Francisella species are widely found in animal reservoirs and aquatic environments. The taxonomy of this genus has undergone numerous changes over the years. There are seven species in the genus, the most important of which is Francisella tularensis. There are three recognized subspecies of F. tularensis: tularensis (type A), holarctica (type B), and mediasiatica. Subspecies tularensis (type A) is the most virulent among this group and the most pathogenic for humans. It is associated with wild rabbits, ticks, and tabanid flies. Subspecies holarctica strains cause milder infection and are associated with hares, ticks, mosquitoes, and tabanid flies. F. tularensis is transmitted to humans by biting arthropods and flies, direct contact with infected animal tissue, inhalation of aerosols, or ingestion of contaminated food or water. The clinical presentation depends on the route of infection; six major syndromes are described (see Pathogenesis and Clinical Findings).

Two other species of Francisella, Francisella philomiragia and Francisella novicida, have been associated with human disease. F. philomiragia has usually been found in situations of near-drowning.

Morphology and Identification

A. Typical Organisms

F. tularensis is a small, Gram-negative coccobacillus. It is rarely seen in smears of tissue (Figure 1).

Fig1. Gram-stain of F. tularensis. These bacteria are tiny, Gram-negative coccobacilli approximately 0.2 × 0.7 μm. Original magnification × 1000. (Courtesy of CDC Public Health Image Library.)

B. Specimens

 Blood is taken for serologic tests. The organism may be recovered in culture from lymph node aspirates, bone marrow, peripheral blood, deep tissue, and ulcer biopsies.

 C. Culture

 Growth requires enriched media containing cysteine. In the past, glucose-cysteine-blood agar was preferred, but F. tularensis grows on commercially available hemin-containing media, such as chocolate agar, modified Thayer-Martin agar, and buffered charcoal yeast extract (BCYE) agar used to grow Legionella species. Media should be incubated in CO2 at 35–37°C for 2–5 days. Caution: To avoid laboratory-acquired infections, biosafety level three (BSL III) practices are required when working with live cultures suspected of containing F. tularensis. Clinical specimens require BSL II facilities and work practices.

D. Serology

All isolates are serologically identical, possessing a polysaccharide antigen and one or more protein antigens that cross react with brucellae. However, there are two major biogroups of strains, called Jellison type A and type B. Type A occurs only in North America, is lethal for rabbits, produces severe illness in humans, ferments glycerol, and contains citrulline ureidase. Type B lacks these biochemical features, is not lethal for rabbits, produces milder disease in humans, and is isolated often from rodents or from water in Europe, Asia, and North America. Other biogroups are of low pathogenicity.

The usual antibody response consists of agglutinins developing 7–10 days after the onset of illness.

Pathogenesis and Clinical Findings

F. tularensis is highly infectious: Penetration of the skin or mucous membranes or inhalation of 50 organisms can result in infection. Most commonly, organisms enter through skin abrasions. In 2–6 days, an inflammatory, ulcerating papule develops. Regional lymph nodes enlarge and may become necrotic, sometimes draining for weeks (ulceroglandular tularemia). Inhalation of an infective aerosol results in peribronchial inflammation and localized pneumonitis (pneumonic tularemia). Oculoglandular tularemia can develop when an infected finger or droplet touches the conjunctiva. Yellowish granulomatous lesions on the eyelids may be accompanied by preauricular adenopathy. The other forms of the disease are glandular tularemia (lymphadenopathy but no ulcers), oropharyngeal tularemia, and typhoidal tularemia (septicemia). All affected individuals have fever, malaise, headache, and pain in the involved region and regional lymph nodes.

Because of the highly infectious nature of F. tularensis, this organism is a potential agent of bioterrorism and is currently classified on the select agent list as a Tier 1 agent. Laboratories that recover a suspected F. tularensis should notify public health officials and should send the isolate to a reference laboratory capable of performing definitive identification.

Diagnostic Laboratory Tests

F. tularensis may be recovered from the clinical specimens listed earlier and by performance of serologic studies. Agglutination testing either in a tubed format or in microagglutination is the standard form of testing. Paired serum samples collected 2 weeks apart can show a rise in agglutination titer. A single-tubed agglutination serum titer greater than 1:160 or a microagglutination titer of greater than 1:128 are highly suggestive if the history and physical findings are compatible with the diagnosis. Because antibodies reactive in the agglutination test for tularemia also react in the test for brucellosis, both tests should be done for positive sera; the titer for the disease affecting the patient is usually fourfold greater than that for the other disease.

Treatment

 Streptomycin or gentamicin therapy for 10 days almost always produces rapid improvement. Tetracycline may be equally effective, but relapses occur more frequently. Fluoroquinolones are other potential agents. F. tularensis is resistant to all β-lactam antibiotics as a result of β-lactamase production.

Prevention and Control

 Humans acquire tularemia from handling infected rabbits or muskrats or from bites by an infected tick or deer fly. Less often, the source is contaminated water or food or contact with a dog or cat that has caught an infected wild animal.

Avoidance is the key to prevention. The infection in wild animals cannot be controlled.

The live attenuated F. tularensis vaccine (LVS) is no longer available to persons at high risk. Newer vaccines are under development.

Concept Checks

 • F. tularensis is a faintly staining Gram-negative coccobacillus that causes the zoonotic infection tularemia that can be mediated by vectors, such as ticks, through direct contact with animals or rarely through ingestion.

 • There are three subspecies of F. tularensis; subspecies tularensis (type A) is the most virulent and pathogenic for humans.

• There are several clinical manifestations of tularemia depending on the type of exposure; the glandular forms are well localized and associated with less mortality than the septicemic or inhalational forms of the disease.

• Diagnosis of tularemia can be made by recovery of the organism from appropriate clinical material and by serology.

• Agents that have been useful in treatment include streptomycin, gentamicin, tetracyclines, and fluoroquinolones. Because of its virulence, F. tularensis is considered a potential agent of bioterrorism.