An#bio#cs

Resistance A Public
Health Crisis
Dr WEE Hwee Lin
Assistant Professor

Department of Pharmacy, Faculty of Science,
& Saw Swee Hock School of Public Health,
Na#onal University of Singapore
 Lecture Outline

Addressing
An#bio#c the
resistance problem
Brief The threat Infec#on
history of Magnitude of Control
Fun Facts infec#ous Global
the problem
disease Dissemina#on surveillance
of resistance An#microbia
l stewardship
New drug
development
 Learning Objec#ves
To describe the challenges posed by an#bio#c
resistance
To describe current eorts in addressing the
issue of an#bio#c resistance
 Lecture Outline

Addressing
the
An#bio#c problem
resistance
Brief Infec#on
history of The threat Control
Fun Facts infec#ous Magnitude of Global
disease the problem surveillance
Dissemina#on An#microbial
of resistance stewardship
New drug
development
 Lecture Outline

Addressing
An#bio#c the problem
resistance
Infec#on
Brief The threat Control
history of
Fun Facts infec#ous
Magnitude of Global
the problem surveillance
disease
Dissemina#on An#microbial
of resistance stewardship
New drug
development
Brief History of Infec#ous Diseases
Germ theory 1500s Antony van Leeuwenhoek (1632-1723)
Gained acceptance through 1800s - Invented the microscope in 1600s
Brief History of Infec#ous Diseases
Louis Pasteur (1822 - 1895 ),
Edward Jenner (1749 1823), Discovered PasteurizaQon;
Pioneer of the Smallpox vaccine (1796) Further developed germ theory
 1972 Last Rou#ne Small Pox
Vaccina#on in American Public

People lined up at clinics throughout SeaXle in March 1946 for smallpox vaccina#ons. SeaXle Times, 2008.
Brief History of Infec#ous Diseases
Robert Koch Seven days aXer the terrorist aYacks of Sept. 11, 2001,
anonymous leYers laced with deadly anthrax spores
(1843-1910), Founder of modern began arriving at media companies and congressional
oces. Over the ensuing months, ve people died from
bacteriology, Nobel Laureate 1905 inhaling anthrax and 17 others were infected aXer
exposure.
 1928 - First An#bio#c

Sir Alexander Fleming (1881 1955), discovered penicillin in 1928

 losing out in 2 ways

- drying of the pipeline (not enough discovery)

The Golden Era will not Last Forever

- drugs are slowly losing effectiveness

Ref. The Journal of An#bio#cs (2014) 67, 722;

 Lecture Outline

Addressing
An#bio#c the problem
resistance
Infec#on
Brief The threat Control
history of
Fun Facts infec#ous
Magnitude of Global
the problem surveillance
disease
Dissemina#on An#microbial
of resistance stewardship
New drug
development
 An#bio#c Resistance
A Major Public Health Issue
 The Threats
Many of the available treatment op#ons for
common infec#ons in some sedngs are
becoming ineec#ve.
 The Threats

European Centre for Disease Preven#on and Control (ECDC) 2005 - 2016
 The Threats
The number of new an#bio#cs has declined.

Figure 1. Systemic (i.e., nontopical) an#bacterial new molecular en##es approved by the US Food
and Drug Administra#on, per 5-year period. Online ISSN 1537-6591 - Print ISSN 1058-4838
 Magnitude of the Problem
Each year in the United States,
at least 2 million people become infected with
bacteria that are resistant to an#bio#cs

at least 23,000 people die each year as a

direct result of these infec#ons.
 Health and Economic Burden of ABR
Compared with pa#ents infected with the
same bacteria not demonstra#ng the
resistance paXern in ques#on, pa#ents
with infec#ons caused by ARB
generally have
increased risk of worse clinical outcomes and
death
consume more healthcare resources
Ref. WHO An#microbial resistance: global report on surveillance, 2014
 Mul#drug-Resistant Tuberculosis
(MDR-TB)
A form of drug-resistant TB in which TB bacteria
can no longer be killed by at least the
two best an#bio#cs, isoniazid (INH) and
rifampin (RIF), commonly used to cure TB.
As a result, this form of the disease is more dicult
to treat than ordinary TB and requires up to 2
years of mul#drug treatment. 2 years of expensive drug treatment

Globally, approximately 3.3% of new TB cases and

20% of previously treated cases have MDR-TB.
Ref.
1. WHO Global Tuberculosis Report, 2015
2. hXp://www.niaid.nih.gov/topics/tuberculosis/understanding/wha#stb/pages/tbdeni#ons.aspx
 MDR-TB
most in russia

policy in singapore has

been largely effective

Source: WHO Global Tuberculosis Report, 2015

 Increased risk of worse
clinical outcomes and
death
Suscep#ble
Strains +
Consume more healthcare
resources

Lower risk of worse

clinical outcomes and
death Resistant
+ Strains
Consume less
healthcare resources
Rising Incidence?

chances are it may go up again

 Qn
There appears to be an increase in incidence
of TB in Singapore. What do you think are
some of the possible reasons for this trend?
 Mechanisms of Dissemina#on of
An#bio#c Resistant Bacteria (ARB)

1. Gene#c muta#on

2. Horizontal gene transfer of an#bio#c resistant gene

(ARG)

3. Selec#ve pressures that are imposed by an#microbial

compounds or other contaminants, such as biocides or
heavy metals

Ref. Nature Reviews Microbiology 2015;(13): 310-317.

 Gene#c Muta#on and Recombina#on

Source: hXps://www.niaid.nih.gov/topics/an#microbialResistance/Understanding/Pages/muta#on.aspx
 Horizontal Gene Transfer
(a) Transforma#on
Transmission of gene#c occurs when naked DNA is
materials between released on lysis of an organism
genomes (i.e. not from and is taken up by another
organism
parents to osprings)

(b) Transduc#on (c) Conjuga#on

ARG are transferred from one direct contact between two
bacterium to another by means bacteria: plasmids form a ma#ng
of bacteriophages and can be bridge across the bacteria and
integrated into the chromosome DNA is exchanged
of the recipient cell

Ref. Nature Reviews Microbiology 2006;(4): 36-45.

Horizontal Gene Transfer
 Selec#ve Pressure

Adapted from Mulvey & Simor (2009)

Retrieved from: hXp://mostlyscience.com/wp-content/uploads/2014/05/F4.large_.jpg
 Contribu#ng Factors

Pa#ent Physician
Factors Factors

Hospital Environmental
Factors Factors
 Pa#ent Factors
Inappropriate use
More of a problem when an#bio#cs is available
without a prescrip#on
especially overseas and online -> use it for treatment even if not for bacteria

Use expired an#bio#cs

 Pa#ent Factors
Non-adherence
Forgequlness
Did not nish the course once feel well
Financial reasons for not comple#ng the course
Do You Need An#bio#c?
virus no, bacteria yes
 Physician Factors
Inappropriate use of broad
Over-prescribing spectrum an#bio#cs

 Hospital Factors
Inadequate infec#on control
 Environmental Factors
Overuse of an#microbial agents in animals
raised commercially for food
sewage may containt MDR
bacteria and when
discharged into seawater,
may develop their own
colonies
 FDA Report 2014
(An#microbials Sold or Distributed for
Use in Food-Producing Animals)
 Animal An#bio#cs are Good???
Animal an#bio#cs make our food supply safer
and people healthier. An#bio#cs are a cri#cal
tool to prevent, control and treat disease in
animals. In doing so, they also reduce the
chance of bacterial transmission from animals to
humans. Thats why for more than 40 years, the
Food and Drug Administra#on (FDA) has
approved the use of an#bio#cs in livestock and
poultry.
~ Animal Health Ins#tute
 The Problem with
Low Dose An#bio#cs

RESISTANCE
 Environmental Factors
Inadequate surveillance and
suscep#bility tes#ng
Environmental Factors
Increased global air travel
Human-Environment Interac#ons in
ARB Transmission
 Lecture Outline

Addressing
An#bio#c the problem
resistance
Infec#on
Brief The threat Control
history of
Fun Facts infec#ous
Magnitude of Global
the problem surveillance
disease
Dissemina#on An#microbial
of resistance stewardship
New drug
development
An#microbial Stewardship (ASP)

Right an#bio#cs

Right Dose

Right Dura#on
ASP
 ASP Is it Worth the Money?
45.8%
Prior to ASP (FY 2001)

reduc#on

U#liza#on: U#liza#on:
$44,181 per $23,933 per

End of ASP (FY 2008)

1,000 1,000
pa#ent-days pa#ent-days
 ASP Is it Worth the Money?

An#microbial
costs
increased
ASP from $23,933
terminated to $31,653 32.3%
in FY 2008 per 1,000 increase
within 2 years
pa#ent-days