Francisella tularensis

OVERVIEW
Tularemia is a highly infectious disease caused by the bacterium Francisella tularensis. Also
has been referred to as rabbit fever, deer fly fever and market’s men disease.

Infections in humans are not contagious and most often result from contact with infected
wildlife, ingestion of or contact with contaminated water, or bites from ticks and other
arthropods that have fed on infected wildlife. Aerosol transmission is another way humans can
become infected.

Disease is expressed in different clinical forms, and varies in severity depending on the
virulence of the organism, dose, and site of inoculum, the immune status of host, the length of
time from infection to diagnosis and treatment.

Tularemia has a broad geographic distribution in the northern hemisphere and is more restricted
elsewhere. A wide variety of species have been naturally infected by F. tularensis; the number
of species reported to be susceptible to infection exceeds 300.
 BACKGROUND

Tularemia is thought to have evolved as a disease of wild animals in both the new world and the old world. The
evolution of Francisella spp. is thought by some to be associated with that of rabbits and hares.

Tularemia was first described as a disease of humans prior to the discovery of the causative agent and probably
occurred in Japan as early as 1818 and in Norway since at least 1890.

The first verified human cases occurred early in the 20th century. Within North America, the first case supported by
laboratory diagnosis occurred in 1914 in an Ohio meat cutter. However, retrospective evaluations indicate that the
first two human cases occurred in 1904 in Tulare, California and in 1907 in Arizona.
.
Dr. Edward Francis provided the linkages between disease syndromes in the United states, Japan, and the former
soviet union as being caused by bacteria of the genus that now bears his name.

The first north american case of tularemia in wild animals supported by a laboratory diagnosis occurred in 1912
during plague studies in California ground squirrels. Francis proposed the name tularemia to differentiate this disease
from rodent plague because of the characteristic septicemia seen. Other investigations established the presence of
tularemia in meat market cottontail rabbits in Washington, D.C.
 CAUSATIVE AGENT

Classification

Domain: Bacteria
Phylum: Pseudomonadota
Class: Gamma proteobacteria
Order: Thiotrichales
Family: Francisellaceae
Genus: Fancisella
Species: F. tularensis
 CAUSATIVE AGENT
F. tularensis( former Bacterium tularense) is a small, aerobic, pleomorphic, non-spore forming, non motile, Gram-
negative (faintly staining) coccobacillus having dimension 0.2μm X 0.2-0.7μm now classified). Combinations of
biochemical, epidemiological, virulence, and pathogenesis data have been used to subdivide F. tularensis into three
major biovars (subspecies) as of 2020.

1. F. t. tularensis (or type A), found predominantly in North America, is the most virulent of the four known
subspecies, and is associated with lethal pulmonary infections. Id50 < 10 CFU via multiple infection routes in many
animals, including humans with the human ulcer isolate, SCHU S4, being the most commonly-used strain in BSL3
laboratories.
2. F. t. holarctica (also known as biovar F. t. palearctica or type B) is found predominantly in Europe and Japan. This
subspecies lacks the citrulline ureidase activity and ability to produce acid from glucose of biovar F. T. Palearctica.
Type B strains are highly-infectious to mice and guinea pigs (pulmonary and intradermal ID 50 < 10 CFU) but higher
doses are needed to infect rabbits (106–109 CFU subcutaneously) and humans (< 103 via multiple routes)
3. F. t. mediasiatica, is found primarily in central Asia. Little is currently known about this subspecies or its ability to
infect humans.
Additionally, F. novicida has sometimes previously been classified as F. t. novicida. It was characterized as a
relatively nonvirulent Francisella; only two tularemia cases in North America have been attributed to the organism,
and these were only in severely immunocompromised individuals.
 Physiology

Gram-negative, tiny pleomorphic, poorly staining, coccobacillus , nonmotile

Oxidase negative.
Weakly catalase positive
urease negative.
Beta-lactamase positive.
X and V factors are not required.
Obligately aerobic, chemoorganotrophic.
Carbohydrates are metabolized slowly with acid resulting but not gas.
 It is a fastidious, facultative intracellular bacterium, which requires cysteine for growth.
Francisella tularensis can survive for several weeks at low temperatures in animal carcasses, soil,
and water. In the laboratory, is grown best at 35–37 °C.
 Tularemia as a Biological Weapon

Because of its low infectious dose, multiple routes of infection, and high morbidity and mortality
rates, F. tularensis has been designated as a tier 1 select agent by the U.S. Centers for disease control
and prevention (CDC), highlighting concerns over its potential use a bioterrorism agent.
F. tularensis is considered to be a serious potential bioterrorist threat because it has substantial
capacity to cause serious illness and death —inhalation of as few as 10 organisms can cause disease.
The bacterium was developed into an aerosol biological weapon by several countries in the past.
Aerosol dissemination of F. tularensis in a populated area would be expected to result in the abrupt
onset of large numbers of cases of acute, nonspecific respiratory febrile illness beginning 3 to 5 days
later.
A world health organization (WHO) expert committee reported in 1970 that if 50 kg (110 pounds) of
virulent
F. tularensis was dispersed as an aerosol over a metropolitan area with a population of 5 million, there
would be an estimated 250,000 incapacitating casualties, including 19,000 deaths.
 EPIDEMIOLOGY AND DISTRUBUTION

1. There is no evidence for human-to-human transmission of tularemia. F. tularensis has been isolated from a variety
of animals which may function as vectors for transmission to hu­mans. Transmission of F. tularensis subspecies
tularensis is associated with rabbits, ticks and sheep, whereas F. tularensis subspecies holarctica is often isolated in
association with streams, ponds, lakes and rivers.
2. There is also evidence that the bacterium can persist for months in watercourses, possibly in association with
protozoa. However, that the epi­zootology of tularemia is not yet fully understood. The respec­tive importance of
various susceptible animals as reservoirs for F. tularensis is still poorly known. Similarly, the role of various
arthropods in the transmission of F. tularensis among animals and between animals and humans is not yet well
understood.
3. Tularemia occurs throughout much of north America and Eurasia. But has a patchy distribution in the northern
hemisphere (holarctica region). In the USA, tularemia has been reported from every state except Hawaii. It has also
been reported in every province of Canada.
4. Although documentation is poor for the remainder of north America, tularemia is known to occur as far south in
north America as Guadalajara, Mexico. The geographic distribution of tularemia in Scandinavia, the former soviet
union, and in Japan is well documented. Far less is known about the geographic distribution and the prevalence of
tularemia in many other countries
 DISEASE TEANSMISSION

The bacterium that causes tularemia is highly infectious and can enter the human body through the skin, eyes, mouth, or lungs. Symptoms of infection vary depending on the route of entry. Transmission of tularemia from person to person has not been reported.

Tick or deer fly bites

In the united states, ticks that transmit tularemia to humans include the dog tick (Dermacentor variabilis), the wood tick (Dermacentor andersoni), and the lone star tick (Amblyomma americanum). Deer flies (Chrysops spp.) Have been shown to transmit tularemia in
the western united states. Infections due to tick and deer fly bites usually take the form of ulceroglandular or glandular tularemia.

Handling infected animals

F. tularensis bacteria can be transmitted to humans via the skin when handling infected animal tissue. In particular, this can occur when hunting or skinning infected rabbits, muskrats, prairie dogs and other rodents. Many other animals have also been known to become
ill with tularemia. Domestic cats are very susceptible to tularemia and have been known to transmit the bacteria to humans. Care should be taken when handling any sick or dead animal. Outbreaks of tularemia have occurred among hamsters purchased from pet stores.
At least one child in the U.S. has developed tularemia after being bitten by a pet hamster. Infection due to handling animals can result in glandular, ulceroglandular, and, Oculoglandular, tularemia. Oropharyngeal tularemia can result from eating under-cooked meat of
infected animals.
Other exposures
Humans can acquire tularemia by inhaling dust or aerosols contaminated with 
F. tularensis bacteria. This can occur during farming or landscaping activities, especially when
machinery (eg. Tractors or mowers) runs over infected animals or carcasses. Although rare, this
type of exposure can result in pneumonic tularemia, one of the most severe forms of the disease.
Water can also become contaminated with the bacteria through contact with infected animals.
Humans who drink contaminated water that has not been treated may contract oropharyngeal
tularemia. This mode of transmission appears to be much more common in Europe than the U.S.
 Interaction with host cells

1. Although a facultative intracellular organism in vitro, F. tularensis has been described as an “obligate intracellular pathogen of
macrophages in vivo”. Early work showed the organism multiplied in murine macrophages, guinea pig hepatic cells, endothelium, and gut
endothelial cells isolated from ticks.
2. F. tularensis enters macrophages using a cytochalasin B-insensitive pathway without triggering the respiratory burst. However,
opsonized F. tularensis has been shown to be actively phagocytosed by polymorphonuclear leukocytes, which are capable of killing the
bacteria by oxidative killing mechanisms.
3. A protein, AcpA, has been identified in F. tularensis which has an acid phosphatase function. AcpA is capable of inhibiting the
respiratory burst more efficiently. Bacteria live within the macrophage in a phagosome which does not fuse with lysosomes, but
acidification of the phagosome does occur and is essential for growth of F. tularensis and acquisition of iron.
4. Phase variation of F. tularensis LPS has been observed, and different forms of the LPS appeared to affect NO induction, thus modulating
the innate immune response. Unlike peritoneal macrophages, NO has been shown not to be involved in killing of F. tularensis by alveolar
macrophages, which can behave differently from other resident macrophage populations.
5. Alveolar macrophages activated by IFN-γ were able to kill F. tularensis, and this killing was resistant to inhibitors of NO production.
Cytokines known to regulate the effector functions of activated macrophages (tumor necrosis factor alpha, interleukin-10, transforming
growth factor beta 1, and IFN-α ) also did not affect the IFN-γ -induced killing by alveolar macrophages, indicating that the IFN-γ-induced
responses of alveolar and peritoneal macrophages are fundamentally different.
 Cont..

6. F. tularensis was shown to upregulate the expression of four proteins during growth in a
macrophage cell line.
The four proteins which showed increased levels of expression relative to broth-grown cells had
molecular masses of 20, 23, 55, and 70 kDa.
7. One operon shown to be essential for growth of F. tularensis inside macrophages is MglAB.
8. Another locus described as necessary for survival in macrophages is minD. minD is a 29-kda
protein, having 2 roles proposed. The minD in F. tularensis may be essential for intracellular
growth either because it acts as a pump for toxic or radical ions.
9. After multiplication within the macrophage, F. tularensis induces cell death by apoptosis. This
releases the bacteria from the cell, allowing infection of fresh cells. Interestingly, relatively large
numbers of bacteria were required to be present within the macrophage before apoptosis could
occur and required a longer time from infection to induction of apoptosis
 PATHOGENESIS and HOST CELL RESPONSE

The pathogenicity of intracellular bacteria depends on their ability to survive within macrophages.
In typical human ulceroglandular tularemia, a skin lesion first appears at the site of infection 3 to 5 days after infective exposure.

During this initial phase, T cells appear to play little role in combating infection. A transient bacteremia occurs, during which the pathogen must resist lysis by complement. Protection appears to be due to the presence of capsule,
as a nonencapsulated mutant was susceptible to killing by nonimmune serum.

The bacteremic phase allows the organism to be seeded throughout the body, infecting all reticuloendothelial tissues. Within days, a wide range of cytokines are expressed in the reticuloendothelial tissues. In the liver, for example,
the bacteria are able to invade and multiply within hepatocytes, and tumor necrosis factor alpha, interleukin-10, interleukin-12, and IFN-γ are produced within 48hrs.

Later during infection, T cells appear to play a major role in protection. . Studies with knockout mice infected with strain LVS confirm these observations, but CD4, 2-microglobulin-deficient/CD8, and T-cell receptor-negative
mice were all able to resolve an infection. However, αβT-cell receptor-negative knockout mice succumbed to infection, indicating that while either CD4 or CD8 T-cells are individually sufficient to resolve infection with strain
LVS, αβT-cell receptor cells are required for protection.

Neutrophils also appear to play a role in defense by ingesting and killing microorganisms, lysing infected hepatocytes and acting as a source of cytokines. One locus which appears to play a role in the natural resistance to primary
infection is Bcg (nramp1). Expression of this allele has many pleiotropic effects associated with activation of macrophages by IFN- or LPS, and mutation of the allele can confer susceptibility to infection by a range of intracellular
pathogens, including F. tularensis.
 VIRULENCE DETERMINANTS

Francisella tularensis is one of the most virulent bacteria known and a CDC category A select agent. Few virulence factors have
been identified for F. tularensis.
A) Capsule: Although essential for serum resistance, is not required for survival following phagocytosis by polymorphonuclear
leukocytes. Many F. tularensis strains express a polysaccharide capsule that it is identical to the O-antigen but lacks other LPS
components including 2- keto-3-deoxyoctulsonic acid (KDO) and lipid A. Biochemical analyses indicated that F. tularensis
capsule was distinct from cell wall material, being composed of ∼51% lipids (primarily 14 and 16 carbon length fatty acids), up
to 35% amino acids, and up to 21% carbohydrates (including mannose and rhamnose). Particularly, blocks IgM and complement
component C3 binding. Noncapsular mutants possess higher neuraminidase activity than capsular wild-type strains. The reason for
this is not known, but the authors proposed a role for neuraminidase in colonization, as the enzyme was active in degrading natural
mucins but not Glycoprotein.
B) LPS: F. tularensis LPS does not exhibit the properties of a classical endotoxin. The atypical lipid A of Francisella is
tetraacylated with fatty acid chains 16–18 carbons in length in comparison to hexaacylated 12–14 carbons in length. This greatly
reduce TLR4 activation and allow for immune evasion. It fails to induce interleukin-1 from mononuclear cells and NO production
from macrophage. LPS from F. tularensis has been shown to undergo phase variation ,affect the organism’s ability to grow
intracellularly.
C) Type IV pili: These are important for adherence, aggregation and DNA uptake, that phenotypically vary depending upon
cultural condition.
 Cont…
D)Type I SS: Type I secretion systems contribute to bacterial virulence through multi-drug efflux and toxin
secretion.
E) Type VI secretion systems: It is related to T4-like bacteriophage injection systems and allow translocation of
various effector proteins into host or competing bacterial cells, also phagosomal escape and intracellular replication.
F) Secreted proteins: Various proteins have been reported to be secreted/released by F. Tularensis but the
mechanisms for their secretion are not known. A study reveals 12 proteins likely released including catalase-
peroxidase KatG, chaperones Dnak, GroEL, and GroES, superoxide dismutase SodB, and bacterioferritin Bfr.

AcpA- associated with Acid phosphatase activity, phospholipase activity, lipase activity, ability to inhibit the
neutrophil respiratory burst, general roles in intracellular growth, phagosomal escape, and virulence in animals.
KatG - has been noted to be important for detoxification of reactive oxygen and nitrogen species.
SodB -it has been found to confer in vitro bacterial resistance to peroxide and the superoxide.
G) OMPS
H) Periplasmic protein: detoxify free radicals
I) inner membrane protein: contains components for signaling system important for interaction.
 CLINICAL MANIFESTATION
Depending on the route of infection, various organs and tissues are heavily colonized by 
F. tularensis, including skin, lymph nodes, lungs, spleen, liver, and kidney,
with bacteremia common in the early stages of infection.
Disease onset is typically very rapid with flu-like symptoms common,
including fever, headache, chills, malaise, and sore throat.
1 Ulceroglandular Tularemia
2 Glandular Tularemia
3 Oculoglandular Tularemia
4 Oropharyngeal Tularemia
5 Tularemia Pneumonia
6 Typhoidal Tularemia
7 Tularemia Sepsis
 Ulceroglandular Tularemia

Most north american cases of tularemia (70 to 85 percent) are of this type and generally arise
from handling contaminated carcasses or following a tick or other infective arthropod bite.

Hunters and trappers are especially prone to exposure from contaminated carcasses during
tularemia outbreaks within the species being pursued because gloves are seldom worn when
handling animals.
Hikers, campers, and others may be exposed to arthropods such as ticks and biting flies that
have previously fed on infected animals.

Ulceroglandular tularemia typically involves a painful, hard, discolored skin lesion that appears
in 3–5 days at the site of exposure. Two days later, a firm, punched-out tender ulcer with raised
edges is formed. Disease progression involves the spread of the organism from the skin lesion
to the lymphatics, producing painful enlargement of the lymphatic glands. Further spread of the
organism through the bloodstream may follow with associated impacts on major organs and
other body systems.
Glandular Tularemia

Similar to the ulceroglandular form, but no skin lesions are evident to indicate the site and
cause of exposure. About 5 to 10 percent of human cases are of this type.

Oculoglandular Tularemia

This form of tularemia can be quite painful and in extreme cases may result in a loss of
vision. Clinical signs may include ulceration of the conjunctiva and the development of
abnormally large amounts of fluids (edema) within the eye. Tearing, pussy discharge from
the area of infection, sensitivity to light, and ocular pain are also associated with the
infection. Enlargement of regional lymph nodes also occurs.
Oropharyngeal Tularemia

This form of tularemia is acquired by drinking contaminated water, ingesting contaminated

food, and, in some instances, by inhaling contaminated droplets or aerosols.
Contaminated wells that serve as public water supply have been a source for numerous
human cases of tularemia in Europe.

Contamination generally results from infected animals contaminating water that feeds the
well, or by those animals entering the well itself. War, civil strife, and other conditions that
may negatively impact the quality of public water supplies in tularemia endemic areas can
contribute to the occurrence of this disease.

The ingestion of inadequately cooked meat from infected game animals, including birds, is
another source for infection. This form of tularemia may result in a painful sore throat
accompanied by inflammation of the mouth, tonsillitis, and swelling of the throat that is
accompanied by fluid discharge. Lymph nodes can also become enlarged.
Tularemia pneumonia
This can result from inhaling contaminated aerosols or, as a secondary outcome, from spread
of the organism from infection at other infected sites within the body.

Cases of tularemia with primary lung involvement are most common in persons in high-risk
occupations, such as laboratory workers. Francisella tularensis-laden aerosols are developed
by handling infected dead animals, examining pets with respiratory infections, and from
handling agar plates on which the organism has been isolated.

Clinical symptoms are highly variable, as is the course and severity of disease. There is an
absence of skin ulcers and enlarged lymph nodes with this form of disease.

The significance of infection is reflected in this form of tularemia rapidly progressing to

severe pneumonia, respiratory failure, and death in some instances. About 10 percent of
cutaneous cases (ulceroglandular) and 50 percent of septicemias are complicated by
pneumonia. Prior to the use of modern antibiotics to treat these infections, pleuropneumonic
cases had a fatality rate of 30 to 60 percent
Typhoidal tularaemia
The diagnosis for this systemic form of tularemia is complicated by the absence of signs that
identify either a site of entry by the organism, location of infection within the body, and a
variety of symptoms also associated with other diseases.
About 5 to 15 percent of human cases of tularemia are of this type. A personal history of
sudden onset of acute illness associated with outdoor activity or contact with animals provides
reason for consideration of this disease in tularemia endemic areas.
The high case fatality rate (30 to 60 percent) associated with this form of tularemia underlines
the importance of providing physicians with a good personal history of recent activities
associated with the outdoors and animal contacts, including companion animals that are
allowed to roam outdoors.

Tularemia sepsis
This form of tularemia, like typhoidal tularemia, lacks specific clinical signs for guiding a
rapid diagnosis. The consequences of tularemia sepsis are often grave, unless treated promptly,
as septic shock (circulatory failure due to the release of endotoxins by high levels of bacteria
within the blood) and other complications lead to severe illness and often to death.
Primary ulcer lymph node enlargement in case of
glandular tularaemia

A. hilar enlargement (13 days after onset of disease)

B. 10 weeks after onset of disease and suc­cessful treatment with oral
doxycycline
 LABORATORY DIAGNOSIS
 F. tularensis is a BSL 2 pathogen so all the samples need to handled carefully.

sample collection ,transport and processing

 Samples: scrapping from the infected ulcers, lymph node biopsies, respiratory samples (sputum,
pharyngeal swab, bronchial or tracheal washes or aspirates , pleural fluids) and blood.
 Serum is generally collected from the patients early in the disease and during convalescence,
may be stored at 2℃ to 8℃ for upto 10 days or frozen if long-term storage is required.
 Sample should be transported within 24 hrs or if delay is suspected then should be refrigerated
in Amie’s transport medium.
 Swab specimen should be placed in transport medium containing charcoal.
 specimen for molecular testing should be placed in guanidine isothiocyanate buffer for upto 1
month.
 Direct detection method
1. Gram staining
It is of little diagnostic use as the organism tends to counterstain poorly with safranin. Replacing safranin with basic fuchsin may
enhance identification.
However, Gram staining of cultured material reveals small (0.2 to 0.5 m by 0.7 to 1.0 m), mainly single gram-negative coccobacilli
which stain weakly

2. Fluorescent antibody stains and immunohistochemical stains:

Commercially available for direct detection of organism in lesion smears and tissues. Indirect fluorescent antibody testing of
suppurative material is rapid and specific. Microscopic examination of tissue and smear specimens is possible using fluorescently
labeled antibodies at reference laboratories, possibly providing rapid confirmation of disease.

3. Histologic studies
Early tularemic lesions may demonstrate areas of focal necrosis surrounded by neutrophils and macrophages. Later, the necrotic areas
become surrounded by epithelioid cells and lymphocytes. Caseating granulomata with or without multinucleated giant cells develops
in some lesions.
 B. Cultivation

F. tularensis is a fastidious organism which requires enriched medium for growth. Traditionally, cysteine glucose blood agar has been the growth
medium of choice.
However, enriched chocolate agar (cysteine heart agar supplemented with 9% heated sheep red blood cells [CHAB] and nonselective buffered
charcoal yeast extract agar also support the growth of the organism and may be used for isolation.

Once growth on the general microbiological agars, such as sheep blood agar, chocolate agar, and Thayer-martin agar, CHAB is recommended to use
for isolation of bacteria from clinical specimens, indicates the pathogen to be present.

F. tularensis grows slowly at 37°C and poorly at 28°C, and this can be exploited to distinguish F. tularensis from Yersinia pestis, F. philomiragia, and
F. tularensis subsp. novicida, all of which grow well at 28°C.

On CHAB, colonies are 2 to 4 mm in size, greenish-white, round, smooth, and slightly mucoid, while on media containing whole blood there is
usually a small zone of alpha-hemolysis surrounding colonies
 C. Serological test

1.Latex agglutination test: A latex agglutination test commercially available from BBL (becton dickinson, franklin lakes, N.J.) has been used by some workers to identify individuals with antibodies to F.
tularensis: reactions at dilutions greater than 1:20 are considered specific and significant. Commercially available antigens can also be used with standard tube agglutination tests. A fourfold increase during illness or
a single titer of 1:160 or greater is considered diagnostic. However, while serological tests are frequently used for diagnosis, strains of F. tularensis have occasionally been isolated which fail to agglutinate
commercially available F. tularensis antigens
2. Immunofluorescence
3. ELISA: Elisa based tests can also be used to detect the bacteria in clinical samples. For example, a capture Elisa using monoclonal antibodies against . Tularensis lipopolysaccharide (LPS)
recognized all strains of F. tularensis tested other than those of subspecies novicida, with no cross reactivity with other bacterial species tested
4. Immunochromatographic test: An immunochromatographic hand-held assay has also been developed based on a polyclonal and a monoclonal antibody to LPS of F. tularensis LVS; the
detection limits of this assay were 107 CFU/ml PBS and 106 107 CFU/ml in spiked human sera. This assay is principally designed for field use, being compact and easy to use and giving results in 15
min, but the relatively low sensitivity means that a negative result does not exclude tularemia.
5. Immunoblots
Serum antibody detection is useful for all forms of tularaemia. After the initial specimen, a convalescent sample should be
collected at 14 days and preferably upto 3-4 weeks after the appearance of symptoms .
A 4 fold rise in titres in conjugation with one additional positive diagnostic test such as culture or molecular is considered a
presumptive diagnosis for tularaemia.
IgM, IgG and IgA all 3 major antibodies may be present during acute illness.

D. Imaging
Chest radiography - to evaluate for pneumonia; this is indicated in any patient in whom the diagnosis of tularemia is suspected
Ultrasonography - to examine lymph nodes for findings suggestive of infection; however, these findings lack specificity
 E. Molecular test

A range of PCR-based assays is used for the detection of F. tularensis or for the
diagnosis of tularemia. Primers are directed against genes encoding outer
membrane proteins such as fopa, the 17-kda outer membrane lipoprotein, tul4
gene which is unique to Francisella spp., iglC, ISUFtu2.
the sensitivity is approximately 75%
PCR assays are limited by the ability to discriminate between F. tularensis and
F. novicida.
MALDI-TOF MS(matrix assisted laser desorption ionization time-of-flight mass
spectrometry) has been used to differentiate the species and subspecies.
 TREATMENT

No standardized antimicrobial susceptibility test exists for F. tularensis spp. The organism is susceptible to aminoglycosides, and
streptomycin is the drug of choice. Gentamicin is possible alternative; doxycycline and chloramphenicol have also been used,
although these two agents have been associated with higher rates of relapse after treatment. Fluoroquinolones appears promising
for treatment of even severe tularaemia.

ANTIBIOTIC RESISTANCE
No natural resistance in F. tularensis to antibiotics used for clinical therapy has been demonstrated. This is true for aminoglycosides,
tetracyclines, chloramphenicol, and quinolones. Erythromycin resistance, however, is prevalent in Europe but not in north America. Al­though
erythromycin is not included among agents used for treatment of tularemia, ery­thromycin resistance may be used as an epidemiological
marker. Due to the potential use of F. tularensis for bioterrorism, antibiotic resistance remains of concern.
 PREVENTION

1. The multiple routes for exposure and the high degree of invasiveness and infectiousness of F. tularensis complicate prevention of human cases of
tularemia in enzootic area.
2. The general population is best protected from tularemia by avoiding contact with arthropod vectors, animal hosts, and contaminated
environments.
3. Precaution is to avoid drinking untreated water from lakes, rivers, and streams. This also provides protection against a variety of other diseases
such as giardiasis. In addition, avoid contact uses of water where dead rodents, hares, or rabbits are observed in those or adjacent environments.
4. As for other arthropod transmitted diseases, the use of insect repellant and protective clothing can provide effective barriers against exposure
when in areas where insect vectors are the primary means for transmission of F. tularensis. 5. Companion animals such as dogs and cats can bring
infected ticks into the home, potentially infecting their owners. The use of tick collars, routine inspection of pets, and the careful removal of ticks
are other actions that can be taken for disease prevention.
6. Surveillance for tularemia should be integrated with broader wildlife disease diagnostic activities and with that for domestic animals and human
health
7. Tularemia has become the “forgotten disease” in many areas therefore, public education, the availability of timely information of tularemia
activity, and the selective use of immunizations for high-risk segments of society if a suitable vaccine should be considered.
 Vaccination
DEVELOPMENT OF LIVE TULAREMIA VACCINES

The LVS vaccine remains the only effective vaccine against tularemia developed to date. However, this vaccine is not currently
available, though work to fully license this vaccine is under way in the united states. The finding that an attenuated mutant of F.
Tularensis can induce protective immunity suggests that this approach to vaccine development is feasible. Administration of the
LVS vaccine has been demonstrated to induce a variable cell-mediated immune response in humans.

DEVELOPMENT OF NONLIVING TULAREMIA VACCINES

Prior to the development of the LVS vaccine, immunologically based therapies against tularemia were reported in the 1930s by
lee Foshay, who suggested that immune serum could be administered to favorably modify the clinical course of tularemia in
humans. This finding stimulated Foshay to work to develop a killed tularemia vaccine that induced humoral immunity. A number
of techniques were employed to prepare the killed bacterial cells, including heating, acetone, and phenol treatment, and the
Foshay vaccines were administered to human volunteers with variable results. There were reports of lesions at the site of

.
administration and that the killed vaccine caused severe local reactions when administered to immune humans Although
animal studies suggest that killed whole-cell vaccines induced only low levels of protection against disease, studies in humans
indicated that immunization with these vaccines reduced the number of infections and considerably modified the course of the
disease
Previous studies with killed vaccines generated a predominantly humoral immune response that was nonprotective and was
believed to have failed to generate a sufficient cell-mediated Immune response.
 REFERENCES

1. Friend Milton, 2006, Tularemia: Reston, Va., U.S. Geological survey, circular 1297, 68 p
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