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Tularemic Meningitis in the United States FREE

Diedre M. Hofinger, MD; Luzma Cardona, MD; Gregory J. Mertz, MD; Larry E. Davis, MD
[+] Author Affiliations

Author Affiliations: Medicine (Dr Hofinger) and Neurology (Drs Cardona and Davis) Services, New Mexico VA Health Care System, and Departments of Internal Medicine (Drs Hofinger and Mertz) and Neurology (Drs Cardona and Davis), University of New Mexico School of Medicine, Albuquerque.


Arch Neurol. 2009;66(4):523-527. doi:10.1001/archneurol.2009.14.
Text Size: A A A
Published online

Background  Tularemia is a zoonotic disease caused by Francisella tularensis. Tularemia presents with various clinical illnesses, but meningitis is rare.

Objectives  To describe a patient who developed typhoidal tularemia with atypical acute meningitis and to review the pathogenesis, clinical and laboratory features, and antibiotic drug treatment of reported cases of tularemic meningitis.

Design  Case study and literature review.

Setting  University hospital, tertiary care center.

Patient  A 21-year-old healthy man who had recently worked as a professional landscaper in the Albuquerque, New Mexico, metropolitan area developed fever, malaise, headache, and a stiff neck.

Main Outcome Measures  Francisella tularensis cerebrospinal fluid culture, antibiotic sensitivity, transmission source, and outcome.

Results  The cerebrospinal fluid contained a lymphocytic pleocytosis, negative Gram stain, and F tularensis isolation with chloramphenicol and streptomycin antibiotic sensitivities.

Conclusions  Although tularemia is uncommon and tularemic meningitis is rare in the United States, attention is drawn to the increasing number of cases in professional landscapers, the atypical cerebrospinal fluid picture, and unusual antibiotic sensitivities.

Tularemia is a zoonotic disease caused by an intracellular, gram-negative coccobacillus, Francisella tularensis, that occasionally causes meningitis.1 There are 4 subspecies of F tularensis, 3 of which are found in North America: holarctica, tularensis, and novicida.2Francisella tularensis is transmitted to humans through several routes: by direct contact with infected animals (particularly rabbits and other rodents), by vectors (biting flies and ticks), by ingestion (contaminated water, raw milk, and undercooked meat), and by inhalation (aerosolized organisms from cutting grass or handling hay).3,4 There have been no reported cases of human-to-human transmission.

Tularemia presents with various clinical illnesses commonly classified as ulceroglandular or glandular, oropharyngeal, oculoglandular, typhoidal, and pneumonic. We describe an unusual case of typhoidal tularemia with meningitis and review the reported cases of tularemic meningitis.

A 21-year-old previously healthy man presented to the emergency department in October 2006 with 7 days of a cough productive of black and yellow sputum, subjective fevers, chills, myalgias, and chest tightness with pleuritic chest pain. For 3 days before admission, he had a progressively worsening headache with neck stiffness and 1 day of 8 episodes of watery diarrhea. The patient reported that he had taken amoxicillin orally for 1 day. He had recently changed jobs and did not initially report that he had worked as a professional landscaper until 7 days before the onset of symptoms. He had performed lawn mowing and leaf blowing services and noted that he had seen dead rabbits in the areas in which he worked.

His temperature was 39.6°C. He was alert and oriented to time, place, and person. He had a stiff neck, without weakness or sensory loss. Bibasilar crackles with expiratory wheezing were noted. There was no lymphadenopathy, skin lesions, or ulcerations. Cranial computed tomography findings were normal. Abnormal laboratory test results included a white blood cell count of 10 400×106/μL (to convert to ×109 per liter, multiply by 0.001) (78% neutrophils) and an erythrocyte sedimentation rate of 40 mm/h. The cerebrospinal fluid (CSF) had a total nucleated cell count of 1416/mm3, with 19% neutrophils and 73% lymphocytes, and a red blood cell count of 23×106/μL (these conversions are for blood; don’t apply to CSF). The CSF glucose concentration was 41 mg/dL, and the total protein level was 2660 g/dL. The concurrent serum glucose level was 123 mg/dL. Gram staining of CSF sediment was negative. Findings from chest radiography were normal. Magnetic resonance imaging showed cerebellar tonsillar herniation consistent with Chiari type 1 malformation without evidence of brainstem syrinx.

The patient was initially treated with intravenous ceftriaxone sodium and vancomycin hydrochloride. On hospital day 4, the patient's headache became worse, and he reported diplopia and nausea. A repeated lumbar puncture demonstrated an opening pressure of 490 mm of CSF and a total nucleated cell count of 2590/mm3, with 32% neutrophils, 43% lymphocytes, and 25% monocytes. The glucose level was 28 mg/dL, the total protein level was 2950 g/dL, and the Gram stain was negative. The concurrent serum glucose level was 128 mg/dL (to convert to millimoles per liter, multiply by 0.0555.

On hospital day 4, the initial CSF culture grew a gram-negative coccobacillus that was confirmed to be F tularensis by the New Mexico State health laboratory the following day, and subtype analysis was not performed. Use of the other antibiotic agents was stopped, and the patient was treated with intravenous chloramphenicol sodium succinate, 1 g every 12 hours, and intravenous streptomycin sulfate, 1 g every 12 hours, for 14 days, followed by 14 days of oral ciprofloxacin hydrochloride, 750 mg twice daily. The patient showed clinical improvement within 48 hours, and he eventually had complete resolution of symptoms. On 8-month follow-up, the patient's only complaint was fatigue, his physical examination findings were normal, and his F tularensis serum antibody titer was 1:1024 by means of microagglutination testing.

Tularemic meningitis is rare; only 16 cases have been reported (Table). The worldwide incidence of tularemia is unknown and likely underrecognized. Tularemia not infrequently occurs in the United States and other developed countries in the northern hemisphere. Between 1990 and 2005, 2000 human cases from 44 states were reported to the Centers for Disease Control and Prevention.21,22

Table Graphic Jump LocationTable. Case Histories of Tularemia Meningitis

The early clinical picture of tularemic meningitis may be relatively nonspecific. Most cases occur in late spring and summer,21 when individuals are exposed to infected arthropods (ticks and biting flies) or to aerosolized bacteria from handling hay, cutting brush, or mowing over dead infected animals.23,24 Occupational exposure has been reported in landscapers in Martha's Vineyard in Massachusetts, with an outbreak of 59 cases of mostly pulmonic tularemia beginning in 2000 and continuing through 2006.25 A serosurvey of landscapers in Martha's Vineyard reported F tularensis antibody titers in up to 15% of workers, and the highest titers were in those who mowed grass, cut brush, and used a power blower.24 Winter outbreaks also occur, although more rarely, and are usually related to hunters coming in contact with infected animal carcasses.21 Cases of tularemia have been reported from 44 states, but 56% of all cases are reported from Arkansas, Missouri, South Dakota, and Oklahoma.21

Francisella tularensis is highly infectious, requiring as few as 10 inhaled bacteria to cause disease, making aerosolization an environmental risk and a potential mode of transmission as a bioterrorist agent.26Francisella tularenesis was studied in several countries as a potential bioterrorist agent and was weaponized by the US military in the 1950s to 1960s as part of an offensive biowarfare program.27 The US military terminated its biological weapons development in 1970, and all stockpiles were destroyed by 1973.27Francisella tularensis is classified as a class A bioterrorist agent due to its potential ease of dissemination and high morbidity and mortality. All human cases of tularemia must be reported to the Centers for Disease Control and Prevention.28 Postexposure prophylaxis with ciprofloxacin, 500 mg orally twice daily, or doxycycline hyclate, 100 mg orally twice daily, for 14 days is thought to be protective against symptomatic infection.27

The incubation period of tularemia is usually 3 to 6 days, but it may range from 1 to 14 days after inoculation.27 In patients with tularemic meningitis, signs and symptoms of meningitis typically developed 5 days after the onset of initial illness but ranged from 3 to 30 days. Seven patients with meningitis presented with ulceroglandular disease, defined as ulcerations on the skin with regional lymph node enlargement. Five patients had the typhoidal form, characterized by an influenzalike syndrome with chills, fever, headache, and generalized aches without lymphadenopathy, skin ulcers, or pneumonia. Four patients had pharyngeal disease (painful sore throat with enlarged tonsils and formation of a yellow-white pseudomembrane). In this series with often incomplete histories and examinations, most patients had confusion, headaches, meningismus, and fevers. Seizures were reported in only 1 patient. Our patient had some symptoms consistent with typhoidal tularemia, but he also had symptoms consistent with possible pneumonia, with crackles and wheezing on physical examination but negative findings on chest radiography. The patient most likely acquired his infection through inhalation as a landscaper.

In tularemic meningitis, patients usually had marked CSF pleocytosis, with a mean white blood cell count of 1788×106/μL (range, 2-13 200×106/μL). In contrast to most other causes of acute bacterial meningitis, in tularemic meningitis, there was usually a mononuclear predominance ranging from 70% to 100%. Levels of CSF glucose were depressed, with a mean of 32 mg/dL (range, 9 -59 mg/dL). The mean CSF protein level was 3600 g/dL (range, 230-18 900 g/dL). In addition, as was found in our patient, the Gram stain of CSF sediment was negative in 90%. Although the reason for the low sensitivity of Gram staining is unclear, it may reflect that an F tularensis Gram stain is weak, is intracellular, or is in low numbers in the CSF (≤103 colony-forming units/mL).2931 Patients with tularemic meningitis had similar blood changes as patients with tularemia without meningitis. Some peripheral white blood cell counts were normal, but most were elevated (range, 3000-49 000×106/μL), with a mononuclear predominance.

The differential diagnosis of mononuclear pleocytosis is broad. Viral infections, including herpes simplex virus, may cause a mononuclear predominance; however, it would be expected that the CSF would have an elevated glucose level. Other etiologies include Mycobacterium and Cryptococcus; however, these infections would be expected in immunocompromised hosts. Spirochete infections with Treponema pallidum or Borrelia burgdorferi may also cause mononuclear pleocytosis along with other infections, including Brucella, Bartonella henselae, and Leptospira. Our patient did not have risk factors for these diseases.

Isolation of F tularensis is difficult and slow because F tularensis is fastidious. Most isolates appear in 2 to 4 days, but it may take as long as 14 days to grow in culture.29,32 In our patient, CSF isolation required 4 days, and the blood specimen did not grow the organism. It is important to notify the microbiology laboratory of suspected tularemia so that they will take appropriate safety precautions and hold the cultures longer. Routine clinical specimens require a biosafety level 2 laboratory, but further processing of initial isolates suspected of being F tularensis usually requires a biosafety level 3 laboratory to protect laboratory personnel.29 Diagnosis of F tularensis DNA by means of polymerase chain reaction assay is also available for the diagnosis of tularemia; however, blood may contain compounds capable of inhibiting the assay.33

Because of the difficulties in culturing or directly detecting the bacteria, most cases of tularemia are diagnosed by demonstrating a diagnostic rise in serum antibodies to F tularensis. Antibodies to F tularensis can be detected approximately 2 weeks after the onset of symptoms.34 Latex agglutination, microagglutination, hemagglutination, and enzyme-linked immunosorbent assay tests are commercially available. A polymerase chain reaction on tissue specimens has been developed but is not widely available. Real-time polymerase chain reactions on samples other than tissue are currently under investigation.35 Due to the time delays in establishing a firm diagnosis, the decision to treat in many patients has to be made on clinical suspicion. In our patient, no acute serologic testing was performed because the patient's CSF culture was positive for F tularensis, but the convalescent antibody titer at 8 months was 1:1024 by means of microagglutination testing.

Treatment for tularemic meningitis differs from the usual antibiotics given for bacterial meningitis. Ceftriaxone and other β-lactam antibiotics commonly used for empirical treatment of meningitis may be ineffective,36 as was the case in our patient. For tularemic meningitis, chloramphenicol with streptomycin is the regimen of choice.37,38 Gentamicin sulfate is an alternative if streptomycin is not available,39 but some studies suggest higher relapse rates for patients with tularemia who are treated with gentamicin vs streptomycin.37 Gentamicin was used in 2 of 17 patients with tularemic meningitis with successful treatment. Chloramphenicol was used in 7 of the 17 patients who were treated successfully; however, it should be used in conjunction with an aminoglycoside. Chloramphenicol is bacteriostatic and aminoglycosides are bactericidal, and the use of streptomycin, in particular, has been associated with lower relapse rates.37 Doxycycline has successfully cured tularemic meningitis in combination with an aminoglycoside and is effective in the treatment of tularemia in animal models.18,20,40 Ciprofloxacin has also been shown to treat tularemia in animal models40 and has successfully treated 2 cases of human tularemia without meningitis.41 In the cases summarized in the Table, tularemic meningitis was most often successfully treated with streptomycin and chloramphenicol for 7 to 21 days.

In conclusion, our patient is typical in that he had recently worked as a professional landscaper performing high-risk activities that included mowing, brush cutting, and using a blower. He is also typical in that his diagnosis was delayed and he had poor response to empiric meningitis treatment with intravenous ceftriaxone. It is unknown whether the asymptomatic Chiari type 1 malformation noted on magnetic resonance imaging in our patient had any role in allowing F tularensis to enter the meninges from the bloodstream.

The outcome of tularemic meningitis is good if the diagnosis is made early, the correct antibiotics are given, and the patient does not have overwhelming bacterial sepsis or organ failure. Deaths have occurred in the patient series from misdiagnosis, use of inappropriate antibiotics, and occurrence during the era before antibiotics.

Correspondence: Diedre M. Hofinger, MD, Department of Internal Medicine, New Mexico VA Health Care System, 1501 San Pedro Dr SE, Albuquerque, NM 87108 (dhofinger@salud.unm.edu).

Accepted for Publication: November 12, 2008.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hofinger, Cardona, Mertz, and Davis. Acquisition of data: Hofinger, Cardona, Mertz, and Davis. Analysis and interpretation of data: Hofinger, Mertz, and Davis. Drafting of the manuscript: Hofinger, Cardona, and Davis. Critical revision of the manuscript for important intellectual content: Hofinger, Mertz, and Davis. Administrative, technical, and material support: Hofinger. Study supervision: Mertz and Davis.

Financial Disclosure: None reported.

Francis  E A summary of present knowledge of tularaemia. Medicine 1928;7411- 432
Staples  JEKubota  KAChalcraft  LGMead  PSPetersen  JM Epidemiology and molecular analysis of human tularemia, United States, 1964-2004. Emerg Infect Dis 2006;12 (7) 1113- 1118
PubMed
Farlow  JWagner  DMDukerich  M  et al.  Francisella tularensis in the United States. Emerg Infect Dis 2005;11 (12) 1835- 1841
PubMed
Eliasson  HBroman  TForsman  MBack  E Tularemia: current epidemiology and disease management. Infect Dis Clin North Am 2006;20 (2) 289- 311
PubMed
Haizlip  JOO’Neil  AE A case of meningitis due to Bacterium tularenseJAMA 1931;97704- 705
Bryant  ARHirsch  EF Tularemic leptomeningitis: report of a case. Arch Pathol 1931;12917- 923
Hartman  FW Tularemic encephalitis: pathology of acute tularemia with brain involvement and coexisting tuberculosis. Am J Pathol 1932;857- 61
Pund  ERHatcher  MB Tularemic meningitis: report of case with post-mortem observation. Ann Intern Med 1937;101390- 1398
David  JKOwens  JN Tularemic meningitis: report of a case and summary of previously reported cases. AJDC 1944;6744- 51
Stuart  BMPullen  RL Tularemic meningitis: review of the literature and report of a case with postmortem observations. Arch Intern Med 1945;76163- 166
Fields  WS Tularemic meningitis: report of a case. Arch Neurol Psychiatry 1949;61 (4) 422- 429
PubMed
Hutton  JPEverett  ED Response of tularemic meningitis to antimicrobial therapy. South Med J 1985;78 (2) 189- 190
PubMed
Lovell  VMCho  CTLindsey  NJNelson  PL Francisella tularensis meningitis: a rare clinical entity. J Infect Dis 1986;154 (5) 916- 918
PubMed
Harper  JLFlorman  ALTso  W Tularemic meningitis in a child with mononuclear pleocytosis. Pediatr Infect Dis 1986;5 (5) 595- 597
PubMed
Hill  BSandstrom  GSchroder  SFranzen  CTarnvik  A A case of tularemic meningitis in Sweden. Scand J Infect Dis 1990;22 (1) 95- 99
PubMed
Alfes  JCAyers  LW Acute bacterial meningitis caused by Francisella tularensis. Pediatr Infect Dis J 1990;9 (4) 300- 301
PubMed
Pittman  TWilliams  DFriedman  AD A shunt infection caused by Francisella tularenisis. Pediatr Neurosurg 1996;24 (1) 50- 51
PubMed
Rodgers  BLDuffield  RPTaylor  TJacobs  RFSchutze  GE Tularemic meningitis. Pediatr Infect Dis J 1998;17 (5) 439- 441
PubMed
Weiner  EStryjewski  GEppes  S Variable presentation of the cause of lymphadenopathy in two children. Pediatr Infect Dis J 2004;23 (10) 972- 973
PubMed
Gangat  N Cerebral abscesses complicating tularemia meningitis. Scand J Infect Dis 2007;39 (3) 258- 261
PubMed
Centers for Disease Control and Prevention, Tularemia: United States, 1990-2000. MMWR Morb Mortal Wkly Rep 2002;51 (9) 181- 184
PubMed
McNabb  SJJajosky  RAHall-Baker  PA  et al. Centers for Disease Control and Prevention, Summary of notifiable diseases: United States, 2005. MMWR Morb Mortal Wkly Rep 2007;54 (53) 1- 92
PubMed
Feldman  KAEnscore  RELathrop  SL  et al.  An outbreak of primary pneumonic tularemia on Martha's Vineyard. N Engl J Med 2001;345 (22) 1601- 1606
PubMed
Feldman  KAStiles-Enos  DJulian  K  et al.  Tularemia on Martha's Vineyard: seroprevalence and occupational risk. Emerg Infect Dis 2003;9 (3) 350- 354
PubMed
Matyas  BTNieder  HTelford  S  III Pneumonic tularemia on Martha's Vineyard: clinical, epidemiologic, and ecological characteristics. Ann N Y Acad Sci 2007;1105351- 377
PubMed
Oyston  PCFSjostedt  ATitball  R Tularaemia: bioterrorism defense renews interest in Francisella tularensis. Nat Rev Microbiol 2004;2 (12) 967- 978
PubMed
Dennis  DTInglesby  TVHenderson  DA  et al. Working Group on Civilian Biodefense, Tularemia as a biological weapon: medical and public health management. JAMA 2001;285 (21) 2763- 2773
PubMed
Moran  GJTalan  DAbrahamian  F Biological terrorism. Infect Dis Clin North Am 2008;22 (1) 145- 187
PubMed
Chu  MCWeyant  RS Manual of Clinical Microbiology. Vol 1.8th ed. Washington, DC ASM Press2003;789- 808
Ellis  JOyston  PCFGreen  MTitball  RW Tularemia. Clin Microbiol Rev 2002;15 (4) 631- 646
PubMed
La Scolea  LJ  JrDryja  D Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. J Clin Microbiol 1984;19 (2) 187- 190
PubMed
Doern  GV Detection of selected fastidious bacteria. Clin Infect Dis 2000;30 (1) 166- 173
PubMed
Fulop  MLeslie  DTitball  R A rapid, highly sensitive method for the detection of Francisella tularensis in clinical samples using the polymerase chain reaction. Am J Trop Med Hyg 1996;54 (4) 364- 366
PubMed
Syrjälä  HKoskela  PRipatti  TSalminen  AHerva  E Agglutination and ELISA methods in the diagnosis of tularemia in different clinical forms and severities of the disease. J Infect Dis 1986;153 (1) 142- 145
PubMed
Tärnvik  AChu  M New approaches to diagnosis and therapy of tularemia. Ann N Y Acad Sci 2007;1105378- 404
PubMed
Cross  JTJacobs  RF Tularemia: treatment failures with outpatient use of ceftriaxone. Clin Infect Dis 1993;17 (6) 976- 980
PubMed
Enderlin  GMorales  LJacobs  RFCross  JT Streptomycin and alternative agents for the treatment of tularemia: review of the literature. Clin Infect Dis 1994;19 (1) 42- 47
PubMed
Amsden  JRWarmack  SGubbins  P Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the United States: a comprehensive review. Pharmacotherapy 2005;25 (2) 191- 210
PubMed
Mason  WLEigelsbach  HLittle  SBates  J Treatment of tularemia, including pulmonary tularemia, with gentamicin. Am Rev Respir Dis 1980;121 (1) 39- 45
PubMed
Russell  PEley  SMFulop  MJBell  DLTitball  RW The efficacy of ciprofloxacin and doxycycline against experimental tularemia. J Antimicrob Chemother 1998;41 (4) 461- 465
PubMed
Limaye  APHooper  CJ Treatment of tularemia with fluoroquinolones: two cases and review. Clin Infect Dis 1999;29 (4) 922- 924
PubMed

Figures

Tables

Table Graphic Jump LocationTable. Case Histories of Tularemia Meningitis

References

Francis  E A summary of present knowledge of tularaemia. Medicine 1928;7411- 432
Staples  JEKubota  KAChalcraft  LGMead  PSPetersen  JM Epidemiology and molecular analysis of human tularemia, United States, 1964-2004. Emerg Infect Dis 2006;12 (7) 1113- 1118
PubMed
Farlow  JWagner  DMDukerich  M  et al.  Francisella tularensis in the United States. Emerg Infect Dis 2005;11 (12) 1835- 1841
PubMed
Eliasson  HBroman  TForsman  MBack  E Tularemia: current epidemiology and disease management. Infect Dis Clin North Am 2006;20 (2) 289- 311
PubMed
Haizlip  JOO’Neil  AE A case of meningitis due to Bacterium tularenseJAMA 1931;97704- 705
Bryant  ARHirsch  EF Tularemic leptomeningitis: report of a case. Arch Pathol 1931;12917- 923
Hartman  FW Tularemic encephalitis: pathology of acute tularemia with brain involvement and coexisting tuberculosis. Am J Pathol 1932;857- 61
Pund  ERHatcher  MB Tularemic meningitis: report of case with post-mortem observation. Ann Intern Med 1937;101390- 1398
David  JKOwens  JN Tularemic meningitis: report of a case and summary of previously reported cases. AJDC 1944;6744- 51
Stuart  BMPullen  RL Tularemic meningitis: review of the literature and report of a case with postmortem observations. Arch Intern Med 1945;76163- 166
Fields  WS Tularemic meningitis: report of a case. Arch Neurol Psychiatry 1949;61 (4) 422- 429
PubMed
Hutton  JPEverett  ED Response of tularemic meningitis to antimicrobial therapy. South Med J 1985;78 (2) 189- 190
PubMed
Lovell  VMCho  CTLindsey  NJNelson  PL Francisella tularensis meningitis: a rare clinical entity. J Infect Dis 1986;154 (5) 916- 918
PubMed
Harper  JLFlorman  ALTso  W Tularemic meningitis in a child with mononuclear pleocytosis. Pediatr Infect Dis 1986;5 (5) 595- 597
PubMed
Hill  BSandstrom  GSchroder  SFranzen  CTarnvik  A A case of tularemic meningitis in Sweden. Scand J Infect Dis 1990;22 (1) 95- 99
PubMed
Alfes  JCAyers  LW Acute bacterial meningitis caused by Francisella tularensis. Pediatr Infect Dis J 1990;9 (4) 300- 301
PubMed
Pittman  TWilliams  DFriedman  AD A shunt infection caused by Francisella tularenisis. Pediatr Neurosurg 1996;24 (1) 50- 51
PubMed
Rodgers  BLDuffield  RPTaylor  TJacobs  RFSchutze  GE Tularemic meningitis. Pediatr Infect Dis J 1998;17 (5) 439- 441
PubMed
Weiner  EStryjewski  GEppes  S Variable presentation of the cause of lymphadenopathy in two children. Pediatr Infect Dis J 2004;23 (10) 972- 973
PubMed
Gangat  N Cerebral abscesses complicating tularemia meningitis. Scand J Infect Dis 2007;39 (3) 258- 261
PubMed
Centers for Disease Control and Prevention, Tularemia: United States, 1990-2000. MMWR Morb Mortal Wkly Rep 2002;51 (9) 181- 184
PubMed
McNabb  SJJajosky  RAHall-Baker  PA  et al. Centers for Disease Control and Prevention, Summary of notifiable diseases: United States, 2005. MMWR Morb Mortal Wkly Rep 2007;54 (53) 1- 92
PubMed
Feldman  KAEnscore  RELathrop  SL  et al.  An outbreak of primary pneumonic tularemia on Martha's Vineyard. N Engl J Med 2001;345 (22) 1601- 1606
PubMed
Feldman  KAStiles-Enos  DJulian  K  et al.  Tularemia on Martha's Vineyard: seroprevalence and occupational risk. Emerg Infect Dis 2003;9 (3) 350- 354
PubMed
Matyas  BTNieder  HTelford  S  III Pneumonic tularemia on Martha's Vineyard: clinical, epidemiologic, and ecological characteristics. Ann N Y Acad Sci 2007;1105351- 377
PubMed
Oyston  PCFSjostedt  ATitball  R Tularaemia: bioterrorism defense renews interest in Francisella tularensis. Nat Rev Microbiol 2004;2 (12) 967- 978
PubMed
Dennis  DTInglesby  TVHenderson  DA  et al. Working Group on Civilian Biodefense, Tularemia as a biological weapon: medical and public health management. JAMA 2001;285 (21) 2763- 2773
PubMed
Moran  GJTalan  DAbrahamian  F Biological terrorism. Infect Dis Clin North Am 2008;22 (1) 145- 187
PubMed
Chu  MCWeyant  RS Manual of Clinical Microbiology. Vol 1.8th ed. Washington, DC ASM Press2003;789- 808
Ellis  JOyston  PCFGreen  MTitball  RW Tularemia. Clin Microbiol Rev 2002;15 (4) 631- 646
PubMed
La Scolea  LJ  JrDryja  D Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. J Clin Microbiol 1984;19 (2) 187- 190
PubMed
Doern  GV Detection of selected fastidious bacteria. Clin Infect Dis 2000;30 (1) 166- 173
PubMed
Fulop  MLeslie  DTitball  R A rapid, highly sensitive method for the detection of Francisella tularensis in clinical samples using the polymerase chain reaction. Am J Trop Med Hyg 1996;54 (4) 364- 366
PubMed
Syrjälä  HKoskela  PRipatti  TSalminen  AHerva  E Agglutination and ELISA methods in the diagnosis of tularemia in different clinical forms and severities of the disease. J Infect Dis 1986;153 (1) 142- 145
PubMed
Tärnvik  AChu  M New approaches to diagnosis and therapy of tularemia. Ann N Y Acad Sci 2007;1105378- 404
PubMed
Cross  JTJacobs  RF Tularemia: treatment failures with outpatient use of ceftriaxone. Clin Infect Dis 1993;17 (6) 976- 980
PubMed
Enderlin  GMorales  LJacobs  RFCross  JT Streptomycin and alternative agents for the treatment of tularemia: review of the literature. Clin Infect Dis 1994;19 (1) 42- 47
PubMed
Amsden  JRWarmack  SGubbins  P Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the United States: a comprehensive review. Pharmacotherapy 2005;25 (2) 191- 210
PubMed
Mason  WLEigelsbach  HLittle  SBates  J Treatment of tularemia, including pulmonary tularemia, with gentamicin. Am Rev Respir Dis 1980;121 (1) 39- 45
PubMed
Russell  PEley  SMFulop  MJBell  DLTitball  RW The efficacy of ciprofloxacin and doxycycline against experimental tularemia. J Antimicrob Chemother 1998;41 (4) 461- 465
PubMed
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PubMed

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