AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Soken first described tularemia in 1837 as a febrile illness with generalized lymphadenopathy among people who had eaten infected rabbit meat. McCoy first isolated the causative organism in 1912 following an outbreak of a plaguelike disease among ground squirrels in Tulare County, California. The genus Francisella was named after Edward Francis, whose investigation of the outbreak expanded bacteriologic and epidemiologic understanding of the disease.

Francisella tularensis is one of the most infectious bacteria known, and it can cause illness in humans with exposure to as few as 10-50 organisms. F tularensis is considered a category A agent because of its high infectivity, ease of dissemination, and ability to cause substantial illness and death. Investigation of Francisella tularensis and its use as a biologic weapon began in World War II during the Japanese occupation of Manchuria. F tularensis was weaponized and stockpiled by the United States, until President Nixon terminated the program. As a result, stores maintained by the United States military were destroyed. According to former Soviet expert Dr Ken Alibek, the former Soviet Union produced and maintained strains that were resistant to antibiotics and vaccines.

The World Health Organization (WHO) conducted modeling studies in 1970 for the possible use of F tularensis as a weapon delivered by aerosol release. The WHO estimated that an aerosol dispersal of 50 kg of virulent F tularensis over a metropolitan area with 5 million inhabitants would result in 250,000 incapacitating casualties, including 19,000 fatalities. This dispersal would also result in relapses occurring for many months after the initial exposure and that it might lead to the establishment of enzootic reservoirs of tularemia in wild animals with possible subsequent outbreaks.

Pathophysiology

F tularensis, a facultative, intracellular, aerobic, gram-negative, nonmotile, pleomorphic, and primarily rod-shaped coccobacillus, causes tularemia. It is ubiquitous in the northern hemisphere from 30-71° latitude and is most common in the western south central region of the United States.

F tularensis is an extremely virulent organism. As few as 50 type A organisms would result in disease if inhaled or injected intradermally, whereas oral ingestion would require as many as 10⁸ organisms. Although lagomorphs, rodents, and ticks are the most well-known sources for transmission of the disease to humans, F tularensis has been identified in more than 100 species, including mosquitos. The lagomorphs were historically recognized as the most common source of transmission, hence the name rabbit skinners' disease. However, with decreased rabbit hunting, ticks have now become the most common vector of transmission.

Ticks and deerflies (Chrysops discalis) are common and important vectors. Hard ticks, primarily Amblyomma americanum, Dermacentor andersoni, and Dermacentor variabilis, are also important reservoirs because vertical transmission of their progeny propagates the presence of the organism. A americanum (Lone Star tick) is prevalent in southeast and south central areas of United States, whereas D andersoni (Rocky Mountain wood tick) predominates in the western regions of United States. D variabilis (American dog tick) is widely distributed and found predominantly in the southeastern parts of the United States.

The primary mode of transmission is contact with infected animals or their carcasses, but transmission can follow consumption of inadequately cooked game meats or the bite of a tick or deerfly. Disease can also result from direct contact with or ingestion of contaminated soil, water, or fomites, as well as by inhalation of water aerosols or dust from soil, grains, or contaminated pelts. Person-to-person transmission is rare, but cases have developed in laboratory workers (who should always be notified in advance if tularemia is suspected).

Six clinical forms of tularemia have been identified (see History). Each form is influenced by factors related to the host, organism, and route of transmission. The incubation period depends on the size of the inoculum but generally 1-21 days (usually 2-6 d). A subcutaneous inoculum of 10 organisms is sufficient to induce disease, whereas an inhalational exposure of only 25 organisms may cause disease.

Frequency

United States

Approximately 200 cases of tularemia are reported annually. Ascertaining the true incidence of tularemia is difficult because it is not a reportable condition and is most likely frequently misdiagnosed. A bimodal prevalence occurs with an increased incidence in May to August (associated with tick-borne transmission) and in December to January (associated with hunting). This bimodal prevalence is also associated with an increased incidence in children during the summer months (May to August) and in adults during the winter months (December to January).

International

Tularemia is found around the world, distributed within 30-71° northern latitude, but its incidence is unknown.

Mortality/Morbidity

Untreated, the mortality rate from tularemia is 5-30%, with the highest rate occurring with the typhoidal (systemic) form, particularly when accompanied by tularemia pneumonia. The mortality rate is also dependent on the strain involved, with type A being significantly more virulent and being responsible for almost all reported deaths. The mortality rate is less than 1% with appropriate antibiotic therapy.

Race

No racial predilection is reported.

Sex

Male individuals are more frequently affected than female individuals, despite the lack of biologic affinity. This distribution results primarily from increased exposure to specific activities (such as hunting and skinning animals) and increased occupational vulnerability among male individuals.

Age

A bimodal prevalence is associated with an increased incidence in children during the summer months (May to August) and increased incidence in adults during the winter months (December to January). This prevalence is most likely related to increased outdoor activities of children during the summer and of adults during hunting season in the winter.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Six clinical forms of tularemia have been described: ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal. These clinical forms are not necessarily distinct entities and may have overlapping features. Children infected with tularemia typically have a clinical presentation similar to that of adults. However, children have been reported to have fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than adults.

• Common to all are the following findings:
• • Abrupt onset of fever and chills (typically last for several days, remit for a brief interval, and then recur)
  • Headache
  • Anorexia
  • Malaise and fatigue or prostration
  • Myalgias
  • Cough
  • Vomiting
  • Pharyngitis
  • Abdominal pain
  • Secondary pneumonitis (may occur in 45-83% of patients with the typhoidal form)
• The ulceroglandular form affects as many as 87% of patients (>75% of adults and 44% of children in some series): This form results in the following findings:
• • A small, erythematous tender or pruritic papule occurs at site of inoculation usually 2-5 days (with a range of 1-10 d) after cutaneous exposure; the papule enlarges and becomes ulcerated 2-3 days later. Gradually, the tender necrotic base develops with a black eschar, often concomitantly with regional adenopathy.
  • • Tick-borne tularemia is usually in the groin and lower extremities (50%), the trunk (30%), and the axillae.
    • The rabbit-associated form is usually on hands or fingers.
    • Ulcers are tender, with raised edges and a jagged floor.
  • Lymphadenopathy, lymphadenitis, or both may occur with tender suppurative local enlargement reflecting site of entry.
  • • The tick-borne form usually involves inguinal or femoral adenopathy.
    • The rabbit (animal)-associated form usually involves axillary or epitrochlear adenopathy.
    • Systemic adenopathy may occur.
• In the glandular form (3-20% of cases, second most common form in adults), tender lymphadenopathy occurs without evidence of local cutaneous lesions.
• In the oculoglandular form (0-5% of cases, secondary to touching or rubbing eyes with contaminated hands), Parinaud oculoglandular syndrome is unilateral conjunctivitis with ipsilateral preauricular adenopathy.
• • Unilateral conjunctivitis (with injection and chemosis)
  • Lymphadenopathy (most commonly cervical, but preauricular and submandibular also observed)
  • Photophobia
  • Lacrimation
  • Lid edema
• The oropharyngeal form (0-12% of cases, as many as 23% of cases secondary to ingesting undercooked infected meat or contaminated water) is the second most common form in children.
• • Exudative pharyngitis or tonsillitis (may occasionally develop a membrane resembling diphtheria), and stomatitis
  • Abdominal pain, nausea and vomiting
  • Cervical lymphadenopathy
  • Diarrhea
  • Gastrointestinal bleeding (occasionally)
• The pneumonic form (7-20% of cases, secondary to inhalation of aerosols of water or dust from soil, grains, or pelts or secondary to hematogenous spread). 30-80% of typhoidal forms and 10-15% of ulceroglandular forms develop pneumonia. The mortality rate can reach 60% if untreated. Inhalational exposure results in the following:
• • Cough (nonproductive to minimal sputum production)
  • Substernal chest tightness or burning
  • Pleuritic chest pain
  • Dyspnea
  • In rare cases, adult respiratory distress syndrome (ARDS) and death
• The typhoidal, or septicemic, form (5-30% of cases) results in the following:
• • Systemic form of tularemia with no obvious source of entry (may result from any portal of entry)
  • Any of the symptoms presented above
  • Weight loss
• The absence of an ulcer or lymphadenopathy may hinder immediate diagnosis.

Physical

Physical findings vary according to the mode of transmission and presentation.

• Systemic findings - Fever
• Hepatic findings - Hepatomegaly (tender) with prolonged illness
• Splenic findings - Splenomegaly (tender) with prolonged illness
• Dermal findings
• • Rash
  • • Generalized maculopapular, approximately 20%
    • Erythema nodosum (1-13%)
    • Erythema multiforme (1-2%)
    • Tularemids: These secondary skin eruptions are common, occurring in 3-25% of cases. These exanthems occur on the extremities and face more than on the trunk. They typically appear during the second week of the disease and may occur in any of the clinical forms of tularemia. Papular, macular, pustular, petechial, and papulovesicular exanthems have been described.
  • Ulcer
  • • Begins as small erythematous papule that enlarges and ulcerates after 2-3 days
    • Raised edges and jagged floor
    • Floor necroses (changing color from yellow to black)
    • Tender
• Lymphatic findings: Regional lymph nodes may become fluctuant, similar to buboes of plague, and ulcerate and drain spontaneously.
• Ocular findings
• • Unilateral injected conjunctivitis
  • Lid edema
  • Purulent exudate
  • Ulcerations or papules on conjunctivae
  • Preauricular, submandibular, and/or cervical lymphadenopathy
• Pulmonary findings
• • Nonproductive cough
  • Rales
  • Pleural rub
  • Normal pulmonary examination findings (possible)
• Oropharyngeal findings
• • Exudative pharyngitis or tonsillitis (may occasionally develop a membrane resembling diphtheria) with ulcers
  • Submandibular and cervical lymphadenopathy

Causes

F tularensis, which is a facultative, intracellular, aerobic, gram-negative, nonmotile, pleomorphic, and primarily rod-shaped coccobacillus, is the causative organism of tularemia. This organism is ubiquitous in the northern hemisphere from 30-71° latitude and is most common in the western south central areas of the United States.

• The organism exists in 2 forms that are serologically identical and that differ primarily in their geographic distribution, fermentation reactions, and virulence.
• • Jellison type A (F tularensis biovar tularensis) is generally found in North American rabbits and ticks and causes severe disease in humans. An inoculum of 10 organisms subcutaneously is sufficient to induce disease, while an inhalational exposure of only 25 organisms may cause disease.
  • Jellison type B (F tularensis biovar palaearctica) is found primarily in Asian and European rodents and results in a milder form of disease in humans.
• Methods of transmission include inhalational, ingestional, and vector-associated exposure.
• • F tularensis has been isolated from more than 100 species of animals, primarily lagomorphs and rodents.
  • Tick reservoirs and vectors
    • A americanum (Lone Star tick) is prevalent in the southeast and south central regions of United States.
    • D andersoni (Rocky Mountain wood tick) predominates in the western areas of the United States.
    • D variabilis (American dog tick) is widely distributed.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Psittacosis
Anthrax
Disseminated mycobacterial disease
Disseminated fungal disease
Lymphogranuloma venereum
Colorado tick fever
Rat-bite fever
Nontuberculous mycobacterial infections

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Standard laboratory results are nonspecific.
• Serum transaminase levels are mildly elevated in about one half of patients.
• Urinalysis may show sterile pyuria in as many as one fourth of patients.
• The CBC may show an elevated WBC count in about one half of patients.
• Mild thrombocytopenia may be present.
• Hyponatremia is occasionally present.
• Elevation of creatine kinase values may be observed and is associated with rhabdomyolysis.
• CSF may show a mild elevation of protein concentration or pleocytosis.
• Although the organism has been cultured from sputum, pleural fluid, wounds, blood, lymph node biopsy samples, and gastric washings, the yield is extremely low and culture poses a danger to laboratory personnel. The plates must be sealed and handled by using a biosafety level-2 (BSL-2) facility, with further testing at BSL-3 facility after a presumptive identification of F tularensis.
• • Other potentially effective media include chocolate, buffered charcoal yeast extract, and Thayer Martin agar. 
  • Specimens should be maintained for at least 10 days because the slow growth of the culture may require 48-72 hours to be identified.
  • Blood cultures have poor sensitivity, which is probably due to the specific medium (cysteine-glucose-blood agar) needed to culture this organism.
• Serologic cross-reactivity is reported with Brucella species, Proteus Ox-19, and Yersinia species. Studies reveal the following:
• • The diagnosis of tularemia is most often made with serologic testing. Antibodies may be measured by means of agglutination and enzyme-linked immunosorbent assay (ELISA).
  • An agglutination titer greater than 1:160 is considered presumptively positive, and treatment may be started if this result is obtained.
  • A second titer demonstrating a 4-fold increase in 2 weeks confirms the diagnosis. Note that although titers begin to rise within 7-10 days after exposure, early titers in the first 2 weeks of illness may be negative in the setting of infection. Detectable titers are identified in the second week of infection in more than 50% of cases.
  • Titers achieve maximum levels between 4-8 weeks and may remain elevated for years after infection, causing an uncertainty in individuals with a remote history of tularemia exposure.

Imaging Studies

• Chest radiography
• • Tularemia pneumonia may be present without respiratory symptoms.
  • Chest radiography is indicated in any patient in whom the diagnosis of tularemia is suspected.
  • Common findings in tularemia pneumonia include bilateral patchy infiltrates or lobar infiltrates (74%), cavitary lesions, which may be better visualized on chest CT, hilar lymphadenopathy (32%), or a pleural effusion (30%).
  • The triad of oval opacities, hilar lymphadenopathy, and pleural effusion is more likely with tularemia than with other tick-borne diseases.

Other Tests

• Indirect fluorescent antibody test of suppurative material is rapid and specific.
• Microscopic examination of tissue and smear specimens is possible using fluorescent-labeled antibodies at reference laboratories, possibly providing rapid confirmation of disease.
• Polymerase chain reaction (PCR) has been used to detect F tularensis, even after initiation of antibiotic therapy. However, it is not yet available in most laboratories. PCR may provide rapid and specific confirmation, possibly including the disease phase.
• Capture ELISA is an advancement based on monoclonal antibodies specific for lipopolysaccharide of the virulent forms of F tularensis. In animal studies, capture ELISA was more sensitive and specific than routine ELISA and in fact rivals PCR without the time and expense associated with PCR.
• Other techniques available include antigen detection assays, immunoblotting, and pulsed-field gel electrophoresis. Unfortunately, availability of these techniques is largely limited to research or reference laboratories.

Histologic Findings

Caseating granulomas may be found on histologic examination of lymph nodes.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Consider the various forms of tularemia in many of the most common emergency department and primary care cases, including cases of conjunctivitis, lymphadenitis, pharyngitis, or pneumonia.
• Start initial supportive care in any unstable patient.
• If tularemia is suspected, obtain serum titers and start antibiotics.
• Postexposure prophylaxis is recommended within 24 hours of airborne exposure using either ciprofloxacin or doxycycline for 2 weeks. It is unlikely that aerosolized exposure to F tularensis is identified within 24 hours, so standard treatment is recommended within 14 days of exposure.

Surgical Care

Drain fluctuant lymph nodes and empyemas.

Consultations

• Consider consulting an infectious diseases specialist for recommendations on commencing antibiotic coverage and any questions involving specific diagnostic studies.
• Consider consultation with a pulmonologist for patients with pulmonary involvement.
• Contact local or federal law enforcement agencies and the Centers for Disease Control and Prevention if multiple cases occur, which would suggest biological or terrorist attack.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of therapy is eradication of F tularensis with antibiotics.

Drug Category: Antibiotic agents

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens for the clinical presentation. Streptomycin is considered the antimicrobial of choice in treating tularemia. Current research reveals increasing evidence supporting the use of other medications. Although aminoglycosides are currently considered the DOCs and though tetracyclines are acceptable alternatives, increasing research supports the use of fluoroquinolones in the treatment of tularemia. Other antibiotics, such as chloramphenicol, are bacteriostatic and have been associated with a high relapse rate following discontinuation of therapy. Fluoroquinolones may be considered an alternative antibiotic for patients who are unable to tolerate aminoglycosides. This option is of great importance because many practitioners have turned to using the newer fluoroquinolones as their monotherapy of choice in treating community-acquired pneumonia.

Drug Name	Gentamicin (Garamycin)
Description	Aminoglycoside used as alternative to streptomycin. Decreased experience with this agent. Dosing regimens numerous and adjusted for CrCl and changes in volume of distribution. May be administered IV or IM. Follow each regimen with a trough level drawn 0.5 h before fourth dose; may draw peak level 0.5 h after 30-min infusion.
Adult Dose	3-5 mg/kg/d IV/IM divided q6-8h Alternative: 5 mg/kg IV qd
Pediatric Dose	<5 years with normal renal function: 2.5 mg/kg/dose IV/IM q8h >5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d with adjustments for renal function prn
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, or amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of various degrees may occur (monitor regularly)
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Narrow therapeutic index; not intended for long-term therapy; caution in renal failure (not managed with dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; dosage adjustment prn in renal impairment

Drug Name	Tetracycline (Sumycin)
Description	Second DOC. Treatment <2 wk increases risk of relapse. Only potential advantage is ability to cover other coexisting tick-borne pathogens. Should be considered when patients unable to tolerate streptomycin or when renal function is concern. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose	500 mg PO bid or 250 mg PO qid for 7-14 d
Pediatric Dose	<8 years: Not recommended >8 years: 25-50 mg/kg/d PO divided qid for 7-14 d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate can decrease tetracycline bioavailability; tetracycline can increase hypoprothrombinemic effects of anticoagulants; monitor PT in patients taking both concurrently; coadministration of tetracycline can decrease pharmacologic effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Prolonged exposure to sunlight or tanning equipment can cause a photosensitivity reaction; use lower than usual doses in renal impairment; use of tetracycline during tooth development (last one half of pregnancy through 8 y) can cause permanent discoloration of teeth; never administer outdated tetracycline (degradation products of tetracycline highly nephrotoxic and can cause Fanconi-like syndrome)

Drug Name	Chloramphenicol (Chloromycetin)
Description	Insufficient data on use in tularemia. Distant third and possibly fourth choice given growing evidence supporting use of fluoroquinolones. Binds to 50S bacterial-ribosomal subunits and interferes with or inhibits protein synthesis. Effective against gram-negative and gram-positive bacteria.
Adult Dose	50-100 mg/kg/d PO/IV divided q6h; not to exceed 4 g/d
Pediatric Dose	50-75 mg/kg/d PO/IV divided q6h
Contraindications	Documented hypersensitivity
Interactions	Taken concurrently with barbiturates, may decrease serum levels and barbiturate clearance, increasing levels or toxicity; clinical manifestations of hypoglycemia may occur when taken concurrently with sulfonylureas; coadministration with rifampin may reduce serum levels, presumably by hepatic enzyme induction; when taken concurrently, may increase effect of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions	Must not be used to treat trivial infections other than ones indicated or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (eg, aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; order baseline and periodic blood studies approximately q2d during therapy; discontinue on appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or any other attributable findings; excessive blood levels may result from use of recommended dose in impaired liver or kidney function (decrease dose); caution during pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

Drug Name	Levofloxacin (Levaquin)
Description	May be useful to treat tularemia.
Adult Dose	500 mg PO qd for 7-14 d
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, periodically evaluate function of organ systems (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; has caused tendon rupture

Drug Name	Ciprofloxacin (Cipro)
Description	Fluoroquinolone that inhibits bacterial DNA synthesis and consequently growth by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. No activity against anaerobes. Continue for at least 2 d (7-14 d typical) after signs and symptoms disappear.
Adult Dose	750 mg PO bid or 250-500 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity; coadministration with steroid combinations after uncomplicated removal of foreign body from cornea
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions	May be used in pregnant women if bioterrorism agent suspected Dosage adjustments (adults) CrCl (mL/min) <10: 50% of PO or IV dose q12h Hemodialysis (HD): 0.25-0.5 g PO or 0.2-0.4 g IV q12h During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h In prolonged therapy, periodically evaluate function of organ systems (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy Not first choice in children because of increased incidence of adverse events (including arthropathy) compared with control subjects; no data for dosage for pediatric patients with renal impairment (ie, CrCl <50 mL/min)

Drug Name	Doxycycline (Vibramycin)
Description	Broad-spectrum, synthetically derived bacteriostatic antibiotic in tetracycline class. Almost completely absorbed, concentrates in bile, and excreted in urine and feces as biologically active metabolite in high concentrations. Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Preferred therapy. May eradicate other tick-related copathogens. Should be used for full 14 d to prevent risk of relapse.
Adult Dose	100 mg PO/IV bid
Pediatric Dose	<8 years: Not recommended >8 years: 2-4 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care should be guided by consultation with an infectious disease specialist.

Further Outpatient Care

• Close outpatient follow-up with a primary care physician is essential for any case of suspected tularemia.

In/Out Patient Meds

• See Medication for treatment of acute tularemia.

Transfer

• Transfer of care depends on the level of clinical support and laboratory capabilities at the treatment facility.
• Any considerations for transfer should be in consultation with an infectious diseases specialist because appropriate care may be provided with consultations.

Deterrence/Prevention

• Limit exposure to ticks and deerflies.
• Use insecticides and protective clothing when exposed to ticks and deerflies.
• Avoid contact with wild animal blood and flesh, including rabbit, particularly when hunting or skinning. Take special care to avoid touching the face or eyes while handling these animals.
• A live attenuated vaccine is available as an investigational agent from the US Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland. The vaccine is derived from avirulent F tularensis biovar palearctica (type B) and produces partial protection.
• Postexposure prophylaxis is recommended within 24 hours of airborne exposure using tetracycline, ciprofloxacin or doxycycline for 2 weeks. It is unlikely that aerosolized exposure to F tularensis is identified within 24 hours. Therefore, standard treatment is recommended within 14 days of exposure.
• Organisms are relatively easily to render harmless by mild heat (55°C for 10 min) and standard disinfectants. Decontamination of inanimate objects may be performed using 10% bleach, which may be followed by a 70% alcohol solution to further decontaminate and to decrease the corrosive effects of the bleach.

Complications

• Suppurative lymphadenitis
• Pneumonitis
• Renal failure
• Respiratory failure
• Rhabdomyolysis
• Pericarditis
• Endocarditis
• Meningitis
• Peritonitis
• Appendicitis
• Perisplenitis
• Osteomyelitis
• Guillain-Barré syndrome
• Hepatitis
• Sepsis

Prognosis

• Untreated typhoidal tularemia can have a mortality rate as high as 30%, but the overall mortality rate for tularemia is less than 10%.
• Treated tularemia has a mortality rate of less than 1%. Life-long immunity usually results after infection.
• Factors affecting the prognosis include the following:
• • Typhoidal (septicemic) presentation
  • Elevated creatine kinase
  • Renal failure
  • Delayed diagnosis
  • Comorbid conditions
• Lifelong immunity usually results after infection.
• Jarisch-Herxheimer-like reactions have been described after initiation of treatment for tularemia.

Patient Education

• Direct patient education at limiting tick and deerfly exposure and instruct the patient regarding the importance of hunter education for contact precautions and good hygiene while handling rabbits and other wild animals.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The primary concern is failure to make the diagnosis. A high index of suspicion and a thorough history identifying rabbit exposure may guide the practitioner in making the appropriate diagnosis.
• The physician must not fail to identify any other potentially lethal causes for the patient's presentation.

Special Concerns

• A tularemia vaccine is available.
• The vaccine is live but does not provide complete immunity, and it has the potential of inducing the illness.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bolgiano EB, Sexton J. Tick-borne illnesses. In: Rosen P, ed. Emergency Medicine: Concepts and Clinical Practice. Vol 3. 4^th ed. St Louis, Mo: Mosby; 1998:2612-4.
• Bratton RL, Corey R. Tick-borne disease. Am Fam Physician. Jun 15 2005;71(12):2323-30. [Medline].
• Cronquist SD. Tularemia: the disease and the weapon. Dermatol Clin. Jul 2004;22(3):313-20, vi-vii. [Medline].
• Daya M, Nakamura Y. Pulmonary disease from biological agents: anthrax, plague, Q fever, and tularemia. Crit Care Clin. Oct 2005;21(4):747-63, vii. [Medline].
• Faul JL, Doyle RL, Kao PN, Ruoss SJ. Tick-borne pulmonary disease: update on diagnosis and management. Chest. Jul 1999;116(1):222-30. [Medline].
• Greenberg SB. Serious waterborne and wilderness infections. Crit Care Clin. Apr 1999;15(2):387-414. [Medline].
• Grunow R, Splettstoesser W, McDonald S, et al. Detection of Francisella tularensis in biological specimens using a capture enzyme-linked immunosorbent assay, an immunochromatographic handheld assay, and a PCR. Clin Diagn Lab Immunol. Jan 2000;7(1):86-90. [Medline].
• Johansson A, Berglund L, Gothefors L, et al. Ciprofloxacin for treatment of tularemia in children. Pediatr Infect Dis J. May 2000;19(5):449-53. [Medline].
• Labayru C, Palop A, Lopez-Urrutia L, et al. [Francisella tularensis: update on microbiological diagnosis after an epidemic outbreak]. Enferm Infecc Microbiol Clin. Nov 1999;17(9):458-62. [Medline].
• Limaye AP, Hooper CJ. Treatment of tularemia with fluoroquinolones: two cases and review. Clin Infect Dis. Oct 1999;29(4):922-4. [Medline].
• Osterbauer PJ, Dobbs MR. Neurobiological weapons. Neurol Clin. May 2005;23(2):599-621. [Medline].
• Schuster GS. Bacterial and protozoal infections. Infect Dis Clin North Am. Dec 1999;13(4):797-816. [Medline].
• Senol M, Ozcan A, Karincaoglu Y, et al. Tularemia: a case transmitted from a sheep. Cutis. Jan 1999;63(1):49-51. [Medline].
• Smego RA, Castiglia M, Asperilla MO. Lymphocutaneous syndrome. A review of non-sporothrix causes. Medicine (Baltimore). Jan 1999;78(1):38-63. [Medline].
• Weber DJ, Isbey S. Tick-borne diseases. In: Emergency Medicine: A Comprehensive Study Guide. 4^th ed. New York, NY: McGraw-Hill; 1996:729-30.

Article Last Updated: Aug 9, 2007