Serious Adverse Events among Participants in the Centers for Disease Control and

Prevention's Anthrax Vaccine and Antimicrobial Availability Program for Persons at Risk for
Bioterrorism-Related Inhalational Anthrax
Author(s): Bruce C. Tierney, Stacey W. Martin, Laura H. Franzke, Nina Marano, Dori B.
Reissman, Randy D. Louchart, Joyce A. Goff, Nancy E. Rosenstein, John L. Sever, Michael M.
McNeil
Source: Clinical Infectious Diseases, Vol. 37, No. 7 (Oct. 1, 2003), pp. 905-911
Published by: The University of Chicago Press
Stable URL: http://www.jstor.org/stable/4462615
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 MAJOR ART CLE

Serious Adverse Events among Participants

in the Centers for Disease Control and Prevention's
Anthrax Vaccine and Antimicrobial Availability
Program for Persons at Risk for Bioterrorism-Related
Inhalational Anthrax

BruceC.Tierney,12StaceyW. Martin,2LauraH. Franzke,2

NinaMarano,3DoriB. Reissman,4
RandyD. Louchart,2
Joyce A. Goff,2NancyE. Rosenstein,3
John L.Sever,5and MichaelM. McNeil2
'Epidemiology
Program 2Anthrax
Office, VaccineSafetyActivity, andSurveillance
Epidemiology National
Division, Immunization
Program,
andSpecialPathogens
3Meningitis Branch,Division
of Bacterial
andMycotic
Diseases,and4Bioterrorism andResponse
Preparedness Program,
National
CenterforInfectious
Diseases,Centers
forDiseaseControl
andPrevention,
Atlanta, and5Departments
Georgia; of Pediatrics,
Obstetrics,
andGynecology, andImmunology,
Microbiology TheChildren'sNational
Medical
Center, George
WashingtonUniversity,
Washington,D.C.

On 20 December2001, the Centersfor Disease Control and Prevention(CDC) initiated the AnthraxVaccine
and AntibioticAvailabilityProgram(hereafter,the "Program")under an investigationalnew drug application
with the US Food and DrugAdministration.This Programprovidedoptions for additionalpreventivetreatment
for persons at risk for inhalation anthrax as a result of recent bioterrorismattackswho had concluded or
were concludinga 60-daycourse of antimicrobialprophylaxis.Participantswere offeredan additional40 days
of antibiotic therapy (with ciprofloxacin,doxycycline,or amoxicillin) or antibiotic therapyplus 3 doses of
anthraxvaccine. By 11 February2002, a total of 5420 persons had receivedstandardizededucationabout the
Programand 1727 persons (32%) had enrolled. Twelveparticipantshave been identified as having serious
adverseevents (SAEs).One SAE,which occurredin a participantwith ciprofloxacin-inducedallergicinterstitial
nephritis, was consideredto be probablyassociatedwith treatmentreceivedin the Program.No SAEswere
associatedwith anthraxvaccine.CDCwill continue to monitor Programparticipantsduringthe next 2 years.

On 4 October2001,the firstcaseofinhalationalanthrax cluding5 fatalcases [1]. Once the riskfor inhalational

in the UnitedStatesin >25 yearswasconfirmed,mark- anthraxwasidentified,recommendations weremadeto
ing the beginningof the firstoutbreakof bioterrorism- begin antimicrobialprophylaxis groups who met
for
relatedanthraxin the United States.This bioterrorist specific exposure criteria [2]. In November2001, in
attack,which involvedthe use of Bacillusanthracis,re- responseto this attack,the Centersfor DiseaseControl
sulted in 11 documentedcases of cutaneousanthrax and Prevention's(CDC;Atlanta,GA) AdvisoryCom-
and 11 documentedcases of inhalationalanthrax,in- mittee on ImmunizationPractices(ACIP)clarifiedan
earlierrecommendationand recommendedthat,in the
absence of availablevaccine, persons potentiallyex-
Received 5 March2003;accepted31 May2003;electronically 12
published posed to B. anthracisaerosolsshould receivea 60-day
September 2003. courseof antibiotictherapy[3].
Reprints Dr.Bruce
orcorrespondence: C.Tierney,
AnthraxVaccineSafetyTeam, Beforethe start of this bioterroristattack,both of
Vaccine
Bacterial Preventable
DiseasesBranch, andSurveillance
Epidemiology
Div.,National
Immunization
Program,Centers andPrevention,
forDiseaseControl the majorUS advisorybodies,the WorkingGroupon
1600CliftonRd.NE,MS-E61, GA30333(bgt2@cdc.gov).
Atlanta, CivilianBiodefense[4] andtheACIP[5], both of which
ClinicalInfectiousDiseases 2003;37:905-11 had recentlyconsideredthe issue of postexposurepro-
? 2003bytheInfectious DiseasesSocietyof America.
Allrightsreserved.
1058-4838/2003/3707-0005$15.00 phylaxisforpreventionof inhalationalanthrax,hadrec-

SAEsamong Persons in CDC's AVAProgram ? CID 2003:37 (1 October) * 905

ommendedthe use of antibioticsin combinationwithAnthrax
VaccineAdsorbed(AVA;Bioport), if available.In December
2001, the US Departmentof Defense releasedAVAfor im-
mediatepurchaseby the US Departmentof HealthandHuman
Services(DHHS)for the AnthraxVaccineandAntibioticAvail-
abilityprogram(hereafterreferredto as "theProgram").The
CDC made the Programavailableon the basis of severalad-
ditionalconsiderations.First,datasuggestthat the sporeform
of the organism,whichis unaffectedby antibiotictherapy,may
persistfor>60 daysbeforegerminatingandcausinginhalational
anthrax[6, 7]; this may be a greaterconcernamong persons
with high-levelexposure.A recentsimulationstudyin Canada
indicateda higher-than-expected potentialfor disseminationof
a large numberof sporeson the basis of the passiveopening
of a contaminatedenvelope [8]. Second, problemswith ad-
herenceto antibiotictherapywere documentedamong those
for whom 60 days of antibioticprophylaxiswas initiallyrec-
ommended [9, 10], which potentiallydecreasedthe effective-
ness of such therapy.Finally,the objectiveof the CDC and the
DHHSis to use all availablemeansto reducethe riskof disease
for exposedindividuals.
Thus,in October2001,the CDCfiledan investigational new
drug application with the US Food and Drug Administration
(FDA)to allowfor off-labeluse of antibiotics,as well as AVA,
shouldit becomeavailable.On 20 December2001,the Program
was initiatedto provideoptionsfor additionalpreventivetreat-
ment of personswho had potentialsignificantexposureto B.
anthracisand for whom 60 days of antibioticprophylaxiswas
recommended[11]. Participantswho enrolledin the Program
were given a choice between 2 options intended to provide
protectionagainstthe possibilitythat B. anthracissporesmight
cause illness up to 100 days afterexposure:(1) 40 additional
days of antimicrobialprophylaxis(with ciprofloxacin,doxy-
cycline, or amoxicillin),or (2) 40 additionaldays of antimi-
crobialprophylaxisplus 3 dosesof AVAadministeredat 2-week
intervalsduring a 4-week period (i.e., duringvisits on weeks
0, 2, and 4 of the Program).
The Programenrolledpersonswho wereexposedat affected
US PostalServicefacilities,affectedgovernmentofficesandmail
facilities,and other affectedbusinesslocationsin 6 statesand
Washington,D.C. In some cases, exposed persons required
transitionalantibiotictreatment,rangingfrom 1 to 16 daysin
duration,until educationregardingProgramoptions couldbe
providedand Programenrollmentprocedurescouldbe imple-
mented.Becauseparticipantswererequiredto signan informed
consentdocumentat enrollment,it was importantto allowfor
an adequateopportunityfor educationabout Programtreat-
ment options.The protocolfor this Programwas reviewedand
approvedby an institutionalreviewboardat the CDC.
906 * CID 2003:37 (1 October) * Tierneyet al.
METHODS
Surveillancefor adverseevents (AEs). Safetymonitoringof
Programparticipantsoccurredvia both passiveand activesur-
veillanceactivities.Passivesurveillancefor AEswas conducted
via the CDC "alertline"(a CDC-sponsored,24-h, 7-days-per-
weekhotlineestablishedfor Programparticipants).Participants
were provideda cardwith the alertlinenumberat enrollment
and wereencouragedto reportany suspectedAEsto the alert-
line at any time and at each clinic visit. Participantswerealso
askedto provideinformationaboutlocalandsystemicAEsthat
occurredduringthe 6-weekperiodafterenrollment,usingdi-
ariesprovidedto them at enrollment.In addition,all partici-
pantswereadvisedto reportAEsto the VaccineAdverseEvent
ReportingSystem(VAERS)and/orMedWatchsystem-both of
whicharepassivesurveillancesystems-after vaccinationor use
of antibiotics.An alternativepassivesurveillancemethodused
by participantswas directcontactwith the CDCvia mail and/
or telephone contact other than the CDC alertlinenumber.
Active surveillancewas conductedby interviewingall partici-
pants duringeach of 3 scheduledclinic visits (duringenroll-
ment and 2-weekand 4-weekfollow-upvisits) aboutany sus-
pected AEs. Additional active surveillancewas conducted
througha telephonesurveyperformed2 months afterenroll-
ment to solicitresponsesto a seriesof healthstatusand safety-
relatedquestions.Additionaltelephonesurveysareplannedfor
6, 12, and 24 months afterenrollment.
Case definitions. Accordingto FDA reportingrequire-
ments, an AE is definedas any untowardmedicaloccurrence
in a participantwho was administeredan investigational drug,
including vaccine,which may have but did not necessarilyhave
a causalrelationshipto the treatment.An AE, therefore,can
be any unfavorableand unintendedsign (includinglaboratory
findings),symptom,or diseasetemporallyassociatedwith the
use of the investigationaltherapy(e.g., a specificlot of AVA),
whetheror not the AE was casuallyassociatedwith the study
therapy[12]. A seriousAE (SAE)was definedas anyuntoward
medicaloccurrencethat may have resultedin any of the fol-
lowing outcomes:(1) death, (2) life-threateningevent, (3) in-
patient hospitalizationor prolongationof an existinghospi-
talization,(4) persistentor significantdisabilityor incapacity,
and/or (5) congenitalanomaly or birth defect. In addition,
importantmedicaleventsthat did not resultin death,werenot
life threatening,or did not requirehospitalizationwere con-
sideredSAEswhen, on the basis of appropriatemedicaljudg-
ment, it was determinedthat they had the potentialto jeop-
ardizethe participant'shealthandmighthaverequiredmedical
or surgicalinterventionto preventone of the outcomeslisted
above [12].
Case attribution. All AE reports receivedat the CDC
throughboth activeand passivesurveillancewerescreenedfor
 Once adequateinformationwas obtainedabout the AE, the
1727participants clinicalprogrammanagerand his staffmade a determination
InProgram
in 35 participants withdrew of whetherthe case met the FDA definitionof an SAE.The
beforestartof 2-month
1 i ia10 I flu orfailedto provide medicalmonitor was selectedbeforethe Program'sinitiation
,----(---- 9 ~ sufficientinformation and was notified of all SAEsby the CDC. He served as an
1692participants fora successful contact
initiallycalledfor independentmedicalconsultantwho was availableto the study
2-month f/u
2-monthf/u-- )390 were staffduringthe entireProgram.AEreportsthatproveddifficult
participants
l ---- ---
unableto be contacted to classifyas either serious or nonseriouswere forwardedto
aftermultipleattempts
1302participants the medicalmonitor for consultation.The medicalmonitor's
successfullycontacted responsibilitiesalso includeddeterminingthe causalrelation-
for 2-month f/u
fo2mothfl f 189participantsdeclined ship betweenSAEsand the treatmentreceivedin the Program.
' ' Inthe
to participate
~I s SAEswere classifiedinto the following6 categories:"unclas-
2-month f/u
1113 participants 2
sifiable,""not related,""unlikely,""possible,""probable,"
and
successfullycompleted
2-monthflu 52 potentialSAEs 10 confirmedSAEs "definite."Casesummariesof all SAEswerethen forwardedto
the CDC'sinstitutionalreviewboardand to the FDA.
Figure 1. Distributionof AnthraxVaccineand AntibioticAvailability
Program at the 2-monthfollow-up(f/u),February-May
participants 2002. RESULTS
SAE,seriousadverseevent.
Openenrollmentinto the Programwas initiatedon 20 Decem-
potential SAEs. The screening was conducted by the clinical ber 2001 and was terminatedon 11 February2002. As of the
program manager or a member of his staff. A broad interpre- terminationdate, a total of 5420 personshad receivedstan-
tation of the case definition of an SAE was used to determine dardizededucationand 1727 persons(32%)had enrolled.Of
whether the report indicated a potential SAE and thereby war- these enrollees,1528 (88%) opted to receiveonly the 40-day
ranted further follow-up. As part of our conservative inter- supply of antibiotictherapy(71%receiveddoxycycline,17%
pretation of persistent or significant disability, all participants receivedciprofloxacin,and 12%receivedamoxicillin)and 199
who reported missing -2 weeks of work were evaluated as enrollees(12%)optedto receivethe 40-daysupplyof antibiotic
having possibly experienced an SAE, and a determination of therapy(55%receiveddoxycycline,36%receivedciprofloxacin,
the cause of the absence was made. If further follow-up was 8%receivedamoxicillin,and 1%receiveda differentantibiotic)
warranted, a member of the clinical program manager's staff plus 3 dosesof AVA.Thesenumbersarebasedon datacollected
attempted to contact the participant to gather additional in- at enrollment.Giventhe natureof this publichealthresponse,
formation about the reported AE, to determine adherence of it is difficultto estimatethe degreeof adherenceor the number
the participant to the prescribed treatment, and to request con- of participantswho completedtheirantibioticregimen.At the
tact information for the participant's health care provider(s). 2-monthpostenrollmentinterval,1302participants(75%)were

71 potential serious adverse events

identified from surveillance methods
(68 total participants)

, , I, ' , 9'
52 from2-month 9 fromCDC 5 from 5 fromdirect
f/u interviews alertlinecalls VAERSreports contactto CDC

CDCand medicalmonitorevaluation
?

10 serious 0 serious 0 serious 2 serious

adverseevents adverseevents adverseevents adverseevents
confirmed confirmed confirmed confirmed

i 1 12 confirmed \
serious adverse events

Figure 2. Sourcesof seriousadverseevents reportedin the AnthraxVaccineand AntibioticsAvailability

Program,December2001-September
2002. CDC,Centersfor Disease Controland Prevention; VaccineAdverseEventReporting
f/u, follow-up;VAERS, System.

SAEsamong Persons in CDC's AVAProgram * CID 2003:37 (1 October) * 907

contactedby phone, and 1113 (64%)respondedto a seriesof
health status and safety-relatedquestions (figure 1). Overall,
35 (2%)of the participantswerenot contactedat the 2-month
follow-up becausethey either voluntarilywithdrewfrom the
Programearlieror could not be reachedbecauseof inadequate
or invalidcontactinformation.An additional390 participants
(23%) could not be reachedby telephone, despite multiple
attemptsto do so at varioustimes of the day.
Initialreviewof all AEreportsfromthe 1727enrolleesiden-
tified 71 reportsof potentialSAEsthat involved68 different
participants.Figure2 illustratesthe distributionof these po-
tential SAEsby each surveillancemethod.Activesurveillance,
usingthe 2-monthfollow-uptelephoneinterview,identified52
potentialSAEs,and passivesurveillance,which included3 dif-
ferentmethods,identifiedanother19 potentialSAEs.Further
evaluationby the clinicalprogrammanagerand medicalmon-
itor foundthatthe AEsexperiencedby 12 of the 68 participants
met the definitionof an SAE(table 1). Analysiswas ongoing
at the time of this writingwith respectto the 59 AEsevaluated
as potentialSAEsand to the other nonseriousAEs that were
identified.AlthoughpotentialSAEswere identifiedby 4 dif-
ferentsurveillancemethods,only those detectedduringthe 2-
month follow-upinterviews(10 cases) and those reportedby
participantswho contactedthe CDC directly(2 cases) com-
prised the AEs that met FDA criteriafor an SAE.These 12
SAEswerefurtherclassifiedon the basisof causalityassessments
as definite (n = 0), probable(n = 1), possible (n = 2), un-
likely (n = 5), not related(n = 4), or unclassifiable(n = 0).
Fromreportsreceivedat the CDCthrough30 September2002,
between0.7% (12 of 1727) and 1.1%(12 of 1113) of partic-
ipantsexperiencedan SAE,regardlessof its relationshipto the
Program.Between0.17% (3 of 1727) and 0.27%(3 of 1113)
of participantsexperiencedan SAEthat had a causalrelation-
ship to the Programthat was classifiedas possibleor probable.
DISCUSSION
This Program,whichwas a partof the emergencypublicheath
responseto the first documentedbioterrorism-associated an-
thrax attack,providedthe first opportunityto evaluateSAEs
associatedwith antimicrobialprophylaxisfor up to 100 days,
with or withoutpostexposureuse of AVAin a 3-dose regimen.
Data collectedthus far indicatethat the rateof reportedSAEs
is low. Therehave been no reporteddeaths,and only 1 par-
ticipant,who receivedantibiotictherapyonly, was identified
with a SAEclassifiedas probablyrelatedto participationin the
Program.Two participants,both of whom receivedantibiotic
therapyonly, reportedhavingSAEsthat wereclassifiedas pos-
siblyassociatedwithprogramparticipation.Theremainingpar-
ticipantsreportedSAEsthat were classifiedas eitherunrelated

Table 1. Characteristics of 12 participantswith serious adverse events in the AnthraxVaccine and Antibiotics
Availability Programfrom December 2001 through September 2002.

Date on which
the clinical
Participant Prophylaxis Causality programmanager
Case age, years Sex received Primarycomplaint(s) assessment was notified
1 44 F Ciprofloxacin Nausea, allergicinterstitialnephritis Probable 24 Jan
2 56 F Doxycycline Abdominalpain,extended work Possible 30 Jan
absence
3 46 M Doxycycline Liverproblems Not related 26 Feb
4 40 M Doxycycline Depression,extended work absence Not related 27 Feb
5 59 F Doxycycline Fatigue,malaise, hypertension, Unlikely 2 Mar
extended
work absence
6 49 M Doxycycline Allergicreactionto ciprofloxacin Not related 4 Mar
7 58 F Doxycycline Bowel obstruction Not related 22 Mar
8 41 M Amoxicillin Chronicsporadicdiarrhea,extended Unlikely 1 Apr
work absence
9 46 M Doxycycline Nausea, back pain,anxiety, Unlikely 1 Apr
extended
work absence
10 50 F Amoxicillina Vomiting,rectal-vaginal
prolapse Unlikely 4 Apr
11 42 M Amoxicillina New-onset type IIdiabetes mellitus, Unlikely 1 May
extended work absence
12 53 F Doxycycline Diarrhea,chest pain Possible 20 May
a also receivedanthraxvaccine.
Participant

908 * CID 2003:37 (1 October) * Tierneyet al.

 Started Entered Hospitalizedfor Renal
prophylaxis1 program4 renal failure5 biopsy6
Pruritic
2 Increasing nausea3
Ciprofoxacin
Ciprofloxacin
Doxycycline

20 25 5 10 15 20 25 5 10 15 20 25 5 10 15 20 25
OCTOBER 2001 NOVEMBER DECEMBER JANUARY 2002

1. Began 10-day course of ciprofloxacin (500-mg b.i.d) for anthrax antimicrobial prophylaxis.
2. Changed to doxycycline(100-mg b.i.d) for remaining 50 days but developed pruritic rash 2 days later. Recommenced
on ciprofloxacin.
3. Participant often took ciprofloxacin only once per day as nausea worsened.
4. Received additional 40-day supply of clprofloxacin. Discontinued medication after 3 days due to continued nausea.
5. Went to emergency department for continued severe nausea. Admission diagnosis of acute renal failure. Received
ciprofloxacin 500-mg q.d. while in the hospital.
6. Renal biopsy showed allergic Interstitial nephritis consistent with ciprofloxacin nephrotoxicity and hypertensive
nephrosclerosls.

Figure3. of the seriousadverseeventfora participant

Timeline Vaccine
(case1)fromtheAnthrax andAntibiotics
Availability
Program

or unlikelyto be associatedwith participationin the Program;
this group included the 2 participantswho receivedpost-
exposureAVA.
Of the 5420peopleeducatedaboutthe Program,1727(32%)
electedto participate;this was a lowernumberof participants
than had been expected.Factorsthat may have resultedin a
relativelylow participationrateincludedpersonalperceptionof
risk,whetherthe programbeganduringor afterthe completion
willingnessto complywithspe-
of initialantibioticprophylaxis,
cific informedconsent requirementsassociatedwith investiga-
tional new drugs,and level of encouragement for participation
receivedfrom supervisorsand managementacrosssubgroups.
Of 1727 participantsinitiallyenrolledin the Program,1113
(64%)successfullycompletedthe 2-monthfollow-upinterview.
The interviewwas the most effectivemeansof identifyingboth
potentialand confirmedSAEs(figure2). However,additional
SAEsmayhavegone unrecognizedamongthe participantswho
eithercould not be contactedor declinedto participatein the
interviews.Becausethis Programwas part of an emergency
public health response and was not a researchstudy, some
participantslost to follow-upmayhaveenrolledto receivepro-
phylaxisonly and were possiblyless motivatedto participate
in the follow-upinterview.
One of the FDA'scriteriafor an SAEwas a persistentor
significantdisabilityor incapacitation.Althoughmissedwork
alonewas not expresslystatedas partof the FDAdefinitionof
an SAE,the clinicalprogrammanagerand his medicalstaff,
workingwith the medicalmonitor,consideredsignificantloss
of work to be a possible indicatorof significantdisabilityor
incapacitation.Participantsmissing >2 weeks of work were
evaluatedas havingexperienceda potentialSAE.Six (50%)of
the 12 participantswith confirmedSAEswereclassifiedassuch,
in part becauseof their extendedabsencefrom work. Only 1
SAEamong these 6 was classifiedas possiblyassociatedwith
the Program,and the remaining5 were classifiedas either
unlikelyto be relatedor not related.Thisindicatorof potential
SAEswas time dependent,and activesurveillancewith the 2-
month follow-up interviewproved valuablefor recognizing
these potentialSAEs.
The CDC received71 notificationsof potentialSAEsthat
involved68 participants.The CDC received2 separateAE re-
portsfor 3 participants.Twoof these3 participantshadreports
that did not meet the criteriafor a confirmedSAEaftereval-
uation of the AE reports.The thirdparticipantwas identified
as havinga confirmedSAEafterreceiptof a secondAE report
duringthe 2-month follow-upinterview.This participantwas
1 of the 6 with confirmedSAEswho was absentfrom work
for an extendedperiodof time.
Of the 12 participantswith confirmedSAEs,2 (17%) had
receivedboth antibioticsand AVA.This is likelya reflectionof
the overalldistributionof participants'enrollmentin the Pro-
gram.The SAEsreportedfor the 2 participantswho received
AVAwereeach classifiedas unlikelyto be associatedwith their
participationin the Program.The abilityto assign causality
may have been limited in some casesby incompleteor inac-
curate information.For each SAE,an attemptwas made to
contactthe participant'shealthcareprovider(s)to obtainfur-
ther informationabout the SAE,but some participantswith-
drewpermissionto contacttheir health careprovider(s).Ad-
ditionally,therewereseveralcasesin whichthe CDCwasunable
to directlycontactthe participantfor furtherfollow-upques-
tioning. As a result of these limitations,a number of these
causalityassignmentswere regardedas provisionaland will be
reevaluatedpendingthe availabilityof additionalinformation.
Of the 9 participantsdeterminedto have an SAEthat was
either unrelatedor unlikelyto be relatedto the prophylaxis

SAEsamong Persons in CDC's AVAProgram * CID 2003:37 (1 October) * 909

 (hematoxyin-eosin
stain;originalmagnification,
x400).
in the Anthrax
withparticipation VaccineandAntibiotic
Availability showingacuteandchronic
Program
occasional
infiltrate,
lymphocytic edema,basement
(arrow),
eosinophils membrane
thickening,
stain;originalmagnification,
(hematoxylin-eosin X400).
providedin the Program,8 had SAEsthat were classifiedas
such, in part becauseof symptomsor medicalproblemsthat
haddevelopedbeforeenrollmentin the Program.Sevenof these
8 participantshad symptomsthat may have resultedin whole
or in part from antimicrobialprophylaxistakenbeforeenroll-
ment in the Program.This supportsthe findingsof Shepard
et al. [10] in theirevaluationof adherenceandAEsexperienced
by personsreceivingantimicrobialprophylaxisfor an initial60
days.Specifically, the occurrenceof AEsduringthe first60 days
of prophylaxisdid not appearto serve as a deterrentto the
decision to enroll in the Program.These investigatorsalso
found that the factormost consistentlyassociatedwith adher-
ence was participationin the Program,and this wasinterpreted
as a surrogatefor the perceptionof individualrisk.
Informationon the expectedoccurrenceof SAEsassociated
with antimicrobialtherapyused in this Programis limited.AEs
requiringdiscontinuationof ciprofloxacinoccurredin 3.5%of
participantsincluded in clinical trials [13]. Gastrointestinal
eventswerethe most common AE reported.Pseudomembran-
ous colitis has been reported with nearly all antimicrobial
agents,includingciprofloxacin,and mayrangein severityfrom
910 * CID 2003:37 (1 October) * Tierneyet al.
tubulointerstitial
nephritiswithdiffuse
andfibrosis
consistent
withallergicinterstitial
nephritis
mild to life threatening.A reviewof AE ratesamong partici-
pantswho receivedlong-term(>30-day)ciprofloxacintherapy
in clinicaltrialsfound an overallAE rate of 32%and a rateof
gastrointestinalAEs of 22%,althoughno pseudomembranous
colitisor previouslyunrecognizedAEwas observed[14]. Renal
toxicity,includinginterstitialnephritis,was also reportedas a
rare but possible SAE associatedwith ciprofloxacinuse, al-
thoughthe dataconsistprimarilyof casereports,whichmakes
the incidence of SAEsdifficultto estimate [15]. The rate of
potentialSAEsassociatedwith doxycyclineis also not clearly
defined.In severalsmallstudies,the rateof AEsassociatedwith
doxycyclinehas rangedfrom 30%to as high as 50%,with rates
of nauseaand vomitingof 31% [16-19]. SAEsassociatedwith
amoxicillinhaveessentiallybeen limitedto sensitivityphenom-
ena, althoughpseudomembranouscolitismay also occur [13].
SAEsassociatedwith AVAthatwerereportedto VAERSwere
evaluatedrecentlyby the AnthraxVaccineExpertCommittee.
The committeedid not find a high frequencyor an unusual
patternof SAEsassociatedwith AVA[20]. A recentreportfrom
the Instituteof Medicine of the NationalAcademies(Wash-
ington, DC) that evaluatedavailablepublishedreportsof AEs
after receiptof AVAfound no evidencethat SAEs,including
life-threatening or permanentlydisablingimmediate-onsetAEs,
occurredat higherratesamongAVArecipients,comparedwith
ratesamong the generalpopulation[21].
Detaileddescriptionsfor all casesand furthercasediscussion
can be found in AppendixA, includedin the online version
of this article in the electronicedition of ClinicalInfectious
Diseases.ThroughSeptember2002, only 1 SAE (case 1) has
been determinedto be probablyassociatedwiththe individual's
participationin the Program(the participantreceivedcipro-
floxacinonly; figure3). After a renalbiopsy was performed,
this participantreceiveda diagnosisof acuterenalfailuresec-
ondaryto allergicinterstitialnephritisand underlyingchronic
hypertensivenephropathy(figure4). TheSAEsof 2 participants
were determinedto be possiblyassociatedwith their partici-
pation in the Program.
In summary,12 participantshave been identifiedwith an
AE that satisfiedthe FDAcriteriafor an SAE.Of these,2 SAEs
were assessedas possibly and 1 as probablyassociatedwith
treatmentreceivedin the Program.Follow-upof these 3 par-
ticipantsby the CDC was ongoingat the time of this writing.
Activesurveillanceby directtelephonecontactwithparticipants
has been the single most importanttool for identifyingSAEs
amongparticipantsin the Program.CDCwillcontinueto mon-
itor the healthand safetyof all Programparticipantsby active
surveillancethroughtelephonefollow-upcalls scheduledat 6,
12, and 24 months afterenrollment.The CDC will use infor-
mationcollectedfromthe Programto betterrefinefutureemer-
gencypublichealthresponsesand programs.
Acknowledgments
We thank Dr. IbikunleKoya (BaltimoreRenalAssociates,
Baltimore,MD) and Dr. Joseph P. Grande (Departmentof
LaboratoryMedicineand Pathology,Mayo Clinic,Rochester,
MN), for theirassistancewith caseinformation;LouisApicella
and KellyBell (Division of Data Management,NationalIm-
munizationProgram),for their assistancewith data manage-
ment; and the many people who volunteeredtheir time and
effortto makethe AnthraxVaccineand AntibioticsAvailability
Programpossible.
References
An additional reference, cited only in Appendix A, appears in the
electronic version of this article as item 22 in the referencelist.
1. Centers for Disease Control and Prevention.Update: investigationof
bioterrorism-relatedanthrax-Connecticut, 2001. MMWRMorbMor-
tal Wkly Rep 2001;50:1077-9.
SAEsamong Persons in CDC's AVAProgram * CID 2003:37 (1 October) ? 911
2. JerniganDB, RaghunathanPL, Bell BP, et al. Investigationof bioter-
rorism-relatedanthrax, United States, 2001: epidemiologic findings.
Emerg Infect Dis 2002;8:1019-28.
3. Centers for Disease Control and Prevention. Use of anthraxvaccine
in response to terrorism:supplementalrecommendationsof the Ad-
visory Committee on Immunization Practices.MMWR Morb Mortal
Wkly Rep 2002;51:1024-6.
4. InglesbyTV, Henderson DA, BartlettJG, et al. Anthraxas a biological
weapon: medical and public health management. JAMA 1999;281:
1735-45.
5. Centers for Disease Control and Prevention. Use of anthraxvaccine
in the United States. MMWR Recomm Rep 2000;49(RR-15):1-20.
6. HendersonDW, PeacockS, BeltonFC.Observationson the prophylaxis
of experimentalpulmonary anthrax in the monkey. J Hyg 1956;54:
28-36.
7. FriedlanderAM, WelkosSL,Pitt MLM,et al. Postexposureprophylaxis
against experimental inhalation anthrax. J Infect Dis 1993;167:
1239-42.
8. KournikakisB, Armour SJ, Boulet CA, Spence M, Barsons B. Risk
assessment of anthrax threat letters. TR-2001-048. Suffield, Canada:
Defense ResearchEstablishmentSuffield,2001.
9. Centers for Disease Control and Prevention. Update: adverse events
associated with anthrax prophylaxisamong postal employees-New
Jersey,New York,and the Districtof Columbiametropolitanarea,2001.
MMWR Morb Mortal Wkly Rep 2001;50:1051-4.
10. ShepardCW, Soriano-GabarroM, Zell ER, et al. Antimicrobialpost-
exposureprophylaxisfor anthrax:adverseeventsand adherence.Emerg
Infect Dis 2002;8:1124-32.
11. Centersfor DiseaseControland Prevention.Notice to readers:Additional
options for preventivetreatment for persons exposed to inhalational
anthrax.MMWR Morb Mortal Wkly Rep 2001;50:1142.Availableat:
http://www.cdc.gov/mmwr/preview/mmwrhtmlmm5050a5.htm.
12. Expeditedsafetyreportingrequirementsfor human drugand biological
products.In: Federalregister.Vol62. Washington,DC:US Government
Printing Office, 1997.
13. In: Physiciansdesk reference.Available(to subscribersonly) at: http:
//www.pdrel.thomsonhc.com.Accessed 16 December 2002.
14. SegevS, YanivI, HaverstockD, ReinhartM. Safetyof long-termtherapy
with ciprofloxacin:data of controlled clinical trials and review. Clin
Infect Dis 1999;28:299-308.
15. LomaestroBM. Fluoroquinolone-inducedrenalfailure.Drug Saf2000;
22:479-85.
16. Bryant SG, Fisher S, Kluge RM. Increasedfrequencyof doxycycline
side effects. Pharmacotherapy1987;7:125-9.
17. Ragnar NS. Atypical pneumonia in Nordic countries: aetiology and
clinical resultsof a trial comparingfleroxacinand doxycycline.J Anti-
microb Chemother 1997;39:499-508.
18. Raoult D, Houpikian P, Tissot Dupont H, Riss JM, Arditi-DjianeJ,
Brouqui P. Treatmentof Q fever endocarditis:comparison of 2 regi-
mens containing doxycycline and ofloxacin or hydroxychloroquine.
Arch Intern Med 1999;159:167-73.
19. SchuhwerkM, BehrensRH. Doxycyclineas first line malarialprophy-
laxis: how safe is it? J TravelMed 1998;5:102.
20. SeverJL,BrennerAI, Gale AD, LyleJM, Moulton LH, West DJ. Safety
of anthraxvaccine:a reviewby the AnthraxVaccineExpertCommittee
(AVEC)of adverseevents reported to the VaccineAdverseEvent Re-
porting System (VAERS).Anthrax Vaccine Expert Committee. Phar-
macoepidemiol Drug Saf 2002; 11:189-202.
21. JoellenbeckLM, ZwanzigerLL, Durch JS, Strom BL, eds. Committee
to assessthe safetyand efficacyof anthraxvaccine.The anthraxvaccine:
is it safe? Does it work? Washington, DC: National Academy Press,
2002.