1. Bioterrorism Agents: Anthrax, Plague, and Brucellosis Jeff Kuper, Pharm.D., BCPS Clinical Associate Professor Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey

2. Potential Agents of Biowarfare CDC Category A Easily disseminated or transmitted person-to-person Easily disseminated or transmitted person-to-person High mortality High mortality Might cause public panic, social disruption Might cause public panic, social disruption Need special public health preparedness Need special public health preparedness Bacillus anthracis (anthrax) Bacillus anthracis (anthrax) Variola major (smallpox) Variola major (smallpox) Yersinia pestis (plague) Yersinia pestis (plague) Clostridium botulinum toxin (botulism) Clostridium botulinum toxin (botulism) Francisella tularensis (tularemia) Francisella tularensis (tularemia) Viral hemorrhagic fever (e.g., Ebola, Marburg, Lassa) Viral hemorrhagic fever (e.g., Ebola, Marburg, Lassa)

3. Potential Agents of Biowarfare CDC Category B Moderately easy to disseminate Moderately easy to disseminate Moderate morbidity, low mortality Moderate morbidity, low mortality Need enhanced diagnostic capacity, disease surveillance Need enhanced diagnostic capacity, disease surveillance Brucella (brucellosis) Brucella (brucellosis) Viral encephalitis Viral encephalitis Ricin toxin Ricin toxin Clostridium perfringens toxin Clostridium perfringens toxin Staph. enterotoxin B Staph. enterotoxin B Foodborne pathogens (e.g., Salmonella, E. coli O157:H7) Foodborne pathogens (e.g., Salmonella, E. coli O157:H7) Waterborne pathogens (e.g., cholera) Waterborne pathogens (e.g., cholera) Others: glanders, melioidosis, psittacosis, Q fever Others: glanders, melioidosis, psittacosis, Q fever

4. Potential Agents of Biowarfare CDC Category C Emerging pathogens with biowarfare potential Emerging pathogens with biowarfare potential Nipah virus Nipah virus Hantavirus Hantavirus Tickborne hemorrhagic fever Tickborne hemorrhagic fever Yellow fever Yellow fever Multidrug-resistant tuberculosis Multidrug-resistant tuberculosis ? West Nile virus, SARS, avian influenza ? West Nile virus, SARS, avian influenza

5. Outline Diseases Anthrax Anthrax Plague Plague Brucellosis BrucellosisTopics History History Epidemiology Epidemiology Manifestations Manifestations Diagnosis Diagnosis Prevention and treatment Prevention and treatment

6. Anthrax Bacillus anthracis from J Jernigan et al., Emerging Infect Dis 2001;7:933 from Borio et al., JAMA 2001; 286:2557

7. Anthrax History 1290 BCE: described in Biblical “Exodus” 1290 BCE: described in Biblical “Exodus” 1876 CE: 1 st disease with proven microbial cause (Koch’s postulates) 1876 CE: 1 st disease with proven microbial cause (Koch’s postulates) 1881: 1 st effective live bacterial vaccine developed by Louis Pasteur 1881: 1 st effective live bacterial vaccine developed by Louis Pasteur 1979: anthrax spores released from military facility in Sverdlovsk, Russia 1979: anthrax spores released from military facility in Sverdlovsk, Russia 2001: civilians in FL, DC, NY, NJ exposed to anthrax via contaminated mail 2001: civilians in FL, DC, NY, NJ exposed to anthrax via contaminated mail

8. Adapted from Anthony Fauci, NIH, and MMWR reports

9. Anthrax Epidemiology Naturally occurs in herbivores around the world Naturally occurs in herbivores around the world Transmitted via direct exposure to spores Transmitted via direct exposure to spores –Inhalation –Direct contact –Ingestion

10. Inhalational Anthrax from J Jernigan et al., Emerging Infect Dis 2001;7:933 mediastinal widening small pleural effusion

11. Inhalational Anthrax Incubation Period Source: The Washington Post

12. Cutaneous Anthrax TV Inglesby et al.; JAMA 1999; 281:1738 KJ Roche et al.; NEJM 2001;345:1611

13. Anthrax Diagnosis Clinical diagnosis in outbreak setting Clinical diagnosis in outbreak setting –CXR/CT showing widened mediastinum in previously healthy patient with overwhelming flu-like illness Lab tests Lab tests –Stain and culture blood, lesion drainage –Lumbar puncture –Serologic tests

14. Inhalational Anthrax Anthrax vs. Influenza-Like Illness (ILI) Adapted from MMWR 2001;50:984-6

15. Inhalational or GI Anthrax Treatment for Adults Including pregnant women and immunocompromised patients Including pregnant women and immunocompromised patients Initial IV therapy Initial IV therapy –Ciprofloxacin 400 mg q12h OR doxycycline 100 mg q12h –AND 1-2 additional active agents Rifampin, clindamycin Rifampin, clindamycin Penicillin, ampicillin, imipenem Penicillin, ampicillin, imipenem Chloramphenicol, vancomycin, clarithromycin Chloramphenicol, vancomycin, clarithromycin MMWR 2001;50:909-19

16. Inhalational or GI Anthrax Treatment for Adults (cont’d.) Ciprofloxacin may be preferred with meningitis (± addition of penicillin, rifampin, or chloramphenicol) Ciprofloxacin may be preferred with meningitis (± addition of penicillin, rifampin, or chloramphenicol) Switch to PO when clinically appropriate to complete 60-day total course Switch to PO when clinically appropriate to complete 60-day total course –Ciprofloxacin 500 mg BID –OR doxycycline 100 mg BID ? Adjunctive corticosteroids ? Adjunctive corticosteroids MMWR 2001;50:909-19

17. Anthrax Treatment Cutaneous Cutaneous –Monotherapy with PO doxycycline or ciprofloxacin for 60 days (doses as before) Use same regimens for pediatrics Use same regimens for pediatrics –Ciprofloxacin 10-15 mg/kg q12h (max. 1 Gm/day) –Doxycycline > 8yo and > 45 kg: 100 mg q12h > 8yo and > 45 kg: 100 mg q12h > 8yo and  45 kg or  8yo: 2.2 mg/kg q12h > 8yo and  45 kg or  8yo: 2.2 mg/kg q12h MMWR 2001;50:909-19

18. Anthrax Post-Exposure Prophylaxis All adults All adults –Ciprofloxacin 500 mg PO BID x 60 days –OR doxycycline 100 mg PO BID x 60 days Same agents for pediatrics (dosed as before) Same agents for pediatrics (dosed as before) Pregnant women and children may switch to amoxicillin 80 mg/kg/d divided TID (max. 500 mg/dose) once penicillin-susceptibility confirmed Pregnant women and children may switch to amoxicillin 80 mg/kg/d divided TID (max. 500 mg/dose) once penicillin-susceptibility confirmed MMWR 2001;50:889-93, 960, 1014-6

19. Anthrax Post-Exposure Prophylaxis AM Friedlander et al.; J Infect Dis 1993;167:1239-42

20. Anthrax Vaccine Adsorbed (AVA) Filtrate containing anthrax protective antigen, lethal factor, and edema factor Filtrate containing anthrax protective antigen, lethal factor, and edema factor Recommended SQ administration schedule Recommended SQ administration schedule –Primary vaccination: 0, 2, and 4 weeks –Boosters: 6, 12, and 18 months, then annually Adverse events Adverse events –Studied by Defense Dept., Institute of Medicine, and others and found to be “acceptably safe” Recommended in addition to antibiotics for post-exposure prophylaxis (if available) Recommended in addition to antibiotics for post-exposure prophylaxis (if available)

21. Anthrax Other Management Issues Infection control Infection control –Standard barrier precautions –Respiratory isolation generally not needed Decontamination Decontamination –Soap and water for exposed skin, clothes –Chemical decontaminants vary with exposed surface, but bleach generally effective –Secondary aerosolization

22. Plague Yersinia pestis

23. Plague History 1320 BCE: described among the Philistines in Biblical “I Samuel” 1320 BCE: described among the Philistines in Biblical “I Samuel” 541-542 CE: 100 million die in plague epidemic of the Byzantine Empire 541-542 CE: 100 million die in plague epidemic of the Byzantine Empire 1346-1352: 24 million die in “the Black Death” plague 1346-1352: 24 million die in “the Black Death” plague –1346-1347: Tatar army catapults plague corpses at attacking Genoese sailors 1900: plague brought to US from China 1900: plague brought to US from China 1940s: Japanese use plague against Chinese 1940s: Japanese use plague against Chinese

24. Plague Epidemiology

25. Bubonic Plague KP Talaro, A Talaro; Foundations in Microbiology; 4 th Ed. (2001) TV Inglesby et al.; JAMA 2000; 283:2284

26. Septicemic Plague “The Black Death” McGovern et al.; Arch Dermatol 1999;135:314

27. Pneumonic Plague

28. Plague Diagnosis Gram (-), fulminant pneumonia with bloody sputum in otherwise healthy host Gram (-), fulminant pneumonia with bloody sputum in otherwise healthy host Lab tests Lab tests –Culture, stain, DFA of bubo aspirate –Culture of blood, sputum, CSF as indicated –Others: leukemoid reactions; fibrin degradation products; AST/ALT –Serologic tests, PCR

29. Plague Treatment Preferred: streptomycin 1 Gm IM q12h OR gentamicin 5 mg/kg IV/IM q24h Preferred: streptomycin 1 Gm IM q12h OR gentamicin 5 mg/kg IV/IM q24h Alternatives: Alternatives: –Doxycycline 100 mg IV/PO q12h –Ciprofloxacin 400 mg IV q12h OR 500 mg PO q12h –Chloramphenicol 25 mg/kg IV q6h Max. 4 Gm/day Max. 4 Gm/day Target serum concentrations = 5-20  g/mL Target serum concentrations = 5-20  g/mL

30. Plague Treatment Duration of therapy: at least 10 days Duration of therapy: at least 10 days Pediatrics: same agents as for adults Pediatrics: same agents as for adults –Strepto. 15 mg/kg q12h (max. 2 Gm/day) –Gent. 2.5 mg/kg q8h –Chlor. 25 mg/kg q6h (max. 4 Gm./day) Avoid in children < 2 yo Avoid in children < 2 yo –Doxy., cipro. dosed as for anthrax Avoid strepto. in pregnant women Avoid strepto. in pregnant women

31. Plague Prophylaxis Flea, rodent control Flea, rodent control Killed vaccine prevents bubonic plague Killed vaccine prevents bubonic plague –Primary vaccination: 0, 1-3, & 5-6 months –Boosters: 12, 18, & 24 mo., then every 1-2 years Preferred post-exposure prophylaxis: Preferred post-exposure prophylaxis: –Doxycycline 100 mg PO BID –Ciprofloxacin 500 mg PO BID –Duration of prophylaxis: 7 days

32. Brucellosis Causative organisms and their hosts Causative organisms and their hosts –Brucella abortus (cattle) –B. melitensis (goats) –B. suis (swine) –B. canis (dogs) –B. ovis (sheep) Transmitted by: ingestion, direct contact, inhalation Transmitted by: ingestion, direct contact, inhalation

33. Brucellosis Clinical Manifestations Classic undulant fever Classic undulant fever Focal (or localized) disease Focal (or localized) disease –Osteoarticular, hepatobiliary disease –Orchitis, ?spontaneous abortions –Endocarditis, meningoencephalitis Chronic infection Chronic infection –Relapse –Undrained localized abscess/necrosis –“Delayed convalescence”

34. Brucellosis Classic Temperature Cycle KP Talaro, A Talaro; Foundations in Microbiology; 4 th Ed. (2001)

35. Brucellosis Diagnosis Culture of blood, bone marrow, other tissue Culture of blood, bone marrow, other tissue Serum agglutination test Serum agglutination test –Detects antibodies to B. abortus, B. suis, and B. melitensis –IgM can remain (+) for years after therapy –Single titer  1:160 or > 4-fold increase in titer usually indicates active infection

36. Brucellosis Treatment Preferred: doxycycline 100 mg PO q12h x 6 wks. PLUS gentamicin x 2-3 wks. Preferred: doxycycline 100 mg PO q12h x 6 wks. PLUS gentamicin x 2-3 wks. Alternatives: Alternatives: –Doxycycline PLUS rifampin 600-900 mg PO q24h x 6 wks. –TMP/SMX 1 DS PO q12h x 6 wks. PLUS gentamicin x 5-14 days Others: streptomycin, ofloxacin Others: streptomycin, ofloxacin

37. Brucellosis Prophylaxis Barrier precautions Barrier precautions Boiling or pasteurization of milk Boiling or pasteurization of milk Live veterinary vaccines Live veterinary vaccines Post-exposure antibiotics may just delay disease presentation and so are not recommended at this time Post-exposure antibiotics may just delay disease presentation and so are not recommended at this time