History

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2. History Disease of the 20th century Only sporadic outbreaks, no epidemics First suspected case in humans in 1907 Isolated in ground squirrel in 1911 First documented human infection 1912 Edward Francis Isolated Bacterium tularense postulated rabbit as reservoir

3. Bioweapon Potential One of top 6 agents listed by CDC Weaponized in 1950s and 60s by U.S. Former Soviet Union weaponizing in 1990s Antibiotic and vaccine resistant strains developed Used on prisoners 1932-45 by Japan

4. Bioweapon Potential Estimated Effect 50kg F. tularensis over a city of 5 million 250,000 incapacitated 19,000 dead Incapacitation occurring within 1 to 2 days Incapacitation lasts for days �weeks Untreated disease is persistent and relapsing

5. Bioweapon Potential Delivery Mechanism Aerosol would be most likely mechanism Could be weaponized wet or dry Proven infectivity in humans via aerosol Pneumonic form would be most likely

6. Bioweapon Potential Delivery particle size Dictates severity and form of disease Form determined by location of deposition along respiratory and GI tracts Difference in severity due to tissue susceptibility

7. Bioweapon Potential Factors suggesting aerosol bioterrorism attack Large number, previously healthy, with sudden constitutional symptoms (fever, myalgias, flu-like) Many then develop cough and dyspnea At first difficult to differentiate from community acquired pneumonia, influenza Rapid worsening to critical illness in high percentage of patients

8. Bioweapon Potential Factors suggesting aerosol release Point or line source outbreak pattern Acute constitutional signs and symptoms Pharyngitis Bronchiolitis Pleuropneumonitis Hilar lymphadenitis

9. Epidemiology Epidemiology clues Risk of disease & severity dependent on exposure instead of underlying illness, age Epizootics, especially in nonendemic area Unlikely oropharyngeal from water supply as chlorine adequate to kill organism Urban epidemic suggests bioterrorism

10. Epidemiology Decline in U.S. 2291 cases reported in 1939 Less than 200/year in 1990s 1409 cases (20 deaths) 1985-1992

11. Epidemiology Primarily rural Endemic Every continental U.S. state Scandinavia, Russia, other parts of Europe Epidemics Vermont 1968 Spain 1997 � 140 confirmed cases Scandinavia less than 500 cases (waterborne) Sweden 1996-97 (farm work creating aerosols) Russia � 1000 cases

12. Epidemiology Untreated mortality 5-15% Type A strains 1-3% Type B strains 5% Ulceroglandular (UG) form 30-60% typhoidal/pneumonic >70% fatal cases have pulmonary involvement

13. Epidemiology Summer peak related to ticks 90% pediatric cases Winter peak related to trapping and hunting of rabbits

14. Epidemiology Risk Factors Handling infected animals Hunting, trapping, farming, butchering Ingestion of contaminated meat, water, soil Bitten by arthropods in endemic areas Microbiology laboratory workers

15. Microbiology Nomenclature Initially named Bacterium tularensis Later changed to Francisella tularensis In honor of Edward Francis

16. Microbiology Taxonomy Family - no human pathogens close relative Jellison Type A (Biovar tularensis) Predominant type in North America (90%) No cases reported in Eurasia but isolated in animals More severe disease LD50 in mice and hares = 1-9 organisms

17. Microbiology Primary sources (Type A) Lagamorphs cottontail and wild hare, not domestic rabbit Rodents muskrat, vole, beaver, squirrel Ticks feeding on above Biochemical tests Acidifies glycerol +citrulline ureidase activity

18. Microbiology Jellison Type B (Biovar palaearctica) Predominant type in Eurasia Less severe disease, more often asymptomatic Also common in U.S. 108 bacteria intraperitonealy in hares not lethal

19. Microbiology Primary sources (Jellison Type B) Aquatic rodents voles, muskrats, lemmings Contaminated water/soil from rodents Hares Mosquito bites Biochemical tests Does not acidify glycerol No citrulline ureidase activity

20. Microbiology No differences in in vitro susceptibility testing between Types A and B Type C (Biovar novicida) Other nonpathogenic types Biovar palaearactica mediasiatica in C. Asia Biovar palaearcticia japonica in Japan

21. Microbiology Staining Gram negative pleomorphic coccobacillus Faint staining Motility Non-motile Spore formation Non-sporulating

22. Microbiology Size Small, 0.2 ?m x 0.2-0.7 ?m Cell wall LPS Metabolism Aerobic Facultative intracellular (macrophages)

23. Microbiology Metabolism � Colony growth Slow May start to appear 24-48 hours under optimal conditions Usually slower Should hold cultures 10 days before calling negative Requires cysteine-enriched medium Grows very slowly if at all on standard media Cysteine heart blood agar Buffered charcoal-yeast agar Chocolate agar

24. Microbiology Colony morphology Small 3-5 mm on cysteine-enriched agar by 96 hours Opalescent, opague

25. Pathogenesis Environmental Survival Hardy (weeks to 3-4 months) in cold (even frozen) and moist conditions, weeks in water, carcasses/hides, soil, hay, frozen rabbit meat Killed by heat (55 C x 10 min) In aerosol, likely short lifespan (sun, drying, oxidation, open exposure to environment)

26. Pathogenesis Natural Life Cycles Tick-rabbit Ticks maintain infection in reservoirs of rabbits, voles Animal-animal Aquatic rodents infect each other and through environment (e.g. contaminated water) Humans Infected when they get in the way of natural cycles

27. Pathogenesis Forms of Disease Depends on route of infection, dose, strain, virulence Ulceroglandular (UG) 45-85% of all cases Glandular 5-25% of all cases Typhoidal 5-15% of all cases Usually but not always from inhalation Most common form for lab-related disease

28. Pathogenesis Forms of disease Oculoglandular 1-5% Oropharyngeal 1-7% of cases Pneumonic Most cases develop some pulmonary symptoms Need CXR findings (pleural or parenchymal) to diagnosis Some discrepancies because many studies do not consider this to be separate entity

29. Pathogenesis Pneumonic Primary Inhalational exposure Secondary Hematogenous spread generally coincident with UG 30% UG cases develop pneumonia 80% typhoidal cases develop pneumonia Unable to differentiate by pathologic findings

30. Pathogenesis Pneumonic Complications ARDS Respiratory failure Rhabdomyolysis Sepsis Death

31. Pathogenesis Routes of infection Infectious dose 10-50 organisms by inhalation/intradermal 108 organisms orally Skin inoculation Susceptible animals are hosts but not reservoirs as they die or recover without carrier state Handling diseased animal carcasses Mostly wild mammals, also birds, fish, amphibian, reptiles Occasionally domestic cats and dogs that have preyed on infected animals

32. Pathogenesis Routes of Infection Arthropod vector bites May be true reservoirs as well as vectors Causes 1/3 to � tularemia cases now Dog tick, wood tick Deer fly, horse fly Mosquito

33. Pathogenesis Routes of infection Inhalation of aerosols/dusts Most humans exposed to aerosol become infected, only 25-50% of those will get radiographic evidence of pulmonary involvement Handling contaminated hay Contaminated water sprays Dust from contaminated soil Handling or in vicinity of dead rabbits Route of most lab-associated infections

34. Pathogenesis Routes of infection Ingestion Inadequately cooked meat from infected animal Contaminated water and soil Inoculation into eye Usually contaminated fluids or hand

35. Pathogenesis Transmission No person to person documented cases Virulence factors Poorly understood LPS envelope

36. Pathogenesis Sequence of events Growth at inoculation site Lymphatic spread to regional nodes May disseminate hematogenously, especially untreated Reticuloendothelial organs (liver, spleen, nodes), lungs, kidneys, skin, meninges Bacteremia common early in course but not usually detected Intense violent tissue inflammatory reaction at sites of infection give way to typical suppurative necrosis

37. Pathogenesis Pathology Focal areas of necrosis, initially PMNs / macros then caseating granulomata like TB May be surrounded by fibroblasts Small firm reddish lesions look like miliary TB, especially in lung

38. Pathogenesis Pneumonic cases pathology Hemorrhagic airway inflammation early Early purulent bronchiolitis, atelectasis Pleuritis with adhesions, effusion common Hilar LAD common 50% have subcentimeter subpleural yellow nodules 30% bronchopneumonia 15% necrotizing lobar pneumonia with consolidation Late complication fibrosis Exudative glomerulitis also common

39. Pathogenesis Immunity Antibody appearance Begin to appear in approximately 1 week Usually not to diagnostic levels until 2 weeks Peak in 3-4 weeks Remains at high levels for 6 months Levels do not correspond with form or severity of disease

40. Pathogenesis Immunity Antibody disappearance Persisted 11 years at titre ? 80 in 6/6 subjects Agglutinin titres dropped from ? 160 to ? 40 in 51/53 cases infected 25 years previously Negative serology does not rule out past infection or lack of cell mediated immunity

41. Pathogenesis Immunity Cell mediated immunity most important Probably 2?/2 intracellular infection 44/52 cases who had tularemia 25 years prior showed substantial in vitro proliferation in response to challenge to F. tularensis membrane proteins Many of these also responded with IFN-gamma production DTH skin testing positive 40 years after infection Reinfection unlikely but possible, > 12 reported

42. Clinical Features Epidemiological features Animal (rabbit) tick exposure Hi-risk occupation or outdoor activity Symptoms Nonspecific Acute onset flu-like Low-back myalgias

43. Clinical Features Signs Skin ulcer Regional LAD Pulse/temperature dissociation Unresponsive to antibiotic therapy Test findings Slow growing small gram negative coccobacilli Pneumonia with pleural involvement & hilar LAD

44. Clinical Features For all 6 forms Very variable � asymptomatic to fulminant Incubation < 24 hours experimentally aerosol infected monkeys Typically 2-5 days Range 1-21 days, practical range 1-14 days, > 30 days in 2% in Japan Dependent on inoculation dose, type/virulence

45. Clinical Features For all 6 forms Usually sudden onset nonspecific constitutional, flu-like symptoms Fever � most common feature (74-91%), chills, profuse sweats May briefly subside without treatment transiently on 3-4th day Temperature may reach 104? F Lasts 2-3 weeks without antibiotics Malaise, fatigue Myalgias, especially low back Headache, sometimes severe

46. Clinical Features For all 6 forms If more chronic, untreated F/C, sweats, anorexia Weight loss if > 2-3 weeks before diagnosis Lymphadenopathy (except in typhoidal) Most common exam finding Up to 50% suppurate Sometimes hepatomegaly

47. Clinical Features For all 6 forms Pulmonary Cough 23-40%, usually non- or slightly productive Effusion 21-31% Chest pain Pharyngitis 15-40%, sore throat (resembles Strep, EBV) Temperature/pulse dissociation � up to 42% Can be asymptomatic, 20%, more likely with B type Symptoms usually progress if untreated

48. Clinical Features Ulceroglandular Most common form in U.S. Papule at inoculation site few days after onset Maculopapular, painful, inflamed Turns pustular, necrotic core, painful ulcer over a few days 0.5 cm diameter Punched out with raised edges Ulcer may have eschar (thing anthrax) Can persist months

49. Clinical Features Ulceroglandular Regional lymphadenopathy � proximal to inoculation Usually present but not necessary for diagnosis if ulcer present Appears about same time as lesion ulcerates May be single or multiple nodes May have overlying erythema Painful, swollen, may suppurate � even with antibiotics

50. Clinical Features Ulceroglandular Regional lymphadenopathy � proximal to inoculation Locations Hand lesions � axillary (65%) > epitrochlear (8%), most common or animal exposures Thumb � can go to supra/infraclavicular Leg lesions � femoral/inguinal nodes, most common for arthropod bites Slow resolution Even with treatment 2-3 months tenderness without treatment

53. Clinical Features Glandular Same as ulceroglandular but without ulcer More likely to follow bite rather than animal contact

54. Clinical Features Typhoidal Fever, weight loss, other constitutional signs and symptoms, prostration, delirium No ulcer, adenopathy, or other localizing signs Often with abdominal pain Most likely form to be severe Often DIC, ARDS, sepsis, multiorgan failure, rhabdo, shock Should not use this term if evidence of pleuropulmonary disease

55. Clinical Features Oculoglandular Conjunctivitis Unilateral, painful, purulent Ulcers +/- palpebral nodules with chemosis, vasculitis, periobital edema Ocular pain, excessive lacrimation, photophobia Local lymphadenopathy � preauicular, cervical Complications � rarely blindness

57. Clinical Features Pneumonic Secondary via hematogenous spread UG typhoidal Primary via inhalation Primary and secondary essentially same clinical features except primary may be more rapid progression

58. Clinical Features Pneumonic Usual routes of infection for primary Handling contaminated hay Lab exposures Handling animal carcasses Environmental aerosols Variable manifestations Mild URI to severe pneumonia Can be constitutional symptoms only, in this case would have been diagnosed as typhoidal, except for radiographic abnormalities

59. Clinical Features Pneumonic Most common symptoms Cough � usually nonproductive, sometimes purulent, sometimes hemoptysis Pleuritic CP Dyspnea Signs Sometimes (25%) mild or nonexistent lung exam abnormalities out of proportion to severity of illness

60. Clinical Features Pneumonic Radiographic Required for diagnosis of tularemic pneumonia Classic � patchy infiltrates (74%), often multiple, bilateral Earliest abnormality � peribronchial infiltrates 2? usually presents with bilateral lower lobe infiltrates Effusion common (60-80%), exudative, lymphocytic, sometimes empyema or bronchopleural fistula Hillar adenopathy Granulomata Abscess � infrequent Oval opacity, described in early literature, now rare

61. Clinical Features Complications ARDS (12%) Fibrosis Sepsis � in most severe cases Bacteremia noted more often in cases with severe disease and underlying comorbidities

62. Clinical Features Other Complications Meningitis � rare, only 13 described as of 1998 May result from UG, oropharyngeal, pneumonic Probably 2?/2 bacteremia, hematogenous spread as usually multiorgan involvement MS changes, delirium, meningismus Monocytic pleocytosis, high CSF protein, hypo Na Treatment � streptomycin best overal, chloramphenicol better across blood-brain barrier, gent + doxy reported effective

63. Clinical Features Other Complications Lymph node suppuration Up to 50% with LAD as late complication, despite abx Lung abscess � infrequent Rhabdomyolyis Infrequent Severely ill patients affected � in series died, 5/8 F. tularensis isolated in blood Muscle pain, tenderness, dark urine Renal failure, high serum CD and urine myoglogin In one case, confirmed direct muscle involvement Pericarditis � rare, serosal involvement

64. Clinical Features Laboratory Features Leukocytosis up to 22K Reversible hepatitis/mildly elevated LFTs (trans, Aphos, LDH) Infrequent rhabdo (elevated Cr, CK, MYO) Sterile pyuria � 32%

65. Clinical Features Pathologic Features Focal necrosis leading to granulomata in reticuloendothelial organs, lungs, kidneys Granulomata, initially PMNs, then caseating like TB

66. Clinical Features Generally not fatal (higher for typhoidal) Generally very incapacitating for 2-3 months without treatment, occasionally not back to normal after 1 year If recover, generally no long-term sequelae

67. Clinical Features Prognostic indicators Form of disease-typhoidal/pneumonic Type A or B Immune status, age Inoculation dose Time to presentation, diagnosis, antibiotics Treatment with drug other than aminoglycoside

68. Clinical Features Prognostic indicators Renal failure reported in > half Underlying illness � alcoholism, lung disease, DM Bacteremia Immunocompromised � � reported have been bacteremic with Type B Elevated CK with or without rhabdo Presence of fluctuant node may increase risk relapse

69. Diagnosis High index of suspicion vital Routine culture drawbacks Dangerous to techs Takes several days Low sensitivity No commercially available rapid diagnostic test Serology often available in labs, but does not detect acute infection

70. Diagnosis Notify Health Department Blood Obtain for send off to reference lab Aids in rapid and confirmatory diagnosis Cultures Susceptibility testing Serology � microagglutination +/- PCR, antigen detection � rapid Virulence testing and molecular genetics

71. Diagnosis Obtain culture If not prohibited by lab Always alert micro lab personnel possible case Cysteine-enriched medium Antimicrobial susceptibility if available Serology

72. Diagnosis Respiratory secretions ( if pulmonary symptoms) Obtain for reference lab � same as for blood Obtain culture � same as for blood Biopsy materials (if available), e.g. skin ulcers Obtain for reference lab Obtain for culture

73. Diagnosis Presumptive Diagnosis Typical presentation (signs/symptoms or exposure history) Sudden onset Febrile illness LAD Tick bite/wild animal exposure Endemic area or travel to one

74. Diagnosis Presumptive diagnosis Direct fluorescent antibody (DFA) Use for secretions, biopsies Rapid (hours after received) Not widely available Indirect FA Used as confirmatory test in one series Used on tissue samples

75. Diagnosis Presumptive diagnosis Immunohistochemical stains Use for secretions, biopsies Rapid Not widely available

76. Diagnosis PCR Rapid-several hours Very sensitive Problems with tissue samples Less risk to lab personnel (no exposure to cx�s) Not affected by prior antibiotics, detects DNA so viability not required Very small quantities needed � can detect 1 cfu/?l Can be used on non-clinical samples 100% specific in animal study Not widely available

77. Diagnosis RNA hybridization Rapid immunochromatographic Advantages � handheld, 15 minutes, can detect LPS antigen in wide range of samples (water & tissues) Disadvantages � less sensitive than PCR, not widely available Other antigen detection assays Urine antigen test

78. Diagnosis Skin test History Developed 1930s Not used in U.S. � initially lot of adverse reactions By 1960�s safer Injecting killed organisms intradermally DTH reaction Adverse reactions Only in positives � pruritis, 1/5 tenderness, rare fever

79. Diagnosis Skin test Positives Sensitivity 98.5% against agglutination gold standard Positives usually >6 mm, negative < 4 mm Good sensitivity 1 (29%) to 2 (95%) weeks after infection Specificity > 98% Also effective at determining vaccination status No correlation of induration with severity or Ab titres Doesn�t usually cause rise in Antibody titre Remains positive > 40 years

80. Diagnosis Skin test Advantages Turns positive faster than agglutination Stays positive longer Disadvantages Read after 48 hours Not easily available Can�t distinguish between vaccinated and disease

81. Diagnosis Serology Has been the gold standard, most cases in literature are confirmed by serology as culture too insensitive Generally only of epidemiological use, not acute infection unless diagnosis delayed Takes at least 2 weeks to reliably get positive titre (1:160)

82. Diagnosis Confirmatory Diagnosis Serology Serum agglutins (combined IgM and IgG) Tube agglutination � standard, more common Microagglutination � available in reference labs, more sensitive, can detect 10 days after illness onset Single ? 1:160 (tube) ? 1:128 (micro) in unvaccinated, presumptive of past or current infection 4-fold rise acute/convalescent Not affected by antibiotic treatment

83. Diagnosis Serology False negatives Takes 3 (29%) to 4 (84%) weeks to turn positive after vaccination

84. Diagnosis Serology False positives Cross reacts with Brucella and Proteus OX-19 and Yersinia Tularemia titre should be 2 fold higher than B. abortus titre for true positive tularemia Prior vaccination Usually convalescent titres are < 1280 May lose abnormality 28 months after vaccination

85. Diagnosis Serology ELISA IgM, IgG,or IgA levels detected Detects LPS Now more preferred Better sensitivity (95.7%) specificity (96%) Less cross-reaction with Brucella, Yersina Becomes positive a little earlier than agglutins

86. Diagnosis Microbiologic Growth from blood, sputum, wound, aspirate, pleural fluid, exudates On cysteine-enriched media In inoculated laboratory mice Controversial Hi-risk transmission to lab workers Must notify lab

87. Diagnosis Microbiologic Gram stain rarely helpful, usually negative Difficult to differentiate from other gram negatives by biotyping

88. Diagnosis Microbiologic Low sensitivity 47.8% positive blood cx in inoculated mouse studies 25% serologically confirmed human type B ulceroglandular cases had positive ulcer swabs Shell vial culture technique may improve sensitivity Same techniques used for rickettsiae and other intracellular organisms Sample homogenized Inoculated onto cell monolayer Positive result achieved earlier in course than serology Probably safer to lab personnel Further reduced sensitivity, but may still grow after starting antibiotics

89. Diagnosis Differential Diagnosis Ulceroglandular/glandular Bubonic plague, cutaneous anthrax, lymphocutaneous syndromes, cat scratch disease, rat-bite fever, lymphogranuloma venereum, strep lymphadenitis, toxo, chancroid, atypical myocobacteria Typhoidal Septicemic plague, typhoid fever, brucellosis, listeriosis, malaria, rickettsial diseases, any cause of sepsis

90. Diagnosis Differential Diagnosis Oropharyngeal Strep pharyngitis, EBV, other causes stomatitis and cervical adenitis, diphtheria Oculoglandular Lymphogranuloma verereum, adult inclusion conjunctivitis, zoster conjunctivitis, listeriosis

91. Diagnosis Differential Diagnosis Pneumonic Pneumonic plague, inhalational anthrax, Q fever, legionellosis, histo, TB, CAP, mycoplasma, influenza, malignancy, other zoonotic pneumonias

92. Treatment Start immediately upon suspicion of diagnosis Differentiate from PEP Who to treat � anyone in whom infection is known or suspected Those with typical symptoms and possible exposure OR positive tests

93. Treatment Contained casualties / natural disease Adults � 1st choices Streptomycin Dose 500-1000 mg IM q 12 hr Cure � 97% Up to 7% relapse Severe Jarisch-Herxheimer-like reaction reported MIC50 � 2-4 ?g/ml, MIC90 - 4 ?g/ml FDA approved

94. Treatment Contained casualties / natural disease Adults � 1st choices Gentamicin � acceptable alternative Dose 3-6 mg/kg/day divided q8hr, follow levels or 5 mg/kg iv/im qd Cure � 86% Has been successful after tetra/chlor failures Failure � 8% Some due to insufficient duration of therapy, severe illness and comorbidities

95. Treatment Contained casualties / natural disease Adults � 1st choices Gentamicin Probably equivalent, less experience May be 1st choice Availability Known streptomycin resistant strains produced Disadvantages Oto/renal toxicity No po equivalent Not FDA approved for tularemia

96. Treatment Contained casualties / natural disease Alternatives Doxycycline Dose 100 mg iv q 12 hr Higher risk relapse, may be only inhibitory at available MICs Can switch to po FDA approved

97. Treatment Contained casualties / natural disease Alternatives Tetracycline Doses equivalent to doxycycline Cure � 88% Relapse 12% Slower defervescence than aminoglycosides MIC50 � 0.2-0.5 ?g/ml Disadvantages Higher relapse Bacteriostatic, not cidal Longer course needed Levels significantly lower if taken with food

98. Treatment Contained casualties / natural disease Alternatives Chloramphenicol Dose � 15 mg/kg iv q 6 hr Higher risk relapse, may be only inhibitory at available MICs Cure � 77% Failure � 2% Relapse � 21% Slower defervescence than amioglycosides

99. Treatment Contained casualties / natural disease Alternatives Chloramphenicol May be best if meningitis; success for meningitis that occurred after gentamicin therapy Best agent for crossing blood brain barrier Normal meninges get 21-50% of serum levels Inflamed meninges get 45-89% MIC50 � 0.2-1 ?g/ml Disadvantages Highest relapse rates Longer course required Not FDA approved for tularemia

100. Treatment Contained casualties / natural disease Alternatives Ciprofloxacin Dose 400 mg iv q 12 hr Multiple anecdotal successes including outpatient pediatric type B bacteremic pneumonics treated with levofloxacin No reported failures One relapse after 7 days Has intracellular activity Achieves high serum levels

101. Treatment Contained casualties / natural disease Alternatives Ciprofloxacin Bactericidal Stable in acidic environment Excellent in vitro activity Can switch to po Norfloxacin may be equivalent Disadvantages Not a good pneumonia drug so would not use alone if pneumonia not certainly attributed to tularemia Not FDA approved

102. Treatment Contained casualties / natural disease Special populations Children � essentially same as adults Streptomycin 15 mg/kg IM q 12 hr (max 2 g/d) 1st choice Gentamicin 2.5 mg/dg IM/IV q 8 hr Alternatives Doxycycline 2.2 mg/kg IV q 12 hr if < 45 kg, o/w 100 mg iv q 12 hr Chloramphenicol 15 mg/kg iv q 6 hr Ciprofloxacin 15 mg/kg iv q 12 hr (max 1 g/day)

103. Treatment Contained casualties / natural disease Special populations Children No chloramphenicol for < 2 years of age Ciprofloxacin theoretical cartilage risk and not FDA approved for use in children, but benefit may outweigh theoretical risk Avoid tetracycline for children < 8 years of age Same duration as adults

104. Treatment Contained casualties / natural disease Special populations Pregnant women 1st choice, gentamicin, same adult dose Minimal fetal risk (renal toxicity) 2nd choice streptomycin, same adult dose Slightly higher fetal risk 3rd choice doxycycline or ciprofloxacin, same adult dose Same duration as adults

105. Treatment Contained casualties / natural disease Special populations Breastfeeding women Same recommendations as pregnant women Immunosuppressed Higher risk relapse Always use aminoglycoside if possible Consider longer duration

106. Treatment Contained casualties / natural disease Duration 10 days for aminoglycosides, ciprofloxacin 10-14 days 14-21 days for doxycycline/chloramphenicol to prevent relapse

107. Treatment Contained casualties / natural disease Switch to po When improved Able to tolerate po If oral equivalent available

108. Treatment Mass casualties � insufficient IV resources Adults Doxycycline 100 po bid Ciprofloxacin 500- 750 po bid � not FDA approved

109. Treatment Mass casualties � insufficient IV resources Special populations Children Doxycycline same po dose as iv above Ciprofloxacin same po dose as iv above Benefits of short courses of these probably outweigh small risks Pregnant women Ciprofloxacin 500 po bid Doxycycline 100 po bid Duration � 14 days for all groups

110. Treatment Anecdotally effective Imipenem/cilastin � 1 case Erythromycin � few cases, may need high dose, slowly resolved Rifampicin has good in vitro activity, may be useful 2nd agent for severe disease, no clinical data

111. Treatment Generally ineffective � Not Recommended Beta lactams Macrolides Usual response Most afebrile within 24-72 hours Pharyngitis, LAD improved in 24-72 hours

112. Treatment Resistance/susceptibility Testing done by reference lab No in vitro susceptibility testing differences between Types A and B except beta lactams E-tests correlated well with agar dilution

113. Treatment Resistance / susceptibility Questionable reliability of in vitro susceptible Ceftriaxone in vitro sensitive multiple times but clearly documented clinical failures E-test susceptibilities showed very poor results for all ?-lactams Advice against using an untested drug based on in vitro data alone

114. Treatment Resistance / susceptibility No known naturally-occurring resistance to aminoglycosides Engineered resistance to streptomycin, chloramphenicol, tetracycline have been produced Susceptibility testing should be done and treatment modified accordingly

115. Post-Exposure Prophylaxis Antibiotics Who to provide PEP Potentially exposed to same aerosol as cases Goal- treat during incubation period to prevent disease Recommended only if knowledge of credible threat before symptomatic cases identified or very early such that potentially exposed cases can be identified and treated very early in incubation period Lab personnel with high-risk exposure

116. Post-Exposure Prophylaxis Antibiotics Who not to provide PEP Contacts of index patient Potentially exposed, who are asymptomatic in covert release where cases identified later Fever watch Start full treatment if fever or flu-like illness within 14 days of probably exposure Potentially exposed to natural infection Lab personnel with low risk exposure

117. Post-Exposure Prophylaxis Antibiotics Same as for mass casualties Duration � 14 days all groups Vaccine � Not recommended Passive immunoprophylaxis, none available

118. Prevention Vaccination Types Killed, prior to 1959 Live attenuated History Developed in 1959 >5000 persons vaccinated to date Availability Was available as IND In jeopardy as re-reviewed by FDA Strain Live vaccine strain, type B

119. Prevention Vaccination Live attenuated Efficacy Protects vs. aerosol exposure SCHU S4 strain (Type A) Incomplete aerosol protection for volunteer human, fails at higher challenges doses 20+ fold better efficacy than Foshay for preventing typhoidal/pneumonic No change ulceroglandular incidence Milder symptoms/signs in ulceroglandular Disease requiring hospitalization nearly eliminated

120. Prevention Vaccination Live attenuated Adverse effects No significant reactions reported ever Proof of adequate response Local reaction 4 fold rise in serum agglutinin titres in 2+ weeks Indications Lab workers at risk of tularemia infection Not recommended for PEP because of short incubation time of disease and incomplete protection Series Given by scarification

121. Prevention Recommended at all times, especially after a bioterrorist release Avoid ticks in endemic areas Tuck in clothes Diethyltoluamide to skin Permethrin to clothing Frequent exams and prompt removal Avoid contact with sick/dead animals Wear gloves when handling carcasses

122. Infection Control Precautions � standard only, no person-person transmission documented Laboratory safety Must alert lab if suspect BSL-2 needed for routine procedures BSL-3 for higher risk (grinding, shaking, centrifuging, large volume cultures) and animal studies

123. Decontamination Environment Likely short half-life if aerosol dispersed Very unlikely secondary aerosolization Covert release likely not detected for several days Not recommended for large areas after release

124. Decontamination Environment Higher risk Smaller laboratory spills Known release with visible wet surface with suspected aerosol 2 step process Spray with 10% bleach hypochlorite 10 minutes later spray with 70% alcohol Lower risk Soap and water adequate

125. Decontamination Clothing exposed to known aerosol or powder Soap and water on body and clothing Corpses Standard precautions only Avoid aerosol-generating procedures at autopsy Patient rooms Clothing, linens disinfect via standard protocols

126. Tularemia Essential Pearls Acute onset flu-like illness Low-back myalgias Pulse/temperature dissociation Pneumonia clinically and on chest X-ray Doesn�t respond to typical antibiotics