Francisella tularensis
Tularemia
Francisella tularensis
• Gram stain
– Poorly staining,
tiny Gram-negative
coccobacilli
Francisella tularensis
- One of the most infectious pathogenic
bacteria known
- Inoculation or inhalation of as few as ten
organisms can cause disease
- Extreme infectivity
- Substantial capacity to cause illness and
death
+ Humans cannot transmit infection to
others
Can Survive For Weeks
•
•
•
•
•
Water
Soil
Moist hay
Straw
Decaying animal carcasses
Because it is….
Hardy, non-spore forming organism
Reservoirs
•
•
•
•
•
•
Small and medium sized mammals are the
principal natural reservoirs for F. tularensis
Rabbits
Aquatic Rodents (Beavers, Muskrats)
Rats
Squirrels
Lemmings
Mice
Vectors
• Ticks
• Mosquitoes
• Biting Flies
Also Known As…
•
•
•
•
•
Deer-fly fever (Utah)
Glandular tick fever (Idaho and Montana)
Market men’s disease (Washington D.C.)
Rabbit fever (Central States)
O’Hara’s disease (Japan)
History
• First isolated in 1911 from a plague-like
disease among ground squirrels in
California
• Its epidemic potential became apparent in
the 1930’s and 1940’s when large
waterborne outbreaks occurred in Europe
and the Soviet Union and epizooticassociated cases occurred in the U.S.
Incidence across the Globe
Country
Years
# of Cases
Japan
1924-1987
1,355
Slovakia
1985-1994
126
Turkey
1988-1998
205
Modern Worldwide Death Rate
• Before antibiotics:
pneumonic tularemia—50%
localized tularemia—5%
• After antibiotics:
2.3%
Reported Cases of Tularemia 1990-1998
Four States
Four states accounted for 56% of all
reported tularemia cases
• Arkansas (23%)
• Missouri (19%)
• South Dakota (7%)
• Oklahoma (7%)
U.S. Outbreaks
• Vermont, 1968
– 47 cases in people who handled muskrats
four weeks before the onset of the illness
• No fatalities, but 14 patients had severe prostrating
illness that lasted an average of ten days
• Utah, 1971
– 39 cases, most contracted from the bite of an
infected deerfly
• All patients recovered
U.S. Outbreaks, cont.
• South Dakota, 1984
– 20 cases of glandular tularemia in children
• Illness was mild
• presumed to be caused by type B
• Martha’s Vineyard, 2000
– 15 cases of tularemia
• 11 patients had primary pneumonic disease
• 1 fatality
• Caused by type A
OUTBREAK!
August, 2002—Prairie Dogs
• Health officials were notified that some
prairie dogs at a Texas pet distribution
facility had died unexpectedly
• After officials determined that they had
died of Tularemia, further investigation
found that several hundreds of potentially
infected dogs were shipped to Ohio, West
Virginia, Florida, Washington, Mississippi,
Nevada, Illinois, and Virginia
It gets even worse, as…
• Shipments also went out to Japan, the
Czech Republic, the Netherlands,
Belgium, Spain, Italy, and Thailand
Case Incidence
• The highest incidence of cases was in
1939, when 2,291 cases were reported
• The number remained high throughout the
1940’s
• Declined in 1950’s to the relatively
constant number of cases it is now—less
than 200 per year
• Most cases occur in rural environments;
rarely do they occur in urban settings
Why the decrease in cases?
• The development of effective antibiotics
• Decrease in hunting in the U.S. and other
developed nations reduced human
exposure
Fransicella tularensis
Historical Background
First described by McCoy in 1912 as
agent responsible for a tularemia outbreak
in Tulare County in California and isolated
the organism from infected squirrels.
Francis one of the premier researchers in
the field elucidated the route of infection in
man as:
• RodentsBlood Sucking InsectsMan
Fransicella tularensis
Arthropod Vectors
• Primary vectors are ticks (United States, former Soviet
Union, and Japan), mosquitoes (former Soviet Union,
Scandinavia, and the Baltic region), and biting flies
(United States [particularly Utah, Nevada, and California]
and former Soviet Union). Examples of specific species
include:
• Ticks: Amblyomma americanum (Lone Star tick),
Dermacentor andersoni (Rocky Mountain wood tick),
Dermacentor variabilis (American dog tick), Ixodes
scapularis, Ixodes pacificus, and Ixodes dentatus
• Mosquitoes: Aedes cinereus and Aedes excrucians
• Biting flies: Chrysops discalis (deerfly), Chrysops
aestuans, Chrysops relictus, and Chrysozona pluvialis
Francisella tularensis
Morphology and Physiology I
• Small, weakly staining gram-negative coccobacillus 0.2
to 0.2 – 0.7 um in size.
• Nonmotile, displays bipolar staining with Giemsa stain,
obligate anaerobe, and is weakly catalase positive.
• Young cultures are relatively uniform in appearance
while older cultures display extreme pleomorphism.
• Carbohydrates are dissimilated slowly with the
production of acid but no gas.
• Displays a thick capsule whose loss is accompanied by
loss of virulence.
Francisella tularensis
Morphology and Physiology II
• The lipid concentration in the capsule and cell
wall (50 – 70%, respectively) is unusually high
for a gram negative organism.
• The lipid composition is unique with relatively
large amounts of long-chain saturated and
monoenoic C20 to C26 fatty acids as well as
alpha and beta hydroxyl fatty acids.
• Biochemical characterization is of little value in
identification (other tests are utilized).
Francisella tularensis
Culture Characteristics
• Optimal growth at 370 C, growth range 240 to 390
C. Survival rate is best at lower temperatures.
• Slow growing with a requirement for iron and
cysteine or cystine.
• No growth on routine culture media but small
colony growth after 2 - 4 days on glucosecysteine-blood agar or peptone-cysteine agar.
• No true hemolysis on blood containing media
only a greenish discoloration.
Francisella tularensis
Microbial Genomics-Introduction
• Little is known about the cellular and molecular modes of
infection, proliferation and immune response to
tularemia.
• Microbial genomics has begun to hopefully shed some
light on the above mechanisms.
• The lack of adequate genetic tools has hampered efforts
to elucidate many questions about F. tularensis most
importantly how it enters cells and the factors required
for intracellular growth.
• At present most of the genome of F. tularensis ShuS4
(high virulence) has been sequenced, compiled into
‘contigs’ and is available at the web site
http://artedi.ebc.uu.se/Projects/Francisella/
Francisella tularensis
Microbial Genomics-Intracellular Growth Genes I
• Five genetic loci with the use of transposon mutagenesis
have been identified in F. novicida that are associated
with intracellular growth.
• Gene 1: Alanine racemase catalyzes the reversible
conversion of the L form of alanine to the D form.
Potential effect: Alter bacterial cell wall making it more
susceptible to microbiocidal agents produced by
macrophages.
• Gene 2: Glutamine phosphoribosylpyrophosphate
amidotransferases (50% identity at a.a. level) which
catalyzes the first step in de novo purine biosynthesis.
Potential effect: Inhibition of de novo purine
biosynthesis.
Francisella tularensis
Microbial Genomics-Intracellular Growth Genes II
• Gene 3: ClpB (60% identity to E.coli protein) an ATPdependent protease stress response protein which
hydrolyzes casein and is part of a system which
hydrolyzes denatured proteins.
Potential effect: Inhibit the removal of denatured
proteins overwhelming cell.
• Gene 4: 23Kd protein (99% identity) unique to
Francisella as the dominantly induced protein after
infection.
Potential effect: Unknown.
• Gene 5: AF374673 no significant similarity to any protein
with a known function.
Potential effect: Unknown.
Francisella tularensis
Microbial Genomics-Intracellular Growth Genes III
• The five genes found to be involved in intracellular
growth all map using the available genomic sequence
map to the intracellular growth locus iglABCD.
• The iglABCD is a putative operon involved in intracellular
growth and it is possible that all of the proteins encoded
by the iglABCD operon are needed for intracellular
growth and some are thought to be transcription factors.
• The predicted molecular masses of the protein products
from these genes corresponds to the masses of the
observed proteins expressed during intracellular growth.
• These observations suggest that these proteins play a
critical role in the intracellular growth of F. tullarensis.
Francisella tularensis
Microbial Genomics-Tools
• Yet another odd characteristic of F. tularensis is the absence of its
own plasmids in any of the biovars. It is not clear whether this
property is associated with the environment of the bacterium or with
the specificity of its genetic apparatus.
• It has been shown that heterologous plasmids can replicate in F.
tularensis but must be maintained by antibiotic resistance selection.
• One isolate, F. novidica-like strain F6168, is the only member of the
genus that carries a native plasmid and this plasmid has no known
function or gene products.
• The 3990-bp cryptic plasmid from F6168 has been used to construct
two recombinant plasmids, pFNL10 and pOM1. These plasmids
were engineered to contain antibiotic selection genes, a polylinker
for cloning, and the ori (origin of replication) from F6168. A third
plasmid pKK214 has been designed to assay promoter activity.
• These plasmid tools will hopefully help to elucidate some of the
mechanisms of intracellular growth and virulence.
Francisella tularensis
Microbial Genomics-Identification
• Extensive allelic variation in the short sequence
tandem repeat, SSTR, (5’-AACAAAGAC-3’) has
been found among F. tularensis.
• With the use of appropriately designed primers
and conditions it is possible through the use of
PCR to identify individual strains.
• The analysis of the SSTR’s is a powerful tool for
the discrimination of individual strains and
epidemiological analysis.
Francisella tularensis
Detection Methods
• PCR is a rapid accurate detection method that
can distinguish between strains.
• ELISA has been used and various antibody
labeling methods can be used for detection.
• Time resolved flourometry (TRF) assay system
is more accurate and sensitive than the ELISA
method and requires at least two hours to
perform.
• Mass spectroscopy (MS) of whole bacteria and
isolated coat proteins has also been developed.
In a clinical lab it is feasible but new portable MS
systems are still unreliable in the field.
Francisella tularensis
New Detection Methods I
• New detection methods should be easy to use,
practical, accurate, highly mobile and developed
in a minimum amount of time.
• Unfortunately development of instrumentation
takes 2-5 years and costs millions of dollars.
• The use of already tested, ‘off the shelf’
components would greatly reduce development
time and cost, time being most important in light
of recent events.
Francisella tularensis
New Detection Methods II
• A cheap easy to use detection system could be
assembled from the following existing products to
perform quick accurate PCR analysis to identify
individual Francisella strains.
• Bacteria would be lysed in water at 940 C for 2 minutes
PCR using a capillary light cycler( 25 cycles in less than
10 minutes) resolve products on either low percent
pre-cast gel (visual identification) or fluorescent capillary
electrophoresis (detection via labeled primer) (5-10 min)
• Entire process less than 20 minutes and cost from 15-50
thousand dollars.
• Requires power 120V, 10amps so can be transported
and operated in a light truck or helicopter.
Francisella tularensis
Immunology-I Internalization
• The mode of infection, proliferation, and the immune
response to tularemia are still not well defined. The cells
targeted are the macrophages and parenchymal cells.
• The mode of entry into cells is still unknown but it is
thought to be similar to the Listeria monocytogenes,
another intracellular bacteria.
• The mode of entry utilized by L. monocytogenes, the
‘zipper-type’ mechanism in which bacterial surface
proteins bind to host cell surface receptors and the
bacteria are internalized.
• In L. monocytogenes the E-cadherin has been identified
as the host cell receptor involved, but to date no receptor
has been identified for Francisella internalization.
Francisella tularensis
Immunology-II Infection Overview
• F. tularensis enters the cell.
• Proliferation inside acidified compartments containing
iron.
• High levels of viable bacteria induce cytopathagenesis
and apoptosis.
• Inflammatory response due to pathogen entry attracts
large numbers of macrophages. These macrophages are
not activated and are easier to infect.
• Due to bacterial capsule, immunity to the effect of
neutrophils and complement.
• Renewed infection in arriving macrophages.
Francisella tularensis
Immunology-III Host Death
• The accumulation of macrophages without
removal of bacteria initiate granuloma formation
and the continued activation of the immune
system.
• Host death due to complications due to
pnuemonia and/or due to septic shock due to
the large quantity of cytokines released.
• Tularemia does not release or contain any
known toxin that causes disease, but it does
usurp the immune system and uses it against
the host.
Francisella tularensis
T-cell Activation Immunology-IV
• In response to antigen CD4 and CD8 are
activated and produce interferon gamma (IFNgamma) activating macrophages.
• The activated macrophages release tumor
necrosis factor alpha (TNF-alpha).
• IFN-gamma and TNF-alpha together act to up
regulate phagocytosis by macrophages, cause
them to sequester iron within activated
macrophages, and to up regulate nitrous oxide
release, levels of which are good indicators of
the extent of action of this mechanism.
Francisella tularensis
T-cell Activation Immunology-V
• No individual antigen has yet to be identified.
Hosts recognize a multide of antigens but no
immuno-dominant antigen.
• The presence of phosphoantigens have been
identified in extracts of F. tularensis.
• Phosphoantigens (alkyl-pyrophoshoesters) are
potent inducers of the gamma/delta subset of T
cells causing clonal expansion.
• The role of the expansion of this subset of T
cells and the relevance of phosphoantigens as
vaccine candidates is still unclear.
Francisella tularensis
Immunology-VI B-cell Involvement
• B-cells play a role in the suppression of neutrophil
mobilization.
• B-cells are necessary to develop an immune response to
future encounters with the antigen in F. tularensis
infection.
• It is not thought that the production of specific antibodies
play a large part in the response.
• IgM and low levels of IgG are detected early (3-10 days
after infection) and are thought to confer early protective
as well as long term immunity.
• Immune responses appear primarily to be in response to
the lipopolysaccharide (LPS) of the outer membrane of
the bacterium which appears to be the major protective
antigen.
Francisella tularensis
Immunology-VII B-cell Involvement
• This year the composition of the core LPS
proteins have been uncovered. The
composition of the core, lipid A and the Oside chain of F. tularensis have been found
to have a unique compositions that does
not confer host protection upon exposure.
• Only the intact LPS has been found to
induce a protective immune response.
Francisella tularensis
Conclusions
• The ongoing sequencing of the SCHU S4 and
LVS Francisella have resulted in a large
increase in information included targets that can
be used for the generation of attenuated strains.
• Large scale proteomic work has begun.
• Together the genomic and proteomic
investigations will lead to the development of
new strategies for genetic manipulation and
hopefully lead to an understanding of the
virulence mechanisms of this potent pathogen.
Francisella tularensis
• Organisms are strict aerobes that grow
best on blood-glucose-cysteine agar at
37°C
• Facultative, intracellular bacterium that
multiplies within macrophages
• Major target organs are the lymph nodes,
lungs, pleura, spleen, liver, and kidney
Tularemia
• Contagious --- no
• Infective dose --- 10-50 organisms
• Incubation period --- 1-21 days (average=3-5
days)
• Duration of illness --- ~2 weeks
• Mortality --- treated: low
untreated: moderate
• Persistence of organism ---months in moist soil
• Vaccine efficacy --- good, ~80%
Two subspecies
• Type A –tularensis
• Most common biovar isolated in North America
• May be highly virulent in humans and animals
• Infectious dose of less then 10 CFU
• Mortality of 5-6% in untreated cutaneous disease
• Type B—palaeartica (holartica)
• Thought to cause all of human tularemia in Europe
and Asia
• Relatively avirulent
• Mortality of less then .5% in untreated cutaneous disease
7 Forms of Tularemia
1.
2.
3.
4.
5.
6.
7.
Ulceroglandular
Glandular
Oropharyngeal (throat)
Oculoglandular (eye)
Typhoidal
Septic
Pneumonic
Mortality Rates
• Overall mortality rate for Severe Type A
strains is 5-15%
• In pulmonic or septicemic cases without
antibiotic treatment, the mortality rate has
been as high as 30-60%
• With treatment, the most recent mortality
rates in the U.S. have been 2%
Infection
• Routes of Infection
–
–
–
–
–
No human to human transmission
Inhalation (fewer than 30 organisms)
Ingestion
Incisions/Abrasions (fewer than 10 organisms)
Entry through unbroken skin
• Example: Ulceroglandular Tularemia
– Transmitted through a bite from an anthropod vector
which has fed on an infected animal
Transmission
• Organisms are
harbored in the blood
and tissues of wild and
domestic animals,
including rodents
• In US chief reservoir
hosts are wild rabbits
and ground squirrels
Transmission
Route of Transmission
Skin or conjunctiva
Skin
GI tract
Respiratory tract
Mode of Transmission
Handling of infected
animals
Bite of infected bloodsucking deer flies and
wood ticks
Ingestion of improperly
cooked meat or
contaminated water
Aerosol inhalation
Infection
• Incubation Period
– 1-14 days, dependent on route and dose
– Usually 3-5 days
• Ulceroglandular and glandular tularemia
are rarely fatal (mortality rate < 3%)
• Typhoidal tularemia is more acute form of
disease (mortality rate 30-60 %)
Symptoms
• Immediate Symptoms:
– Fever, headache, chills, rigors, sore throat
• Subsequent Symptoms:
– Loss of energy, appetite, and weight
• Rare Symptoms:
– Coughing, chest tightness, nausea, vomiting,
diarrhea
Symptoms and Reaction
• Symptoms are severe enough to
immobilize people within first two days of
infection.
• Symptoms depend on route of infection.
• Have localized reaction when there is a
specific infection site (cut, tick bite).
• Localized infection can develop into
systemic infection through
haematogenous spread.
Symptoms by Route of Infection
• Aerosol or Ingestion
– Systemic infections, no localized ulcers or lymph
gland swelling
• Aerosol
– Pneumonia
• Ingestion
– Gastrointestinal irritation
• Localized
– Enlargement of local lymph glands, ulcer at infection
site
Outbreaks
Chest X-ray of patient
demonstrating complete
whiteout of the left lung
Tularemia Lesion
Skin Ulcer of Tularemia
Diagnosis
• Confirmed by:
– Successful culture of bacteria
– Significant rise in specific antibodies
• Problems with above methods:
– Culture is difficult and dangerous
– Response from antibody does not occur until
several days after onset of disease
Future Diagnostic Techniques
• New PCR based technique produces
higher success level for identification than
culturing currently does.
• Future tests may allow for identification of
the specific strain infecting a patient.
– Could be useful for a bioterrorist attack.
Prevention
• Best Immunity (Permanent)
– Previous infection with a virulent strain
• Dr. Francis
• Live Vaccine Strain (LVS)
– Best prophylactic
• Foshay’s Vaccine (killed bacteria)
– Provides lesser immunity towards systemic
and fatal aspects of disease than LVS
Prevention and Treatment
• Vaccines take too long to have an effect,
so can’t be used for treatment after
exposure
• Antibiotics are effective for treatment after
exposure
– Antibiotic treatment must begin several days
post-exposure to prevent relapse
Live Vaccine
• Live Virus Strain (LVS)
– Pros
• Only effective vaccine against tularemia
– Cons
• Doesn’t provide 100% immunity
• Possibility of varying immunogenicity between
different batches
• Possibility of a spontaneous return to virulence
The incidence of acute inhalational
Tularemia
Use of a killed vaccine
5.70 cases per 1000
people at risk
Use of a live vaccine
0.27 cases per 1000
people at risk
Antibiotics to Treat Tularemia
• Streptomycin and aminoglycoside gentamicin
– Pros
• Effective against tularemia
– Cons
•
•
•
•
Require intramuscular or intravenous administration
High toxicity profile
Can be relapses of tularemia on aminoglycosides
There exist streptomycin-resistant strains of F. tularensis
Antibiotics to Treat Tularemia
• Tetracyclines and chloraphenicol
– Pros
• Effective against tularemia
• Can be administered orally
• Low toxicity
– Cons
• Higher relapse rate than aminoglycosides
Antibiotics to Treat Tularemia
• Quinolines (including ciprofloxacin)
– Pros
• Generally works well
• Low relapse rate
• Can be administered orally
– Cons
• Has not been used extensively for treatment
Outbreaks
• No large recorded outbreaks of
inhalational tularemia in United States
• Single cases or small clusters including:
– Laboratory exposures
– Exposure to contaminated animal carcasses
– Infective environmental aerosols
Outbreaks
• Laboratory Workers
– Began with a fatal case of pulmonary tularemia in a
43 year old man
– Total of 13 people in the microbiology laboratory and
autopsy services used were exposed despite
adhering to established laboratory protocol
– Services should have been notified of possibility of
tularemia
– Tularemia ranks second in the US and third worldwide
as a cause of laboratory associated infections
Outbreaks
• Sweden 1966-1967
– More than 600 patients infected with strains of
milder European biovar of F. tularensis
– Farm work created aerosols which caused
inhalational tularemia
– Cases peaked during the winter when rodentinfested hay was being sorted and moved
from field storage sites to barns
– No deaths were reported
Category A Agents
•
•
•
•
•
•
Based on probability of use, distribution,
availability, and risk assessment, the CDC
specified 6 agents that have the highest
likelihood of successful use
Anthrax
Plague
Tularemia
Botulinum toxin
Smallpox
Viral Hemorrhagic Fevers
Bioterrorism Agents: Laboratory Risks
Agent
BSL Laboratory Risk
B. anthracis
Y. pestis
F. tularensis
Botulinum toxin
Smallpox
VHF
2
2
2/3
2
4
4
Low
Medium
High
Medium
High
High
Why Use Tularemia?
Col. Gerald Parker, director of USAMRIID
• Ideal agent has availability, easy
production, high rate of lethality or
incapacitation, stability, infectivity, and
aerosol deliverability
• Tularemia and anthrax most potent by far,
with the least amount necessary for a 50%
kill in a 10 km area
However…
Col. Parker went on to prioritize smallpox
and anthrax first for probable use, followed
by plague and tularemia, followed by
botulinum toxin and hemorrhagic fever
viruses
Anthrax v. Tularemia
• U.S. test involving dropping light bulbs on
the subway tracks
– Observed amount of bacteria seen throughout
the system
– Numbers of passengers per train
– Average time per person spent on the subway
• 12,000 cases of anthrax
• 200,000 cases of Tularemia
“I know of no other infection of animals communicable to
man that can be acquired from sources so numerous
and so diverse. In short, one can but feel that the status
of Tularemia, both as a disease in nature and of man,
is one of potentiality.”
R. R. Parker
History of use as a Biological
Weapon
• During WWII, its potential use was studied both
by Japan and by the U.S. and its allies
• In the 1950’s and 1960’s, the U.S. developed
weapons that could deliver aerosolized
organisms of F. tularensis
• It was stockpiled by U.S. military in the late
1960s, and the entire stock was destroyed by
1973
• The Soviet Union continued weapons production
of antibiotic and vaccine resistant strains of F.
tularensis into the early 1990s.
High Exposure to Infection Rate
• 2500 spores to cause inhalational anthrax
• Fewer than 10 organisms for
intracutaneous tularemia infection
• Fewer then 30 F. tularensis organisms
through an aerosol
Indications of intentional release
of biologic agent
• An unusual clustering of illness
(temporal or geographical)
• An unusual age distribution for
common diseases
• Patients presenting with clinical signs
or symptoms that suggest an
infectious disease outbreak
“Outbreaks of
pneumonic tularemia,
particularly in low
incidence areas, should
prompt consideration
of bioterrorism”
Can assume bioterrorism if
• There is an abrupt onset and a single peak of
cases
– Among exposed people
• Attack rates would be similar across age and sex groups
• Risk would be related to degree of exposure to the point
source
• Rapid progression of a high proportion of cases from upper
respiratory symptoms to life threatening pleuropneumonitis
• An outbreak of inhalational tularemia in an urban
setting
World Health Organization Study
In the event that a tularemia mass
casualty biological weapon was used
against a modern city of 5 million people
an estimated 250,000 people would get
sick, and 19,000 people would die
Economic impact
• Referring to this model, the CDC
examined the expected economic impact
of bioterrorist attacks and estimated the
total base costs due to an F. tularensis
aerosol attack to be $5.4 billion for every
100,000 people exposed
Would expect
• Short half-life due to
– Desiccation
– Solar radiation
– Oxidation
– Other environmental factors
• Limited risk from secondary dispersal
Vaccine
• A vaccine for Tularemia is under review by
the FDA and is not currently available in
the U.S.
• Because of the 3-5 day incubation period,
and post-vaccination immunity takes two
weeks to develop, post exposure
vaccination is not considered a viable
public health strategy to prevent disease in
the event of mass exposure
“Careful proactive initiation of post
exposure prophylaxis should not be
underestimated for its medical, public
health, psychological and political merits in
coping with a terrorist attack”.
Center for Infectious Disease
Postexposure Prophylaxis
• One study involving volunteer subjects
demonstrated that use of tetracycline
within 24 hours after exposure can prevent
disease occurrence
…for inhalational tularemia
• If release of the agent becomes known
during the incubation period, people in the
exposed population should be placed on
oral doxycycline or ciprofloxacin for 14
days
• If release does not become apparent until
the appearance of clinical cases,
potentially exposed people should be
placed on a fever watch
…what would happen?
• Any person in whom fever or flu like illness
develops should be evaluated and placed
on appropriate antibiotic therapy for
treatment of tularemia
– Parenteral therapy in a contained casualty
setting
– Oral therapy in the mass casualty setting
• Treatment should continue for fourteen days
Where are these helpful items
coming from?
• Antibiotics for treating patients infected
with tularemia in a bioterrorism scenario
are included in a national pharmaceutical
stockpile maintained by the CDC, as are
ventilators and other emergency
equipment
Where antibiotics fail
• There is a possibility that genetically induced
antibiotic resistant strains could be used as
weapons
– Should be considered if patients deteriorate despite
early initiation of antibiotic therapy
• This increases the need to create a test which
could rapidly identify the antibiotic susceptibility
of tularemia strains
Genetic Manipulation
• Scientists generated a plasmid to insert
resistance genes for tetracycline and
chloraphenicol
• Plasmid was capable of replicating within
F. tularensis and E. coli
Genes to be worried about
•
•
•
•
Antibiotic resistance
Radiation resistance
Desiccation resistance
Genes that code for toxins from other
bacteria
• Genes that would decrease the incubation
time of tularemia
Possible Vaccines
• The construction of a defined attenuated
mutant of F. tularensis could provide a
safe, effective, and licensable tularemia
vaccine that could induce protective
immunity
• The construction of a vaccine that does
not use a live pathogen
It’s critical to develop…
• Simple, reliable, and rapid diagnostic test
to identify F. tularensis in people
• Fast and accurate procedures to quickly
detect F. tularensis in environmental
samples
• A system to monitor for the appearance of
antibiotic resistant strains
• New, effective antibiotic
To Prevent Infection
• Isolation would not be helpful given lack of
human-to-human transmission
So….
• Avoid infected animals
• Wash your hands
• Wear gloves, masks, face-shields, eyeprotection, gowns
• Handle patient equipment with care
Dialogue!!!
• Local practitioners, national health
organizations, and the international
community must all communicate to
control any outbreak
Limitations of Commercial
Identification Systems
• Potential of generating aerosols
• High probability of misidentification
Who’s working for our safety?
• 1970- The US terminated its biological weapons
development program by executive order
• 1973- The US had destroyed its entire biological
arsenal
• Since then, USAMRIID has been responsible for
defensive medical research on potential
biological warfare agents
• The CDC operates a national program for
bioterrorism preparedness and response