Antibiotic Resistance
And
Vaccines
Marilyn C. Roberts PhD
Professor
marilynr@u.washington.edu
Antibiotic Resistant Microbes
Become an issue over the last 30 years
Alternatives Prior to Antibiotics
(pre-1950)
1. Vaccines
2. Antisera therapy
3. Phage therapy
4. Surgery (M. tuberculosis)
5. Herbal medicine
6. Food (Chicken soup)
7. Behavioral changes (quarantine)
8. Probiotics- use living microbes to compete with the potential
Pathogens; 1950’s neonatal wards painted belly buttons with
nonpathogenic S. aureus to protect against virulent strains
WHY ANTIBIOTIC THERAPY FAILS
1. Patient does not comply with therapy- longer therapy harder
Mycobacterium diseases
2. Inappropriate antibiotic prescribed
Antibiotics for viral infection; Gram-positive antibiotics for Gramnegative diseases
3. Antibiotic not given in correct dose or taken long enough
4*. Pathogen is resistant to therapy
5. Patient is immunocompromised-major issue in hospitals today
1. Antibiotic resistant bacteria is a product of antibiotic use over the last
50 years
2. Shortly after introduction of penicillin (1945) first resistant staphylococci
cultured
3. Today some multi-drug resistant pathogens have few or no available
antibiotics for use-return to “the pre-antibiotic age”
a) Staphylococcus aureus - vancomycin
b) Enterococcus spp.
c) Streptococcus pneumoniae
d) Plasmodium spp. [malaria]
4. Few new agents becoming available for clinical use - most are
modification of current drugs not new classes of agents - easier and
faster for bacteria to become resistant
5. “Simplest way to enhance a bacterial bioweapon is to make it resistant to
antibiotics” Nature 411:232, 2001
6. Technology available for most biological agents of bioweapon potential
7. Russians reportedly made Y. pestis resistant to 16 different antibiotics
doxycycline therapy of choice - naturally resistant strains have been
isolated
8. Clostridium spp. (toxin producers) resistance genes to variety of drugs used
for therapy already in the genus - easy to transfer to toxin producer(s) of
interest
Antibiotic Targets
1. Bacteria usually structurally different than man with different biological
pathways, enzymes, and nutritional requirements
2. Biological pathways, enzymes and nutritional requirements may or may not
be different in virus, fungi, yeast, parasite
3. Antibiotics (Bacteria) usually have minimal affect on host, while
anti-infective for treatment of virus, fungi, yeast, parasites therapy
may impact the host to varying degrees
4. Antibiotics and anti-infectives often work directly on the pathways which
produce DNA, RNA, protein, cell wall, other microbial pathways
5. Bacteriostatic: inhibits bacterial growth without killing in vitro
6. Bactericidal: kills in vitro
7. In vivo antibiotics/anti-infectives work with the host immune system to
stop infection CAN NOT CURE INFECTION ALONE
Resistance: Organisms have acquired the ability to grow on high levels of
drug to which it was originally susceptible
a) Usually only some strains of a group are resistant not all members
b) Early strains are susceptible, recent strains are resistant
Innate Resistance: All members including strains isolated in 1940-50’s or
1800’s are resistant
Reason for Resistance:
a) Lack target - no cell wall; innately resistant to penicillin; lack pathway
b) Target is modified to prevent antibiotic from working- A2058 is
another base in 23S rRNA- innately resistant to macrolides; resistance
to antiviral agents
c) Innate efflux pumps; drug is blocked from entering cell or increased
export of the drug so does not achieve adequate internal
concentration
Resistance
1. Virtually all pathogens (bacterial, viral, fungal, parasite and cancer) will develop
resistance to therapies
2. All pathogens develop resistance by mutation of innate host machinery
3. Bacteria also develop resistance by acquisition of new genes on mobile elements
(plasmids, transposons, conjugative transposons, integrons) or acquisition of
pieces of genes to create mosaics
a) Eukaryotic pathogens and man also carry mobile elements but these
have not been associated with increased drug resistance
4. Most bacterial resistance of clinical significance is due to acquisition
a) Lateral DNA exchange is why resistance is able to move quickly
through a bacterial population
b) Allows unrelated bacteria to acquire resistance genes
c) Allows multiple resistance genes and /or others genes [toxins,
virulence factors, heavy metal resistance] packaged and move
as a single unit
Antibiotic Resistant Bacteria
Treatment of multidrug resistant MDRTB: 10 times more costly vs susceptible
NY City spent ~$1 billion MDRTB control during the 1990’s
Multidrug resistant TB [MDRTB] Short course 1st therapy cure rates 5%-60%
2nd therapy cure rates 48%->80%: death rates: 0-37%, < 89% for HIV
+ pts
Hospital stays; MRSA disease 1.3 times longer
Treatment of MRSA $6,000-$30,000 more than treatment of MSSA
Treatment of multidrug resistant Gram-negative infections 2.7 times more costly
vs susceptible
Hospital stays; resistant Gram-negative disease 1.7-2.6 times longer than
susceptible disease
Generally resistant bacteria are not more virulent but disease course acts as
though no therapy provided when antibiotics are used that the microbe
is resistant to
Plasmids, Transposons, Conjugative transposons, Integrons
1. These elements can exchange genes resulting in antibiotic resistance gene
reassortment and linkages
a) One plasmid can carry multiple different antibiotic resistances
genes in various combinations, toxins and virulence factors
b) Same is true for transposons, conjugative transposons & integrons
c) Many have hotspot for recombination so collect these genes
d) Allow resistance genes to be maintained in a population
Still see resistance to chloramphenicol when the antibiotic has not
been used in the US for 30 years
e) Join virulence factors and antibiotic resistance genes in 1 element
create “super bug”
JAMA Oct 2007 15:1763; estimate 94,360 MRSA infections in 2005 in USA
with 13.7% community associated; number of deaths ~18,000 more than
AIDS death in US for 2005:
MRSA is now in both the hospital and the community
Community MRSA has more virulence factors so is able to infect all ages
groups regardless of their medical status
The same class of antibiotics are used for food production and human
medicine in N. America
Share resistant bacteria and resistance genes between food animals and man
Antibiotic resistant bacteria develop, both potential pathogens and
commensals, in the animal/plants, local environment surrounding
community, and can contaminate human and animal food in
multiple ways
Transgenic plants may carry viable antibiotic resistance genes which
could possibly transfer to human/animal bacteria
Once an antibiotic resistance gene is acquired by a bacterium it has
the potential to transferred throughout the bacterial world
What antibiotics are used in food production?
 Penicillins
 Tetracyclines
 Macrolides
 Lincomycins
 Bacitracin
 Virginiamycin
 Aminoglycosides
 Sulfonamides
 Streptomycins
Many of these drugs can not be easily washed off by the consumer
Apples from Mexico have gentamicin impossible to wash off and the
flesh is contaminated as the skin is peeled
Prawns from SE Asia grown in soup of antibiotics: prawns often have
antibiotics in their flesh which may be destroyed with cooking
Potential Spread from Food to Man
Some probiotic Lactobacillus spp. used in food production and starter cultures
are antibiotic resistant and carry acquired genes that are on mobile elements
Various studies have shown that resistant animal bacteria such as VRE can
become established in man and/or the complete mobile elements and/or
the antibiotic resistance genes can become established in human isolates
Antibiotic residues on food may select for resistant bacteria directly in man
Commensal and environmental bacteria exposed to antibiotics will acquire
resistance genes; become a reservoir for these genes and transfer them to
pathogens/opportunists in their ecosystem
Commensal and environmental population become stably resistant: common
in environments that continually use antibiotics
Commensal and environmental population may maintain antibiotic resistant
population even when antibiotics are removed
Bacterial populations exposed to antibiotics for extended time and then
removed rarely return to baseline susceptibility: multiple reasons
FUTURE
1. If there is no change we will have diseases which are no longer treatable with
available antibiotics
a) Already happens in much of developing world because of cost
b) In US occurs if patient is poor, may not be able to get therapy needed
2. Education of the public and clinicians on appropriate use
a) This summer a virus went around many got antibiotics needlessly
b) Reduce use in pediatric population
c) Reduce inappropriate use in hospital, community and agriculture - all 3
are linked
3. Cost issues with newest antibiotics - need to be affordable in all parts of the
world
Immunization/ Vaccines
Principle of Vaccination
Immunization [Vaccination] is a way to trigger the immune system
and prevent serious, life-threatening diseases
Mimics protection that occurs during natural disease without risk
of disease
Aim: Individual will develop immunity and immunologic memory
similar to natural infection without risk of infection
Antigen: A live microbe or inactive substance from microbe
(protein, polysaccharide capsule) capable of trigger immune system
Live attenuated (reduced virulence) bacteria/virus
Inactivated whole [bacteria/virus]; specific component
[protein-based sub-unit, or inactive toxin (toxoid);
polysaccharide-based]
Antibody: Protein molecules (immunoglobulin) produced by B
lymphocytes in response to antigen in the vaccine
Disadvantages of live attenuated vaccines
Severe reactions possible
Interference from circulating antibody
Unstable, may have to be stored cold
May cause disease (live polio vaccine)
May gave false positive test (BCG vaccination; + skin TB test)
Disadvantages of component vaccines
Generally not as effective as live vaccines
Generally require 3-5 doses
Antibody titer diminishes with time
Possibly variation of antigen with each batch of vaccine made
Polysaccharide vaccines are not consistently immunogenic in
children <2 years of age
Some polysaccharides have proven impossible to use as antigen
No available vaccine for N. meningitidis type B after 30
years of work
Polysaccharide vaccines usually mixed with protein to increase
immunogenic properties
Types of Immunity
Active Immunity
Passive Immunity
Protection by persons’ own
immune system
Protection transferred from
from another person/animal
Transplacental from mom to
fetus
Usually permanent
Temporary protection
May wane in old age
Used for prevention after
exposure to disease
tetanus, rabies
Current Vaccines Available
Viral Diseases
Bacterial Diseases
Measles
Mumps
Rubella (German measles)
Polio
Pertussis* (whooping cough)
Diphtheria*
Tetanus*
Haemophilus influenzae type b
[Hib]
Pneumococcal (S. pneumoniae)
Influenza (flu)
Hepatitis A, B
Varicella (chickenpox)
Human papillomavirus (HPV)
*
Rotavirus
toxin disease
No Vaccines Available
Viral Diseases
Bacterial Diseases
HIV
Hepatitis C
Staphylococcus aureus
MRSA
E. coli O157:H7
Sexually transmitted diseases
Today
From 0-5 years of age ~150 vaccine shots given
In addition to the antigen vaccines have preservatives (ethylmercury)
to keep the vaccine sterile; stabilizers to protect composition of
the vaccine and adjuvants which increase the ability to respond to
the vaccine
Some additives can cause redness and/or soreness on the skin where
the vaccination has been given
Today, with the exception of some flu vaccines, no vaccines used in
the U.S. to protect preschool-aged children against 12 infectious
diseases contain ethylmercury (thimerosal) as a preservative
Controversy over whether ethylmercury in the MMR measles, mumps
rubella) vaccine causes autism: No scientific data to support this
claim
Some people are not vaccinating their children because of this
concern or for religious reasons
Takes a long time once new vaccine is put in place to find out if
There are side effects and/or if immunity is life long
Disease
2000
% change
31,054
1
-99
Measles
390,852
86
-99
Mumps
21,342
338
-99
Pertussis
117,998
7,867
-93
Polio (wild)
4,953
0
-100
Rubella
9,941
176
-98
Cong. Rubella Synd. 19,177
9
-99
1,314
35
-97
24,856
112
-99
566,706
8,624
-98
Diphtheria
Tetanus
Invasive Hib Disease
Total
Pre-vaccine Era*
Vaccine Adverse Events
0
13,497
What We As Individuals Can Do
1. Stress good hygiene at all times, home, work, community
2. Hand washing, appropriate food preparation, stay home when sick
3. Comply with prescription when provided
4. Do not ask for antibiotics
5. Check where food is coming from- do not buy if antibiotics are being
used: much of the imported shell fish and fish use lots of antibiotics
Domestic animal production antibiotics use-varies by state
6. Become an educated consumer
7. Get your vaccines, as well as, your children and pets as recommended