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

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Easily
disseminated or
transmitted
person-to-person
High mortality
Might cause public
panic, social
disruption
Need special public
health
preparedness



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
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





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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
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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
e
B
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da
th
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a
N
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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

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> 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)

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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
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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
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
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
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
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
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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