Francisella tularensis

Tularemia, also known as rabbit fever or deer-fly fever, is a zoonotic disease caused by the gram-negative intracellular pathogen Francisella tularensis.

Francisella is the only genus within the family Francisellaceae and, on the basis of small subunit RNA sequences, is a member of the gamma-subclass of proteobacteria . The organism most closely related to Francisella is Wolbachia persica, a tick endosymbiont. As defined by DNA similarity and fatty acid composition, there are two species within the Francisella genus: tularensis and philomiragia. In addition, there are five subspecies of F. tularensis: tularensis (also called F. tularensis type A), novicida, mediasiatica, holarctica (F. tularensis type B), and a variant of holarctica found in Japan. Of these, only F. tularensis subsp. tularensis and subsp. holarctica cause disease in humans; and highly virulent type A organisms are evolutionarily older than moderately virulent type B bacteria.

This bacterium was first identified in 1912 following reports of a plaguelike illness in ground squirrels in Tulare County, California. One of the most pathogenic microorganisms known, F. tularensis is currently listed as a category A select agent because of its potential as a bioterrorism agent.

F. tularensis has been classified into four distinct subspecies, tularensis, holarctica, mediasiatica, and novicida. Of the four subspecies, subsp. tularensis, also known as Type A, has the highest mortality rate. Infections due to Type A have been limited to North America. In comparison, F. tularensis subsp. holarctica, also known as Type B, has been documented throughout the Northern Hemisphere. Thus, in North America, both Type A and Type B are present and often over-lap within a given sub-region. The subsp. novicida and mediasiatica have more focal distributions with mediasiatica isolated only from the Central Asian regions of the former USSR, and novicida isolated from North America and more recently Australia. These two subspecies are infrequently associated with human disease.

Francisella tularensis subsp. holarctica; Francisella tularensis var. palaearctica

Francisella tularensis subsp. holarctica

F. tularensis subsp. holarctica (previously palaearctica), the type B biovar, is less virulent and is the most widely distributed subspecies recovered from human and animal cases in North America, Europe and Central and Far-East Asia.

F. tularensis subsp. holarctica strains produce milder disease symptoms in humans.

Francisella tularensis subsp. holarctica FSC200; Francisella tularensis subsp. holarctica strain FSC200

Francisella tularensis subsp. holarctica FSC200

Francisella tularensis subsp. holarctica strain FSC200. This strain was isolated from a patient with type B tularemia. The genome sequencing of Francisella tularensis subsp. holarctica FSC200 is in progress at University of Washington (Project ID: 16087)

Francisella tularensis subsp. holarctica LVS; Francisella tularensis subsp. holarctica str. LVS

Francisella tularensis subsp. holarctica LVS

An attenuated live vaccine strain (LVS) was derived from repeated passage of a type B strain sometime between the 1930s and 1950s in the former Soviet Union. LVS provides protection against both type A and type B infection but is not licensed for use in the United States because its immunogenicity in humans is poorly characterized, the mechanism of attenuation for this strain is unknown, and the strain kills mice with a 50% lethal dose of <10 CFU when it is introduced via intraperitoneal injection.

Francisella tularensis subsp. holarctica OSU18; Francisella tularensis subsp. holarctica str. OSU18

Francisella tularensis subsp. holarctica OSU18

A low-passage type B strain (OSU18) isolated from a dead beaver found near Red Rock, Oklahoma, in 1978.

Francisella tularensis subsp. holarctica HN63; Francisella tularensis subsp. holarctica str. HN63

Francisella tularensis subsp. holarctica HN63

F. tularensis HN63 (subsp. holarctica) was originally isolated in Norway from an infected hare.

Francisella tularensis subsp. mediasiatica

Francisella tularensis subsp. mediasiatica; Francisella tularensis var. mediasiatica

F. tularensis subsp. mediasiatica has only been recovered sporadically from ticks and animals in prescribed regions of Central Asia, without any human disease association.

Francisella tularensis subsp. novicida; Francisella novicida; Francisella tularensis bv. novicida; Francisella tularensis var. novicida; Pasteurella novicida; Francisella tularensis biogroup novicida

Francisella tularensis subsp. novicida

F. tularensis subsp. novicida was first recovered from water in Utah, USA, in 1951 (Utah 112 prototype strain). Subsequently, isolates recovered from four hospitalized patients, first identified as atypical F. tularensis, were classified as 'F. tularensis subsp. novicida' or, more conservatively, as novicida-like organisms. These patients recovered from their infections with comparatively milder disease than type A infections.

Francisella tularensis subsp. novicida is nonvirulent, however this organism may cause disease in immunocompromised individuals.

Francisella tularensis subsp. tularensis; synonym: Francisella tularensis var. tularemia; Francisella tularensis subsp. nearctica

Francisella tularensis subsp. tularensis

F. tularensis subsp. tularensis, also known as the type A biovar, causes the most severe form of tularemia and is limited in its distribution to North America.

Until recently, isolates of F. tularensis subsp. tularensis were isolated only in North America, but a mite-derived isolate from Slovakia showed the phenotypic characteristics of the subspecies.

Type A isolates have been recovered from arthropod vectors in Europe but have not been associated with human disease there.

Francisella tularensis subsp. tularensis FSC 198; Francisella tularensis subsp. tularensis strain FSC 198

Francisella tularensis subsp. tularensis FSC 198

FSC198, a Slovakian isolate derived from a mite and reported to show the biochemical characteristics and virulence typical of F. tularensis subsp. tularensis strains

Francisella tularensis subsp. tularensis SCHU S4; Francisella tularensis Biovar A str. SCHU S4; Francisella tularensis subsp. tularensis strain SCHU S4

Francisella tularensis subsp. tularensis SCHU S4

Originally isolated by Foshay in 1941 from a human ulcer.

F. tularensis subspecies tularensis strain SCHU S4 is a fully virulent human isolate.

Among the biotypes of F. tularensis that are recognised, subspecies (subsp.) tularensis strains, e.g. F. tularensis SchuS4, are one of the most infective agents for humans known, with an infectious dose by the aerosol route of approximately 20 colony forming units (cfu) and a mortality rate of 30% in untreated cases.

0.2 um x 0.2-0.7 um.

Pleomorphic, poorly staining, gram-negative coccobacillus

Two disease cycles, terrestrial and aquatic, have been described. In the terrestrial cycle, rabbits and hares typically serve as amplifying hosts and ticks or biting flies are arthropod vectors. In the aquatic cycle, beaver, muskrat and voles serve as important mammalian hosts and appear to shed live organisms into their environments. In Sweden, mosquitoes have been strongly implicated as vectors of tularemia and may acquire infection from other components of the aquatic cycle. Curiously, mosquitoes are not thought to be significant contributors to disease transmission in the United States, despite their sharing of the same environments as other components of the aquatic system. Recently, protozoa have been shown to harbor F. tularensis and may play an important role in aquatic cycles. The interaction between aquatic and terrestrial cycles is largely unknown.

1,895,727 bp

1932

The complete genome sequence and annotation for a low-passage type B strain (OSU18) isolated from a dead beaver found near Red Rock, Okla., in 1978. A comparison of the F. tularensis subsp. holarctica sequence with that of F. tularensis subsp. tularensis strain Schu4 highlighted genetic differences that may underlie different pathogenicity phenotypes and the evolutionary relationship between type A and type B strains. Despite extensive DNA sequence identity, the most significant difference between type A and type B isolates is the striking amount of genomic rearrangement that exists between the strains. All but two rearrangements can be attributed to homologous recombination occurring between two prominent insertion elements, ISFtu1 and ISFtu2. Numerous pseudogenes have been found in the genomes and are likely contributors to the difference in virulence between the strains. In contrast, no rearrangements have been observed between the OSU18 genome and the genome of the type B live vaccine strain (LVS), and only 448 polymorphisms have been found within non-transposase-coding sequences whose homologs are intact in OSU18.

3990 bp

pFNL10, is a 3990-bp cryptic plasmid of Francisella novicida-like F6168. The plasmid was maintained in F. novicida Utah 112 and F. tularensis LVS strains. Pomerantsev and co-workers sequenced the entire plasmid and found six open reading frames (ORFs)-ORF1, ORF2, ORF3, ORF4, ORF5, and ORFm. ORF3, ORF4, ORF5, and ORFm are located on the same strand, designated the plus strand. ORF1 and ORF2 are on the complementary strand. The ORFs appear to be arranged in two operons, one comprising ORF5 and ORF4 and the other ORF1 and ORF2. There exist two distinct promoters similar to the Escherichia coli sigma 70 promoter, one 5' to ORF1-ORF2 operon and the other 5' to ORF5-ORF4 operon. In both promoters the transcriptional start is an adenosine. ORF3 is positioned in tandem with ORF5-ORF4, but has its own transcriptional start, a thymidine. However, sequence analysis revealed no recognizable promoter in physical proximity to ORF3. Sequence analysis revealed transcriptional terminators immediately downstream of the two operons. Experimental results showed that the ORF1-ORF2 terminator is authentic. Two sets of direct repeats, one 31 and the other 13 bp, characteristic of ori are positioned between the two promoters. ORF1 encodes a protein that bears homology to the replication initiation protein RepA of various bacteria, and disruption of this ORF indeed blocked pFNL10 replication. In contrast, ORF2 disruption caused formation of plasmid multimers, suggesting aberrant replication. Analysis also suggests that pFNL10 replicates by the theta mode. The ORF5-ORF4 operon resembles the phd-doc operon of Escherichia coli bacteriophage P1, but the significance of this similarity is unclear.

1,892,616 bp

1852

Chaudhuri, R.R., Ren, C.P., Desmond, L., Vincent, G.A., Silman, N.J., Brehm, J., Elmore, M.J., Hudson, M.J., Forsman, M., Isherwood, K.E., Gurycova, D., Minton, N.P., Titball, R.W., Pallen, M.J. and Vipond, R. The complete genome sequence of the European Francisella tularensis subspecies tularensis isolate FSC 198 suggests that it is derived from the archetypal laboratory strain Schu S4, originally isolated in North America. Unpublished.

1,910,031 bp

1781 genes, 1719 protein coding

Brittnacher,M., Rohmer,L., Zhou,Y., Abmayr,S., D'Argenio,D., Bovee,D., Chang,J., Chen,J., Drees,B., Ernst,R., Fong,C., Forsman,M., Gallagher,L., Gallis,B., Gillett,W., Goodlett,D., Guina,T., Guenthner,D., Haugen,E., Hayden,H., Jacobs,M., Kang,A., Larson Freeman,T., Levy,R., Lim,R., Manoil,C., Olson,M.V., Radey,M., Shaffer,S., Svensson,K., Taylor,G., Wasnick,M., Kaul,R. and Miller,S.I. Unpublished.

2019

1,895,994 bp

Chain, P., Larimer, F., Land, M., Stilwagen, S., Larsson, P., Bearden, S., Chu, M., Oyston, P., Forsman, M., Andersson, S., Lindler, L., Titball, R. and Garcia, E. Complete genome sequence of Francisella tularensis LVS (Live Vaccine Strain). Unpublished.

1892819 bp

1852

The genome of the F. tularensis strain SCHU S4 consists of a 1,892,819-bp circular chromosome, with an overall G+C content of 32.9% and 1,804 predicted coding sequences (CDSs; including pseudogenes). The low G+C content is typical of that found in small (0.9-2.0 Mb) bacterial genomes (range 25-40%). The origin of replication (ori) was identified with the aid of the strand specific mutation bias and was flanked by genes also present at this position in other species, such as dnaA and rng. In total, 1,281 genes in F. tularensis SCHU S4 had homologs (E < 1 times 10-10) in one or more gamma-proteobacterial genomes. These were randomly distributed around the genome, with the exception of a duplicated region of 33.9 kb (nucleotides 1,374,371-1,408,281 and 1,767,715-1,801,625), which lacked homologs in 16 other gamma-proteobacterial genomes. In F. tularensis strain LVS, duplication of one of the genes in this region (iglC) has been reported, suggesting that this region is also duplicated in this strain. The origin of the duplicated regions is not clear, because these genes do not show significant sequence homology with any other genes in GenBank. The genes encoding hypothetical proteins in these duplicated regions have a low G+C content (27.5%). But the G+C content of genes in the iglABCD operon and their codon usage are similar to those of other F. tularensis genes. In contrast to the genomic islands of other species, there are no flanking insertion elements or tRNA genes on both sides, although both copies are flanked on one side by rRNA operons and on the other an ISFtu1 element. Mutation of some genes within the duplicated regions can be attenuating; therefore, we believe that these regions are pathogenicity islands.

4442 bp

pOM1 is a recombinant 4442-bp plasmid that includes the replicon of the Francisella novicida-like strain F6168 cryptic plasmid pFNL10 and the tetracycline resistance gene (tetC) of plasmid pBR328. pOM1 can stably replicate and is maintained in Francisella tularensis biovars tularensis, palaearctica, and palaearctica var. japonica. The replicon of pOM1 includes the ori region and the repA gene. The ori region, located upstream of the repA gene includes two sets of 31- and 13-bp direct repeats (DR), with AT-rich regions preceding each of the DRs. Two putative promoters of the repA gene were found connected with the DR regions. A 40-kDa protein was encoded by the repA gene and found essential for replication. Expression of the tetC gene is regulated by an Escherichia coli sigma 70 -like promoter and is dependent on the F. tularensis strain and its environment.

Until 1925, it was widely believed that tularemia was a disease with risk limited to the United States. This perception soon changed. Ohara, studying hare disease (Yato-byo) in Japan, recognized the similarity of the disease to tularemia and sent specimens to Edward Francis (USA), who confirmed the presence of F. tularensis. In the USSR (1928), F. tularensis was recognized as the causative agent of "waterrat-trappers' disease", an illness acquired by trappers who skinned water-rats for their pelts. Soon thereafter, tularemia was also reported in Norway (1929), Canada (1930), Sweden (1931) and Austria (1935).

Today, tularemia is recognized as a widely dispersed disease throughout the Northern Hemisphere with foci in certain parts of North America, Europe, and northern Asia. Few, if any, zoonotic diseases have a broader or more complex host distribution and epizootiology. F. tularensis infection has been evidenced in a staggering number of wildlife species including various lagomorphs, rodents, insectivores, carnivores, ungulates, marsupials, birds, amphibians, fish and invertebrates. Arthropods, including ticks, biting flies, and possibly mosquitoes, serve as vectors and potentially, long-term reservoirs. Despite the complexity of the global picture of tularemia, the main components of regional disease cycles are much more narrow, typically involving only one to a few, key mammalian and arthropod species.

The worldwide incidence of tularemia is not known, and the disease is probably greatly underrecognized and underreported. In the United States, reported cases have dropped sharply from several thousand per year prior to 1950 to less than 200 per year in the 1990s. Between 1985 and 1992, 1409 cases and 20 deaths were reported in the United States, for a mean of 171 cases per year and a case-fatality rate of 1.4%. Persons in all age groups were affected, but most were children younger than 10 years and adults aged 50 years or older. Of 1298 cases for which information on sex was available, 942 (72.6%) occurred in males, and males outnumbered females in all age groups. Most cases occur in June through September, when arthropod-borne transmission is most common. Cases in winter usually occur among hunters and trappers who handle infected animal carcasses. In the United States, cases are mostly sporadic or occur in small clusters; in Eurasia, waterborne, arthropod-borne, and airborne outbreaks involving hundreds of persons have been reported.

Risk factors associated with human disease are linked to local disease ecology. For example, in the Western United States, biting fly exposures, tick bites and animal contact are all significant risks factors. In contrast, human cases in the central United States are rarely linked with biting flies and most often associated with tick bites and animal exposure. Similarly, mosquito exposure is an important risk factor in Sweden, whereas tabanid exposure is more strongly linked to cases in Russia.

USA: In the summer of 2000, an outbreak of primary pneumonic tularemia occurred on Martha's Vineyard, Massachusetts. The only previously reported outbreak of pneumonic tularemia in the United States also occurred on the island in 1978. A study of this outbreak of primary pneumonic tularemia implicates lawn mowing and brush cutting as risk factors for this infection.

Although, Tularemia is a recognized disease of the United States, yet in 2002 it emerged in a rather unusual and unexpected setting. The site of the outbreak was a Texas exotic pet facility where a variety of animal species were housed together and sold to domestic and international distributors. Thousands of wild-caught prairie dogs were supplied to this facility for commercial purposes and in July 2002 a large die-off (approximately 250 prairie dogs) occurred. Type B was isolated from the dead prairie dogs at the Texas facility as well as prairie dogs distributed to the Czech Republic and to a Texas pet shop.

France: Fifteen tularemia cases were identified after a holiday spent at a converted mill in the Vendee region (an endemic area for tularemia) in France, between 9 and 12 August 2004. Twelve of the cases (80%) had the pulmonary form. None of the patients was admitted to hospital. There was a strong association between infection and participation in a dinner at the mill on 4 August. One of the three dogs present in the dining room was serologically positive for F. tularensis.

Bulgaria: The 1997-2005 tularemia outbreaks in Bulgaria affected 285 people.

The majority of the patients presented with oropharyngeal tularemia. Less common were the glandular, pulmonary and oculoglandular forms.

Ten strains were isolated from humans, a tick, a hare, and water. Amplified fragment length polymorphism typing of the present isolates and of the strain isolated in 1962 suggests that a new genetic variant caused the outbreak.

Finland: In a tularemia epidemic during 1982 in northern Finland, 53 patients showed no peripheral portal of entry for infection or associated lymphadenopathy. Respiratory symptoms were observed in 72% of the patients. 26/38 cases had abnormal chest films. Hilar adenopathy was the most common finding (36%). 50 patients acquired the infection during common farming activities, such as making fresh hay with a hay-cutter, handling dry hay, threshing, etc.

Spain: Although tularemia has been reported throughout much of Europe, it first emerged as a human disease in Spain in 1997-1998, when a large outbreak occurred. A total of 559 cases of tularemia were reported with 519 cases from the community of Castille-Leon in northwestern Spain. A study of 142 patients in this region indicated that 97.2% had previous contact with hares; 83.8% had prepared hare carcasses and 13.3% had handled hare meat. As expected based on contact with infected animals, ulceroglandular tularemia was the most common form of clinical disease observed (87% of patients). In 1998, a second outbreak of tularemia in humans was reported, this time in the central province of Cuenca, a region distant from the outbreak the previous year. Nineteen cases of ulceroglandular tularemia were identified in persons who had contact with crayfish. This outbreak was most unusual in that tularemia had not previously been associated with fishing. Transient contamination of the river and crayfish was implicated as the cause of the outbreak, with most patients incurring crayfish-related scratches, cuts, and abrasions while fishing. A sewage plant, which intermittently discharged water into the river, was linked to the cause of the outbreak.

Kosovo: The first report of tularemia in Kosovo occurred in early 2000, at the end of 10 years of political crisis and warfare in the region, when a cluster of patients was identified with an unusual syndrome of fever, pharyngitis and pronounced cervical lymphadenopathy. Active case-finding and serology testing confirmed 327 cases of tularemia in 21 Kosovo municipalities, with most cases presenting as oropharyngeal tularemia. Ingestion of F. tularensis was suspected as the cause of the outbreak and a follow-up case-control study indicated that the outbreak was food and water related.

Epidemiologists believed a runaway population of rats and mice gorging on unharvested crops and contaminating human food and water supplies triggered the outbreak.

Australia: Although F. tularensis has long been considered to cause disease in the Northern Hemisphere, in 2002 F. tularensis subsp. novicida emerged in the Southern Hemisphere with the first report of human infection. A 53-year old man presented with a swollen toe and swollen inguinal lymph nodes as a result of a cut received in brackish waters in the Northern Territory of Australia. The toe wound yielded an isolate of F. tularensis subsp. novicida.

Norway: The outbreak of tularemia in central Norway led to sporadic cases over an area of 42,000 square km, indicating that F. tularensis was widespread. Only a few cases were reported from areas outside of central Norway. In certain areas of northern Europe, tularemia occurs with epidemic outbreaks at fairly regular intervals. Before the outbreak described, tularemia cases were not diagnosed in central Norway for at least 15 years. Thus, not one patient with a positive MA (microagglutination) test has been recorded for the last 5 years before the outbreak described, the period we used to test for diagnostic serology. New cases have not been registered since December 1985. These data emphasize that epidemic outbreaks of tularemia may occur suddenly in areas which usually are not endemic for this disease.

Sweden: The largest recorded airborne tularemia outbreak occurred in 1966-1967 in an extensive farming area of Sweden. This outbreak involved more than 600 patients infected with strains of the milder European biovar of F tularensis (F tularensis biovar palaearctica) [type B]), most of whom acquired infection while doing farm work that created contaminated aerosols. Case exposures and disease onsets occurred during a period of months but peaked during the winter, when rodent-infested hay was being sorted and moved from field storage sites to barns.

In the northern part of central Sweden, an extensive epidemic of tularemia with 529 cases, 400 of which were confirmed by laboratory tests, occurred in the summer of 1981. The outbreak was of short duration and was restricted to certain communities within a narrow geographical area. It began in the middle of July and progressed during that month and August, with only sporadic cases in September and October. During the 2 years preceding the outbreak only 3 and 7 cases were reported in Sweden. The infection was mainly transmitted by mosquitoes and most cases were ulceroglandular. The later cases in September and October were infected by contact with hares or rodents. All age groups were affected, with a slight predominance of women and the 30-60 yr age groups.

China: An outbreak of tularemia caused by contact with infected hares was first reported in Heilongjiang Province in 1959. Thereafter, 6 cases were diagnosed in Qinghai Province in 1965. Epidemiologic investigation identified several natural foci of the disease in Tibet from 1962 to 1972 and in Xinjiang Autonomous Region in 1986, where F. tularensis was isolated from patients, Ixodes liberelis and Dermacentor marginatus ticks, and woolly hares (Lepus oiostolos). The latest outbreak occurred in 1986 at a food processing factory in Shandong Province, where 31 of 36 workers who slaughtered hares became ill.

Infected vertebrate or invertebrate

Humans

Humans become infected with Francisella tularensis through inoculation of the skin, conjunctival sac or oropharyngeal mucosa with blood or tissue while handling infected animals, or through contact with fluids from infected flies, ticks or other animals.

Transmission occurs through arthropod bites (especially ticks and deerflies), ingestion of contaminated food or water, inhalation of contaminated aerosols, and handling of infected animal tissues.

The most important mammalian species involved in human infection include lagomorphs, voles, mice, squirrels, muskrats, and beavers.

Its principal animal reservoir appears to be the cottontail rabbit (Sylvilagus spp.).

Type B is reported to have a mainly water-borne cycle with aquatic rodents as reservoirs, e.g. muskrats (Ondatra zibethicus) and beaver (Castor canadensis) in North America.

Francisella tularensis type B is reported to have mainly ground voles (Arvicola terrestris) as reservoirs in the former Soviet Union.

Francisella tularensis does not form spores but can survive in water, soil, and decaying animal carcasses. The organism has been isolated from water and mud samples stored at 7 C for as long as 14 weeks, in tap water for as long as three months, and in dry straw litter for at least 6 months.

The interaction between F. tularensis and amoebae (A. castellanii) indicates that ubiquitous protozoa might be an important environmental reservoir for F. tularensis.

The inhalation of Francisella tularensis biovar A causes pneumonic tularemia associated with high morbidity and mortality rates in humans. Exposure to F. tularensis usually occurs by accident, but there is increasing awareness that F. tularensis may be deliberately released in an act of bioterrorism or war.

Japanese germ warfare research units studied F. tularensis subsp. tularensis, and this organism may have been used against Chinese civilians, Russian troops, and American prisoners of war between 1932 and 1945. In addition, the appearance of tularemia in thousands of Russian and German troops at the siege of Stalingrad may have been the result of deliberate use by the Soviets. However, a natural cause for this outbreak has not been eliminated, and military personnel may have acquired F. tularensis from mice and rats whose numbers multiplied owing to the widespread disruption of sanitation and hygiene during battle. During the Cold War both the Soviet Union and the United States prepared and stockpiled tons of infectious agents for potential use against the civilian populations of their enemies

A former Soviet Union biological weapons scientist, Ken Alibek, has suggested that tularemia outbreaks affecting tens of thousands of Soviet and German soldiers on the eastern European front during World War II may have been the result of intentional use. In the 1950s and 1960s, the US military developed weapons that would disseminate F. tularensis aerosols; concurrently, it conducted research to better understand the pathophysiology of tularemia and to develop vaccines and antibiotic prophylaxis and treatment regimens. In some studies, volunteers were infected with F. tularensis by direct aerosol delivery systems and by exposures in an aerosol chamber. A live attenuated vaccine was developed that partially protected against respiratory and subcutaneous challenges with the virulent Schu 4 strain of F. tularensis, and various regimens of streptomycin, tetracyclines, and chloramphenicol were found to be effective in prophylaxis and treatment. By the late 1960s, F. tularensis was one of several biological weapons stockpiled by the US military.

Suspicion of inhalational tularemia must be promptly reported to local or state public health authorities so timely epidemiological and environmental investigations can be made.

Subsequent to intentional release of a biological agent, public health services attempt to ensure the dissemination of accurate information to communities, but the media and the internet may serve as potential sources of inflammatory material, thereby aggravating public insecurity and leading to hoarding of antimicrobial agents, as was observed after the 2001 U.S anthrax attacks. This behavior should be proactively discouraged by infectious diseases experts so it does not contribute to the potential development of antimicrobial resistance.

In 1969, a World Health Organization expert committee estimated that aerosol dispersal of 50 kg of virulent F. tularensis bacteria over a metropolitan area with five million inhabitants would result in 250,000 casualties requiring extensive medical care and 19,000 deaths

In circumstances of a laboratory spill or intentional use in which authorities are concerned about an environmental risk (eg, inanimate surfaces wet with material thought to contain F tularensis), decontamination can be achieved by spraying the suspected contaminant with a 10% bleach solution (1 part household bleach and 9 parts water). After 10 minutes, a 70% solution of alcohol can be used to further clean the area and reduce the corrosive action of the bleach. Soap water can be used to flush away less hazardous contaminations. Persons with direct exposure to powder or liquid aerosols containing F. tularensis should wash body surfaces and clothing with soap water. Standard levels of chlorine in municipal water sources should protect against waterborne infection.

Human; man

Homo sapiens

Humans become infected with Francisella tularensis in various ways, including bites by infective arthropods, handling infectious animal tissues or fluids, direct contact with, or ingestion of, contaminated water, food, or soil, and inhalation of infective aerosols. Persons of all ages and both sexes appear to be equally susceptible to tularemia. Certain activities, such as hunting, trapping, butchering, and farming, are most likely to expose adult men. Laboratory workers are especially vulnerable to infection, either by accidentally inoculating themselves or by inhaling aerosolized organisms.

Francisella tularensis is a highly infectious aerosolizable intracellular pathogen that is capable of causing a debilitating or fatal disease with doses as low as 25 colony-forming units.

Inhaling as few as 10 of the microbes can cause debilitating illness. A few grams of a virulent strain of F. tularensis dispersed in a city could quickly sicken thousands, says Anders Sjostedt of the University of Umea in Sweden.

Inhalation of 10-25 organisms can cause tularemia, accompanied by a pronounced inflammatory response. However, the bacterial component that causes such a response is unknown.

Human infection ranges from asymptomatic forms to a wide variety of clinical manifestations, basically depending on the route of infection. Six clinical forms are usually distinguished: ulceroglandular, which is the most common, glandular, typhoidal, ocular, oropharyngeal and pulmonary.

Initial efforts to develop a live attenuated tularemia vaccine began in the former Soviet Union prior to the Second World War. Attenuation of strains was achieved either by repeatedly subculturing fully virulent strains in media supplemented with antiserum or by drying the strains. In 1934, El'bert et al. inoculated animals with a weakly virulent tularemia culture. Protection was demonstrated when these immunized animals were challenged with a virulent culture, and it was suggested that the same immunization procedure might be applicable to humans. Strain Moscow was reported to show weakened virulence and high immunogenicity and was used as a live vaccine in humans in 1942. In subsequent years it was shown that strain 15 had become so attenuated that it was no longer virulent in mice. The strain was passaged in animals and a variant, strain 15 restored, was derived. Another attenuated vaccine, strain 155, was also developed at this time, and both strains were produced as live vaccines at the Gamaleya Institute in Moscow. These strains were transferred to the United States in 1956.

The effectiveness of vaccination was successfully demonstrated in volunteers, and several thousand individuals were reportedly vaccinated before the strain was apparently lost.

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. Gentamycin should be effective for this purpose as well but this has not been confirmed. Doxycycline and ciprofloxacin also were examined in murine tularemia model, and both can be effective as preemptive therapy in mice after intraperitoneal challenge. Thus, currently either doxycycline or ciprofloxacin given orally for 14 days is recommended for adults with suspected or proven high-risk exposure to F. tularensis. Individuals with lower-risk exposures may be observed for fever or other signs of illness without antibiotics.

Prior to determining treatment strategy, case clusters should be evaluated for mass casualty potential, wherein large numbers of potentially infected people prohibit individual medical management, as would be possible in a contained casualty situation. Hence the recommended regimens above differ for the two circumstances. Treatment using bacteriostatic drugs should be continued for a longer duration than the traditional 10-day course recommended for bacteriocidal drugs. When treating individuals with ciprofloxacin, doxycycline, or chloramphenicol, intravenous regimens can be changed to oral regimens after a substantial clinical improvement is noted. Note that in mass casualty situations a minimum of 14 days is recommended for all regimens; this is due to the excessive use of oral agents beginning from the initiation of therapy. The bacteriostatic agents are not recommended for immunosuppressed patients because of the higher rates of treatment failure generally observed with the agents. Futhermore, giving the entire minimum of 10 days of therapy parenterally should be considered for immunocompromised patients. Although quinolones and tetracyclines have been associated with adverse consequences in children and immature laboratory animals, short courses of these agents in children have not been detrimental in prospective studies. The risks should be weighed in proportion to the potential benefits in children with severe disease.

Avoiding exposure to the organism is the best prevention of tularemia. Wild animals should not be skinned or dressed using bare hands, or when the animal appeared ill. Gloves, masks, and protective eye covers should be worn when performing such tasks and when disposing of dead animals brought home by household pets. Wild game should be cooked thoroughly before ingestion. Wells or other waters that are contaminated by dead animals should not be used. Treatment of community water supplies with standard chlorination protects against waterborne tularemia. The most important measure to avoid tick bites in infected areas is wearing clothing that is tight at the wrists and ankles and that covers most of the body. Chemical tick repellants also may 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 pre-antibiotic era secondary cases were not found. Standard universal precautions for contaminated secretions are adequate when handling drainage from the wounds and eyes.

Francisella tularensis can infect humans through the skin, mucous membranes, gastrointestinal tract, and lungs. It is a facultative intracellular bacterium that multiplies within macrophages. The major target organs are the lymph nodes, lungs and pleura, spleen, liver, and kidney. Untreated, bacilli inoculated into skin or mucous membranes multiply, spread to the regional lymph nodes and further multiply, and may then disseminate to organs throughout the body. Bacteremia may be common in the early phase of infection. The initial tissue reaction to infection is a focal, intensely suppurative necrosis consisting largely of accumulations of polymorphonuclear leukocytes, followed by invasion of macrophages, epithelioid cells, and lymphocytes. Suppurative lesions become granulomatous, and histopathological examination of the granulomas shows a central necrotic, sometimes caseating zone surrounded by a layer of epithelioid cells, multinucleated giant cells, and fibroblasts in a radial arrangement, typical of other granulomatous conditions, such as tuberculosis and sarcoidosis. Monkeys that inhaled the virulent SCHU S-4 strain of F tularensis (type A) developed acute bronchiolitis within 24 hours of exposure to 1-um particles and within 48 hours of exposure to 8-um particles. By 72 hours following challenge, inflammation was present in peribronchial tissues and alveolar septa. Bronchopneumonia was most pronounced in animals exposed to the smaller particles and was characterized by tracheobronchial lymph node enlargement and reddish, firm, 0.2- to 0.5-cm-diameter discrete inflammatory lesions scattered throughout the lungs. In the absence of treatment, the disease progressed to pneumonic consolidation and organization, granuloma formation, and eventual chronic interstitial fibrosis. Humans with inhalational exposures also develop hemorrhagic inflammation of the airways early in the course of illness, which may progress to bronchopneumonia. Histopathological examination of affected lungs shows alveolar spaces filled with an exudate of mononuclear cells. Pleuritis with adhesions and effusion and hilar lymphadenopathy are common radiological and pathological findings.

The incubation period of the disease is 2 to 6 days (range: 1 to 20 days).

The median incubation period for the disease is 3 to 5 days (range: 1 to 14 days)

Patients with chronic debilitating conditions or immunocompromise are at increased risk for severe forms of the disease. In these patients, infection may be quite dramatic with acute prostration and rapid death. Unless treated promptly, septic shock and multiorgan system failure may ensue. Renal involvement, has been associated with a worse prognosis. Fatality rates as high as 30-60% have been reported in patients with acute tularemia. In other patients, the infection may manifest as a more indolent febrile illness that lasts several days, remits briefly, and then recurs. Progressive weakness, malaise, anorexia, and weight loss may persist for months in the absence of treatment.

Ulceroglandular tularemia generally arises from contact with an infected animal or by the bite of an infected vector and is characterized by the presence of an ulcerated lesion and enlargement of regional lymph nodes. This type of exposure is exemplified by cases in a recent outbreak in Spain.

In ulceroglandular tularemia, a local cutaneous papule appears at the inoculation site at about the time of onset of generalized symptoms, becomes pustular, and ulcerates within a few days of its first appearance.

Ulceroglandular disease accounts for most (80%) clinical illness resulting from Francisella tularemia.

Patients typically present with fever, enlarged and tender lymph nodes, and an ulcer at the place of entry. The skin lesion is usually slight, and the appearance of an infected insect bite need not actually differ from that of a noninfected bite.

Typically, one or more regional afferent lymph nodes may become enlarged and tender within several days of the appearance of the papule. Even with antibiotic treatment, the affected nodes may become fluctuant and rupture.

The ulcer is tender, generally has an indolent character, and may be covered by an eschar.

Pharyngeal tularemia, another variant of ulceroglandular disease, is the result of primary invasion through the oropharynx. The source may be contaminated foods or water or contaminated droplets. This form which represents 0% to 12% of cases overall, has been seen with increasing frequency in Japan, and predominate in outbreaks. Children have been involved more often than adults, and several family members may be affected simultaneously. In pharyngeal tularemia, the patient's predominant complaint typically is of fever and severe throat pain. Exudative pharyngitis or tonsillitis is the rule, and one of more ulcers may be seen. A pharyngeal membrane has been described in some patients that is similar to a diphtheric membrane. Cervical, preparotid, and retropharyngeal adenopathy may be present, occasionally with bilateral involvement or abscess formation. When there is a delay in seeking care the dominant manifestation may be cervical adenopathy without prominent fever or pharyngotonsillitis.

0% to 12% of all cases.

Glandular tularemia, is an uncommon but significant cause of cervical lymphadenopathy in children.

Glandular tularemia represents essentially the same process as ulceroglandular disease, except that a skin lesion either healed before presentation or was minimal or atypical and overlooked. Enlarged lymph nodes may persist for prolonged periods, and in some patients an exposure or prior febrile illness will be forgotten. For this reason, tularemia may not be considered in the initial differential diagnosis of some patients whose primary presentation is lymphadenopathy. In either ulceroglandular or glandular tularemia the lymph nodes may suppurate.

Glandular disease may occur in 15% of patients with tularemia.

This form accounts for 3% to 20% of the cases in the United States, although 62% of cases in Japan have been of this type.

The clinical illness was mild, consisting of fever, headache, and lymphadenopathy.

Lymphadenopathy is very unusual in typhoidal tularemia and is most often observed in cases of ulceroglandular or glandular disease.

All lymphadenopathy was in the head and neck area.

Oculoglandular tularemia occurs when the conjunctiva is the initial site of infection, usually a result of mechanical transfer of organisms from an infectious source to the eye by the fingers. This form of disease is characterized by the appearance of ulcers and nodules on the conjunctiva and regional lymph node swelling.

Tularemia is one etiology of Parinaud's oculoglandular syndrome. Parinaud's oculoglandular syndrome is a unilateral granulomatous follicular conjunctivitis associated with mucopurulent discharge as well as painful preauricular and submandibular lymphadenopathy. Corneal ulceration and perforation may occur. The patient usually has fever, malaise, headache, fatigue, myalgias, and a history of exposure to animals, especially cats.

Oculoglandular tularemia is much rarer, occurring in approximately 1% of cases.

The etiology is usually unknown but has been associated with cat scratch disease, tularemia, sporotrichosis, tuberculosis and other mycobacteria, syphilis, lymphogranuloma venereum, certain fungal, viral and rickettsial diseases, and mononucleosis. A reported case of exposure of a patient to a wild rabbit, which subsequently died, suggested that tularemia was the likely etiology.

26%

The portal of entry is the oropharynx in the oropharyngeal form of tularemia.

Oropharyngeal tularemia is acquired by drinking contaminated water, ingesting contaminated food, and, sometimes, by inhaling contaminated droplets or aerosols. Affected persons may develop stomatitis but more commonly develop exudative pharyngitis or tonsillitis, sometimes with ulceration. Pronounced cervical or retropharyngeal lymphadenopathy may occur.

Most human cases in the recent outbreak of tularemia in Kosovo were of this form.

Oropharyngeal disease also is relatively rare, accounting for less than 5% of cases of tularemia.

The main signs are pharyngotonsillitis and cervical lymphadenitis.

A dry or slightly productive cough and substernal pain or tightness frequently occur with or without objective signs of pneumonia, such as purulent sputum, dyspnea, tachypnea, pleuritic pain, or hemoptysis.

Francisella tularensis can cause open sores. It was weaponized by Japan, the United States, and the Soviet Union.

Depending on the infecting dose, gastrointestinal tularemia ranges from mild but persistent diarrhea to an acute fatal disease with extensive ulceration of the bowel.

It is characterized by general symptoms such as fever, headache, sore throat, malaise, myalgias, cough and cutaneous lesions.

It is often described as a painful sore throat with enlargement of the tonsils and the formation of a yellow-white pseudomembrane. This is most often accompanied by swollen cervical lymph nodes.

It is characterized by a severe sore throat with enlargement of the tonsils and swollen cervical lymph nodes.

31%

Pneumonic tularemia, the most severe form of disease, occurs by direct inhalation of the organism, or may develop secondarily by septicemic spread of infection from a primary site of infection. Historically, farming, and more recently landscaping, have been significant occupational risk-factors associated with pneumonic tularemia in certain endemic areas.

An aerosol release of F tularensis would be expected to result in acute illness with signs and symptoms of 1 or more of pharyngitis, bronchiolitis, pleuropneumonitis, and hilar lymphadenitis, accompanied by various manifestations of systemic illness. Inhalational exposures, however, commonly result in an initial clinical picture of systemic illness without prominent signs of respiratory disease. The earliest pulmonary radiographic findings of inhalational tularemia may be peribronchial infiltrates, typically advancing to bronchopneumonia in 1 or more lobes, and often accompanied by pleural effusions and hilar lymphadenopathy. Signs may, however, be minimal or absent, and some patients will show only 1 or several small, discrete pulmonary infiltrates or scattered granulomatous lesions of lung parenchyma or pleura. Although volunteers challenged with aerosols of virulent F tularensis (type A) regularly developed systemic symptoms of acute illness 3 to 5 days following exposure, only 25% to 50% of participants had radiological evidence of pneumonia in the early stages of infection. On the other hand, pulmonary infection can sometimes rapidly progress to severe pneumonia, respiratory failure, and death. Lung abscesses occur infrequently.

Tularemia pneumonia may complicate the various clinical presentations of tularemia, or present as an uncommon zoonosis. Approximately 200 cases of tularemia are reported in the United States per year, and 10% to 20% present with pneumonia either as a primary event or as a complication of ulceroglandular or typhoidal tularemia. Tularemia pneumonia also occurs with the other tularemic forms, glandular, oculoglandular, and oropharyngeal tularemia as a result of secondary bacteremic spread to the lungs. Pneumonia usually occurs within 2 days to months after infection. The mortality rate of primary tularemic pneumonia and pneumonia complicating typhoidal tularemia is high. The clinical and roentgenographic presentations of tularemia pneumonia are highly variable and is one of the zoonotic atypical pneumonias. Tularemic pneumonia may mimic fungal and bacterial pneumonias, tuberculosis, or malignancy.

Infiltrates in left lower lung, tenting of diaphragm, probably caused by pleural effusion, and enlargement of left hilum. Source: Armed Forces Institute of Pathology.

Typhoidal tularemia refers to febrile illness caused by F. tularensis that is not associated with prominent lymphadenopathy and does not fit into any of the other major forms. This form of tularemia may result from any mode of acquisition

Typhoidal tularemia is used to describe systemic illness in the absence of signs indicating either site of inoculation or anatomic localization of infection. This should be differentiated from inhalational tularemia with pleuropneumonic disease.

The case-fatality rate among humans can reach 30%-60% in untreated typhoidal cases.

From 5% to 30% of cases are typhoidal.

Diarrhea, a major manisfestation only in typhoidal tularemia, is loose and watery but only rarely bloody. Children may have more severe intestinal involvement, including focal areas of bowel necrosis.

Tularemia sepsis is potentially severe and fatal. As in typhoidal tularemia, nonspecific findings of fever, abdominal pain, diarrhea, and vomiting may be prominent early in the course of illness. The patient typically appears toxic and may develop confusion and coma. Unless treated promptly, septic shock and other complications of systemic inflammatory response syndrome may ensue, including disseminated intravascular coagulation and bleeding, acute respiratory distress syndrome, and organ failure.

Culture recovery and characterization remains the "gold standard" for laboratory confirmation of tularemia infection according to the CDC. However, this approach has historically proven itself challenging, particularly with F. tularensis subsps., Type A and Type B. F. tularensis subsps., Type A and Type B, are slow-growing, fastidious organisms requiring sulfhydryl compounds and 24-72 h for growth on artificial media at 37 C. F. tularensis is also notorious for causing laboratory acquired infections and has to be handled under BSL-3 conditions. Despite these concerns, culture provides a conclusive diagnosis of infection and an invaluable resource for molecular epidemiology, subtyping and discovery of novel species and subspecies.

Francisella tularensis may be identified by direct examination of secretions, exudates, or biopsy specimens using direct fluorescent antibody or immunohistochemical stains.

Serology: Serology is the most commonly used laboratory approach for confirmation of suspected disease. However, specific antibody responses are typically not detectable prior to two weeks of infection with currently available tests. IgM, IgA and IgG antibodies appear simultaneously after initial infection and IgM antibodies can last for many years. Agglutination based on formalin-killed whole cells is the standard serology test used for determining the presence of antibody against F. tularensis. ELISAs based on LPS or outer membrane carbohydrate-protein fractions have also been utilized.

PCR: A variety of PCR methods have been described for the detection of F. tularensis DNA in both clinical and environmental specimens. PCR can be an invaluable diagnostic tool when organisms are noncultivable or nonviable. The majority of PCR tests for F. tularensis have been gel-based PCR assays targeted at the genes encoding the outer membrane proteins, fopA or tul4. These PCR assays show good specificity and allow for rapid detection of F. tularensis in specimens.

16S rDNA sequencing: Several studies have shown the usefulness of 16S rDNA sequence identification in the diagnostic laboratory, especially as relates to slow-growing, unusual, and fastidious bacteria. For identifying true emergence of F. tularensis, in areas where it has not previously been reported, 16S rDNA sequencing is a particularly useful diagnostic test. 16S rDNA sequencing played an important role in the first identification of F. tularensis in the Southern Hemisphere and also in the tularemia outbreak associated with crayfish in Spain. For identification of recovered bacterial isolates, the universal 16S rDNA primers as well as the Francisella specific 16S rDNA primers, provide good sequence data. For diagnostic identification of Francisella spp. in contaminated samples (ticks, water, field specimens), the Francisella specific 16S rDNA primers should be considered.

Molecular subtyping: PCR subtyping assays have been developed that allow for discriminating F. tularensis subsp., Type A and Type B, in the absence of a culture. These assays are gel-based and center on the detection of differences in amplified product sizes. More recently, a gel-based PCR assay targeted at the region of difference 1 (RD1), has been reported to distinguish between all four subspecies of F. tularensis, Type A, Type B, novicida, and mediaasiatica, although evaluation of a larger panel of isolates, especially novicida, will be required before this assay can be employed routinely for F. tularensis subtyping.

The drug of choice for the treatment of all forms of tularemia except meningitis is streptomycin, although gentamycin is an acceptable substitute.

The minimum 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. The pediatric weight-based regimens for streptomycin are similar (up to a maximum of the adult dose): 30 to 40 mg/kg/day intramuscularly in two divided doses for a total of 7 days; or 40 mg/kg/day intramuscularly in two divided doses for the first 3 days, followed by 20 mg/kg/day intramuscularly in two divided doses for the next 4 days.

In patients with impaired renal function, doses and/or frequency of administration of streptomycin must be modified in response to serum concentrations of the drug and the degree of renal impairment. The manufacturer states that peak serum concentration of streptomycin should not exceed 20-25 mcg/mL. When serum streptomycin concentrations are not available, dosage may be based on creatinine clearance. Streptomycin should not be used in patients with documented hypersensitivity, for long term therapy, or in patients suffering from non-dialysis-dependent renal failure. Streptomycin should be used with caution in patients with myasthenia gravis, hypocalcemia, and other conditions that depress neuromuscular transmission.

The first few days of streptomycin rarely may induce a Jarish-Herxheimer-like reaction, with an increase in symptoms and a transient drop of the serum agglutination titer. Nephrotoxicity may be increased if streptomycin is coadministered with other aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics. Aminoglycosides enhance neuromuscular blocking agents potentially causing respiratory depression.

The rate of cure for streptomycin was 97%, with no relapses.

Antibiotic therapy of tularemia has been determined empirically; streptomycin treatment exhibits a 100% cure rate.

A fully virulent streptomycin-resistant strain of Francisella tularensis was developed in the past for use in biologic warfare.

Gentamycin has proved to be effective therapy. In pediatric patients, gentamycin was shown to be effective for treatment of tularemia without relapse or failure.

Gentamycin is given intravenously at a dose of 3 to 5 mg/kg/day in divided doses for 7 to 14 days, with desired peak serum levels of a least 5.0 mcg/mL. The efficacy of single-daily dosing has not been studied. The doses of both streptomycin and gentamycin need to be adjusted for renal insufficiency. Penetration of these drugs into CSF is poor and erratic and may be inadequate in tularemia menningitis.

Gentamicin should not be used for long term therapy, in patients suffering from non-dialysis-dependent renal failure, or in patients with myasthenia gravis, hypocalcemia, and other conditions that depress neuromuscular transmission.

Serious adverse reactions including ototoxicity and nephrotoxicity have occurred in patients receiving systemic gentamycin therapy. Coadministration of gentamicin with other aminoglycosides, cephalosporins, penicillin, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance neuromuscular blocking agents potentially causing respiratory depression. Coadministration with loop diuretics may increase auditory toxicity of aminoglycosides with possible irreversible hearing loss of varying degrees.

A review of the literature revealed that gentamycin was effective for treatment except that the relapse and failure rates were high with gentamycin.

Tetracycline is bacteriostatic for F. tularensis.

Tetracyclines (usually doxycycline) are used as alternative agents for the treatment of tularemia caused by Francisella tularensis.

Tetracycline has been used to treat tularemia; however relapses and primary treatment failures occur at a higher rate than with aminoglycosides.

Tetracycline is most effective in adults when given a 2 g/day in divided doses for at least 14 days, a suggested oral regimen in children is 30 mg/kg/day, to a maximum 2/g/day, in divided doses for the same duration. Docycycline may also be used and provides the convenience of twice daily dosing.

Tetracycline should not be used in children younger than 8 years of age, during pregnancy, or during lactation. It should not be coadministered with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; oral contraceptives; or anticoagulants.

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment. Fanconi-like syndrome can occur with outdated tetracyclines. Tetracycline can decrease the effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy. It can also increase hypoprothrombinemic effects of anticoagulants.

Tetracycline and chloramphenicol are bacteriostatic for F. tularensis, and this accounts for the high rate of relapse after treatment with these agents. Doxycycline has a higher relapse rate compared with the aminoglycosides.

Alternatives for the treatment of tularemia include tetracyclines (doxycycline, chloramphenicol, or ciprofloxacin.

In general choloramphenicol should not be used to treat tularemia because of its potentially serious toxicity and the availability of more effective alternatives with less dangerous potential side effects. However, chloramphenicol, 50 to 100 mg/kg/day intravenously in divided doses may be added to streptomycin to treat menningitis. When used in the past for other forms of tularemia, the oral dose of chloramphenicol has been 30 to 50 mg/kg/day in three or four divided doses for at least 14 days. However, the oral preparation is no longer available in the United States.

Chloramphenicol is contraindicated in patients with a history of hypersensitivity and/or toxic reactions to the drug.

Chloramphenicol has been used to treat tularemia; however, relapses and primary failures occur at a higher rate than with aminoglycosides, and they should be given for at least 14 day to reduce the chance of relapse.

Recent in vitro susceptibility studies have found that the fluoroquinolones are active against F. tularensis subsp. tularensis as well as subsp. holarctica. In mice, liposome-encapsulated ciprofloxacin delivered by aerosol inhalation was highly effective in the treatment of respiratory F. tularensis infection.

Fluoroquinolones, which have intracellular activity, are promising candidates for treating tularemia. Ciprofloxacin, which is not labeled for use in tularemia, has been shown to be active in vitro and in animals and has been used successfully to treat tularemia in both adults and children.

Ciprofloxacin has been found to be effective in treating tularemia in mice and in a recent outbreak in Spain, ciprofloxacin was the antibiotic with the lowest level of therapeutic failure and fewest side effects. Ciprofloxacin was also shown to be suitable for the treatment of tularemia in a case where relapse was evident after initial gentamicin therapy.

Fluoroquinolones (including ciprofloxacin) have been reported to cause cartilage damage in immature animals and are not approved for use in patients under 18 years old.

Clinical experience with the fluoroquinolones as therapy for tularemia caused by F. tularensis subsp. holarctica is growing and has been favorable even in immunocompromised hosts. A patient with a knee prosthesis chronically infected by F. tularensis subsp. holarctica was cured following a prolong course of ciprofloxacin and rifampin. However, the outcome with fluoroquinolone therapy may be suboptimal and there is minimal experience using these agents for infections caused by the more virulent F. tularensis subsp. tularensis. During the initial Spanish tularemia outbreak, therapy with ciprofloxacin was overall statistically equivalent to that with streptomycin and superior to doxycycline. However relapses occurred in 7 of 14 patients at one Spanish hospital following ciprofloxacin given as either primary or secondary treatment. Ciprofloxacin also have been effective in children with tularemia. Johansson and colleagues described 12 children, ranging in age from 1 to 10 years, with tularemia given ciprofloxacin 15 to 20 mg/kg daily in two divided doses. The two patients who completed only 3.5 and 7 days of treatment relapsed but all 12 were cured after completing 10 to 14 days of uninterrupted therapy.

Surgical therapies are limited to drainage of abscessed lymph nodes and chest tube drainage of empyemas.

ADULTS (Serious Disease): Streptomycin 1 g IM q 12 hours for 10 days. Gentamycin 5 mg/kg IM or IV qd for 10 days. (Alternatives for Less Serious Disease): Streptomycin or gentamycin in doses listed above. Doxycycline 100 mg IV BID for 14-21 days. Ciprofloxacin 400 mg IV BID for 10 days. Chloramphenicol 15 mg/kg IV QID for 14-21 days.

CHILDREN (Serious Disease): Streptomycin 15 mg/kg IM q 12 hours for 10 days, not to exceed 2 g/day. Gentamycin 2.5 mg/kg IM or IV q 8 hours for 10 days. (Alternatives for Less Serious Disease): Streptomycin or gentamycin in doses listed above. Doxycycline 100 mg IV q 12 for 14-21 days if weight is equal or greater than 45 kg; 2.2 mg/kg IV q 12 hours if weight <45 kg. Ciprofloxacin 15 mg/kg IV q 12 hour for 10 days.

PREGNANCY (Serious Disease): Gentamycin 5 mg/kg IM or IV qd for 10 days. Streptomycin 1 g IM q 12 hours for 10 days. (Alternatives for Less Serious Disease): Gentamycin or Streptomycin in doses listed above. Doxycycline 100 mg IV q 12 hours for 14-21 days. Ciprofloxacin 400 mg IV q 12 hours for 10 days. Chloramphenicol 15 mg/kg IV QID for 14-21 days.

IMMUNOSUPPRESSED PERSONS: Minimum of 10 days of treatment. Gentamycin 5 mg/kg IM or IV in divided doses. Streptomycin 1 g IM q 12 hours.

ADULTS: Doxycycline 100 mg PO BID for 14 days. Ciprofloxacin 500 mg PO BID for 14 days.

CHILDREN: Doxycycline 100 mg PO BID for 14 days if weight is equal or greater than 45 kg; 2.2 mg/kg PO BID if weight <45 kg. Ciprofloxacin 15 mg/kg PO BID for 14 days.

PREGNANCY: Ciprofloxacin 500 mg PO BID for 14 days. Doxycycline 100 mg PO BID for 14 days.

NOTE: Prior to determining treatment strategy, case clusters should be evaluated for mass casualty potential, wherein large numbers of potentially infected people prohibit individual medical management, as would be possible in a contained casualty situation. Hence the recommended regimens above differ for the two circumstances. Treatment using bacteriostatic drugs should be continued for a longer duration than the traditional 10-day course recommended for bacteriocidal drugs. When treating individuals with ciprofloxacin, doxycycline, or chloramphenicol, intravenous regimens can be changed to oral regimens after a substantial clinical improvement is noted. Note that in mass casualty situations a minimum of 14 days is recommended for all regimens; this is due to the excessive use of oral agents beginning from the initiation of therapy. The bacteriostatic agents are not recommended for immunosuppressed patients because of the higher rates of treatment failure generally observed with the agents. Futhermore, giving the entire minimum of 10 days of therapy parenterally should be considered for immunocompromised patients. Although quinolones and tetracyclines have been associated with adverse consequences in children and immature laboratory animals, short courses of these agents in children have not been detrimental in prospective studies. The risks should be weighed in proportion to the potential benefits in children with severe disease.

BALB/c mouse.

The in vivo efficacy of ciprofloxacin, gatifloxacin and moxifloxacin were assessed in an experimental Francisella tularensis Schu S4 infection in the BALB/c mouse model. Mice were given 100 mg/kg of antibiotic by oral administration twice daily commencing at 6, 24 or 48 h post-exposure and continued for 14 days post-exposure. All mice were challenged subcutaneously with 1 x 10(6) cfu F. tularensis Schu S4 and observed for a period of 56 days. Treatment initiated 6 h post-exposure resulted in 94, 100 and 100% survival for ciprofloxacin, gatifloxacin and moxifloxacin, respectively. When treatment was delayed until 24 h post-exposure the survival rates were ciprofloxacin 67%, gatifloxacin 96% and moxifloxacin 100%. Treatment initiated at 48 h post-exposure resulted in a significant reduction in the survival rate of the ciprofloxacin-treated mice, with 0% survival compared with 84 and 62% for gatifloxacin and moxifloxacin, respectively. Non-treated infected control mice died within 96 h post-exposure. Dexamethasone given at day 42 for 7 days to suppress the animals' immune system caused relapse in all of the treatment groups. Both gatifloxacin and moxifloxacin were more effective at preventing mortality than ciprofloxacin and could be considered as alternative antibiotics in the treatment of systemic F. tularensis infection.

AKR/J mouse

An experimental model was developed in which passively transferred spleen cells from immunized AKR/J mice enabled nonimmume syngeneic recipients to survive an otherwise fatal infection with fully virulent Francisella tularensis. Donor immunization was achieved by administering live attenuated tularemia vaccine and, subsequently, the virulent streptomycin-sensitive SCHU S4 strain of F. tularensis. At selected intervals after immunization, donor spleen cells were transferred to streptomycin-treated recipients challenged subcutaneously, intravenously, or intraperitoneally with 25 to 50 minimal lethal doses of virulent streptomycin-resistant F. tularensis SCHU S5. The protection afforded by immune spleen cells was maximal (essentially 100%) 12 days after the SCHU S4 secondary immunization.

Common vole (M. arvalis).

The possibility of the atypical course of tularemia with the prolonged persistence of Francisella tularensis strain 165 in common voles (M. arvalis), the twin species of East European voles (M. rossiaemeridionalis), was studied. 7 out of 33 voles showed the atypical course of tularemia: in 3 voles the disease took a prolonged course with bacteriuria and death on days 25-34; 3 other voles with bacteriuria registered before days 33, 66 and 172 (the term of observation) survived. The surviving animals were killed on day 183, and the presence of bacteria in their organs and seroconversion were established. One vole excreted no bacteria with urine and had no bacteria in its organs (the animal was examined on day 156), but in its blood specific antibodies were detected. Thus, M. arvalis, like M. rossiaemeridionalis, can harbor F. tularensis at the period between epizootics. When voles of the former species penetrate stacks of straw and hayricks, conditions appear for the transfer of the infection to the latter species, M. rossiaemeridionalis. Therefore, in the foci of the meadow-field type each of these two species of voles may be not only of epizootic, but also of epidemic importance.

Common voles (Microtus subarvalis) were infected with tularemia by feeding them with the corpses of animals infected with a Francisella tularensis strain of decreased virulence. This resulted in non-lethal infection in 14 out of 433 voles. A considerable part of the animals having had the infection developed bacterial carriership (11 out of 13 animals) with bacteriuria (8 out of 11 animals) lasting up to 2 months. The persistence of Francisella tularensis in the body of the animals having had the infection could last as long as 6-11 months.

Black-and-red tamarin

Saguinus nigricollis

In an episode of tularemia in a Canadian zoologic garden, three black and red tamarins (Sanguinus nigricollis) and one talapoin (Cercopithecus talapoin) died. A second talapoin developed abscesses in the tongue and submandibular area; this animal recovered with treatment. Francisella tularensis was isolated from lung, liver, and spleen from each dead monkey and from pus collected from the tongue abscess of the sick talapoin. The attending veterinarian contracted the disease from a tamarin bite. The source of the disease was identified as wild ground squirrels, and the causative organism was recovered from the liver and spleen of one squirrel and from fleas found on it.

Gold-and-black lion tamarin

Leontopithecus chrysomelas

Tularaemia in a captive golden-headed lion tamarin (Leontopithecus chrysomelas) in Switzerland.

Squirrel monkey

Saimiri sciureus sciureus

A 3-year-old female squirrel monkey (Saimiri sciureus sciureus) was examined because of sudden onset of lethargy and fever.

Following collection, blood samples were slow to clot. During the next week, the monkey developed anemia and thrombocytopenia; Francisella tularensis was isolated from blood samples.

Francisella tularensis was isolated from blood samples of a 3-year-old female squirrel monkey (Saimiri sciureus sciureus).

Talapoin

Cercopithecus talapoin

American beaver

Castor canadensis

F. tularensis subsp. holarctica, found in Europe, North America, and Japan, is often associated with lagomorphs in Scandinavia, continental Europe, and Japan, ground voles in the former USSR, and beavers and muskrats in North America.

Type B is reported to have a mainly water-borne cycle with aquatic rodents as reservoirs, e.g. muskrats (Ondatra zibethicus) and beaver (Castor canadensis) in North America.

Bank vole

Clethrionomys glareolus

Studies on Lyme borreliosis and other tick-borne zoonoses in the Austrian and Slovakian borderland, a region endemic for tularemia, revealed a relatively high prevalence of infection with Borrelia burgdorferi s.l. and Francisella tularensis in small terrestrial mammals, as well as in the ticks, during a one-year survey.

Infection with B. burgdorferi s.l. and also with F. tularensis was found in all the most abundant rodent species. A significant difference was observed in the time period of isolation of these agents. Borrelia was cultured from May to January (PCR detected borrelia up to April), while F. tularensis was isolated from August to December. Coinfection was seen in two species of voles, Clethrionomys glareolus trapped in August and Microtus arvalis in October. The Borrelia strains isolated from these animals were identified as B. garinii. Isolates of F. tularensis belonged to the subspecies holarctica, biovar II.

Black-tailed prairie dog

Cynomys ludovicianus

Oropharyngeal tularemia was identified as the cause of a die-off in captured wild prairie dogs at a commercial exotic animal facility in Texas. From this point source, Francisella tularensis-infected prairie dogs were traced to animals distributed to the Czech Republic and to a Texas pet shop. F. tularensis culture isolates were recovered tissue specimens from 63 prairie dogs, including one each from the secondary distribution sites. All seropositive animals remained culture positive, suggesting that prairie dogs may act as chronic carriers of F. tularensis.

Common vole

Microtus arvalis

A five-year ecological study of the largest tularemia natural focus in Croatia (Yugoslavia) has revealed that the focus is of a meadow-field type and that the common vole is the crucial member of the local tularemia pathobiocenosis.

During the tularemia epizooty of 1981-1982 the population of common voles (Microtus arvalis) was very numerous, while the population of house mice (Mus musculus) was comparatively scarce. Francisella tularensis strains were isolated from different species of rodents (Microtus arvalis, Mus musculus, Apodemus sylvanicus, Rattus norvegicus, Lepus, etc.), from fleas and ticks, as well as from environmental objects (well-water, hay).

Eurasian pygmy shrew

Sorex minutus

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from animals in Slovakia. Species: Sorex minutus. Number of isolates: 1. Years of Isolation: 1978. District: Senica.

European woodmouse; long-tailed field mouse

Apodemus sylvaticus

In a survey of F. tularensis strains isolated from animals in Slovakia, a total of twelve isolates of F. tularensis was isolated from the long-tailed field mouse (Apodemus sylvaticus) in the districts of Dunajska Streda and Senica between 1978 and 1996.

Ground vole, European water vole

Arvicola terrestris

Two subspecies of F. tularensis are most commonly associated with human and animal disease: tularensis (Type A) and holarctica (Type B). Type A is found almost exclusively in North America and is associated with a severe form of disease in humans and rabbits (Lepus spp.). It is commonly differentiated from Type B by its ability to produce acid from glycerol. Type B is found throughout the Northern Hemisphere (holarctic region); it does not produce acid from glycerol and rarely causes death in humans. Type B is most frequently isolated from rodent species, including muskrats (Ondatra zibethicus), mice (Mus musculus), beaver (Castor canadensis), voles (Microtus spp.), and water voles (Arvicola terrestris).

Hamsters

Cricetinae

Pet hamsters are a potential source of tularemia.

Lemmings

Lemmus

Lemmings and beavers in Scandinavia might also play a role in the maintenance of Francisella tularensis in watercourses.

Microtus subterraneus, Pitymys subterraneus

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from animals in Slovakia. Species: Pitymys subterraneus. Number of isolates: 1. Years of Isolation: 1978. District: Senica.

Muskrat

Ondatra zibethicus

Beavers and muskrats in North America and lemmings and beavers in Scandinavia might also play a role in the maintenance of the bacterium in watercourses.

F. tularensis subsp. holarctica, is often associated with beavers and muskrats in North America.

Southern water shrew

Neomys anomalus

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from animals in Slovakia. Species: Neomys anomalus. Number of isolates: 1. Years of Isolation: 1978. District: Senica.

Water vole

Microtus richardsoni

Shedding nephritis in voles with chronic tularemia is the probable source of frequent contamination of streams over wide areas of the northern hemisphere.

Yellow-necked field mouse

Apodemus flavicollis

Marked activation of natural foci of tularemia in the known endemic area of Central Europe, comprising the borderland of Slovakia, Austria and the Czech Republic, led to an epidemic outbreak in western Slovakia and an increase in the number of human tularemia cases in the adjoining regions of northeastern Austria and southern Moravia from 1995 to 1997.

In four localities under investigation (three localities in western Slovakia and one in Austria), a nearly simultaneous flare-up of tularemia epizootics was recorded in the autumn of 1994. The highest mean prevalence of infection in small mammals was 3.9% in the last quarter of the year, which along with isolations of F. tularensis from Dermacentor reticulatus ticks collected from vegetation in the locality of Austria (1.3% positivity), indicated the high epizootic activity of foci. F. tularensis was isolated from five rodent species--Apodemus flavicollis, A. sylvaticus, Clethrionomys glareolus, Microtus arvalis and Sorex araneus.

From 1978 to 1994, a total of twelve F. tularensis strains was isolated from the yellow-necked field mouse (Apodemus flavicollis) in Slovakia.

Eastern cottontail

Sylvilagus floridanus

Cottontail rabbits (Sylvilagus floridanus) usually are thought to succumb to infection with Francisella tularensis. Reports of a rabbit population from southern Illinois (USA) with a high prevalence of F. tularensis antibodies suggested that some cottontails survived infection with this typically fatal bacterium. Our goal was to examine the humoral response of cottontails from a study area in southern Illinois for which multiple serum samples existed. Multiple sera were collected from 79 cottontails from 1986 to 1990 and 63% gained, lost, or maintained ELISA titers of IgM and IgG isotype antibodies. The typical pattern of antibody response appeared to be IgM isotype antibodies first, followed by IgG isotype antibodies, with both generally increasing to high titers. Negative culture attempts of liver tissue from 51 cottontails with varying antibody responses suggested that chronic infection did not occur in rabbits that developed antibody. The significance of the cottontail antibody response in resolution or prevention of tularemia infection remains unclear.

European hare

Lepus europaeus

To elucidate the importance of different causes of mortality which could explain the downward trend of the hare populations in Switzerland and for monitoring selected zoonoses, the health and reproductive status of 167 perished brown hares (Lepus europaeus) was assessed. Concerning causes of mortality, traumas were by far the most frequent diagnosis, 80% of the hares dying because of injuries. Animals killed by road traffic were highly represented. Predators (such as dogs, domestic cats, lynx, martens, buzzards, and golden eagles) killed 16% of the analysed animals. In juveniles, predation was significantly more frequent than in adults. Infectious diseases led to death in 15% of the animals, and cases of pasteurellosis, brucellosis, pseudotuberculosis, tularaemia, listeriosis, and toxoplasmosis were diagnosed.

Mountain hare

Lepus timidus

The occurrence of tularemia was studied in 1,500 hares submitted to the National Veterinary Institute, Uppsala, Sweden for postmortem examination during 1973 through 1985. A total of 109 tularemia cases was recorded based on the fluorescent antibody (FA) test for Francisella tularensis and on the gross and microscopic pathology. Tularemia was diagnosed only in the varying hare (Lepus timidus) and not in the European brown hare (Lepus europaeus).

American black bear

Ursus americanus

Between 1988 and 1991, 644 serum samples were collected from 480 grizzly bears (Ursus arctos horribilis) and 40 black bears (Ursus americanus) from Alaska, United States of America, and were tested for selected canine viral infections and zoonoses. Antibody prevalence in grizzly bears was 0% for parvovirus, 8.3% (40/480) for distemper, 14% (68/480) for infectious hepatitis, 16.5% (79/480) for brucellosis, 19% (93/480) for tularaemia and 47% (225/478) for trichinellosis. In black bears, prevalence ranged from 0% for distemper and parvovirus to 27.5% for trichinellosis and 32% for tularaemia. Antibody prevalence for brucellosis (2.5%) and tularaemia (32%) were identical for grizzly bears and black bears from the geographical area of interior Alaska.

Cat; domestic cat; Korat cats

Felis catus; Felis domesticus; Felis silvestris catus

Ten cases of naturally occurring tularemia in cats were positive both by isolation of F. tularensis and immunohistochemical identification of F. tularensis antigen. Nine additional cases with lesions typical of tularemia were positive for F. tularensis antigen, although bacterial cultures were not performed.

Cats living in Connecticut and New York State were naturally exposed to F. tularensis or a closely related organism. With exposure to ticks, other biting arthropods, mice, and rabbits, cats are at risk for acquiring F.tularensis infections and can be an important source of information on the presence of this agent in nature.

Coyote

Canis latrans

Swift foxes (Vulpes velox) and coyotes (Canis latrans) are sympatric canids distributed throughout many regions of the Great Plains of North America. The prevalence of canid diseases among these two species where they occur sympatrically is presently unknown. From January 1997 to January 2001, we collected blood samples from 89 swift foxes and 122 coyotes on the US Army Pinon Canyon Maneuver Site, Las Animas County, SE Colorado (USA).

No swift foxes had antibodies against Francisella tularensis, whereas seroprevalence was 4% among both adult and juvenile coyotes.

Least weasel

Mustela nivalis

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from animals in Slovakia. Species: Mustela nivalis. Number of isolates: 3. Years of Isolation: 1978. District: Senica.

Ursus arctos horribilis

European shrew

Sorex araneus

American dog tick

Dermacentor variabilis

In the United States, several blood-feeding arthropods serve as vectors for F. tularensis, including ticks (Ixodidae) and biting flies (Tabanidae). Three ixodid tick species are important vectors in the United States: the American dog tick (Dermacentor variabilis), the Rocky Mountain wood tick (D. andersoni), and the Lone Star tick (Amblyomma americanum).

Castor bean tick

Ixodes ricinus

F. tularensis subsp. tularensis isolates in North America are often associated with tick-borne tularemia in lagomorphs and are highly virulent for many mammalian species, including primates.

Dermacentor reticulatus revealed a significantly higher infection rate (2.6%) than I. ricinus (0.2%). This tick species acts as principal vector for tularemia in the enzootic focus.

Dermacentor reticulatus

Twenty-one isolates of Francisella tularensis were recovered from two haematophagous arthropods. Dermacentor reticulatus revealed a significantly higher infection rate (2.6%) than I. ricinus (0.2%). This tick species acts as principal vector for tularemia in the enzootic focus.

Haemaphysalis concinna

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from ectoparasites in Slovakia. Species: Haemaphysalis concinna. Number of isolates: 3. Years of Isolation: 1984-1987. District: Bratislava, Senica.

Ixodes trianguliceps

A total of 155 F. tularensis strains were examined in biological tests, including 65 strains isolated in Slovakia from different species of small mammals and 90 strains isolated from ectoparasites.

Survey of F. tularensis strains isolated from ectoparasites in Slovakia. Species: Ixodes trianguliceps. Number of isolates: 14. Years of Isolation: 1984-1996. District: Bratislava, Bratislava-surroundings, Levice, Nitra, Nove Zamky, Trnava.

Lone Star tick

Amblyomma americanum

Rocky Mountain wood tick; Rocky Mountain tick

Dermacentor andersoni

Common wood ticks (Dermacentor andersoni) collected from Saskatchewan Landing Provincial Park, Saskatchewan in the spring of 1982 transmitted a lethal tularaemia infection to four of six rabbits. Francisella tularensis organisms were isolated from tissues taken from the dead rabbits and identified from subcultures using an indirect immunofluorescent antibody assay. One human associated with the animals developed symptoms of tularaemia and, after successful therapy, had a significant increase in titre of specific antibodies to F. tularensis. This is the first time tick-transmitted tularaemia has been reported in Saskatchewan in more than 25 years.

Androlaelaps fahrenholzi

A total of 155 F. tularensis strains were examined in biolog