Francisella tularensis (Tularemia)

Authors: Richard F. Jacobs, M.D., F.A.A.P.

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History

Tularemia is an epizootic infection caused by Francisella tularensis (19). Any age, sex, or race is universally susceptible to infection (12, 28, 52). Tularemia is primarily a disease of wild animals that is transmitted to humans by a contaminated environment or ectoparasites. Infection is incidental and usually the result of interaction with biting or blood-sucking insects, wild animals, or their environment (7, 9, 12). Tularemia is a common illness in certain geographic regions of the southeastern to midwestern United States with highly endemic areas including Arkansas, Oklahoma and Missouri (17, 26, 59).

Microbiology

Culture and isolation of Francisella tularensis is difficult (46, 62). In a study of over one thousand human cases, 84% of which were laboratory confirmed by serology, the organism was isolated in only 10% of the cases. The medium of choice is cysteine glucose blood agar. Good growth has also been achieved on modified Mueller-Hinton broth, chocolate agar supplemented with IsoVitale X and modified charcoal yeast extract agar. The requirement of cysteine and enriched medium for stimulated growth has traditionally served as a useful characteristic for presumptive identification of Francisella tularensis. Recently, strains of Francisella tularensishave been described which, on primary isolation, failed to demonstrate a requirement for cysteine-enriched media, but grew well on conventional laboratory medium (3). Therefore, isolation of a strictly aerobic, tiny, weakly-staining, Gram-negative coccobacillus which lacks the aforementioned growth requirements may represent strains ofFrancisella tularensis. A heavy inoculum on appropriate medium will yield a growth mass in eighteen hours, while individual colonies may require two to four days. Overgrowth by contaminating microorganisms can be reduced by incorporating 100-500 U of penicillin per milliliter into the medium.

Epidemiology

Francisella tularensis is the etiologic agent of tularemia and, with rare exception, the only disease produced by this genus. The organism is a small, Gram-negative, pleomorphic, nonmotile, nonspore-forming coccobacillus measuring 0.2 x 0.2 to 0.7 mm. It is a non-piliated strict aerobe that infects the host as a facultative, intracellular bacterium. The two main biovars, Francisella tularensis biovar tularensis (Type A) and Francisella tularensis biovar palearctica (Type B) are found in the United States (29). Type A produces the more serious disease in humans with an untreated fatality rate of approximately 5% and is found in the North American continent. Type B produces a milder, often subclinical disease, and has usually been associated with water or aquatic mammals. Recent evidence of more serious disease and an increased incidence have been found in Scandinavian countries, eastern Europe, and Siberia (24, 61). In nature, it is a rather hardy organism persisting for weeks to months in mud, water and decaying animal carcasses (29). Animal reservoirs include wild rabbits, sheep, beavers, and muskrats. Animal bites, including those from cats and squirrels, have transmitted infection (14, 20, 37, 14, 48). Numerous biting and blood-sucking insects can serve as vectors. Ticks and wild rabbits are the source for most of the human cases in endemic areas (26, 27).

Clinical Manifestations

The illness is characterized by six clinical syndromes: ulceroglandular, glandular, oropharyngeal, oculoglandular, gastrointestinal (typhoidal), and pneumonic (5,6, 16). The most common syndrome presents with an ulcerative lesion at the site of inoculation and regional lymphadenopathy/lymphadenitis (ulceroglandular tularemia). Systemic manifestations with pneumonia, typhoidal tularemia, or fever without localizing findings will present a more challenging differential diagnosis (4,8,15,21).

Laboratory Diagnosis

Direct isolation can be achieved from infected ulcer scrapings, lymph node biopsy specimens, gastric washings, sputum and blood cultures. Colonies are blue-gray, round, smooth and slightly mucoid. On media containing blood, a small zone of alpha-hemolysis usually surrounds the colony. Direct application of slide agglutination tests or direct fluorescent antibody using commercially-available antisera can be performed on culture suspensions for identification. Although biochemical reactions are of no particular value, fermentation of glycerol or evidence of citrulline ureadase production may serve to differentiate biovar Type A from Type B. Polymerase chain reaction testing for Francisella tularensis DNA has been used to demonstrate the infection with blood used as the primary source of detection (34). However, this test has not been shown to be more sensitive than direct culturing and remains, at this time, a research tool.

Tularemia is most frequently confirmed by serology (27, 28). In a standard tube agglutination test, a titer of less than 1:20 is not considered diagnostic because of nonspecific cross reactions that are common at this level. A single titer of 1:160 should be interpreted as a presumptive positive test. A four-fold increase in titers is considered diagnostic. Late in infection, titers into the thousands are common and titers of 1:20 to 1:80 may persist for years. A microagglutination test which may be up to one hundred-fold more sensitive than the standard tube agglutination test is currently used in clinical microbiology laboratories. Enzyme-linked immunosorbent assays have proven useful in detecting both antibodies and antigens (55). Analysis of urine for Francisella tularensis antigen has shown promising results in clinical trials, but is not widely available. Although extremely rare, Francisella philomiragia and Francisella tularensis biovar novicida have been associated with human disease and can cause serologic cross reactions.

Pathogenesis

Ticks pass the organism to their offspring via a transovarian route. The organism is found in tick feces, but not in salivary glands. In the United States, the disease can be carried by Dermacentor andersoni (Rocky Mountain wood tick), Dermacentor variabilis (American dog tick), Dermacentor occidentalis (Pacific Coast dog tick), and Amblyomma americanum (Lone Star tick). Most cases of tularemia result from blood meals taken by embedded ticks (27, 39). Tularemia is most likely to occur in adult males and person-to-person transmission is rare, if it ever occurs. Transmission of the organism occurs mainly in the spring and summer; however, continued transmission in the winter months has been documented. The organism is extremely infectious. The most common portal of entry for human infection is through skin or mucous membranes, either directly through the bite of a tick, other arthropods, or via in apparent abrasions. Inhalation or ingestion of Francisella tularensis can also result in infection (51). Although more than 108 organisms are usually required to produce infection via the oral route (oropharyngeal or gastrointestinal tularemia), fewer than fifty organisms will result in infection when injected into the skin (ulceroglandular/glandular tularemia) or inhaled (pneumonia) (27, 42). Following inoculation into the skin, the organism multiplies locally and, after two to five days (range one to ten days), produces an erythematous, tender or pruritic papule. The papule rapidly enlarges and forms an ulcer with a black base. The bacteria spread to regional lymph nodes producing lymphadenopathy and may spread further with bacteremia. With bacteremia, organisms are cleared from the blood by the phagocytic cells of the reticuloendothelial system and may survive intracellularly for long periods of time. Biosafety level 2 is recommended for clinical laboratory work with suspected material and biosafety level 3 is required for culturing the organism in large quantities.

SUSCEPTIBILITY IN VITRO AND IN VIVO

In vitro studies have shown Francisella tularensis to be susceptible to a wide range of antimicrobial agents, many of which have not been studied for the treatment of patients with tularemia. Several articles have reported the details of antimicrobial susceptibility testing; the methods used differed by investigator (2, 39, 40,57, 61). Such testing showed no difference between type A and type B strains of Francisella tularensis (39). The results of tests with isolates from ticks and from humans are summarized in Tables 1 and 2, respectively.

In light of the in vitro susceptibility data reported by Baker et al., in 1985 and by Markowitz et al., in 1985, it appears that the third generation cephalosporins or amikacin would be effective against tularemia. However, Cross and Jacobs have compiled data showing that ceftriaxone is ineffective for the treatment of tularemia (Table 3) (11). In eight documented cases of tularemia, patients were initially treated empirically with ceftriaxone for adenitis and pneumonia, but the condition of all patients worsened. With the institution of standard therapy for tularemia, symptoms resolved quickly. These results indicate that in vitro data on Francisella tularensis do not always correlate with clinical response. Of interest are the markedly lower MICs of ceftazidime compared to ceftriaxone. However, no cases treated with ceftazidime have yet been reported, and given the disappointing results obtained with ceftriaxone, cephalosporins should not be used until their clinical efficacy has been demonstrated. Similarly, no case reports have documented the efficacy of amikacin.

Syrjala et al determined the in vitro susceptibility of ten strains of Francisella tularensis to ciprofloxacin, norfloxacin, ofloxacin, and pefloxacin (Table 4) (57). They noted a narrower range among the MBCs of ciprofloxacin and norfloxacin for the various strains; this finding suggested that these agents may be preferable to others in this class.

ANTIMICROBIAL THERAPY

Drug of Choice

Streptomycin

Streptomycin, at a dose of 7.5-10 mg/kg every 12 hours intramuscularly, is considered the drug of choice in adults (13, 18). Streptomycin, in a dose of 30-40 mg/kg/day divided into two daily doses intramuscularly, is considered the drug of choice in children. Following a clinical response in three to five days, the dose can be reduced in children to 10-15 mg/kg/day in two divided doses. Therapy is typically continued for seven to ten days, however, in mild-to-moderate cases of tularemia with 48-72 hours of afebrile course, five to seven days of therapy have been used successfully. A reference review identified 224 patients who received streptomycin as the primary therapeutic agent (8,14,21,22,27,31,41) (Table 3). Of these 224 patients, 217 were treated successfully, one became more ill, and six died. No instances of relapse were noted. Some patients received other antibiotics either before or concurrently with streptomycin, but in no case were these other agents considered effective against tularemia.

Evans et al., described one patient whose infection worsened despite treatment with streptomycin and one patient who died after experiencing a Jarisch-Herxheimer-like reaction to streptomycin (15). The latter reaction is attributed to excess antigen resulting from the drug’s "bactericidal efficiency" and leading to exacerbation of signs and symptoms. Continuation of therapy usually results in the patient’s recovery (12). No instances of this reaction to other drugs were documented.

Giddens et al., in 1957 reported the use of streptomycin in 141 cases of tularemia. Most patients received 1-3 grams of streptomycin or dihydrostreptomycin daily. The duration of fever was the best indicator of response; the patient’s temperature usually fell within three days, but duration ranged from one day to 40 days. The authors concluded that doses of streptomycin of > 2 grams in adults provided no additional benefit. In this series, five patients treated with streptomycin died (mortality, 3%), as did six patients treated with other antibiotics. Renal dysfunction was the most serious complication, occurring in six of these 11 patients. Typhoidal tularemia was the most frequent fatal form of infection. The authors reported a mortality of 33% among 169 patients treated before streptomycin became available (21).

Gentamicin

Gentamicin, at a dose of 1.7 mg/kg intramuscularly or intravenously every eight hours, is also effective (13). The published experience in adults is based on two reports of nine patients and an additional eight patients receiving effective treatment with gentamicin (13, 25,40). In the second report, fever was present in all patients treated with gentamicin and all eight became afebrile within 24-72 hours (40). Other symptoms, such as tender lymphadenitis and pharyngitis, also responded within 24-72 hours of starting gentamicin therapy in a recent pediatric study (11). With the recent advent of home intravenous therapy for hospitalized patients, intravenous gentamicin is an option. Recently, the use of once-daily gentamicin for other infections has been reported, but no data using once-daily gentamicin for tularemia currently exists. Virtually all strains of Francisella tularensis are susceptible to streptomycin and gentamicin. In successfully treated patients, temperature response usually occurs within two days, but skin lesions and lymph nodes may take one to two weeks to heal. When therapy is not initiated within several days to weeks of illness, the temperature response may be delayed. Relapses are very uncommon with streptomycin or gentamicin therapy (47). Relapses did not occur in any of the patients recently described with gentamicin therapy. Twenty-one articles described 36 patients who received gentamicin (1, 5, 6, 14,15, 16, 20, 23, 26, 25, 30, 36, 38,40, 44, 45, 46, 48, 49, 56, 58) (Table 3). Of these patients, 31 had their infections cured, 2 experienced a relapse, 2 became more ill, and 1 died. Of the 31 successfully treated patients, 13 received gentamicin only, 10 received gentamicin along with other antibiotics not effective against tularemia, 4 received gentamicin after the failure of therapy with a tetracyclineor chloramphenicol or a tetracycline, and 1 received gentamicin but also received tetracycline on discharge, despite the resolution of disease. Of the articles reviewed, that by Mason, Eigelsbach, Little and Bates in 1980 reported the largest-scale experience with gentamicin treatment - i.e., a study of 9 patients.

Gallivan et al., in 1980 reported a case of ulceroglandular tularemia that resulted in the death of a 65-year-old man. The patient presented with a five-day history of spiking fever, shaking chills, and a nonhealing ulcer on his left hand. After ten days of hospitalization, he reported abdominal pain and underwent exploratory laparotomy; he developed progressive bilateral pneumonitis postoperatively. Treatment with cephalothin and gentamicin was started 15 days after the onset of symptoms. Therapy with doxycycline and streptomycin was begun after documentation of the presence of antibody to Francisella tularensis. Pneumonitis worsened; disseminated intravascular coagulation and renal failure developed. The patient died 28 days into the course of the disease.

Evans et al., in 1985 described two patients, one of whom had chronic lymphocytic leukemia and was admitted with a rectal temperature of 105°F, diffuse pneumonia, and septic shock. Blood cultures were positive for Francisella tularensis and treatment with gentamicin was initiated. Because of a dramatic response, gentamicin therapy was stopped after six days, but relapse occurred 17 days later. The second patient had been gravely ill, with fever, confusion, pneumonia and hepatitis. This patient did not respond to four days of treatment with gentamicin and responded only slowly after the regimen was changed to streptomycin.

Lovell et al., in 1986 reported a case of glandular tularemia in a 13-month-old child; in this case the diagnosis and the initiation of appropriate therapy were delayed for 43 days. The patient responded to nine days of treatment with gentamicin and ampicillin. However, five days after discharge, he experienced a relapse, with tularemic meningitis. The infecting organism was not identified until the patient’s second admission, when CSF cultures yielded Francisella tularensis. The patient was successfully treated with a two-week course of chloramphenicol.

Roy et al., in 1989 reported on a 42-year-old man admitted to the hospital with a seven day history of fever, anorexia, malaise, nonproductive cough and diarrhea. The patient was treated with erythromycin and gentamicin for coverage of tularemic pneumonia and legionella infection. His respiratory status deteriorated, and the administration of gentamicin was discontinued after 24 hours. Therapy with rifampin was initiated for increased coverage of legionella pneumonia. Tularemia was later diagnosed on the basis of positive cultures, and the patient made slow but steady progress. He was discharged during a course of treatment with doxycycline.

Quinolones

Although no controlled studies show absolute efficacy of quinolone treatment of tularemia, there is continued evidence from Europe and Scandinavia thatciprofloxacin is a potentially valuable treatment of this disease. There are no controlled studies and little anecdotal evidence for the successful treatment of the serovar of tularemia found predominantly in the United States.

Three patients with pneumonic tularemia and one with ulceroglandular tularemia who have been successfully treated with ciprofloxacin (750 mg twice a day) (57). Neither the severity of illness nor the presence of underlying complications was discussed. All four patients responded to treatment within 48 hours and no relapses occurred with six months. A case of a veterinarian with ulceroglandular tularemia relapsed after treatment with doxycycline; ciprofloxacin was given for two weeks with a successful clinical response (52).

Johansson A and colleagues reported on 12 children with ulceroglandular tularemia who were successfully treated with ciprofloxacin (29a). In these children, median age of 4 years (range: 1-10 years), a 10- to 14-day course of oral ciprofloxacin, 15 to 20 mg/kg in two divided doses was prescribed. Seven of these cases were culture proven with antibiotic susceptibilities demonstrating an MIC of 0.03 mg/l for all isolates. Defervescence occurred within 4 days in all patients. Treatment was withdrawn after 3 and 7 days in two patients due to rash. All children recovered without complications.

More compelling is the report in 2002 by Perez-Castrillon and colleagues on a tularemia epidemic in Northwestern Spain ( 45a). 142 cases of tularemia were diagnosed with a treatment failure rate of 22.5%. The treatment of Francisella tularensis biovar palaearctica infections revealed success rates of: streptomycin (76.6%), ciprofloxacin (95.5%), doxycycline (57.1%), and azithromycin or ceftriaxone (50%). The types of tularemia in this epidemic included: ulceroglandular (61.3%), typhoidal (20.4%), glandular (9.2%), oculoglandular (4.2%), and pneumonic (3.5%). Finally, in a practice guideline on the management of patients exposed to biologic weapons published in 2002, ciprofloxacin was listed as an alternative therapy for adults exposed to suspected tularemia (63). Controlled trials and continued experience are necessary prior to listing quinolones in general and ciprofloxacin specifically as a treatment for tularemia especially in children and for treatment of the biovar predominant in the United States.

Tobramycin

Four articles described six cases of tularemia in which tobramycin was used (6, 30, 46, 60) (Table 3). Three patients recovered and two patients died; the outcome of the remaining case was not stated. All six patients were severely ill, with complications including sepsis, diabetes, rhabdomyolysis, and renal failure. The total duration of tobramycin therapy was not stated in four cases.

Kaiser et al., in 1985 described the death of a 63-year-old woman with a seven-day history of fever, chills, cough, malaise, myalgias, lethargy, and confusion. The patient had symptoms suggestive of typhoidal tularemia and developed renal failure secondary to rhabdomyolysis. She was initially treated with cefazolin and tobramycin and became afebrile within 24 hours. The therapeutic regimen was changed to chloramphenicol and cefotaxime because of the need for dialysis on day six. The patient subsequently developed disseminated intravascular coagulation and died.

Provenza et al., in 1986 described the death of a 75-year-old woman who was septic upon presentation to the hospital after several weeks of symptoms. The patient had renal insufficiency and hypertension. She was initially treated with vancomycin, tobramycin, and corticosteroids and died two days after admission.

Tetracycline

A total of 13 articles described 50 patients treated with tetracycline (7, 8, 15, 26, 33, 35, 38, 40, 45, 50, 54, 61, 62) (Table 3). Forty-four patients had their infections cured, while six patients had a relapse. Of the 44 successfully treated patients, 31 received tetracycline alone, three received tetracycline and gentamicin, and ten received tetracycline and other antibiotics not effective against tularemia. Of the six patients with relapses, two were treated with tetracycline and other antibiotics not effective against tularemia, three with tetracycline alone, and one with tetracycline and streptomycin.

Caruso et al., in 1983 reported on a 38-year-old woman who presented with a nine-day history of oropharyngeal tularemia, which was treated initially with ampicillin and then with erythromycin. Approximately 22 days after the onset of symptoms, therapy with tetracycline (250 mg orally every six hours) and streptomycin (500 mg intramuscularly every 12 hours) was initiated. The duration of therapy was not stated. This patient was readmitted two months later with enlarged cervical nodes and was treated with chloramphenicol and gentamicin. The wounds stopped draining after two weeks and healed after two months; cultures were negative. Adenitis with late suppuration of regional lymph nodes has been reported in successfully treated cases, although drainage of these nodes reveals necrotic tissue that is sterile (28).

Evans et al., in 1985 reported three relapses of infections treated with tetracycline and described two of these instances. One case involved a 13-year-old girl whose oropharyngeal tularemia was treated first with cefaclor and then with tetracycline. She continued to have low-grade fever and tender lymph nodes, and her regimen was changed to streptomycin. Her fever responded to this therapy, but her lymphadenopathy persisted. The other case involved a 72-year-old man with ulceroglandular tularemia who defervesced 24 hours after the start of tetracycline therapy. Administration of the drug was inadvertently discontinued, and fever returned. After tetracycline therapy was reinitiated, the patient defervesced and his pneumonia cleared. He later received a course of streptomycin, but further details were not given.

Penn and Kinassewitz in 1987 described two patients whose infections relapsed despite tetracycline therapy. Both patients received less than seven days of therapy and had underlying medical conditions (e.g., diabetes) that may have contributed to the relapse.

Alternative Therapy

Chloramphenicol

A total of seven articles reported on 43 patients who received chloramphenicol (5, 12, 15, 21, 23) (Table 3). Of these patients, 33 had their infections cured, one became more ill, and nine experienced a relapse. Of the 33 patients whose therapy was successful, 31 received chloramphenicol only and two received both chloramphenicol and gentamicin. The one patient whose condition worsened and the nine patients who had relapses received chloramphenicol only.

Dienst in 1963 reported cures of tularemia in 16 patients treated with chloramphenicol, although the condition of one patient later worsened and one patient’s infection relapsed. The latter patient responded to a continuation of chloramphenicol therapy. Evans et al., in 1985 described three patients whose infections relapsed after the discontinuation of treatment with chloramphenicol; these infections were cured by streptomycin therapy. Jacobs and Narain in 1983 described four children treated with chloramphenicol. One infection was cured, but three relapsed within 72 hours of the completion of a seven to ten-day course of therapy.

Parker et al., in 1950 described a 27-year-old man with pneumonic tularemia who was treated with chloramphenicol beginning on day six of disease. An initial oral dose of three grams was followed by doses of one gram every eight hours. The patient was afebrile and asymptomatic after 36 hours, and therapy was discontinued after five days. On the 17th day, a relapse resulted in the initiation of a second course of treatment with chloramphenicol (total, ten grams); the patient became asymptomatic after twelve hours. Two days after the discontinuation of this second course, recrudescence was again documented. A third course of chloramphenicol (18 grams over seven days) was curative. In another case, a 35-year-old patient with ulceroglandular tularemia presented with fever, chills, and headache. An initial dose of 3.5 grams of chloramphenicol was followed by doses of 0.5 grams every four hours for five days; the patient defervesced. Three days later, fever and symptoms returned. Therapy with chloramphenicol was reinstituted for four more days, and the patient’s condition improved.

Imipenem/Cilastatin; Meropenem; Carbapenems

Lee et al., in 1991 described a patient who had pneumonic tularemia with renal failure and chronic obstructive airway disease, as well as alcohol-related cardiomyopathy. Although seriously ill, the patient responded to therapy with i mipenem/cilastatin (500 mg intravenously every eight hours for 14 days). No relapse was evident at a one-year follow-up examination.

ENDPOINTS FOR MONITORING THERAPY

Late lymph node suppuration may occur in up to 40% of children regardless of the treatment received (29). These nodes have typically been found to contain sterile, necrotic lymph node tissue without evidence of active infection. If untreated, symptoms of tularemia usually last one to four weeks, but may continue for months. The mortality of severe, untreated infection, which includes all untreated tularemia pneumonia and typhoidal tularemia cases, can be as high as 30%. However, the overall mortality rate for untreated tularemia is less than eight percent. Mortality is less than one percent with appropriate treatment and is often associated with long delays in diagnosis and treatment. Following tularemia, there is usually life-long immunity (29).

VACCINES

No commercially available vaccines are currently licensed for use.

PREVENTION

Prevention of tularemia is based on avoidance of exposure to biting and blood-sucking insects (28). Vaccination of high-risk populations who primarily work with and are exposed to large quantities of cultured organisms can be effective. Avoidance of skinning wild animals, especially rabbits, and wearing gloves while handling animal carcasses will decrease the risk of transmission. Use of insect repellents, tick-attachment preparations, and prompt removal of ticks can be helpful. Prophylactic treatment of patients exposed to embedded tick bite exposures has not been proven to be effective in preventing tularemia. However, in patients known to be exposed to large quantities of organisms (laboratory exposure), and who are incubating Francisella tularensis, early treatment has been shown to prevent the development of significant clinical disease (51).

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Tables

Table 1: Antimicrobial Susceptibility of Francisella tularensis Isolates from Ticks.*

Drug	Result (mg/mL)*
Drug	MIC50	MIC50	MIC90
Cefotaxime	0.5	2	4
Moxalactam	£0.12	£0.12	0.25
Cefoperazone	8	16	>32
Ceftazidime	0.25	£0.5	£0.5
Ceftriaxone	0.5	2	8
Streptomycin	4	2	4
Gentamicin	1	1	2
Amikacin	2	1	2
Tobramycin	...	1	2
Netilmicin	...	1	2
Tetracycline	1	2	2
Doxycycline	2	...	...
Chloramphenicol	0.5	1	1
Rifampin	0.5	...	...
Erythromycin	2	1	2
Clindamycin	...	>2	>2
Rifampin	...	0.5	1
Vancomycin	...	>16	16

*Table modified and adapted from Baker, Hossis and Thornsberry in 1985 and Markowitz, Hynes, de la Cruz, Campos, Barbaree, Plikaytis, Mosier, Kaufmann, 1985.

Table 2: Antimicrobial Susceptibility of Francisella tularensis Isolates From Patients.+

Drug	Result (mg/mL)*
Drug	MIC	MBC
Erythromycin	0.5, 1	0.5, 1
Tetracycline	0.5, 0.5	0.5, 0.5
Chloramphenicol	1, 1	1, 1
Trimethoprim-sulfamethoxazole	6	6
Gentamicin	0.2, 1	0.2, 1
Clindamycin	8,8	8, 16

+ Adapted from Westerman and McDonald, 1983.

* The listing of two values indicates two isolates.

Table 3: Summary of the Results of Antimicrobial Treatment of Tularemia

Drug (Number of Articles Reviewed)	Total	Cure*	Relapse	Deterioration	Death	Not Stated
Streptomycin (8)	224	217 (97)	0	1	6	0
Gentamicin (21)	36	31 (86)	2	2	1	0
Chloramphenicol (7)	43	33 (77)	9	1	0	0
Tobramycin (4)	6	3 (50)	0	0	2	1
Tetracycline (13)	50	44 (88)	6	0	0	0
Ceftriaxone (1)	8	0 (...)	0	8	0	0
Imipenem/cilastatin (1)	1 (100)	0	0	0	0	0
Ciprofloxacin (2)	5	5 (100)	0	0	0	0
Norfloxacin (1)	1	1 (100)	0	0	0	0