on 28-Aug-2023 (Mon)

Severe infection — For patients with severe infection, we suggest gentamicin (given intramuscularly or intravenously) or streptomycin (given intramuscularly). Aminoglycosides are the drugs of choice for such patients, as there is the most successful clinical experience with these agents. Severe infection includes prolonged or extensive systemic symptoms prior to therapy, sepsis with or without renal failure in any form of tularemia, typhoidal tularemia, and symptomatic pneumonic tularemia.

In addition, timely blood levels are usually more readily obtained for gentamicin than streptomycin, and gentamicin has less vestibular toxicity. Gentamicin is the preferred aminoglycoside for the treatment of tularemia in children for these reasons [51].

The doses are outlined in the table (table 1). The duration of aminoglycoside treatment is generally 7 to 10 days; in children, the usual duration is 10 days [51]. However, the duration should be tailored to clinical signs and symptoms, including resolution of fever, and should be extended (eg, to 14 days) for especially severe cases or for patients whose response to treatment is delayed.

Once-daily gentamicin dosing has been used successfully and is a more convenient option for outpatient therapy of adults [19,70,71].

As an example, in a review of case reports and series, the cure rate among 244 patients who received streptomycin for tularemia was 97 percent, with no relapses (table 1) [68].

Some experts have recommended that severe disease be managed with a combination of an aminoglycoside and a fluoroquinolone, although this has not been proven to be superior to an aminoglycoside alone [72].

Dosing for gentamicin must be adjusted according to serum concentrations for individuals with renal insufficiency, individuals over age 50 years, and for pediatric patients. For pediatric patients, adjust the dose of gentamicin to maintain a peak serum concentration of at least 5 mcg/mL. For adults with normal renal function, once-daily dosing of gentamicin is also acceptable. For obese patients, dosing should be determined based on adjusted weight. (Refer to Calculator on ideal body weight (method of Devine) and dosing weight.)

¥ Doxycycline is administered for a longer duration than other agents because of a higher risk of relapse with shorter courses.

‡ Levofloxacin has also been used successfully, although there is more clinical experience with ciprofloxacin, and the optimal dose is uncertain.

Adults — Initial oral treatment is reasonable for adult patients who can be managed reliably as outpatients and for hospitalized patients without severe disease. We suggest an oral fluoroquinolone (eg, ciprofloxacin) for adults with mild or moderate infection. Doxycycline is an alternative.

We prefer fluoroquinolones to a tetracycline as oral treatment of tularemia in appropriate adults given their efficacy with lower likelihood of relapse [13,72].

Ciprofloxacin and levofloxacin are the most active fluoroquinolones in vitro; both agents have been used successfully, although there is more published experience with ciprofloxacin.

Most published data on the use of tetracyclines in tularemia have evaluated tetracycline; doxycycline is now more commonly used because it is given only twice daily and likely has similar efficacy. In a review of case reports and series, the cure rate among 50 patients who received tetracycline was 88 percent; 12 percent relapsed [68].

Children — We suggest gentamicin for treatment of children with mild or moderate infection [51]. The usual duration of gentamicin is 10 days, although in children with mild disease and no complications, it can be shortened to five to seven days if there is an adequate clinical response [51]. Oral ciprofloxacin is an appropriate alternative regimen for children with mild illness who would be expected to complete the recommended 10- to 14-day course of treatment [51]; doses are listed in the table (table 1).

For adults and children with tularemic meningitis, we suggest an aminoglycoside combined with doxycycline or ciprofloxacin [51]. A combination regimen is preferred because cerebrospinal fluid levels of aminoglycosides may be erratic [51]. In general, the duration of treatment for tularemic meningitis is 14 to 21 days but should be tailored to clinical signs and symptoms, including resolution of fever.

Endocarditis should also be managed initially with a combination regimen of an aminoglycoside plus a fluoroquinolone. Studies informing the optimal treatment of F. tularensis endocarditis are extremely limited, but case reports, including cases of prosthetic valve endocarditis, have documented favorable outcomes with two weeks of gentamicin plus a fluoroquinolone followed by another two to four weeks of a fluoroquinolone [35,39,40].

Azithromycin was effective in a pregnant patient in Arkansas, and a prolonged course of azithromycin was effective in a patient in France where erythromycin-sensitive strains of F. tularensis subspecies holarctica predominate [67,81]. Exposure to these antibiotics early in pregnancy has been associated with an increased risk of spontaneous abortion [85].

Immunosuppressed patients with tularemia have an increased risk of treatment failure or relapse, and their optimal antibiotic management is unknown. We prefer an aminoglycoside for treatment of tularemia in immunocompromised patients, as used in patients with severe infection (see 'Severe infection' above). Case reports of tularemia patients with various underlying immunosuppressing conditions have documented successful treatment with gentamicin, a fluoroquinolone, or doxycycline, alone or in combination (table 1) [9,22,25,73,86-92]. Treatment may need to be prolonged beyond the usual recommended duration in patients who are slow to respond.

Adjunctive management — Even with appropriate antibiotic therapy, enlarged lymph nodes can progress to fluctuance and suppuration. In such cases, incision and drainage of the lymph node are warranted.

Debridement and drainage are also warranted for empyema in the setting of pneumonic tularemia.

Relapses — Relapses can occur following any regimen but are more common when tetracyclines (bacteriostatic antimicrobials) are used for fewer than 14 days. Retreatment with the initial agent used is reasonable since resistance in clinical isolates has not been reported. If doxycycline was used initially, it can be used again but for a longer time (such as 21 days); alternatively, the patient can be retreated with an aminoglycoside or a fluoroquinolone.

Minimizing exposure — Preventive measures include behavioral strategies to minimize the risk of exposure to the organism:

● Not using bare hands to skin or dress wild animals

● Avoiding sick or dead animals

● Wearing masks, eye protection, and gloves when disposing of dead animals, including those brought home by cats and other pets

● Wearing clothing that covers exposed skin and that is tight at the wrists and ankles

● Using insect repellents that are also effective against ticks

● Removing ticks promptly

● Only drinking potable water

● Adequately cooking wild meats

Standard precautions are adequate for hospitalized patients with tularemia; person-to-person transmission does not occur.

Watchful waiting without antibiotics while monitoring for fever or other symptoms of tularemia is an appropriate strategy for individuals with lower-risk exposures, those identified later in the incubation period (eg, more than a week after exposure), and in vaccinated individuals. As examples, prophylaxis is not indicated following a tick bite [1,2] or if the only risk was close contact with a patient with tularemia [1,47].

Management without antibiotics following exposure to a bioterrorism event is also recommended for persons identified after others have become symptomatic (ie, later in the incubation period) [ 47].