Francisella

Transmission route: Blood, direct contact, inhalation

Definition

Francisella are small, nonmotile, gram-negative coccobacilli that are found in water, soil, plants, and mammals. The bacteria may be vectored by ticks, flies, or mosquitoes. The clinical manifestations of infection vary greatly depending upon the portal of entry, virulence of the strain, and host immunity.

Natural Habitat and Features

The bacteria of the Francisella genus are found in the natural environment. They have been isolated from soil, water, and plants. Mammalian natural reservoirs include rodents (muskrats, voles, and lemmings), lagomorphs (rabbits and hares), and insectimorphs (shrews, moles, and hedgehogs). Humans, wild animals (such as deer and foxes), and domestic animals (such as dogs and cats) also serve as hosts. Blood-feeding arthropods and insects serve as vectors. In the United States, there is a summer peak in cases associated with tick bites and a smaller peak in the winter associated with hunting.

The tiny coccobacilli comprising the Francisella genus are only weakly gram-negative, as they take up the safranin counterstain poorly. They are nonmotile, aerobic, non-spore-forming organisms that are weakly catalase positive and that ferment only a few sugars. Each possesses a capsule that is rich in fatty acids and that functions as a major virulence factor.

Francisella bacteria are fastidious, and nearly all strains require supplementation with sulfhydryl compounds, such as cysteine, cystine, or thiosulphate, to grow on artificial media. The organisms grow slowly with a generation time of one hour, and cultures usually take three to five days for colonies to appear when incubated aerobically at 95° to 98.6° Fahrenheit (35° to 37° Celsius). The bacteria are potentially infectious for laboratory workers, either by inoculation through small breaks in the skin or by inhalation. All specimens and cultures must be handled in a biological safety cabinet using gloves. Francisella have been isolated from skin ulcers, biopsies of skin and internal organs, lymph node aspirates, sputum, bone marrow, and blood.

There are four subspecies of F. tularensis that are identified by biochemical, cultural, and molecular methods. F. tularensis sub. tularensis is the most common subspecies in North America and is also the most virulent. F. tularensis sub. holarctica is also found in North America and is the usual species identified in Europe and Asia. The live vaccine strain of F. tularensis is derived from subspecies holarctica, and there is also a variant, biovar japonica, which is found in Japan. The subspecies novicida is of lower virulence and is associated with disease in immunocompromised persons and in persons who nearly drowned in fresh-water sources. Subspecies mediasiatica is found only in Kazakhstan and Turkmenistan.

F. philomiragia is an uncommon opportunistic pathogen that infects the immunocompromised human host and persons who have survived a drowning in salt-water sources. A closely related bacterium causes granulomatous disease in salt-water fish such as the Atlantic cod.

Pathogenicity and Clinical Significance

F. tularensis is a virulent pathogen that can infect a suitable host with a dose of only ten to fifty bacteria when injected into the skin or inhaled into the lungs. Infection through the gastrointestinal tract from ingestion requires a much larger dose. The most common route of infection is cutaneous inoculation, which allows the organism to multiply at the site and produce a papule that matures into an ulcer in about one week. The organism then spreads to the regional lymph glands.

Further dissemination to multiple organs may occur through the lymphatics and blood vessels. This form of infection is called ulceroglandular tularemia and usually results from contaminated tick or other insect bites and from direct contact with an infected animal or animal product. The host responds with an acute inflammatory reaction to both the organism and the necrotic tissue produced by the infection. Antibody is produced, but is insufficient to resolve the infection. Neutrophils and macrophages are able to ingest, but not kill, this facultative intracellular pathogen. Indeed, F. tularensis not only is able to survive macrophage ingestion; the pathogen also proliferates intracellularly, killing the cell and releasing progeny. Development of an adequate cell-mediated immune response is necessary for recovery.

The inhalation of F. tularensis as an aerosol or in an aqueous milieu, such as occurs in near-drowning, usually results in pneumonia. The acute inflammatory response is much the same as occurs in cutaneous inoculation, and the neutrophilic response may further damage the lung. Again, the ability of the organism to survive and multiply after ingestion by alveolar macrophages allows for progression of the infection and for systemic spread.

The combination of virulence and a small minimal-infecting dose makes F. tularensis an ideal agent for bioterrorism. Additionally, virtually an entire targeted population would be susceptible to infection. While a live vaccine strain was developed in the mid-twentieth century, there have been many problems with vaccine development. No vaccine is available for general use.

Diagnosis of the illnesses caused by Francisella still depends largely on clinical suspicion with serology, culture, and the polymerase chain reaction test. Before the existence of antibiotics, tularemia mortality was as high as 60 percent; it is now less than 4 percent. In the United States, tularemia is an uncommon illness; it occurs at a rate of only 0.05 cases per 100,000 persons.

Drug Susceptibility

Francisella bacteria are susceptible to many classes of antibiotics, including aminoglycosides, tetracyclines, chloramphenicol, fluoroquinolones, macrolides, rifamycins, and some cephalosporins. However, the efficacy of these agents in treating the diseases caused by these organisms has been demonstrated only with a few agents. The aminoglycosides, streptomycin and gentamicin, are bactericidal and provide effective treatment. Bacteriostatic agents, such as doxycycline and chloramphenicol, are less efficacious. Fluoroquinolones have been shown to provide good therapy.

Bibliography

Guillemin, Jeanne. Biological Weapons. New York: Columbia University Press, 2005. Covers the history of terrorist- and state-sponsored development of biological weapons.

Hodges, Lisa S., and Robert L. Penn. “ Francisella tularensis (Tularemia) as an Agent of Bioterrorism.” In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John F. Bennett, and Raphael Dolin. 7th ed. New York: Churchill Livingstone/Elsevier, 2010. A discussion of the history and potential use of this organism as an agent of attack.

Penn, Robert L. “ Francisella tularensis (Tularemia).” In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John F. Bennett, and Raphael Dolin. 7th ed. New York: Churchill Livingstone/Elsevier, 2010. A complete description of tularemia and the causative bacterium.

Staples, J. Erin, et al. “Epidemiologic and Molecular Analysis of Human Tularemia, United States, 1964-2004.” Emerging Infectious Diseases 12 (2006): 1113-1118. An analysis of organisms from 316 human cases of tularemia from thirty-nine U.S. states.

Wenger, Jay D., et al. “Infection Caused by Francisella philomiragia (Formerly Yersinia philomiragia): A Newly Recognized Human Pathogen.” Annals of Internal Medicine 110 (1989): 888-892. A comprehensive review of this unusual organism and infection in fourteen persons.

World Health Organization. WHO Guidelines on Tularemia. Geneva: Author, 2007. An extensive monograph on tularemia around the world that includes a discussion of the infectious organism.