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Suppuration of involved lymph nodes is currently the most common complication of tularemia (see Fig. 227.3), and this may occur even after directed antibiotic therapy.

Among the tularemia patients from Missouri with lymphadenopathy reported between 2000 and 2007, 19% required drainage of suppurative nodes. Lymph node suppuration was associated with a longer delay in starting effective antibiotic therapy.164 Nodes that suppurate after appropriate therapy are often sterile but benefit from drainage.201

Patients with severe disease may manifest disseminated intravascular coagulation, renal failure, rhabdomyolysis, jaundice, and hepatitis. Meningitis, encephalitis, pericarditis, peritonitis, osteomyelitis, splenic rupture, and thrombophlebitis have become very rare since antibiotic therapy has become available.

Guillain-Barré syndrome rarely has been described complicating cases of ulceroglandular tularemia.202

Rare cases of otitis media,203 otomastoiditis,204 endocarditis,205,206 aortitis,207 prosthetic joint infection with and without bacteremia,208,209 and peritonitis210 caused by F. tu la re nsi s have been reported. Endocarditis complicated typhoidal disease in all four patients reported in a recent series.206

Meningitis occurs rarely with ulceroglandular and typhoidal disease, and the cerebrospinal fluid in these patients almost always shows a mononuclear cell pleocytosis, with a high protein concentration and hypoglycorrhachia.211 Brain abscesses may be seen as a complication of meningitis.212

A recent outbreak of waterborne oropharyngeal tularemia in the Republic of Georgia was marked by delayed diagnosis and treatment, the frequent occurrence of neuropsychiatric symptoms, and slow resolution of adenopathy. Neuropsychiatric symptoms in this cohort included headaches, chronic fatigue, difficulty concentrating, and sleep distur- bances.213 Features that are associated with a worse prognosis include increasing age, serious coexisting medical conditions, symptoms lasting 1 month or longer before treatment, significant pleuropulmonary disease, typhoidal illness, renal failure, a delay in the diagnosis, and inappropriate antibiotic therapy.1,179

Overall death rates in the modern antibiotic era have been 2% to 4% but may range up to 24% depending on the strain.196 Mortality had been as high as 60% before the introduction of streptomycin as treatment.214

The diagnosis of tularemia ultimately rests on clinical suspicion. Results of routine laboratory testing are nonspecific. The leukocyte count and sedimentation rate may be normal or elevated. Thrombocytopenia, hyponatremia, elevated serum aminotransferase values, increased creatine phosphokinase level, myoglobinuria, and sterile pyuria are occasionally found.1

Because of its potential danger to laboratory personnel, individuals working in the area or who may come in contact with patient specimens should be notified if tularemia is suspected.

The organism is rarely seen on Gram-stained smears or in tissue biopsy specimens and it does not grow in routinely plated cultures.

Isolations by blood culture have included the less virulent F. tularensis subsp. holarctica as well as the more virulent F. tularensis subsp. tularensis.

For clinicians concerned about this infection, Biosafety Level 2 is sufficient for laboratory handling of routine clinical specimens, but Biosafety Level 3 should be used to process isolates suspected of being F. tu larensi s.20

Misiden- tification of F. tul ar en si s may occur when commonly available automated laboratory identification systems are used; it is most often reported as Haemophilus influenzae (satellite test or X and V factor test positive) or Aggregatibacter spp

Newer methods that may limit the need for laboratory manipulation of unknown culture isolates and that can identify the organism to the subspecies level include real-time PCR and MALDI-TOF.223–226

A review of three reports from Sweden found that PCR assay using primers for the 17-kDa lipoprotein F. tularensis gene tul4 was 77% sensitive and culture was 63% sensitive for the diagnosis of ulceroglandular tularemia.214

Serologic studies are the most common way the diagnosis of tularemia is confirmed. Antibodies to F. tularensis may be demonstrated by tube agglutination, microagglutination, hemagglutination, enzyme-linked immunosorbent assay, and immunochromatographic assay; the tube agglutination and microagglutination tests are the standard methods in the United States, and enzyme-linked immunosorbent assays also are used in Europe.20,229,230

Standard serologic tests detect infections with F. tularensis subsp. tularensis and F. tularensis subsp. holarctica equally well. They are usually negative with F. tu la re nsi s subsp. novicida and with F. philomiragia.

Standard tube agglutination titers are usually negative in the first week of illness, are positive in most patients after 2 weeks, and peak after 4 or 5 weeks.

The microagglutination assay is up to 100-fold more sensitive than tube agglutination.

IgM and IgG antibodies appear together, and high titers of both may persist for longer than a decade after infection, limiting the value of a single positive result.231

A presumptive diagnosis is supported by an acute tube agglutination titer of 1 : 160 or more, or an acute microag- glutination titer of 1 : 128 or more, in the presence of compatible disease, but this may also reflect remote infection.

Definitive serologic diagnosis requires a fourfold or greater change in titer between acute and con- valescent specimens, and at least one test must be positive.20

Serologic studies may need to be repeated at 7- to 10-day intervals before a rise is demonstrated.

Antibodies may cross react with Brucella spp., Proteus OX19, Legionella spp., and Yersinia spp., but titers to F. tularensis are almost always higher. False-positive heterophil agglutinins also rarely occur during tularemia

Tests for cell-mediated immunity, such as whole-blood IFN-γ release assay in response to tularemia antigens, are promising and may be positive earlier than serologic studies, but they are not commercially available.229

Antimicrobials with good in vitro activity include aminoglycosides, tetracyclines, and fluoroqui- nolones, though only aminoglycosides and tetracyclines are approved by the US Food and Drug Administration for treatment of tularemia

As an intracellular organism and a β-lactamase producer, not unexpect- edly, there is resistance to the β-lactam antibiotic class.43

The macrolide class also tends to have poor activity, although different susceptibilities occur between A and B strains.236,237

Streptomycin is preferred in adults because it is efficacious with minimal relapses and has been approved in the United States for tularemia treatment by the US Food and Drug Administration. Gentamicin is an acceptable substitute that may be given intravenously, is often more readily available, and has less vestibular toxicity than streptomycin; in addition, gentamicin blood levels are usually easier to obtain in a timely fashion (Table 227.2).

The Centers for Disease Control and Prevention and the World Health Organization recommend aminoglycosides as the drugs of choice for the treatment of severe tularemia.238,239

The recommended dosage of streptomycin that is effective therapy for tularemia is 7.5 to 10 mg/kg intramuscularly every 12 hours for 7 to 14 days. An alternative regimen is 15 mg/kg intramuscularly every 12 hours for the first 3 days, followed by half this dose to complete treatment. For patients who are very ill, 15 mg/kg every 12 hours may be given throughout a 7- to 10-day course. Doses greater than 2 g/day of streptomycin in adults do not increase efficacy and should not be given.

The first few days of streptomycin rarely may induce a Jarisch-Herxheimer–like reaction, with an increase in symptoms and a transient decrease of the serum agglutination titer

The pediatric weight-based regimens for streptomycin are up to a maximum of the adult dose (see Table 227.2)

The desired gentamicin peak serum level is at least 5 μg/mL.

The efficacy of single daily gentamicin dosing has been reported for small numbers of adult cases but has not been rigorously studied.109,242

Nonetheless, it is efficacious, and some practitioners consider once-daily gentamicin an acceptable alternative for adults that facilitates completing treatment as an outpatient.109 However, divided dosing of gentamicin is recom- mended for children (see Table 2 27. 2).240

Penetration of the aminoglycosides into the cerebrospinal fluid is poor and erratic, and it may be inadequate in tularemic meningitis. Pittman and colleagues243 reported a central nervous system shunt infection caused by F. tularensis that was successfully treated with intrathecal gentamicin.

Contentin and colleagues 244 reported a case of F. tularensis subsp. holarctica meningitis that was cured after 4 weeks of high-dose ciprofloxacin combined with 18 days of gentamicin and 6 days of thiamphenicol

Additional cases of tularemic meningitis have been documented, and successful treatment has included a combination of streptomycin with chloramphenicol or a combination of doxycycline with either streptomycin or gentamicin (see Table 227.2).211,245

Chlor- amphenicol may be unavailable or in short supply in the United States; it should not be chosen to treat other forms of tularemia because of its potentially serious toxicity and the availability of more effective alterna- tives with less dangerous potential side effects

Selected children with mild disease and adults with mild to moderate disease may be treated with one of the oral antibiotics listed in Table 227.2, either alone or after initial treatment with an aminoglycoside.240

Doxycycline and tetracycline are bacteriostatic for F. t ul aren si s . Histori- cally, use of this class led to higher rate of relapse after treatment, which is why they are recommended to be given for at least 14 days (see Table 227.2). A recent retrospective case series from Missouri reported no relapses among 17 patients receiving either doxycycline (16 patients) or tetracyclines (1 patient) as their tularemia therapy (median treatment duration of 21 days, range 10–42 days), suggesting that selected patients treated with a tetracycline for the recommended duration may have better outcomes than previously reported failure rates of 15% to 48%.246

Doxycycline is not recom- mended for the treatment of tularemia in children, although it is thought not to cause tooth enamel staining under the age of 8, and is now recom- mended for other tick-borne infections by the American Academy of Pediatrics.240,247,248

Relapses may follow any regimen but are more common when tetracyclines are used for less than 14 days. Although a relapse after initial treatment with doxycycline may be re-treated with doxycycline given for at least 14 to 21 days, re-treatment with a different agent such as streptomycin or gentamicin may be preferred.

In vitro susceptibility studies have found that the fluoroquinolones are active against F. tularensis subsp. tularensis and F. tularensis subsp. holarctica, as well as F. tularensi s subsp. mediasiatica and F. tu lare nsis subsp. novicida.31,249,250

Clinical experience with the fluoroquinolones as therapy for tularemia caused by F. t ulare nsi s subsp. holarctica has been favorable, even in immunocompromised hosts.

Impor- tantly, acquired fluoroquinolone resistance has not been documented in natural tularemia, even among patients who failed fluoroquinolone treatment.255

However, there is less published experience using these agents in the United States or for infections caused by the more virulent F. tu laren si s subsp. tularensis. Among tularemia cases reported in Missouri between 2000 and 2007, 9 of 10 patients given ciprofloxacin alone or combined with ineffective agents were cured.164

Other agents with relatively low minimal inhibitory concentrations have included erythromycin, rifampin, cefoxitin, cefotaxime, ceftriaxone, and ceftazi- dime. The effectiveness of these drugs in treating tularemia is not fully established, and ceftriaxone has failed in several patients treated as outpatients.257

Ceftriaxone exhibited poor intracellular inhibitory activity against a strain of F. tu la re nsi s subsp. holarctica grown in macrophage-like cell monolayers, whereas aminoglycosides, doxycycline, telithromycin, fluoroquinolones, and rifampin were active in this assay.236

However, rifampin is not recommended to treat tularemia because of its potential to induce the emergence of resistance.238

Although erythromycin has been used successfully in a few patients who were believed to have Legionella infections, resistance to erythromycin is prevalent in many areas in Europe and Russia and in general the drug is considered unreliable as therapy.31,182,238,258,259

Ikäheimo and associates262 found that all 38 type B clinical isolates they tested were resistant to imipenem in vitro

Treatment of pregnant or immunocompromised patients with tularemia is challenging, and optimal antibiotic regimens are unknown.

Aminoglycosides, tetracyclines, and fluoroquinolones have potential risks to the fetus when used during pregnancy; immunocompromised patients with tularemia may have an increased risk for relapse or treatment failure

Before the availability of effective antibiotics, Pullen and Stuart266 reported three patients with tularemia during pregnancy and all gave birth to normal children.

Among three pregnant women with tularemia in Turkey, one patient was treated with gentamicin and two patients were untreated; all three patients had uncomplicated pregnancies and delivered healthy babies.268

Tularemia in a pregnant woman in France, where macrolide-sensitive strains of F. tularensis subsp. holarctica predominate, was successfully treated with a 6-week course of azithro- mycin.269 However, a review of 101 patients with tularemia in France identified two pregnant patients, and both were unsuccessfully treated with macrolides.174

Case reports of tularemia in patients with hematopoietic stem cell transplantation, renal transplantation, acquired immunodeficiency syndrome, chronic graft-versus-host disease, and TNF inhibitor therapy have described successful treatment with at times prolonged courses of gentamicin, fluoroquinolones, or doxycycline, alone or in various combinations.270–273,274,275,276

Potentially immunocompromising illnesses were present in another 8 of the 101 French patients, but their treatments and outcomes were not specifically identified.174

Multiple nonprospective series reported fewer treatment failures when antibiotic therapy is combined with surgical drainage when feasible.201,277

Antibodies to F. t ul ar en si s and serum from vaccinated people are effective passive therapies for murine infection.135,278,279

Specific treatment options depend on whether there are contained or mass casualties; smaller numbers of infected people permit individual medical care that would not be possible with larger numbers of patients. Thus treatment options for contained casualties are similar to those listed in Table 227.2 and as discussed earlier

For contained casualties, the Working Group recom- mended that streptomycin, gentamicin, or ciprofloxacin be given for 10 days and that doxycycline or chloramphenicol be given for 14 to 21 days.197

In mass casualty situations, only oral ciprofloxacin or doxycycline for 14 days is recommended by the Working Group for both children and adults.197

Susceptibility testing of the F. tularensis strain used as a bioweapon will be important because it may have been modified to select for resistance to standard antibiotic treatments.

The Working Group preferred gentamicin for the treatment of pregnant patients among contained casualties and preferred oral cip- rofloxacin for pregnant patients among mass casualties.197

Group recommended treatment with either streptomycin or gentamicin for immunocompromised patients in both contained and mass casualty situations.197

Wild animals should not be skinned or dressed using bare hands, and bare hands should not be used to handle an animal that appears ill

Gloves, masks, and protective eye covers should be worn when perform- ing such tasks and when disposing of dead animals brought home by household pets.

Treatment of community water supplies with standard chlorination protects against waterborne tularemia.197,282,283

Wild game should be cooked thoroughly before ingestion.

The most important measure to avoid tick bites in infested areas is wearing clothing that is tight at the wrists and ankles and that covers most of the body. Chemical tick repellents may also be of benefit. Frequent checks should be made for attached ticks so that they may be removed promptly; this must not be done with bare hands, and care should be taken not to crush the tick

Hospitalized patients with tularemia do not need special isolation because person-to-person spread does not occur, and even in the preantibiotic era, secondary cases were not found. Standard universal precautions for contaminated secretions are adequate when handling drainage from wounds or eyes

Va c ci n e s pr e p ar e d f ro m k i ll e d F. tul ar en si s are ineffective, in part because they only induce an antibody response

However, the LVS vaccine is not approved and is no longer available for general use in the United States. Removal was prompted by questions about its stability, basis of attenuation, efficacy after challenge with other Francisella strains by varied routes of exposure, usefulness in immunocompromised patients, and the need to administer it by scarification.284,28

The LVS vaccine is an attenuated F. tularensis strain that occurs in two colony phenotypes, only one of which is immunogenic. This vaccine does not spread from the inoculation site, induces cell-mediated and humoral immunity, is effective in preventing typhoidal disease, and reduces the severity of ulceroglandular disease but does not prevent it.284,28

However, the live vaccine strain of F. tularensis cannot provide high immune response in the presence of antimicrobial agents such as doxycycline. Importantly, the LVS vaccine has been ineffective in protecting against pulmonary challenge with virulent F. tul ar ens is subsp. tularensis.286

In humans and animal models, protection against pulmonary challenge is enhanced when the LVS vaccine is given by aerosol or intranasally. This and other observations suggest that mucosal immunity may contribute to vaccine-induced protection against respiratory tularemia.

An improved LVS vaccine was produced using accepted good manufacturing practices that had limited toxicity in rabbits; this vaccine induced IgG, IgM, and IgA antibodies that cross reacted with F. t ul a re n si s subsp. tularensis strain Schu S4. A phase I dose-escalating trial of this new LVS vaccine in humans found it to be safe and immunogenic, eliciting both antibody and IFN-γ responses.294

However, there are many biologic and regulatory issues that will need to be addressed before this or another vaccine is available for human use.113,296

Antibiotic prophylaxis after potential exposures of unknown risk, such as tick bites, is not recommended.

In the past, intramuscular streptomycin was given for preemptive treatment of documented exposures from laboratory accidents because streptomycin successfully aborts illness when given in the incubation period after experimental inoculation. Gentamicin should be effective for this purpose as well, but this has not been confirmed

Currently, either ciprofloxacin, 500 mg, or doxy- cycline, 100 mg, given orally twice daily for 14 days is recommended for adults with suspected or proven high-risk exposure to F. tu la r e ns i s . 107,197

Exposed children may be observed for fever or other signs of illness without antibiotics, except during a bioterrorist event.107

Observation without antibiotics is also appropriate for individuals with lower-risk exposures and in vaccinated individuals.

Recovery from tularemia is believed to confer protective immunity for life, although a few recurrent infections have been documented.297,298

Most recurrences have been clinically mild ulceroglandular disease, and systemic symptoms have been uncommon. Therefore previously infected individuals are not likely candidates for vaccination or preemptive antibiotic therapy after a known exposure.

All people, regardless of age or history of past tularemia, identified early in the incubation period after exposure to an F. tularensis bioterrorist event are candidates for antibiotic prophylaxis. The Working Group for Civilian Biodefense recommended either doxycycline or ciprofloxacin orally for 14 days for all exposed people except immunocompromised patients.197

Mice are significantly protected from lethal F. tularensis subsp. tularensis respiratory infection by fluoroquinolones, and this is true even when the fluoroquinolone is delayed up to 72 hours after infection; however, delay of doxycycline beyond 24 hours is ineffective.299,300 These results suggest that a fluoroquinolone may be preferred for oral prophylaxis after exposure to an F. tularensis bioweapon.

The doxycycline dosing recommended by the Working Group is 2.2 mg/kg twice daily for children weighing less than 45 kg and 100 mg twice daily for children weighing 45 kg or more.197 The dosing of ciprofloxacin recommended by the Working Group for children exposed to an F. t ul a re n si s bioweapon is 15 mg/kg orally twice daily, not to exceed 1 g daily

As to methods, there may be a million and then some, but principles are few. The man who grasps principles can successfully select his own methods. The man who tries methods, ignoring principles, is sure to have trouble. —RALPH WALDO EMERSON, ESSAYIST AND POET