Emerging Infectious Diseases
Lecture 5 & Sample Questions
Y.J. Johnson
1.
Discuss the roles of antibiotics in medicine and animal
production
2.
Describe the mechanisms by which bacteria express and transfer
antibiotic resistance
3.
Determine the role of antibiotic misuse in the development
of resistant bacterial strains
4.
Discuss the implications of bacterial resistance for human
and animal health
Antibiotic: Use, Misuse, and Bacterial Resistance
I. How is this
relevant to emerging infectious diseases ?
The term 'emerging disease' refers to:
A.
previously undiscovered pathogens, or
B.
known pathogens, previously controlled or treated that have:
1.
acquired new forms of virulence, or
2.
acquired new means surviving standard treatment
II.
Terminology
A.
Antimicrobial
- an agent that kills microorganisms or suppresses their growth
B.
Antibiotic - a
chemical substance produced by a microorganism which has the capacity,
in dilute solutions, to inhibit the growth of or kill other
microorganisms
C.
Antibiotic
Resistance - the ability of a microorganism to withstand the
effects of an antibiotic that is lethal to most members of its
species. It refers to acquired genotypic
changes which persist during cultivation in the absence of the
antibiotic.
1.
It is a naturally
occurring phenomenon
a)
antibiotic resistance genes have been characterized in
coliforms from glacial water and ice estimated to be more than 2000 years old
b)
hence there is evidence of resistance prior to the use of antibiotics
2.
Antibiotic resistance is a
manifestation of genetic diversity
3.
Those organisms with the genetic potential to withstand
exposure to antibiotics that are lethal to most members of its species have a
competitive advantage - natural
selection.
4.
Antibiotic life-span
a)
Given the above, we can expect any antibiotic to have a limited effective lifespan
b)
The concern is that there has been a pattern of an increased rate of resistance developing
within the past decade, thus antibiotics have a much shorter effective lifespan
III.
Uses of Antibiotics
A.
In the US, antibiotic use is approximately evenly divided
between human and agricultural use.
B.
The bulk of agricultural antibiotic use is for intensive
livestock production
C.
Human and pet uses of antibiotics
1.
Therapeutic uses - treatment of an existing infection
2.
Prophylactic uses - preventing an infection
D.
Animal production uses of antibiotics
1.
Therapeutic uses - approximately 10% of the antibiotics used
2.
Prophylactic uses
3.
Growth promotion
a)
Approximately 90% of the antibiotics used in animal
production are for prophylactic or growth promotion purposes
b)
Growth promotants consist of low-level, long-term mass
administration of antibiotics usually via feed or water
c)
Growth promotants -
·
boost an animal's genetic potential for growth
·
result in improved feed conversion
·
reduce waste product output from intensive livestock
production
·
there is a reported 3 - 5% increased rate of gain and feed
efficiency attributed to the use of antibiotic growth promotants
E.
Crop Production - primarily spraying of fruit trees
IV.
Issues in the Use of Antibiotics
A.
How does exposure to antibiotics facilitate development of
resistant strains?
1. Given
a population of bacteria exposed to an antibiotic; most of the bacteria are
sensitive however a small number of spontaneously resistant mutants are in the
population. Those bacteria that are
sensitive to the antibiotic die and the resistant strain survives and
reproduces. In the absence of the
antibiotic the resistant strain continues to reproduce. Over time the bacterial population is
dominated by the antibiotic resistant mutant.
B.
Paradoxically both under
and over use of antibiotics promotes
development of resistance
1.
Examples of overuse
of antibiotics in human and animal populations
a)
Treatment of mild self-limiting infections with antibiotics
b)
Use of powerful broad-spectrum antibiotics to treat an
infection susceptible to a limited spectrum antibiotic.
c)
Long-term, low dose administration for prophylaxis (usually
with debilitated, chronically ill patients)
d)
Prescribing antibiotics to patients with viral infections
(often in response to patient/client
demands)
2.
How does overuse
promote resistance?
a)
Exposing normal bacterial flora to antibiotics confers a
selective advantage to resistant strains
b)
The resistant strains then colonize the host
c)
Resistant strains may now pass from the host into the
environment
d)
In the environment, other bacterial species are exposed to
the resistance genes and they are transferred to other species
3.
Examples of under-use
of antibiotics in human and animal populations
a)
Failure to complete the full treatment regimen
·
Poor patient compliance - when the symptoms abate, the
patient stops taking the medication
·
Economics/Access to medication - attempting to 'stretch' a
single prescription to more than 1 illness or more than 1 patient
b)
Poor product quality - This is particularly important in
developing countries
·
Expired products may be distributed or imported into
countries with limited 'hard currency'.
·
Poor quality control - Substandard or adulterated products
may be distributed or imported into countries without the infrastructure to
adequately monitor and enforce product quality regulations.
c) Group dosing - In intensive livestock
production systems therapeutic group dosing of animals via feed or water
results in uneven consumption of the medication, animals that consume less may
not receive the desired dose.
4.
How does under-use
promote resistance?
a)
As a result of under-use of a therapeutic dose of an
antibiotic, there is a failure to achieve an adequate concentration of the antibiotic
at the site of the infection.
b)
Alternatively, there may be a failure to maintain an
adequate concentration of the antibiotic at the site of infection.
c)
As a result, only the most sensitive organisms are
eliminated from the host.
d)
As in the over-use scenario, a selective advantage is then
conferred to resistant mutants.
e)
The host is colonized by resistant strains
f)
Resistance genes may then be transferred to the hosts'
normal bacterial flora and to the pathogen population.
g)
Resistant organisms may then pass from the host and spread
to the environment.
5.
The use of antibiotics as growth promotants has become controversial due to concerns with
antibiotic resistance.
a)
Growth promotants result in long term exposure to antibiotics during the animals' productive
life.
b)
Growth promotants are group-dosed,
usually in the form of feed additives
c)
Antibiotic growth promotants are used at sub-therapeutic levels.
6.
Effect of antibiotic growth promotants on host bacterial
flora
a)
The effect is analogous to the under-use scenario: a sub-therapeutic
concentration inhibits the sensitive flora; selects for the resistant flora;
the resistant flora multiply within the host, pass into the environment and
transfer resistance to other bacterial species in the host and environment.
b)
The impact of growth promotants is exacerbated by the fact
that the host flora is exposed over a long
span of time, perhaps through the entire rearing period.
V.
How Do we Measure Resistance?
A.
In vitro - Tracking changes in the in vitro indicators of resistance allows
one to monitor patterns of resistance and offers guidance in making clinical
decisions.
1. Minimum Inhibitory Concentration
·
The lowest concentration of an antibiotic that will inhibit
visible growth of the isolate after incubation.
2. Breakpoint Concentration
·
A specific concentration of antibiotic that is used to
classify and isolate as sensitive or resistant.
3. Zone of Inhibition
·
Using the disc diffusion method, the size of the zone
containing no bacterial growth is used to determine the level of susceptibility
to the antibiotic.
B.
In vivo - Clinical Outcome: This is
much more complex than in vitro determinations of resistance because it is
dependent upon the interaction between Agent, Environment, and Host
1.
Agent factor: Type of
bacterium determines whether the agent is intrinsically resistant to the
antibiotic and its virulence factors.
2.
Environmental factors: Location
of the infection in the host body; Distribution
of the antibiotic in the host body; and Concentration of the antibiotic at the site of infection - all impact
the efficacy of the antibiotic.
Infections in regions with low tissue perfusion or barriers to
antibiotic diffusion may require increased dosages, more powerful antibiotics,
or antibiotics with the diffusion characteristics necessary to cross physiological
barriers.
3.
Host factor: Patient
immune status: determines whether or not the infection can be successfully
treated with a bacteriostatic treatment regimen versus a bacteriocidal
treatment regimen.
VI.
Molecular Epidemiology of Resistance
A. Intrinsic Resistance
1.
Species that are
inherently resistant to specific antibiotics, i.e.
a)
This may be due to the permeability of the bacterium for a
given class of antibiotic
b)
This bacterium may not possess the target site of action for
a given class of antibiotic
2.
One clinical effect
of intrinsic resistance is seen with Opportunistic
Infections
a)
Use of an antibiotic may result in an overgrowth of
inherently resistant organisms.
b)
Seen commonly when a patient develops Candidiasis (yeast
infection/Thrush) secondary to antibiotic therapy.
B.
Acquired
Resistance - When we speak of 'increasing antibiotic resistance' or
resistant strains of bacteria as an 'emerging disease' we are referring to acquired
resistance.
1.
Acquired resistance is when a bacterial strain that was
sensitive to a particular antibiotic, develops resistance. There are 2 ways in which this may occur:
a) Mutation
·
This is a spontaneous event
·
It occurs regardless of antibiotic presence
·
It confers a selective advantage in the face of subsequent
exposure to the antibiotic
b)
Acquisition
of New DNA - via 4
means: plasmid, transposon, bacteriophage, or transformation
VII.
Methods of Transfer of
Acquired Resistance
A.
Plasmids are
self-replicating circular DNA that are smaller than the bacterial genome. They can carry and transfer multiple
resistance genes but they have a limited range of spread between bacterial
species.
B. Transposons are known as "jumping
genes" and may be transferred from cell to cell. They can either integrate into the recipient's plasmid or into
the bacterial genome. Unlike plasmids,
they can spread resistance across a wide range of bacterial species.
C. Bacteriophages are viruses that infect
bacteria. They are capable of
transferring resistance as they infect the bacterial cell. This method of transfer of resistance is
important for Staphylococci spp.
D. Transformation occurs when DNA that is
released from a dying bacterial cell is taken-up by competent bacteria. This method of transfer of resistance is
important in the environment (i.e. soil).
It is an important factor in the transfer of penicillin resistance in S. pneumoniae
VIII.
Mechanisms of Acquired Resistance
A. Modification or destruction of the antibiotic
1.
Beta-lactamases (over 200 types)
·
Enzymes that cleave beta-lactam rings
·
Confers resistance to penicillins, cephalosporins,
carbapenems, monobactams
2.
Aminoglycoside-modifying enzymes (at least 20 enzymes)
·
Found in Gram negative and Gram positive orgranisms
3.
Others
·
Acetyltransferase -
chloramphenicol resistance
·
Esterase - macrolide resistance
B. Reduced Uptake of the Antibiotic
1.
In Gram negative bacteria this is mediated via porins
·
Porins are aqueous channels that provide a hydrophilic route
into the periplasmic space
·
Genetic mutations result in reduced number of porins or
altered shape
·
As a result, permeability of the antibiotic into the
bacterium is reduced.
C. Increased Efflux of the Antibiotic
·
ATP binding proteins, membrane located efflux proteins and
diffusion are 3 mechanism for increasing the efflux of antibiotic from the
bacterial cell.
D.
Production
of altered/new target site - examples
1.
Alteration in penicillin binding protein
2.
Production of a new cytoplasmic membrane protein
3.
Altered target enzymes
4.
Altered ribosomal RNA binding site
E.
Over-expression
of the drug target - this is only described in Mycobacterium spp.
IX.
Current Public Health Concerns related to Antibiotic
Resistance
A.
Enteric bacteria
1. Multi-drug resistant S. typhimurium DT 104
·
Food borne or due to exposure to infected animals
·
90% of all S.
typhimurium DT 104 isolated from humans are multi-drug resistant
·
resistant to chloramphenicol, streptomycin, sulfonamides,
tetracycline
·
resistance to trimethoprim and fluoroquinolones are now
being reported
2.
Campylobacter jejuni
·
Usually food borne disease
·
Poultry products are the most common source
·
Ciprofloxacin resistance has risen to 10%
·
The rises in resistance from human isolates has paralleled
increasing resistance from chicken isolates
B. Mycobacterium tuberculosis
1.
8 million new cases annually worldwide
2. Tuberculosis
is the most common infectious cause of adult death worldwide
·
3 million deaths annually
3.
Most deaths are NOT due to bacterial resistance but failure
to properly treat susceptible strains.
4.
Multi-drug
resistant Tuberculosis
·
Resistant to at least isoniazid and rifampicin
·
Now reported in 104 countries with a worldwide distribution
C.
Gram Positive Bacteria
1.
Methicillin resistant S.
aureus
·
The infection is readily transmissible and 33% of the
population carries the agent on healthy skin.
·
It is the second most common cause of bacteremia.
·
It causes superficial and deep skin, wound, and tissue
infections.
·
An exponential rise in resistance has been reported between
1989 - 1996.
·
It is only susceptible to glycopeptides
2.
Strep. pneumoniae
·
It is the most common cause of community acquired pneumonia
·
It also causes meningitis and otitis media
·
It is the third most common cause of bacteremia
·
There has been a reported rising increase in in vitro resistance
3. Enterococcus
spp.
·
These organisms are considered normal gut flora
·
They are responsible for both community acquired and
nosocomial infections
·
Vancomycin resistance has risen from 0.4% to 10% between
1989 - 1995
X.
The Future
A.
World
Health Organization (WHO)
Recommendations - In response to the growing concern over the increasing rate
of acquired bacterial antibiotic resistance, the WHO held a meeting on the
subject in Berlin, Germany in October of 1997.
The conference report, entitled "The Medical Impact of Antimicrobial Use in Food Animals" makes
the following recommendations:
1.
Terminate use of human antibiotics for growth promotion
2.
Establish threshold resistance levels
3.
Develop Risk Assessment and Post-Approval Monitoring
Procedures
4.
Replace antibiotic growth promoters
5.
Record antibiotic import and export data
6.
Develop international residue standards
B.
Conclusions
1.
Increasing antibiotic resistance is a growing threat to
public health
2.
Human and agricultural use and misuse of antibiotics has
hastened the emergence of resistant bacterial strains
3.
Veterinarians and physicians must respond to the problem
1.
All of the following are TRUE statements EXCEPT:
a)
Treatment of self-limiting infections with antibiotics, is
an example of antibiotic overuse.
b)
A broad-spectrum antibiotic should always be the first
choice selected by a veterinarian or physician for treating an infectious
disease.
c)
Exposure of normal bacterial flora to antibiotics selects
for antibiotic resistance.
2.
Antibiotic growth promotants:
a)