Status and prevention of antibiotic resistance

1. Antimicrobial
resistance
Photo by Uwe Gille / CC BY-SA 3.0

2. Contents
• Definition
• Causes
• Prevention
• Mechanisms
• Organisms
• Applications
• Society and culture

3. Definition
• Resistance is unresponsiveness of
microorganisms (such as bacteria, fungi,
viruses, and parasites) to antimicrobial
agents in standard doses
• A natural biological unstoppable
phenomenon
• Resistance is generally slow to reverse or
irreversible
• All antimicrobial agents have the potential
to select drug-resistant subpopulations of
microorganisms
• Microorganisms that develop antimicrobial
resistance are sometimes referred to as
“superbugs”
• All classes of microbes develop resistance:
fungi develop antifungal resistance, viruses
develop antiviral resistance, protozoa
develop antiprotozoal resistance, and
bacteria develop antibiotic resistance.

4. Why worry?
• New resistance mechanisms are emerging
and spreading globally, threatening our
ability to treat common infectious diseases,
resulting in prolonged illness, disability, and
death
• Without effective antimicrobials for
prevention and treatment of infections,
medical procedures such as organ
transplantation, cancer chemotherapy,
diabetes management and major surgery
(for example, caesarean sections or hip
replacements) become very high risk
• Antimicrobial resistance increases the cost
of health care with lengthier stays in
hospitals and more intensive care required
• Antimicrobial resistance is putting the gains
of the Millennium Development Goals at
risk and endangers achievement of the
Sustainable Development Goals

6. Spread of Antibiotic Resistant Bacteria
North America
• USA: ARB causes majority
of 99,000 deaths/yr.. from
infections acquired in
hospitals
• Health care costs of ARB
are US$ 21 – 34 bn/yr.
South America
• Peru, Bolivia: >51% of
hospital infections caused
by ARB
• Brazil: Rates of ARB are up
>60%
Europe
• EU: ARB costs
society € 1.5 bn/yr.
and 600 million days
of lost productivity
• Russia: ARB a major
concern with 83.6%
of families
imprudently use
antibiotics at home
Middle East and North
Africa
• Egypt: 38% of blood
infections contracted by
young cancer patients are
from ARB
• Israel: ARB found fatal in
50% cases when resistant
to our strongest antibiotics
Asia
• Thailand: >140,000 ARB
infections/yr. and
>30,000/yr. patients die;
83.6% in productivity
losses/yr.
• Japan: extensive levels of
ARB found in Tokyo’s urban
watershed
• China: extreme over-
prescription of antibiotics
and rapid growth rate of
ARB
• India: within 4 years (02-
06) ARB went from being
resistant to 7, to 21 drugs
• Vietnam: farming practices
contributing to spread of
ARB through environmental
contamination
• Pakistan: 71% of infections
in newborns are from ARB
Sub-Saharan Africa
• Tanzania: Death rate of
ARB infected children are
double that of malaria
• Nigeria: Rapid spread of
ARB that came to Africa
from Asia

7. How antibiotic resistance happens
1.
Lots of germs, few are
drug resistant.
3.
The drug resistant
bacteria are now
allowed to grow and
take over.
5.
Spread and invasion of
body tissues causing
infections that are
difficult to cure or treat.
2.
Antibiotics kill bacteria
causing the illness, as
well as good bacteria
protecting the body
from infection.
4.
Some bacteria give their
drug-resistance to other
bacteria causing more
problems.

8. Antibiotic Resistance
• Antimicrobial resistance occurs naturally over time,
usually through genetic changes. However, the misuse
and overuse of antimicrobials is accelerating this
process. In many places, antibiotics are overused and
misused in people and animals, and often given without
professional oversight.
• Overuse and misuse of antibiotics can promote the
development of antibiotic-resistant bacteria.
• Every time a person takes antibiotics, sensitive bacteria
(bacteria that antibiotics can still attack) are killed, but
resistant bacteria are left to grow and multiply. This is
how repeated use of antibiotics can increase the
number of drug-resistant bacteria.
• Antibiotics are not effective against viral infections like
the common cold, flu, most sore throats, bronchitis, and
many sinus and ear infections. Widespread use of
antibiotics for these illnesses is an example of how
overuse of antibiotics can promote the spread of
antibiotic resistance.
• Smart use of antibiotics is key to controlling the spread
of resistance.

9. How it
spreads

10. Causes
Photo by CDC / Public domain

12. Resistance is accelerated
through inappropriate
use of antimicrobials
• Standard treatment guidelines not
provided to physicians or provided but
not adhered to
• Drugs available without prescription
• Accessible but poor quality
• Inadequate monitoring
• Irrational self-administration or
prescription

13. Resistance is fallout of
inappropriate use of
antimicrobials in different
settings
• In animals and plants:
• Therapeutic and non-therapeutic (e.g. as
growth promoters)
• In community acquired infections
• In hospital-associated infections
• Irrational use of antibiotics is the greatest
driver of resistance
50% of antibiotics are prescribed
inappropriately
50% of patients have poor compliance
50% of populations do not have access
to essential antibiotics

14. Mechanisms
Photo by Gerard D Wright / CC BY 2.0

15. Mechanisms
• Emergence of resistance among the
most important bacterial pathogens is
recognized as a major public health
threat affecting the humans worldwide
1. INACTIVATE DRUG
A. Particularly to penicillins and
cephalosporins
B. Cleavage by β – lactamases
(penicillinases and
cephalosporinases)
C. β-Lactamases produced by various
organisms have different
properties:
• Staphylococcal penicillinase: Inducible
by penicillin and secreted into medium

16. Mechanisms
• Some β-lactamases (produced by several
gram-negative rods):
 Located in the periplasmic space
 Not secreted into medium
• Some β-lactamases are more active against
cephalosporins, others against penicillins
1. 1.gvncgb
D. Clavulanic acid, Sulbactam,
Penicillin analogues - Binds
strongly to β-lactamases -
Inactivate them
E. Clavulanic Acid + Amoxicillin: Can
overcome resistance mediated by
many but not all β-lactamases

17. Mechanisms
2. MODIFY DRUG TARGET IN BACTERIA
A. Mutation in penicillin-binding proteins
• In the bacterial cell membrane
• These changes account for both the low-level
and the high-level resistance exhibited by
Strep. Pneumonia to Penicillin G; S. aureus to
nafcillin
• Enterococci faecalis resistant to penicillins:
altered penicillin-binding proteins
B. Replace alanine with lactate in
peptidoglycan
• Resistance to vancomycin
• A change in peptide component from D-alanyl-
D-alanine (normal binding site of vancomycin)
to D-alanine-D-lactate (drugs does not bind)
• Vancomycin-resistant strains of enterococci
(VRE)
• S. Aureus exhibit resistance to vancomycin
• S. Pneumonia as well

18. Mechanisms
C. Mutation in catalase-peroxidase
• Resistance of Mycobacterium tuberculosis to isoniazid
• Catalase / peroxidase enzyme: required to synthesize
the metabolite of isoniazid that inhibits the growth of
M. tuberculosis
D. Mutation in protein in 30s ribosomal subunits
• Such in Aminoglycosides like streptomycin
• Other mechanisms in which develop resistance to
Aminoglycosides:
• Modification of drugs by plasmid – encoded
phosphorylating, adenylating and acetylating
enzymes (most important mechanism)
• Decreased permeability of the bacterium to
the drug

19. Mechanisms
E. Mutation in DNA gyrase
• Resistance to Quinolones – chromosomal
mutations
• Resistance can also be caused by changes in
bacterial outer-membrane proteins that results
in reduced uptake of drug into the bacteria
F. Mutation in RNA polymerase
• Resistance in rifampin
• Chromosomal mutation in the gene for β
subunit of bacterial RNA polymerase results in
ineffective binding of drug
• Not prescribed for treatment, but prevention of
certain infections

20. Mechanisms
3. EXPORT OF DRUG FROM BACTERIA
A. Tetracyclines
• Failure of drug to reach an inhibitory
concentration inside the bacteria.
• Due to plasmid – encoded processes that either
reduce uptake of the drug or enhance its
transport out of the cell
B. Sulphonamides
• Resistance is mediated by 2 mechanisms:
• A plasmid-encoded transport system that
actively exports the drug of the cell
• A chromosomal mutation in the gene coding for
the target enzyme dihydropteroate synthetase,
which reduces the affinity of the drug
4. REDUCE PERMEABILITY OF DRUG
A. Mutation in porin proteins
• Drugs commonly affected:
 Penicillins
 Aminoglycosides
 N. gonorrheae

21. Organisms

22. Resistant organisms also move
rapidly across borders through
humans and the food-chain
• Two outbreaks of methicillin-resistant Staph.
aureus (MRSA) in hospitals in Canada
⁻ Origin in North India
• Multidrug-resistant typhoid fever in USA
⁻ Originated in 6 countries (including India)
• MDR Salmonella schwarzengrund
⁻ Imported through Thai food into Denmark and the
USA
• Multidrug resistant Mycobacteria
• Resistant malaria at Thai-Cambodia border
• Resistance in H1N1 and HIV are global
concerns

23. Important examples of
antibiotic-resistant
bacteria
• Methicillin-resistant Staphylococcus
aureus (MRSA)
• Vancomycin-resistant Enterococcus
(VRE)
• Multi-drug-resistant Mycobacterium
tuberculosis (MDR-TB)
• Carbapenem-resistant
Enterobacteriaceae (CRE) gut bacteria

24. 1. STAPHYLOCOCCUS
AUREUS (MRSA)
• First Documented: 1884
• Illness Caused: Pneumonia, Flesh Eating Disease
• Antibiotic Resistance: Medium
• Virulence: Dangerous
• More commonly known as MRSA.
• Very easily spread through human contact and can
cause a range of illnesses from skin disorders to deadly
diseases like meningitis and pneumonia.
• Most often treated with Penicillin type antibiotics, by
1960, 80 per cent of hospital samples were antibiotic
resistant.

25. 2. BURKHOLDERIA
CEPACIA
• First Documented: 1949
• Illness Caused: Pneumonia
• Antibiotic Resistance: Low
• Virulence: Worrying
• Discovered in 1949 as the bacterium that causes onions to rot.
• Can be very dangerous to humans in the worst cases.
• Mostly responds well to treatment with a combination of
antibiotics -it has been shown to have high levels of resistance
to several types of antibiotics and is able to survive in extreme
conditions.
• Particularly dangerous to humans with preexisting lung
conditions such as cystic fibrosis.

26. 3. ESCHERICHIA COLI
(E.COLI)
• First Documented: 1895
• Illness Caused: Diarrhoea, Urinary Tract Infection, Meningitis
• Antibiotic Resistance: High
• Virulence: Worrying
• Most E.coli is completely harmless and survives happily in the
human digestive system.
• However, some strains of E.coli can cause serious illness and
most commonly lead to severe food poisoning as well as
meningitis and infections.
• A high level of resistance to antibiotics has been found across
several strains of E.coli and while it is rare to find these strains
causing illness, it is another concerning example of a bacteria
that has the potential to cause problems if our use of
antibiotics goes unchecked.

27. 4. PSEUDOMONAS
AERUGINOSA
• First Documented: 1872
• Illness Caused: Pneumonia, Various Infections
• Antibiotic Resistance: Medium
• Virulence: Worrying
• Quick to mutate and adapt to counter different antibiotic
treatments.
• Shows an innate ability to develop resistance to antibiotics.
• Described as ‘opportunistic’ because it primarily affects
humans that are already critically ill.
• Can cause serious complications in the treatment of AIDS,
cancer or cystic fibrosis patients.

28. 5. CLOSTRIDIUM
DIFFICILE
• First Documented: 1935
• Illness Caused: Diarrhoea
• Antibiotic Resistance: Low
• Virulence: Dangerous
• Consistent presence in hospitals around the world.
• Primarily an easily spread type of diarrhoea that can lead to
complications in the colon.
• Several significant outbreaks of C.difficile have made the news
in the Uk.
• Despite major efforts in improving hygiene in hospitals, the
bacteria is responsible for a significant number of deaths
globally.

29. 6. ACINETOBACTER
BAUMANNII
• First Documented: 1911
• Illness Caused: Pneumonia, Meningitis, Urinary Tract Infection
• Antibiotic Resistance: High
• Virulence: Worrying
• Acinetobacter baumannii have become resistant to many
antibiotics and like other bacteria are currently being
countered most effectively through thorough hygiene in
healthcare situations.
• The bacteria can survive in harsh conditions for long periods
of time & so are often difficult to deal with in weaker patients,
and coupled with increasing resistance presents a tough
challenge when encountered by doctors.
• Sometimes called Iraqibacter, Acinetobacter
baumannii became very prevalent during the Iraq war
amongst injured soldiers who passed through several different
medical facilities.

30. 7. KLEBSIELLA
PNEUMONIAE
• First Documented: 1886
• Illness Caused: Lung infections, Pneumonia
• Antibiotic Resistance: Medium
• Virulence: Worrying
• Klebsiella pneumoniae can cause a range of infections and has
proven to be very resistance to a range of antibiotics.
• Primarily affecting middle-aged and older men with weakened
immune systems, this bacteria can be dangerous but is mostly
‘opportunistic’ and is far less likely to affect healthy adults.
• Due to its high levels of resistance, it is common in the US to
perform tests to identify which strain is present in a patient to
better inform doctors of how to treat them.

31. 8. STREPTOCOCCUS
PYOGENES
• First Documented: 1884
• Illness Caused: Sore throat, skin disorders
• Antibiotic Resistance: Low
• Virulence: Deadly
• Can be found in 5-15% of all humans, residing in the
lungs or throat without causing any harm.
• Causes over 700 million infections globally every year
and has a high mortality rate of 25 per cent in serious
cases.
• Once you have an infection the bacteria can cause a
range of diseases ranging from sore throat and
impetigo up to scarlet fever.
• Luckily, the bacteria is affected by penicillin so is
treated easily in most cases.
• However several strains are building resistance to
various other antibiotics.

32. 9. MYCOBACTERIUM
TUBERCULOSIS
• First Documented: 1882
• Illness Caused: Tuberculosis
• Antibiotic Resistance: Medium
• Virulence: Deadly
• Tuberculosis has been know by many names including
scrofula and the White Plague and has been a huge
cause of death and distraction throughout history, with
evidence found in bodies estimated to be around
9,000 years old.
• While instances of the disease reduced to only 5,000 a
year in the UK in 1987, the increase in antibiotic
resistance has seen a rise in cases in the early 90s.

33. 10.
NEISSERIA GONORRHOEAE
• First Documented: 1885
• Illness Caused: Gonorrhoea
• Antibiotic Resistance: Medium
• Virulence: Worrying
• Gonorrhoea is spread through sexual contact and causes
various infections in both men and women.
• Certain strains of the bacteria have shown resistance to
antibiotics and have mutated over the course of 50 years or
so, slowly adapting different resistances as doctors change
their approach by using different antibiotics to counter the
disease.
• The small hairs or ‘pili’ on the bacteria act like hooks that are
used to move the cell and attach it to other healthy cells.

34. WHO priority pathogens list for research and
development of new antibiotics
1) Critical 2) High 3) Medium

35. WHO priority
pathogens list for R&D
of new antibiotics
• Priority 1: CRITICAL
• Acinetobacter baumannii, carbapenem-
resistant
• Pseudomonas aeruginosa, carbapenem-
resistant
• Enterobacteriaceae, carbapenem-
resistant, ESBL-producing

36. WHO priority
pathogens list for R&D
of new antibiotics
• Priority 2: HIGH
• Enterococcus faecium, vancomycin-
resistant
• Staphylococcus aureus, methicillin-
resistant, vancomycin-intermediate and
resistant
• Helicobacter pylori, clarithromycin-
resistant
• Campylobacter spp., fluoroquinolone-
resistant
• Salmonellae, fluoroquinolone-resistant
• Neisseria gonorrhoeae, cephalosporin-
resistant, fluoroquinolone-resistant

37. WHO priority
pathogens list for R&D
of new antibiotics
• Priority 3: MEDIUM
• Streptococcus pneumoniae, penicillin-
non-susceptible
• Haemophilus influenzae, ampicillin-
resistant
• Shigella spp., fluoroquinolone-resistant

38. Prevention

40. International
Collaboration National Plans
And Other
Strategies
Infection
Prevention And
Control
Programmes Public
Awareness
Access To Quality-
assured
Antimicrobial
Medicine
Surveillance
And Laboratory
Capacity

43. WHO Response
• Tackling antibiotic resistance is a high
priority for WHO. A global action plan on
antimicrobial resistance, including antibiotic
resistance, was endorsed at the World
Health Assembly in May 2015. The global
action plan aims to ensure prevention and
treatment of infectious diseases with safe
and effective medicines.
The “Global action plan on antimicrobial
resistance” has 5 strategic objectives:
• To improve awareness and understanding of
antimicrobial resistance.
• To strengthen surveillance and research.
• To reduce the incidence of infection.
• To optimize the use of antimicrobial
medicines.
• To ensure sustainable investment in
countering antimicrobial resistance.

44. WHO has been leading multiple initiatives to
address antimicrobial resistance:
World Antibiotic Awareness Week
• Held every November since 2015 with
the theme “Antibiotics: Handle with
care”, the global, multi-year campaign
has increasing volume of activities during
the week of the campaign.
The Global Antimicrobial Resistance
Surveillance System (GLASS)
• The WHO-supported system supports a
standardized approach to the collection,
analysis and sharing of data related to
antimicrobial resistance at a global level
to inform decision-making, drive local,
national and regional action.

45. Global Antibiotic Research and Development
Partnership (GARDP)
• A joint initiative of WHO and Drugs for Neglected
Diseases initiative (DNDi), GARDP encourages
research and development through public-
private partnerships. By 2023, the partnership
aims to develop and deliver up to four new
treatments, through improvement of existing
antibiotics and acceleration of the entry of new
antibiotic drugs.
Interagency Coordination Group on Antimicrobial
Resistance (IACG)
• The United Nations Secretary-General has
established IACG to improve coordination
between international organizations and to
ensure effective global action against this threat
to health security. The IACG is co-chaired by the
UN Deputy Secretary-General and the Director
General of WHO and comprises high level
representatives of relevant UN agencies, other
international organizations, and individual
experts across different sectors.

46. •Talk to patients about
preventing infections (e.g.
vaccination, hand washing,
safer sex, covering nose and
mouth when sneezing)
•Prevent infections by ensuring
that your hands, instruments
& environment are clean &
safe for use at the right times
•Use diagnostics to make
informed decisions (when
possible)
•Only prescribe and dispense
antibiotics when they are
needed, according to current
guidelines
•When patients are seeking
treatment for cold or flu,
explain that antibiotics are not
needed
•Talk to patients about how to
take antibiotics correctly,
antibiotic resistance and the
dangers of misuse
•Ask your patient about their
previous & present antibiotic
use
•Implement programmes to
optimize antibiotic use &
monitor prescribing &
resistance patterns
•Keep your patients’
vaccinations up to date

47. Global Action to Respond Better
• Awareness and education: Raising public awareness
about this threat is an important first step.
• Surveillance: Countries need systems to track
antimicrobial resistance and share findings with
international partners.
• Infection, prevention and control: Infection control and
hygiene are critical to stopping spread of resistant germs
in healthcare settings.
• Optimize use: Ensuring that antibiotics are still effective
in the future requires that they be used correctly today.
• R&D and investment: Research and development of
new drugs, diagnostic tools and vaccines are a global
priority.

48. Awareness and Education
Raising awareness about the threat of resistance and
the need to improve use is critical to tackling the
issue. Almost two thirds (64%) of some 10,000 people
surveyed by the World Health Organization (WHO)
across 12 countries say they know antibiotic resistance
is an issue that could affect them and their families, but
how it affects them and what they can do to address it
are not well understood. For example, 64% of
respondents believe antibiotics can be used to treat
colds and flu, despite the fact that antibiotics have no
impact on viruses.

49. Instances of antibiotic misuse

51. Antibiotics in
livestock
• There has been massive use of antibiotics in animal
husbandry.
• The most abundant use of antimicrobials
worldwide are in livestock; they are typically
distributed in animal feed or water for purposes
such as disease prevention and growth promotion.
• Policies and regulations have been placed to limit
any harmful effects.
• On January 1, 2017, the FDA enacted that all
human medically important feed-grade antibiotics
(many prior over the counter drugs) become
classified as Veterinary Feed Directive drugs (VFD).
This action requires that farmers establish and
work with veterinaries to receive a written VFD
order.
• The effect of this act places a requirement on an
established veterinarian-client-patient relationship
(VCPR). Through this relationship, farmers will
receive an increased education in the form of
advice and guidance from their veterinarian.

52. Status of Resistance in
WHO’s South-East Asia Region

53. Tuberculosis
• MDR-TB < 3%: 180000 cases annually
• XDR-TB: Reported from Bangladesh, India,
Indonesia, Thailand

54. Malaria
400 million
people at risk of
infection with
resistant parasites

55. HIV and STIs
• Data on HIV resistance being generated
• STIs: Gonorrhoea widely resistant to penicillin
& fluoroquinolones

56. Kala-azar
60% resistance in
pentavalent
antimony and
25% in
pentamidine

57. Epidemic Prone
Diseases
• Cholera
₋ Resistance to Nalidixic acid, fluorazolidone,
cotrimoxazole: India
₋ Tetracycline resistance: India
• Shigellosis
₋ Multidrug resistant, causing extensive
outbreaks
• Typhoid fever
₋ MDR Salmonella typhi prevalent all over
Region
₋ Causing 10% Case Fatality Rate (CFR) in
children (pre-antibiotic era: 12.8%)
• Acute respiratory infections (pneumonias)
₋ 69% of Strep. pneumoniae resistant to
penicillin in Thailand

58. Hospital Acquired
Infections
• Staphylococcus aureus
₋ >50% isolates in hospitals are
methicillin-resistant
₋ 48% of patients with bacteraemia
died in Thailand
• Acinetobacter baumannii
₋ >50% of patients infected with
resistant strains die
• Pseudomonas, Klebsiella, Serratia
₋ Multidrug-resistance, persist in
hospital settings, and cause huge
mortality morbidity

59. Current Scenario in Malaysia,
India and Sri Lanka

61. The battle against
antibiotic resistance -
NEW STRAITS TIMES
• November 27, 2017- The culmination of
probably the most important global health
awareness campaign in recent decades. This
follows a week of healthcare policy, educational
and community-based activities centred on
World Antibiotic Awareness Week (Nov 13 to
19). The message was simple: “Seek advice
from a qualified healthcare professional before
taking antibiotics.”
• The rationale behind the campaign is the
growing incidence of anti-microbial resistance;
in everyday language, resistance to common
antibiotics in Malaysia, according to the World
Health Organization (WHO) data for 2015, the
incidence of TB is 89 per 100,000 population,
HIV (0.27), malaria (1.9) and hepatitis B (99).
The UN’s Sustainable Development Goals for
global healthcare has set a target of 3.3 per
100,000 population for the diseases by 2030.

62. Article from The Star
We need to fight antibiotic resistance
• Fight antibiotic resistance – it’s in your
hands’ was this year’s slogan for the
World Health Organization’s (WHO)
Hand Hygiene Day on May 5,
emphasising the link between infection
and control practices like handwashing
and the prevention of antibiotic
resistance.
• Healthcare-associated infections (HAI)
have caused harm, and even death,
particularly in those with impaired
immunity.

66. Social and economic impact

67. Resistance has huge
negative impact on
health
• Longer duration of illness
• Longer treatment
• Higher mortality
• Treatment with expensive drugs
• Increased burden on health system
• Negates technological advances in
medical sector
₋ Complex surgeries
₋ Transplantations and other
interventions
• Patient acts as reservoir of resistant
organisms which are passed to
community and health-care workers
• Huge economic impact

68. Superbugs* are visible manifestations of our prolonged failure to preserve antibiotics
** Methicillin resistant Staph aureus, MDR-and XDR Mycobacteria, ESBL producing Gram negative bacteria and NDM-1 producing
enterobacteriaceae bacteria are few examples of superbugs because these fail to respond to large number of commonly used antibiotics
Known but
neglected.
Need immediate
action
Known but
inevitable
Accumulation of resistance to multiple antibiotics
Self medication and poor compliance
Inappropriate use of antibiotics selection and
multiplication of resistant strains
Weak surveillance and regulatory systems
Continuous natural evolution of resistance in bugs

74. The Antibiotic
Apocalypse Explained

76. Possible solutions
• Discover new drugs faster than
emergence of resistance
• Rationalize the use of available
antimicrobial agents
• Prevent emergence of resistance by
reducing selection pressure by
appropriate control measures
• Promote discovery, development and
dissemination of new antimicrobial
agents

77. Conclusion
• Are antibiotics at the end of the
road?
• Antibiotics are a precious resource
• We need to preserve this resource
by working together
• Combating antimicrobial
resistance requires action today, or
there will be no cure tomorrow

78. Thank You!