Tularemia

Treatment Overview

Treatment. Initial empiric therapy for systemic disease caused by F. tularensis includes at least one of the following antibiotics:

Preferred

  • Streptomycin*, 1g IM bid (15 mg/kg IM bid for children), or
  • Gentamicin 5 mg/kg IM or IV qd ( 2.5 mg / kg IM or IV q8 hr for children), or

Alternatives

  • Doxycycline, 100 mg IV q12 hr for adults or children > 45kg (2.2 mg/kg IV q 12 hr for children <45 kg), or
  • Ciprofloxacin 400 mg IV every 12 hr for adults (for children use 15 mg/g IV q 12 hr (up to 1g/day)), or
  • Chloramphenicol, 15 mg/kg IV q 6 hr

*Streptomycin has historically been the drug of choice for tularemia and is the only aminoglycoside antibiotic approved by the FDA for treatment of tularemia; however, since it may not be readily available immediately after a large-scale BW attack, gentamicin and other alternative drugs should be considered first. Requests for streptomycin should be directed to the Roerig Streptomycin Program at Pfizer Pharmaceuticals in New York (800-254-4445).

Intravenous antibiotics can be switched to oral antibiotics as the improvement in the patient's course dictates. Length of therapy depends upon the antibiotic used. Chloramphenicol and tetracyclines (doxycycline) have been associated with relapse with courses lasting even 2 weeks and thus should be continued for at least 14-21 days. Streptomycin, gentamicin, and ciprofloxacin should be continued for at least 10-14 days. It is quite possible that any intentional use of tularemia as a weapon will employ a strain of the organism which is resistant to our preferred antibiotics. Thus testing the strain for antibiotic susceptibilities is of paramount importance. A clinical clue to resistance would be failure of the patient to improve dramatically after 24-48 hr of antibiotics.

Infection Control. Because there is no known human-to-human transmission of tularemia, neither isolation nor quarantine is necessary. Standard precautions are appropriate for care of patients with draining lesions or pneumonia. Strict adherence to the drainage / secretion recommendations of standard precautions is required, especially for draining lesions, and for the disinfection of soiled clothing, bedding, equipment, etc. Heat and disinfectants easily inactivate the organism. Laboratory workers should not attempt to grow the organism in less than BSL-3 conditions.

Treatment

Available data support the following statements about treatment of tularemia:

  • Streptomycin and gentamicin have been shown to be effective and are considered the first-line therapies (see References: AAP 2006, Enderlin 1994, Evans 1985, Hassoun 2006, Mason 1980).
  • Ciprofloxacin and other fluoroquinolone antibiotics have been used effectively to treat tularemia, although experience with these medications is somewhat limited to date (see References: Johansson 2000, Limaye 1999). In one outbreak, ciprofloxacin showed a lower treatment failure rate than streptomycin or doxycycline (see References: Perez-Castrillon 2001).
  • Tetracycline and chloramphenicol can be used to treat tularemia; however, because these drugs are bacteriostatic, relapses occur more often than with use of aminoglycosides (see References: Evans 1985, Overholt 1961).

The Working Group on Civilian Biodefense has made the following recommendations for treatment of tularemia during a bioterrorist attack (see References: Dennis 2001):

  • In a contained casualty setting where the medical care delivery system can effectively manage the number of patients, parenteral antibiotics should be administered to all patients whenever possible, according to the table below.
  • In a mass casualty setting where the medical care delivery system is not able to meet the demands for patient care, use of oral antibiotics may be necessary. In such a situation, the medications listed below in the table on antibiotic postexposure prophylaxis should be used and therapy should be continued for 14 days.
  • Supportive care of patients also is critical, including fluid management and hemodynamic monitoring as indicated. Some patients would require intensive care with respiratory support owing to complications of gram-negative sepsis (eg, shock, adult respiratory distress syndrome, multisystem failure, disseminated intravascular coagulation).
  • Bioterrorist use of an F tularensis strain resistant to conventional antibiotic therapy is of concern and should be considered, particularly if patients deteriorate despite early initiation of antibiotic therapy.

Recommendations for Treatment of Tularemia During a Bioterrorism Event

Choices by Patient Category

Therapy Recommendationsa,b

Adults: Preferred choices

Streptomycin: 1 g IM twice daily for 10 daysc,d,e
or
Gentamicin: 5 mg/km IM or IV once daily for 10 daysc,e

Adults: Alternative choices

Doxycycline: 100 mg IV twice daily for 14-21 dayse
or
Chloramphenicol: 15 mg/kg IV 4 times daily for 14-21 daysf
or
Ciprofloxacin: 400 mg IV twice daily for 10 daysc

Children: Preferred choices

Streptomycin: 15 mg/kg IM twice daily (maximum daily dose, 2 g) for 10 daysc
or
Gentamicin: 2.5 mg/kg IM or IV 3 times daily for 10 daysc

Children: Alternative choices

Doxycycline:
   >45 kg: same as adult
   <45 kg: 2.2 mg/kg IV twice daily for 14-21 days
or
Ciprofloxacin: 15 mg/kg IV twice daily for 10 days (maximum daily dose, 1 g)
or
Chloramphenicol: 15 mg/kg IV 4 times daily for 14-21 days (maximum daily dose, 4 g)f

Abbreviations: IM, intramuscularly; IV, intravenously.

aIn the mass casualty setting where the medical care delivery system is not able to meet the demands for patient care, oral antibiotics may need to be substituted for intravenous antibiotics for treatment of patients with tularemia. In such a situation, the recommendations in the table below on postexposure prophylaxis should be followed for treatment.
bThese treatment recommendations reflect those of the Working Group on Civilian Biodefense and may not necessarily be approved by the Food and Drug Administration.
cAcceptable for pregnant women.
dStreptomycin is not as acceptable as gentamicin for use in pregnant women because irreversible deafness in children exposed in utero has been reported with streptomycin use.
eAminoglycosides must be adjusted according to renal function.
fConcentration should be maintained between 5 and 20 mcg/mL; concentrations >25 mcg/mL can cause reversible bone marrow suppression.

Adapted from Dennis 2001 (see References).

Some have suggested that doxycycline is a good first choice for treatment, because it has greater efficacy than ciprofloxacin, has less potential for development of resistance, and is less expensive. Patient relapse is possible with this drug, however (see References: Brouillard 2006, Tarnvik 2007).

A recent study of 145 patients with oropharyngeal tularemia showed that 55 (38%) of those treated experienced initial therapeutic failure (defined as persistence or recurrence of fever, persistence of constitutional symptoms, or increase in size or appearance of new lymphadenopathies). Those patients required a second course of antibiotics, usually using an alternative agent. Logistic regression analysis found that initial therapeutic failure was significantly associated with delay of treatment exceeding 14 days and was not associated with the type of antibiotic used initially (see References: Meric 2008).

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