Bioterrorism Agents: Bioterrorism Agents: Anthrax, Plague, and Anthrax, Plague, and BrucellosisBrucellosis

Jeff Kuper, Pharm.D., BCPSJeff Kuper, Pharm.D., BCPSClinical Associate ProfessorClinical Associate ProfessorErnest Mario School of PharmacyErnest Mario School of PharmacyRutgers, The State University of Rutgers, The State University of New JerseyNew Jersey

Potential Agents of Potential Agents of BiowarfareBiowarfareCDC Category ACDC Category A

Easily Easily disseminated or disseminated or transmitted transmitted person-to-person-to-personperson

High mortalityHigh mortality Might cause Might cause

public panic, public panic, social disruptionsocial disruption

Need special Need special public health public health preparednesspreparedness

Bacillus anthracisBacillus anthracis (anthrax)(anthrax)

Variola major (smallpox)Variola major (smallpox) Yersinia pestisYersinia pestis (plague) (plague) Clostridium botulinumClostridium botulinum

toxin (botulism)toxin (botulism) Francisella tularensisFrancisella tularensis

(tularemia)(tularemia) Viral hemorrhagic fever Viral hemorrhagic fever

(e.g., Ebola, Marburg, (e.g., Ebola, Marburg, Lassa)Lassa)

Potential Agents of Potential Agents of BiowarfareBiowarfareCDC Category BCDC Category B

Moderately Moderately easy to easy to disseminatedisseminate

Moderate Moderate morbidity, low morbidity, low mortalitymortality

Need Need enhanced enhanced diagnostic diagnostic capacity, capacity, disease disease surveillancesurveillance

BrucellaBrucella (brucellosis) (brucellosis) Viral encephalitisViral encephalitis Ricin toxinRicin toxin Clostridium perfringens Clostridium perfringens

toxintoxin Staph. enterotoxin BStaph. enterotoxin B Foodborne pathogens (e.g., Foodborne pathogens (e.g.,

SalmonellaSalmonella, , E. coli E. coli O157:H7)O157:H7) Waterborne pathogens Waterborne pathogens

(e.g., cholera)(e.g., cholera) Others: glanders, Others: glanders,

melioidosis, psittacosis, Q melioidosis, psittacosis, Q feverfever

Potential Agents of Potential Agents of BiowarfareBiowarfareCDC Category CCDC Category C

Emerging pathogens with biowarfare Emerging pathogens with biowarfare potentialpotential

Nipah virusNipah virus HantavirusHantavirus Tickborne hemorrhagic feverTickborne hemorrhagic fever Yellow feverYellow fever Multidrug-resistant tuberculosisMultidrug-resistant tuberculosis ? West Nile virus, SARS, avian influenza? West Nile virus, SARS, avian influenza

OutlineOutline

DiseasesDiseases AnthraxAnthrax PlaguePlague BrucellosisBrucellosis

TopicsTopics HistoryHistory EpidemiologyEpidemiology ManifestationsManifestations DiagnosisDiagnosis Prevention and Prevention and

treatmenttreatment

AnthraxAnthraxBacillus anthracisBacillus anthracis

from J Jernigan et from J Jernigan et al., al., Emerging Emerging

Infect DisInfect Dis 2001;7:9332001;7:933

from Borio et from Borio et al., al., JAMA JAMA

2001; 2001; 286:2557286:2557

AnthraxAnthraxHistoryHistory

1290 BCE: described in Biblical “Exodus”1290 BCE: described in Biblical “Exodus” 1876 CE: 11876 CE: 1stst disease with proven disease with proven

microbial cause (Koch’s postulates)microbial cause (Koch’s postulates) 1881: 11881: 1stst effective live bacterial vaccine effective live bacterial vaccine

developed by Louis Pasteurdeveloped by Louis Pasteur 1979: anthrax spores released from 1979: anthrax spores released from

military facility in Sverdlovsk, Russiamilitary facility in Sverdlovsk, Russia 2001: civilians in FL, DC, NY, NJ exposed 2001: civilians in FL, DC, NY, NJ exposed

to anthrax via contaminated mailto anthrax via contaminated mail

Adapted from Anthony Fauci, NIH, and MMWR reportsAdapted from Anthony Fauci, NIH, and MMWR reports

AnthraxAnthraxEpidemiologyEpidemiology

Naturally occurs in herbivores Naturally occurs in herbivores around the worldaround the world

Transmitted via direct exposure Transmitted via direct exposure to sporesto spores– InhalationInhalation– Direct contactDirect contact– IngestionIngestion

Inhalational AnthraxInhalational Anthrax

from J Jernigan et al., from J Jernigan et al., Emerging Infect Emerging Infect DisDis 2001;7:933 2001;7:933

mediastinal mediastinal wideningwidening

small pleural small pleural effusioneffusion

Inhalational AnthraxInhalational AnthraxIncubation PeriodIncubation Period

Source: Source: The Washington PostThe Washington Post

Cutaneous AnthraxCutaneous Anthrax

TV Inglesby et TV Inglesby et al.; al.; JAMAJAMA 1999; 1999; 281:1738281:1738

KJ Roche et al.; KJ Roche et al.; NEJM NEJM 2001;345:16112001;345:1611

AnthraxAnthraxDiagnosisDiagnosis

Clinical diagnosis in outbreak settingClinical diagnosis in outbreak setting– CXR/CT showing widened mediastinum CXR/CT showing widened mediastinum

in previously healthy patient with in previously healthy patient with overwhelming flu-like illnessoverwhelming flu-like illness

Lab testsLab tests– Stain and culture blood, lesion drainageStain and culture blood, lesion drainage– Lumbar punctureLumbar puncture– Serologic testsSerologic tests

Inhalational AnthraxInhalational AnthraxAnthrax vs. Influenza-Like Illness Anthrax vs. Influenza-Like Illness (ILI)(ILI)

0102030405060708090

% o

f Pati

ents

SOB

Chest pain

Headach

e

Sore throat

Rhinorrhea

Nausea

AnthraxInfluenzaOther ILI

Adapted from MMWR 2001;50:984-6

Inhalational or GI Inhalational or GI AnthraxAnthraxTreatment for AdultsTreatment for Adults Including pregnant women and Including pregnant women and

immunocompromised patientsimmunocompromised patients Initial IV therapyInitial IV therapy

– Ciprofloxacin 400 mg q12h Ciprofloxacin 400 mg q12h OROR doxycycline 100 mg q12hdoxycycline 100 mg q12h

– ANDAND 1-2 additional active agents 1-2 additional active agents Rifampin, clindamycinRifampin, clindamycin Penicillin, ampicillin, imipenemPenicillin, ampicillin, imipenem Chloramphenicol, vancomycin, Chloramphenicol, vancomycin,

clarithromycinclarithromycin MMWRMMWR 2001;50:909-19 2001;50:909-19

Inhalational or GI Inhalational or GI AnthraxAnthraxTreatment for Adults (cont’d.)Treatment for Adults (cont’d.)

Ciprofloxacin may be preferred with Ciprofloxacin may be preferred with meningitis (± addition of penicillin, meningitis (± addition of penicillin, rifampin, or chloramphenicol)rifampin, or chloramphenicol)

Switch to PO when clinically Switch to PO when clinically appropriate to complete 60-day total appropriate to complete 60-day total coursecourse– Ciprofloxacin 500 mg BIDCiprofloxacin 500 mg BID– OROR doxycycline 100 mg BID doxycycline 100 mg BID

? Adjunctive corticosteroids? Adjunctive corticosteroidsMMWRMMWR 2001;50:909-19 2001;50:909-19

AnthraxAnthraxTreatmentTreatment

CutaneousCutaneous– Monotherapy with PO doxycycline or Monotherapy with PO doxycycline or

ciprofloxacin for 60 days (doses as before)ciprofloxacin for 60 days (doses as before) Use same regimens for pediatricsUse same regimens for pediatrics

– Ciprofloxacin 10-15 mg/kg q12h Ciprofloxacin 10-15 mg/kg q12h (max. 1 Gm/day)(max. 1 Gm/day)

– DoxycyclineDoxycycline > 8yo and > 45 kg: 100 mg q12h> 8yo and > 45 kg: 100 mg q12h > 8yo and > 8yo and 45 kg 45 kg oror 8yo: 2.2 mg/kg q12h 8yo: 2.2 mg/kg q12h

MMWRMMWR 2001;50:909-19 2001;50:909-19

AnthraxAnthraxPost-Exposure ProphylaxisPost-Exposure Prophylaxis

All adultsAll adults– Ciprofloxacin 500 mg PO BID x 60 daysCiprofloxacin 500 mg PO BID x 60 days– OROR doxycycline 100 mg PO BID x 60 days doxycycline 100 mg PO BID x 60 days

Same agents for pediatrics (dosed as Same agents for pediatrics (dosed as before)before)

Pregnant women and children may Pregnant women and children may switch to amoxicillin 80 mg/kg/d switch to amoxicillin 80 mg/kg/d divided TID (max. 500 mg/dose) once divided TID (max. 500 mg/dose) once penicillin-susceptibility confirmedpenicillin-susceptibility confirmed

MMWRMMWR 2001;50:889-93, 960, 1014-6 2001;50:889-93, 960, 1014-6

AnthraxAnthraxPost-Exposure ProphylaxisPost-Exposure Prophylaxis

0

20

40

60

80

100

% S

urv

ival

Control Vaccine PEN CIP DOXY DOXY +Vacc

Simian Inhalation Exposure

AM Friedlander et al.; AM Friedlander et al.; J Infect DisJ Infect Dis 1993;167:1239-42 1993;167:1239-42

Anthrax Vaccine Adsorbed Anthrax Vaccine Adsorbed (AVA)(AVA)

Filtrate containing anthrax protective Filtrate containing anthrax protective antigen, lethal factor, and edema factorantigen, lethal factor, and edema factor

Recommended SQ administration scheduleRecommended SQ administration schedule– Primary vaccination: 0, 2, and 4 weeksPrimary vaccination: 0, 2, and 4 weeks– Boosters: 6, 12, and 18 months, then annuallyBoosters: 6, 12, and 18 months, then annually

Adverse eventsAdverse events– Studied by Defense Dept., Institute of Medicine, Studied by Defense Dept., Institute of Medicine,

and others and found to be “acceptably safe”and others and found to be “acceptably safe” Recommended in addition to antibiotics for Recommended in addition to antibiotics for

post-exposure prophylaxis (if available)post-exposure prophylaxis (if available)

AnthraxAnthraxOther Management IssuesOther Management Issues

Infection controlInfection control– Standard barrier precautionsStandard barrier precautions– Respiratory isolation generally not neededRespiratory isolation generally not needed

DecontaminationDecontamination– Soap and water for exposed skin, clothesSoap and water for exposed skin, clothes– Chemical decontaminants vary with Chemical decontaminants vary with

exposed surface, but bleach generally exposed surface, but bleach generally effectiveeffective

– Secondary aerosolizationSecondary aerosolization

PlaguePlagueYersinia pestisYersinia pestis

PlaguePlagueHistoryHistory

1320 BCE: described among the Philistines 1320 BCE: described among the Philistines in Biblical “I Samuel”in Biblical “I Samuel”

541-542 CE: 100 million die in plague 541-542 CE: 100 million die in plague epidemic of the Byzantine Empireepidemic of the Byzantine Empire

1346-1352: 24 million die in “the Black 1346-1352: 24 million die in “the Black Death” plagueDeath” plague– 1346-1347: Tatar army catapults plague 1346-1347: Tatar army catapults plague

corpses at attacking Genoese sailorscorpses at attacking Genoese sailors 1900: plague brought to US from China1900: plague brought to US from China 1940s: Japanese use plague against 1940s: Japanese use plague against

ChineseChinese

PlaguePlagueEpidemiologyEpidemiology

Bubonic PlagueBubonic Plague

KP Talaro, A Talaro; KP Talaro, A Talaro; Foundations in Foundations in MicrobiologyMicrobiology; 4; 4thth Ed. (2001) Ed. (2001)

TV Inglesby et al.; TV Inglesby et al.; JAMAJAMA 2000; 2000; 283:2284283:2284

SepticemicSepticemic PlaguePlague“The Black Death”“The Black Death”

McGovern et al.; McGovern et al.; Arch DermatolArch Dermatol 1999;135:314 1999;135:314

Pneumonic PlaguePneumonic Plague

PlaguePlagueDiagnosisDiagnosis

Gram (-), fulminant pneumonia with Gram (-), fulminant pneumonia with bloody sputum in otherwise healthy bloody sputum in otherwise healthy hosthost

Lab testsLab tests– Culture, stain, DFA of bubo aspirateCulture, stain, DFA of bubo aspirate– Culture of blood, sputum, CSF as indicatedCulture of blood, sputum, CSF as indicated– Others: leukemoid reactions; fibrin Others: leukemoid reactions; fibrin

degradation products; AST/ALTdegradation products; AST/ALT– Serologic tests, PCRSerologic tests, PCR

PlaguePlagueTreatmentTreatment

Preferred: streptomycin 1 Gm IM Preferred: streptomycin 1 Gm IM q12h q12h OROR gentamicin 5 mg/kg IV/IM gentamicin 5 mg/kg IV/IM q24hq24h

Alternatives:Alternatives:– Doxycycline 100 mg IV/PO q12hDoxycycline 100 mg IV/PO q12h– Ciprofloxacin 400 mg IV q12h Ciprofloxacin 400 mg IV q12h OROR

500 mg PO q12h500 mg PO q12h– Chloramphenicol 25 mg/kg IV q6hChloramphenicol 25 mg/kg IV q6h

Max. 4 Gm/dayMax. 4 Gm/day Target serum concentrations = 5-20 Target serum concentrations = 5-20 g/mLg/mL

PlaguePlagueTreatmentTreatment

Duration of therapy: at least 10 daysDuration of therapy: at least 10 days Pediatrics: same agents as for adultsPediatrics: same agents as for adults

– Strepto. 15 mg/kg q12h (max. 2 Gm/day)Strepto. 15 mg/kg q12h (max. 2 Gm/day)– Gent. 2.5 mg/kg q8hGent. 2.5 mg/kg q8h– Chlor. 25 mg/kg q6h (max. 4 Gm./day)Chlor. 25 mg/kg q6h (max. 4 Gm./day)

Avoid in children < 2 yoAvoid in children < 2 yo

– Doxy., cipro. dosed as for anthraxDoxy., cipro. dosed as for anthrax Avoid strepto. in pregnant womenAvoid strepto. in pregnant women

PlaguePlagueProphylaxisProphylaxis

Flea, rodent controlFlea, rodent control Killed vaccine prevents Killed vaccine prevents bubonicbubonic plague plague

– Primary vaccination: 0, 1-3, & 5-6 monthsPrimary vaccination: 0, 1-3, & 5-6 months– Boosters: 12, 18, & 24 mo., then every 1-2 Boosters: 12, 18, & 24 mo., then every 1-2

yearsyears Preferred post-exposure prophylaxis:Preferred post-exposure prophylaxis:

– Doxycycline 100 mg PO BIDDoxycycline 100 mg PO BID– Ciprofloxacin 500 mg PO BIDCiprofloxacin 500 mg PO BID– Duration of prophylaxis: 7 daysDuration of prophylaxis: 7 days

BrucellosisBrucellosis

Causative organisms and their Causative organisms and their hostshosts– Brucella abortus Brucella abortus (cattle)(cattle)– B. melitensisB. melitensis (goats) (goats)– B. suisB. suis (swine) (swine)– B. canisB. canis (dogs) (dogs)– B. ovisB. ovis (sheep) (sheep)

Transmitted by: ingestion, direct Transmitted by: ingestion, direct contact, inhalationcontact, inhalation

BrucellosisBrucellosisClinical ManifestationsClinical Manifestations

Classic undulant feverClassic undulant fever Focal (or localized) diseaseFocal (or localized) disease

– Osteoarticular, hepatobiliary diseaseOsteoarticular, hepatobiliary disease– Orchitis, ?spontaneous abortionsOrchitis, ?spontaneous abortions– Endocarditis, meningoencephalitisEndocarditis, meningoencephalitis

Chronic infectionChronic infection– RelapseRelapse– Undrained localized abscess/necrosisUndrained localized abscess/necrosis– ““Delayed convalescence”Delayed convalescence”

BrucellosisBrucellosisClassic Temperature CycleClassic Temperature Cycle

KP Talaro, A Talaro; KP Talaro, A Talaro; Foundations in MicrobiologyFoundations in Microbiology; 4; 4thth Ed. Ed. (2001)(2001)

BrucellosisBrucellosisDiagnosisDiagnosis

Culture of blood, bone marrow, other Culture of blood, bone marrow, other tissuetissue

Serum agglutination testSerum agglutination test– Detects antibodies to Detects antibodies to B. abortusB. abortus, , B. suisB. suis, ,

and and B. melitensisB. melitensis– IgM can remain (+) for years after IgM can remain (+) for years after

therapytherapy– Single titer Single titer 1:160 or > 4-fold increase 1:160 or > 4-fold increase

in titer usually indicates active infectionin titer usually indicates active infection

BrucellosisBrucellosisTreatmentTreatment

Preferred: doxycycline 100 mg PO Preferred: doxycycline 100 mg PO q12h x 6 wks. q12h x 6 wks. PLUSPLUS gentamicin x 2-3 gentamicin x 2-3 wks.wks.

Alternatives:Alternatives:– Doxycycline Doxycycline PLUSPLUS rifampin 600-900 mg rifampin 600-900 mg

PO q24h x 6 wks.PO q24h x 6 wks.– TMP/SMX 1 DS PO q12h x 6 wks. TMP/SMX 1 DS PO q12h x 6 wks. PLUSPLUS

gentamicin x 5-14 daysgentamicin x 5-14 days Others: streptomycin, ofloxacinOthers: streptomycin, ofloxacin

BrucellosisBrucellosisProphylaxisProphylaxis

Barrier precautionsBarrier precautions Boiling or pasteurization of milkBoiling or pasteurization of milk Live veterinary vaccinesLive veterinary vaccines Post-exposure antibiotics may Post-exposure antibiotics may

just delay disease presentation just delay disease presentation and so are and so are notnot recommended at recommended at this timethis time