chandy et al 2013)

18. In Humans…
Prescription for non-bacterial illnesses
 Common cold, sore throat etc.
Self medication
 To avoid financial burden of expensive allopathic medical visits
 Access to antibiotics without prescription (GARP India 2011; Barker et al 2017)
 Source: previous doctors prescription, leftover medicines from previous illness

19. High consumption of broad spectrum antibiotics
 Diagnostic uncertainties
 Lack of microbiology diagnostic laboratory services
 Incentives to prescribe new broad spectrum antibiotic
 Less time to counsel against use of antibiotic and instead prescribe them
 To dispose near to expire antibiotics (Kotwani et al., 2010; GARP India 2011)
Failure to complete a course of treatment
Prescription/treatment from informal healthcare providers/quacks/pharmacists
 Consider themselves not less than doctor
 Lack knowledge of when to use antibiotics

20. Non -therapeutic use of antibiotics
Overuse In intensive livestock farming
 More antibiotics are given to healthy animals than are used to treat diseases among
human patients (WHO, 2012).
 India accounts for 3% of the global consumption and is the fourth highest in the
world, behind China (23%), the United States (13%) and Brazil (9%) in 2010.
 The consumption of antibiotics in food animals in India will be double by 2030.
(Inter-ministerial Review Meeting on Antimicrobial Resistance, 2016).
Substitute for healthier living conditions (Laxminarayan 2016)
 Routine feeding -to help them endure crowded, dirty, and stressful conditions.
Use of enrofloxacin in FMD vaccines as preservative (Singh 2016)

21.  As a growth promoter
 Poultry farmers – prevention is better than cure
 Common practice
 Cheap antibiotics
 Antibiotics critical to human health such as tetracycline , doxycycline, ciprofloxacin and
even colistin are commonly used for growth promotion in poultry. (Brower et al 2017; CSE
2014).
 Residues of antimicrobials -detected in chicken meat (Sahu and Saxena 2014).
 Use of polymixins in food animals-Emergence of plasmid mediated mcr-1 gene with (Liu
et al 2016)
 149 unique resistance genes detected- manure from pigs –China
Non -therapeutic use of antibiotics

22.  "Some veterinarians' profit margins are bigger than those of cocaine dealers. When a
veterinarian finds a sick chick among 20,000 other chicks, he treats the discovery as
justification to preventively treat the entire flock with antibiotics.
( Der Spiegel 2012)
Report on factory use of antibiotics in Germany, 2012 Spiegel, Addicted to
Antibiotics: How Factory Farm Drug Abuse Makes Vets Rich.

23. Pharmaceutical industry
 The Indian pharmaceutical industry supplied 20 percent of generic drugs – US $15 billion
in 2014 ( Nordea Asset Management, 2014)
 Almost 80 percent of the antibiotics sold by multinational companies on global market are
manufactured in India and China (Sum of Us 2015).
Release of antibiotics into the environment
 Waste water effluents (Lubbert et al 2017)
 Resistance to three major classes of antibiotics- cephalosporins, carbapenems and the
fluoroquinolones detected in water samples from river, sewage treatment plant etc. in and
around pharmaceutical companies in Hyderabad and Chennai (Sum of Us 2015).
 Improper disposal of expired or leftover antibiotics- ideal breeding ground for drug
resistant bacteria.

25. Antibiotic Fixed dose Combination (FDCs)
 Lack of diagnostic precision
 Unavailability of diagnostic laboratory services – increased use of antibiotics FDCs
in India (Gautam and Saha 2008).
 Approximately 118 FDCs are available in India (Shankar et al 2016).
 Of these 118 formulations, 64 per cent are not approved by the national drugs
regulator, the Central Drugs Standard Control Organisation (Business world 2018).
 The lack of investment in new drug discovery.
 In 2004, in the 15 largest pharma companies, only 1.6% of the drugs in the
development stages were antibiotics- none from novel classes, nor were they
targeted to treat multidrug resistant agents.
Pharmaceutical industry

27. Double Standards
 According to pharmaceutical company Zoetis (a former subsidiary of Pfizer )-They are
leader in providing ongoing education to veterinarians and livestock producers on the
proper use of antimicrobial drugs.
 In 2013, Zoetis said it “supports the FDA’s efforts to voluntarily phase out growth
promotion indications for medically important antibiotics.
 But company still sells its antibiotics to Indian farmers - regulation and enforcement is
more lax (Bureau of Investigative Journalism). Ban - European countries and USA-
removed growth promoter labels but continued supply in India.
 In India Zoetis (Neftin-T), Venkys (Colis-V), Vetline (PROGRO-VET), Kaizen Bio Sciences,
Vet-Needs Labs, NeoSpark (DoxiStin-FS, RimoDox-2%-FS CTC-150-FS etc.)
 Zoetis recommends feeding Neftin-T to chickens to “improve weight gain and FCR.

29. Double Standards

30. Justification provided by companies
 Officially there is no ban in India for the specified usage of colistin in farm animals… As
law abiding company, we will never deviates the law of the land……..Neospark.
 Each country enacts regulations appropriate for their market needs and standards, and we
work with the national regulatory authorities in various countries, including India, to
understand, respect and comply with local regulatory interpretation and oversight……….Pfizer
and Venkys.
 “If an American company follows one policy in America, they should follow the same policy in
India- Chennai Declaration.
Source: The Bureau of Investigative Journalism, The Hindu, The Daily Telegraph

31. Lack of overall hygiene and sanitation
 Poor sanitation plays major role in the spread of resistant bacteria and ARGs (antibiotic
resistant genes).
 More than 50 percent Indian population lack access to sanitation facilities for safe
disposal of human waste (World Bank 2017).
 Untreated sewage into water bodies - contamination of rivers with antibiotic residues,
antibiotic resistant organisms and ARGs (Marathe et al 2017).
 Risk of asymptomatic colonization with ESBL producing E. coli among Swiss travelers
visiting India was 87 percent (Kuenzli et al 2014).

32. Cultural activities
 Mass bathing in rivers
 blaNDM-1 was found to be 20 times greater in the river during pilgrimage season than
at other times of year in Upper Ganges (Ahammad et al 2014).
 Pilgrimage sites thus can act as hot spots for transmission of resistant bacteria and
genes.

33. Hospital acquired
 Medical equipment, such as ventilators and catheters, might be transmission sites for these
new strains.
 Human-to- human transmission may also be possible, but clinical settings are most
vulnerable.
 For eg; HA-MRSA, infections aquired with use of catheters and other surgical and diagnostic
procedures.

34. WHO list of superbugs
Priority 1: Critical Priority 2: High Priority 3: Medium
1. Acinetobacter baumannii,
carbapenem-resistant
4.Enterococcus faecium, vancomycin-
resistant
10. Streptococcus pneumoniae,
penicillin-non-susceptible
2. Pseudomonas aeruginosa,
carbapenem-resistant
5. Staphylococcus aureus, methicillin-
resistant, vancomycin-intermediate and
resistant
11. Haemophilus influenzae,
ampicillin-resistant
3. Enterobacteriaceae, carbapenem-
resistant, ESBL-producing
6. Helicobacter pylori, clarithromycin-
resistant
12. Shigella spp., fluoroquinolone-
resistant
7. Campylobacter spp.,
fluoroquinolone-resistant
8. Salmonellae, fluoroquinolone-
resistant
9. Neisseria gonorrhoeae,
cephalosporin-resistant,
fluoroquinolone-resistant WHO, 2017

35. MRSA
 Most recognized superbugs - common in many hospitals throughout the world.
 Methicillin- introduced in 1959 -treatment of penicillin-resistant S. aureus.
 MRSA was first detected in 1961 (Ippolito et al., 2010).
 At first- limited to hospitals and healthcare settings -hospital acquired MRSA infection.
 Since the late 1990s- emergence of community-acquired MRSA strains with rapid
spread and causing fatal diseases (Ippolito et al., 2010).
 Most MRSA strains exhibit resistance to multiple drugs including penicillin, methicillin,
tetracycline, erythromycin and vancomycin (de Lencastre et al., 1996; Smith et al., 2014).

36. LA-MRSA
 LA-MRSA- increasingly identified in humans and could be associated with very severe
diseases and even death(Chen et al 2018).
 MRSA - reported in diverse species - dogs, cats, sheep, chickens, horses, rabbits, seals,
birds, one turtle, bat, guinea pig and chinchilla (Morgan et al 2008).
 In one report, four dogs suffered postoperative infections with MRSA after a surgery at
veterinary hospital.
 Around 5-7% of veterinary personnel and students found to be nasal carriers in
Netherland and USA.
 LA-MRSA was identified in 78% of 373 MRSA-colonized patients upon admission to two
hospitals during 2008 and 2009 (Bruinsma et al 2015).
 These studies are enough to introduce the challenge to veterinarians in form of newer
and stronger zoonoses.

38. NDM-1
 Escherichia coli and Klebsiella pneumoniae harboring New Delhi metallo β-
lactamase (NDM-1)
 The NDM-1 gene encodes β-lactamase enzymes carbapenemases -resistance to a
broad range of β-lactams.
 Produced by Gram-negative bacteria, in particular E. coli and K. pneumoniae
(Paterson, 2006).
 Gene - first detected in a K. peumoniae isolate- Swedish patient who travelled to
New Delhi in 2008 (Yong et al., 2009) and emerged as a newest superbug - most
feared pathogens.

39.  Apart from the Enterobacteriaceae family NDM-1 has also recently been found in
Acinetobacter species in India, China, and Egypt.
 After NDM- 1 a variant in Egypt is designated as NDM-2.
 Infections caused by bacteria carrying NDM-1 have been reported in many other
countries, including the USA, Canada, Australia, France, Germany, Belgium, Sweden,
Denmark, the Netherlands, Norway, Oman, Kenya, China, South Korea, Japan(Luo et al., 2013;
Yoo et al., 2013).
 Mcr-1 gene conferring resistance against colistin and other polymixins has been found in
multiple countries around the world (Liu et al, 2015; Roschanski et al., 2016)
NDM-1…..

41. NDM 1 controversy
Don’t blame superbug on India, it’s everywhere
Thursday, Dec 06, 2018 New Delhi °C

42.  “ridiculous to call it NDM-1 when none of the samples
that tested positive were picked in New Delhi,” -
Chairman, Medanta-The Medicity.
 Commercially motivated campaign to hurt India’s Rs
1,200-crore medical tourism industry.
 Lead researcher from Chennai KK Kumarasamy got
funding from Wyeth, a pharma company, while another
author has shares in companies such as AstraZeneca,
Merck, pfizer and GlaxoSmithKline.
 A frightening picture not supported by any scientific
data.
 Many British NDM-1 positive patients had no travel or
connection to India : Union Health Ministry official.
Shrivastva et al 2011

43. Alternatives
 Antimicrobial peptides- host defense peptides-short and generally positively charged
pptides found in variety of life forms from microorganisms to humans.
 Potential therapeutic source of future antibiotics-broad spectrum activities and different
mechanisms of actions (Seo et al 2012).
 Phage therapy
 Intraperitoneal administration of a single phage strain was sufficient to rescue 100%
mice in bacteremia model using ESBL producing E. coli and imipenem resistant P.
aeruginosa (Wang et al 2006).

44. Alternatives
 Antimicrobial polymers/polymeric biocides- engineered polymers to mimic
antimicrobial peptides –used by immune system to kill bacteria.
 Positive charge- attach to bacteria –polymer crosses cell membrane- solidification of
proteins and DNA in cell.
 Endophytes
 Microbes colonizing living internal tissues of plant without causing any immediate
overt negative effects.
 Wide range of antimicrobial producing strains-important potential source of
antimicrobial substance (Ryan et al 2008).

45. Containment of AMR
 AMR related policies were initiated in 2011 by publishing the National Policy on
Containment of AMR.
 NGO initiative such as Chennai Declaration-published to create a roadmap to tackle AMR
problem.
 ICMR launched the program on Antimicrobial Stewardship, Prevention of Infection and
Control (ASPIC) in 2012.
 The Antimicrobial Resistance Surveillance Research Network (AMRSN) established by the
ICMR.
 The Red Line Campaign developed along with Organization of Pharmaceutical Producers of
India (OPPI) was launched in New Delhi in February 2016.
 In 2017, a comprehensive National Action Plan for Containment of AMR - launched.

46. Focus areas of NAP-AMR strategic priorities