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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
Potential Agents of Biowarfare
CDC Category A
Easily
disseminated or
transmitted
person-to-person
High mortality
Might cause public
panic, social
disruption
Need special public
health
preparedness
Bacillus anthracis (anthrax)
Variola major (smallpox)
Yersinia pestis (plague)
Clostridium botulinum toxin
(botulism)
Francisella tularensis
(tularemia)
Viral hemorrhagic fever
(e.g., Ebola, Marburg, Lassa)
Potential Agents of Biowarfare
CDC Category B
Moderately easy
to disseminate
Moderate
morbidity, low
mortality
Need enhanced
diagnostic
capacity, disease
surveillance
Brucella (brucellosis)
Viral encephalitis
Ricin toxin
Clostridium perfringens toxin
Staph. enterotoxin B
Foodborne pathogens (e.g.,
Salmonella, E. coli O157:H7)
Waterborne pathogens (e.g.,
cholera)
Others: glanders, melioidosis,
psittacosis, Q fever
Potential Agents of Biowarfare
CDC Category C
Emerging pathogens with biowarfare
potential
Nipah virus
Hantavirus
Tickborne hemorrhagic fever
Yellow fever
Multidrug-resistant tuberculosis
? West Nile virus, SARS, avian influenza
Outline
Topics
Diseases
Anthrax
Plague
Brucellosis
History
Epidemiology
Manifestations
Diagnosis
Prevention and
treatment
Anthrax
Bacillus anthracis
from Borio et
al., JAMA
2001;
286:2557
from J Jernigan et
al., Emerging Infect
Dis 2001;7:933
Anthrax
History
1290 BCE: described in Biblical “Exodus”
1876 CE: 1st disease with proven microbial
cause (Koch’s postulates)
1881: 1st effective live bacterial vaccine
developed by Louis Pasteur
1979: anthrax spores released from military
facility in Sverdlovsk, Russia
2001: civilians in FL, DC, NY, NJ exposed to
anthrax via contaminated mail
Adapted from Anthony Fauci, NIH, and MMWR reports
Anthrax
Epidemiology
Naturally occurs in herbivores around
the world
Transmitted via direct exposure to
spores
– Inhalation
– Direct contact
– Ingestion
Inhalational Anthrax
mediastinal
widening
small pleural
effusion
from J Jernigan et al., Emerging Infect Dis
2001;7:933
Inhalational Anthrax
Incubation Period
Source: The Washington Post
Cutaneous Anthrax
TV Inglesby et al.;
JAMA 1999;
281:1738
KJ Roche et al.;
NEJM
2001;345:1611
Anthrax
Diagnosis
Clinical diagnosis in outbreak setting
– CXR/CT showing widened mediastinum in
previously healthy patient with
overwhelming flu-like illness
Lab tests
– Stain and culture blood, lesion drainage
– Lumbar puncture
– Serologic tests
Inhalational Anthrax
% of Patients
Anthrax vs. Influenza-Like Illness (ILI)
90
80
70
60
50
40
30
20
10
0
Anthrax
Influenza
Other ILI
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B
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Adapted from MMWR 2001;50:984-6
Inhalational or GI Anthrax
Treatment for Adults
Including pregnant women and
immunocompromised patients
Initial IV therapy
– Ciprofloxacin 400 mg q12h OR
doxycycline 100 mg q12h
– AND 1-2 additional active agents
Rifampin, clindamycin
Penicillin, ampicillin, imipenem
Chloramphenicol, vancomycin, clarithromycin
MMWR 2001;50:909-19
Inhalational or GI Anthrax
Treatment for Adults (cont’d.)
Ciprofloxacin may be preferred with
meningitis (± addition of penicillin, rifampin,
or chloramphenicol)
Switch to PO when clinically appropriate to
complete 60-day total course
– Ciprofloxacin 500 mg BID
– OR doxycycline 100 mg BID
? Adjunctive corticosteroids
MMWR 2001;50:909-19
Anthrax
Treatment
Cutaneous
– Monotherapy with PO doxycycline or
ciprofloxacin for 60 days (doses as before)
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 or 8yo: 2.2 mg/kg q12h
MMWR 2001;50:909-19
Anthrax
Post-Exposure Prophylaxis
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)
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
Anthrax
Post-Exposure Prophylaxis
Simian Inhalation Exposure
% Survival
100
80
60
40
20
0
Control Vaccine
PEN
CIP
DOXY DOXY +
Vacc
AM Friedlander et al.; J Infect Dis 1993;167:1239-42
Anthrax Vaccine Adsorbed (AVA)
Filtrate containing anthrax protective
antigen, lethal factor, and edema factor
Recommended SQ administration schedule
– Primary vaccination: 0, 2, and 4 weeks
– Boosters: 6, 12, and 18 months, then annually
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)
Anthrax
Other Management Issues
Infection control
– Standard barrier precautions
– Respiratory isolation generally not needed
Decontamination
– Soap and water for exposed skin, clothes
– Chemical decontaminants vary with exposed
surface, but bleach generally effective
– Secondary aerosolization
Plague
Yersinia pestis
Plague
History
1320 BCE: described among the Philistines
in Biblical “I Samuel”
541-542 CE: 100 million die in plague
epidemic of the Byzantine Empire
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
1940s: Japanese use plague against Chinese
Plague
Epidemiology
Bubonic Plague
TV Inglesby et al.;
JAMA 2000;
283:2284
KP Talaro, A Talaro;
Foundations in Microbiology;
4th Ed. (2001)
Septicemic Plague
“The Black Death”
McGovern et al.; Arch Dermatol 1999;135:314
Pneumonic Plague
Plague
Diagnosis
Gram (-), fulminant pneumonia with bloody
sputum in otherwise healthy host
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
Plague
Treatment
Preferred: streptomycin 1 Gm IM q12h
OR gentamicin 5 mg/kg IV/IM q24h
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
Target serum concentrations = 5-20 g/mL
Plague
Treatment
Duration of therapy: at least 10 days
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
– Doxy., cipro. dosed as for anthrax
Avoid strepto. in pregnant women
Plague
Prophylaxis
Flea, rodent control
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:
– Doxycycline 100 mg PO BID
– Ciprofloxacin 500 mg PO BID
– Duration of prophylaxis: 7 days
Brucellosis
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
Brucellosis
Clinical Manifestations
Classic undulant fever
Focal (or localized) disease
– Osteoarticular, hepatobiliary disease
– Orchitis, ?spontaneous abortions
– Endocarditis, meningoencephalitis
Chronic infection
– Relapse
– Undrained localized abscess/necrosis
– “Delayed convalescence”
Brucellosis
Classic Temperature Cycle
KP Talaro, A Talaro; Foundations in Microbiology; 4th Ed. (2001)
Brucellosis
Diagnosis
Culture of blood, bone marrow, other
tissue
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
Brucellosis
Treatment
Preferred: doxycycline 100 mg PO q12h x 6
wks. PLUS gentamicin x 2-3 wks.
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
Brucellosis
Prophylaxis
Barrier precautions
Boiling or pasteurization of milk
Live veterinary vaccines
Post-exposure antibiotics may just
delay disease presentation and so are
not recommended at this time