anthrax vaccine research participant outcome

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Serious Adverse Events among Participants in the Centers for Disease Control andPrevention's Anthrax Vaccine and Antimicrobial Availability Program for Persons at Risk forBioterrorism-Related Inhalational AnthraxAuthor(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.McNeilSource: Clinical Infectious Diseases, Vol. 37, No. 7 (Oct. 1, 2003), pp. 905-911Published by: The University of Chicago PressStable URL: http://www.jstor.org/stable/4462615Accessed: 04/11/2009 05:16

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ommendedthe use of antibioticsin combinationwithAnthraxVaccineAdsorbed(AVA;Bioport),if available.In December2001, the US Departmentof Defense releasedAVAfor im-mediatepurchasebythe USDepartmentofHealthand HumanServices(DHHS)forthe AnthraxVaccineand AntibioticAvail-abilityprogram(hereafterreferredto as "theProgram").TheCDCmadethe Programavailableon the basis of severalad-ditionalconsiderations.First,datasuggestthat the sporeformof theorganism,whichis unaffectedbyantibiotictherapy,maypersistfor>60daysbeforegerminatingandcausinginhalationalanthrax[6, 7]; this maybe a greaterconcernamongpersonswithhigh-levelexposure.A recentsimulationstudyin Canadaindicatedahigher-than-expectedpotentialfor disseminationofa largenumberof sporeson the basisof the passiveopeningof a contaminatedenvelope[8]. Second,problemswith ad-herenceto antibiotictherapywere documentedamongthosefor whom 60 daysof antibioticprophylaxiswas initiallyrec-ommended[9, 10], whichpotentiallydecreasedthe effective-nessof suchtherapy.Finally,the objectiveof the CDC and theDHHSis to useall availablemeansto reducethe riskof diseasefor exposedindividuals.Thus,in October2001,the CDCfiledaninvestigationalnewdrugapplicationwith the US Food andDrugAdministration(FDA)to allowfor off-labeluse of antibiotics,as well asAVA,shoulditbecomeavailable.On20 December2001,theProgramwas initiatedto provideoptionsforadditionalpreventivetreat-ment of personswho had potentialsignificantexposureto B.anthracisand for whom 60 daysof antibioticprophylaxiswasrecommended[11].Participantswho enrolledin the Programwere given a choice between2 options intendedto provideprotectionagainstthepossibilitythatB.anthracissporesmightcauseillnessup to 100daysafterexposure:(1) 40 additionaldays of antimicrobialprophylaxis(with ciprofloxacin,doxy-cycline,or amoxicillin),or (2) 40 additionaldaysof antimi-crobialprophylaxisplus3 doses of AVAadministeredat 2-weekintervalsduringa 4-weekperiod(i.e., duringvisits on weeks0, 2, and4 of the Program).TheProgramenrolledpersonswhowereexposedataffectedUSPostalServicefacilities,affectedgovernmentofficesandmailfacilities,and other affectedbusinesslocationsin 6 statesandWashington,D.C. In some cases, exposed persons requiredtransitionalantibiotictreatment,rangingfrom 1 to 16daysinduration,until educationregardingProgramoptionscouldbeprovidedandProgramenrollmentprocedurescouldbe imple-mented.Becauseparticipantswererequiredto signan informedconsentdocumentatenrollment,it wasimportantto allowforan adequateopportunityfor educationaboutProgramtreat-mentoptions.Theprotocolfor thisProgramwasreviewedandapprovedby an institutionalreviewboardat the CDC.

METHODSSurveillancefor adverseevents(AEs). SafetymonitoringofProgramparticipantsoccurredvia bothpassiveand activesur-veillanceactivities.Passivesurveillancefor AEswas conductedvia the CDC "alertline"(a CDC-sponsored,24-h,7-days-per-weekhotlineestablishedforProgramparticipants).Participantswereprovideda cardwith the alertlinenumberat enrollmentand wereencouragedto reportanysuspectedAEsto the alert-line at anytime and at each clinicvisit.Participantswerealsoaskedto provideinformationaboutlocalandsystemicAEsthatoccurredduringthe 6-weekperiodafterenrollment,usingdi-ariesprovidedto them at enrollment.In addition,allpartici-pantswere advisedto reportAEsto the VaccineAdverseEventReportingSystem(VAERS)and/orMedWatchsystem-both ofwhicharepassivesurveillancesystems-aftervaccinationor useof antibiotics.An alternativepassivesurveillancemethodusedby participantswas directcontactwith the CDCvia mailand/or telephonecontact other than the CDC alertlinenumber.Active surveillancewas conductedby interviewingallpartici-pantsduringeach of 3 scheduledclinic visits (duringenroll-mentand2-weekand 4-weekfollow-upvisits)aboutanysus-pected AEs. Additional active surveillancewas conductedthrougha telephonesurveyperformed2 monthsafterenroll-ment to solicitresponsesto a seriesof healthstatusandsafety-relatedquestions.Additionaltelephonesurveysareplannedfor6, 12,and 24 monthsafterenrollment.Case definitions. Accordingto FDA reportingrequire-ments,an AE is definedas anyuntowardmedicaloccurrencein a participantwho was administeredaninvestigationaldrug,includingvaccine,whichmayhavebut did not necessarilyhavea causalrelationshipto the treatment.An AE,therefore,canbe anyunfavorableand unintendedsign (includinglaboratoryfindings),symptom,or diseasetemporallyassociatedwiththeuse of the investigationaltherapy(e.g.,a specificlot of AVA),whetheror not the AEwas casuallyassociatedwith the studytherapy[12].A seriousAE(SAE)was definedasanyuntowardmedicaloccurrencethatmayhave resultedin anyof the fol-lowingoutcomes:(1) death,(2) life-threateningevent,(3) in-patient hospitalizationor prolongationof an existinghospi-talization,(4) persistentor significantdisabilityor incapacity,and/or (5) congenitalanomalyor birth defect.In addition,importantmedicaleventsthatdid not resultin death,werenotlife threatening,or did not requirehospitalizationwerecon-sideredSAEswhen,on the basisof appropriatemedicaljudg-ment, it was determinedthat theyhad the potentialto jeop-ardizetheparticipant'shealthandmighthaverequiredmedicalor surgicalinterventionto preventone of the outcomeslistedabove[12].Case attribution. All AE reportsreceivedat the CDCthroughboth activeandpassivesurveillancewerescreenedfor

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


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1727participantsin Program 35 participantswithdrewInProgram beforestartof 2-month1 i a10i I fluorfailedto provide,----(---- 9 ~ sufficientinformation1692participants fora successful contactinitiallycalledfor2-monthf/u2-monthf/u-- )390 participantswerel unableto becontacted---- --- aftermultipleattempts1302participantssuccessfullycontactedfor 2-monthf/ufo2mothfl f 189participantsdeclined' '~I s to participateInthe2-monthf/u1113participants 2successfullycompleted2-monthflu 52potentialSAEs 10 confirmedSAEs

Figure 1. Distributionof AnthraxVaccineandAntibioticAvailabilityProgramparticipantsat the 2-monthfollow-up(f/u),February-May2002.SAE,seriousadverseevent.

potential SAEs. The screening was conducted by the clinicalprogram manager or a member of his staff. A broad interpre-tation of the case definition of an SAE was used to determinewhether the report indicated a potential SAE and therebywar-ranted further follow-up. As part of our conservative inter-pretation of persistent or significant disability, all participantswho reported missing -2 weeks of work were evaluated ashaving possibly experienced an SAE, and a determination ofthe cause of the absence was made. If further follow-up waswarranted, a member of the clinical program manager's staffattempted to contact the participant to gather additional in-formation about the reported AE, to determine adherence ofthe participant to the prescribedtreatment, and to requestcon-tact information for the participant's health care provider(s).

Once adequateinformationwas obtainedabout the AE,theclinicalprogrammanagerand his staffmadea determinationof whetherthe case met the FDAdefinitionof an SAE.Themedicalmonitor was selectedbeforethe Program'sinitiationand was notified of all SAEsby the CDC. He served as anindependentmedicalconsultantwho wasavailableto thestudystaffduringthe entireProgram.AEreportsthatproveddifficultto classifyas eitherserious or nonseriouswereforwardedtothe medicalmonitor for consultation.The medicalmonitor'sresponsibilitiesalso includeddeterminingthe causalrelation-shipbetweenSAEsandthetreatmentreceivedin theProgram.SAEswereclassifiedinto the following6 categories:"unclas-sifiable,""notrelated,""unlikely,""possible,""probable,"and"definite."Casesummariesof allSAEswerethen forwardedtothe CDC'sinstitutionalreviewboardandto the FDA.

RESULTSOpenenrollmentinto theProgramwas initiatedon 20 Decem-ber 2001 andwas terminatedon 11 February2002. As of theterminationdate,a total of 5420 personshad receivedstan-dardizededucationand 1727persons(32%)had enrolled.Ofthese enrollees,1528 (88%)optedto receiveonly the 40-daysupplyof antibiotictherapy(71%receiveddoxycycline,17%receivedciprofloxacin,and 12%receivedamoxicillin)and 199enrollees(12%)optedto receivethe40-daysupplyof antibiotictherapy(55%receiveddoxycycline,36%receivedciprofloxacin,8%receivedamoxicillin,and1%receivedadifferentantibiotic)plus3 doses of AVA.Thesenumbersarebasedon datacollectedat enrollment.Giventhe natureof thispublichealthresponse,it is difficultto estimatethedegreeof adherenceor the numberof participantswho completedtheirantibioticregimen.At the2-monthpostenrollmentinterval,1302participants(75%)were

71 potential serious adverse eventsidentified from surveillance methods(68 total participants)

, , I, ' , 9'52from2-month 9 fromCDC 5 from 5 fromdirectf/u interviews alertlinecalls VAERSreports contactto CDCCDCandmedicalmonitorevaluation?

10 serious 0 serious 0 serious 2 seriousadverseevents adverseevents adverseevents adverse eventsconfirmed confirmed confirmed confirmedi 1 12 confirmed \serious adverse events

Figure 2. Sourcesof seriousadverseevents reportedin the AnthraxVaccineand AntibioticsAvailabilityProgram,December2001-September2002.CDC,CentersforDisease ControlandPrevention;f/u, follow-up;VAERS,VaccineAdverseEventReportingSystem.

SAEsamong Personsin CDC'sAVAProgram* CID 2003:37 (1 October) * 907


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contactedby phone,and 1113(64%)respondedto a seriesofhealth statusand safety-relatedquestions (figure1). Overall,35 (2%)of theparticipantswerenot contactedat the2-monthfollow-upbecausethey eithervoluntarilywithdrewfromtheProgramearlieror couldnot be reachedbecauseof inadequateor invalidcontactinformation.An additional390participants(23%)could not be reachedby telephone,despite multipleattemptsto do so at varioustimesof the day.Initialreviewof allAEreportsfromthe 1727enrolleesiden-tified71 reportsof potentialSAEsthat involved68 differentparticipants.Figure2 illustratesthe distributionof thesepo-tential SAEsby each surveillancemethod.Activesurveillance,usingthe 2-monthfollow-uptelephoneinterview,identified52potentialSAEs,andpassivesurveillance,whichincluded3 dif-ferentmethods,identifiedanother19potentialSAEs.Furtherevaluationby the clinicalprogrammanagerand medicalmon-itorfound thattheAEsexperiencedby 12of the68participantsmet the definitionof an SAE(table 1). Analysiswasongoingat the time of thiswritingwithrespectto the 59 AEsevaluatedas potentialSAEsand to the othernonseriousAEs thatwereidentified.AlthoughpotentialSAEswere identifiedby 4 dif-ferentsurveillancemethods,onlythosedetectedduringthe 2-month follow-upinterviews(10 cases)andthosereportedbyparticipantswho contactedthe CDC directly(2 cases)com-prisedthe AEs that met FDA criteriafor an SAE.These 12

SAEswerefurtherclassifiedon the basisofcausalityassessmentsas definite(n = 0), probable(n = 1), possible(n = 2), un-likely (n = 5), not related(n = 4), or unclassifiable(n = 0).Fromreportsreceivedat the CDCthrough30September2002,between0.7%(12 of 1727)and 1.1%(12 of 1113)of partic-ipantsexperiencedan SAE,regardlessof its relationshipto theProgram.Between0.17%(3 of 1727)and 0.27%(3 of 1113)of participantsexperiencedan SAEthat hada causalrelation-shipto the Programthat was classifiedaspossibleorprobable.DISCUSSIONThisProgram,whichwasa partof theemergencypublicheathresponseto the firstdocumentedbioterrorism-associatedan-thraxattack,providedthe firstopportunityto evaluateSAEsassociatedwith antimicrobialprophylaxisfor up to 100days,with or withoutpostexposureuse of AVAin a 3-doseregimen.Data collectedthusfarindicatethat the rate of reportedSAEsis low. Therehave been no reporteddeaths,and only 1 par-ticipant,who receivedantibiotictherapyonly,was identifiedwith a SAEclassifiedasprobablyrelatedto participationin theProgram.Twoparticipants,both of whom receivedantibiotictherapyonly, reportedhavingSAEsthat were classifiedaspos-siblyassociatedwithprogramparticipation.Theremainingpar-ticipantsreportedSAEsthat were classifiedas eitherunrelated

Table 1. Characteristics of 12 participantswith serious adverse events in the AnthraxVaccine and AntibioticsAvailability ProgramfromDecember2001throughSeptember2002.Date on which

the clinicalParticipant Prophylaxis Causality programmanagerCase age, years Sex received Primarycomplaint(s) assessment was notified1 44 F Ciprofloxacin Nausea,allergicinterstitialnephritis Probable 24 Jan2 56 F Doxycycline Abdominalpain,extended work Possible 30 Janabsence3 46 M Doxycycline Liverproblems Not related 26 Feb4 40 M Doxycycline Depression,extended work absence Not related 27 Feb5 59 F Doxycycline Fatigue,malaise,hypertension, Unlikely 2 Marextendedworkabsence6 49 M Doxycycline Allergicreactionto ciprofloxacin Not related 4 Mar7 58 F Doxycycline Bowel obstruction Not related 22 Mar8 41 M Amoxicillin Chronicsporadicdiarrhea,extended Unlikely 1 Aprworkabsence9 46 M Doxycycline Nausea, backpain,anxiety, Unlikely 1 Aprextendedworkabsence10 50 F Amoxicillina Vomiting,rectal-vaginalprolapse Unlikely 4 Apr11 42 M Amoxicillina New-onsettype IIdiabetes mellitus, Unlikely 1 Mayextended workabsence12 53 F Doxycycline Diarrhea,chest pain Possible 20 May

a Participantalso receivedanthraxvaccine.



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Started Entered Hospitalizedfor Renalprophylaxis1 program4 renal failure5 biopsy6Pruritic

Ciprofoxacin2 Increasing nausea3

CiprofloxacinDoxycycline

20 25 5 10 15 20 25 5 10 15 20 25 5 10 15 20 25OCTOBER 2001 NOVEMBER DECEMBER JANUARY 20021. 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. Recommencedon 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. Receivedciprofloxacin 500-mg q.d. while in the hospital.6. Renal biopsy showed allergic Interstitial nephritis consistent with ciprofloxacin nephrotoxicity and hypertensivenephrosclerosls.

Figure3. Timelineof theseriousadverseeventfora participant(case1)fromthe AnthraxVaccineandAntibioticsAvailabilityProgramor unlikelyto be associatedwithparticipationin theProgram;this group included the 2 participantswho receivedpost-exposureAVA.Ofthe 5420peopleeducatedabouttheProgram,1727(32%)electedto participate;thiswas a lower numberof participantsthan had been expected.Factorsthat may have resultedin arelativelylowparticipationrateincludedpersonalperceptionofrisk,whethertheprogrambeganduringor afterthecompletionof initialantibioticprophylaxis,willingnessto complywithspe-cific informedconsentrequirementsassociatedwithinvestiga-tionalnewdrugs,andlevel of encouragementforparticipationreceivedfromsupervisorsandmanagementacrosssubgroups.

Of 1727participantsinitiallyenrolledin the Program,1113(64%)successfullycompletedthe 2-monthfollow-upinterview.The interviewwas the most effectivemeansof identifyingbothpotentialand confirmedSAEs(figure2). However,additionalSAEsmayhavegone unrecognizedamongtheparticipantswhoeithercouldnot be contactedor declinedto participatein theinterviews.Becausethis Programwas part of an emergencypublic healthresponseand was not a researchstudy,someparticipantslost to follow-upmayhaveenrolledto receivepro-phylaxisonly and werepossiblyless motivatedto participatein the follow-upinterview.

One of the FDA'scriteriafor an SAEwas a persistentorsignificantdisabilityor incapacitation.Althoughmissedworkalone wasnot expresslystatedaspartof the FDAdefinitionofan SAE,the clinicalprogrammanagerand his medicalstaff,workingwith the medicalmonitor,consideredsignificantlossof work to be a possibleindicatorof significantdisabilityorincapacitation.Participantsmissing>2 weeks of work wereevaluatedashavingexperienceda potentialSAE.Six(50%)ofthe 12participantswith confirmedSAEswereclassifiedassuch,in partbecauseof their extendedabsencefrom work.Only1

SAEamongthese6 was classifiedas possiblyassociatedwiththe Program,and the remaining5 were classifiedas eitherunlikelyto be relatedor not related.ThisindicatorofpotentialSAEswas time dependent,and activesurveillancewiththe 2-month follow-up interviewprovedvaluablefor recognizingthesepotentialSAEs.The CDC received71 notificationsof potentialSAEsthatinvolved68 participants.TheCDC received2 separateAEre-portsfor 3 participants.Twoof these3 participantshadreportsthat did not meet the criteriafor a confirmedSAEaftereval-uation of the AEreports.The thirdparticipantwas identifiedashavinga confirmedSAEafterreceiptof a secondAEreportduringthe 2-monthfollow-upinterview.Thisparticipantwas1 of the 6 with confirmedSAEswho was absent fromworkfor an extendedperiodof time.Of the 12 participantswith confirmedSAEs,2 (17%)hadreceivedboth antibioticsandAVA.This is likelya reflectionofthe overalldistributionof participants'enrollmentin the Pro-gram.The SAEsreportedfor the 2 participantswho receivedAVAwere each classifiedas unlikelyto be associatedwith theirparticipationin the Program.The abilityto assign causalitymayhave been limitedin some casesby incompleteor inac-curateinformation.For each SAE,an attemptwas made tocontactthe participant'shealthcareprovider(s)to obtainfur-therinformationabout the SAE,but some participantswith-drewpermissionto contacttheir health careprovider(s).Ad-ditionally,therewereseveralcasesin whichthe CDCwasunableto directlycontactthe participantfor furtherfollow-upques-tioning. As a resultof these limitations,a number of thesecausalityassignmentswereregardedasprovisionalandwillbereevaluatedpendingthe availabilityof additionalinformation.Of the 9 participantsdeterminedto have an SAEthat waseitherunrelatedor unlikelyto be relatedto the prophylaxis

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withparticipationinthe AnthraxVaccineandAntibioticAvailabilityProgramshowingacuteandchronictubulointerstitialnephritiswithdiffuselymphocyticinfiltrate,occasionaleosinophils(arrow),edema,basementmembranethickening,andfibrosisconsistentwithallergicinterstitialnephritis(hematoxyin-eosinstain;originalmagnification,x400).

(hematoxylin-eosinstain;originalmagnification,X400).

providedin the Program,8 had SAEsthat were classifiedassuch, in partbecauseof symptomsor medicalproblemsthathaddevelopedbeforeenrollmentintheProgram.Sevenof these8 participantshadsymptomsthatmayhave resultedin wholeor in partfrom antimicrobialprophylaxistakenbeforeenroll-ment in the Program.This supportsthe findingsof Shepardet al. [10]in theirevaluationof adherenceand AEsexperiencedbypersonsreceivingantimicrobialprophylaxisfor an initial60days.Specifically,the occurrenceof AEsduringthe first60daysof prophylaxisdid not appearto serveas a deterrentto thedecision to enroll in the Program.These investigatorsalsofound that the factormost consistentlyassociatedwith adher-ence wasparticipationin theProgram,and this wasinterpretedas a surrogatefor the perceptionof individualrisk.Informationon the expectedoccurrenceof SAEsassociatedwithantimicrobialtherapyusedin thisProgramis limited.AEsrequiringdiscontinuationof ciprofloxacinoccurredin 3.5%ofparticipantsincluded in clinical trials [13]. Gastrointestinaleventswere the most common AEreported.Pseudomembran-ous colitis has been reportedwith nearlyall antimicrobialagents,includingciprofloxacin,andmay rangein severityfrom

mild to life threatening.A reviewof AEratesamongpartici-pantswho receivedlong-term(>30-day)ciprofloxacintherapyin clinicaltrialsfoundan overallAE rate of 32%and a rate ofgastrointestinalAEs of 22%,althoughno pseudomembranouscolitis or previouslyunrecognizedAEwas observed[14].Renaltoxicity,includinginterstitialnephritis,was alsoreportedas arare but possibleSAE associatedwith ciprofloxacinuse, al-thoughthe dataconsistprimarilyof casereports,which makesthe incidence of SAEs difficultto estimate[15]. The rate ofpotentialSAEsassociatedwith doxycyclineis also not clearlydefined.In severalsmallstudies,the rateof AEsassociatedwithdoxycyclinehasrangedfrom30%to ashighas50%,withratesof nauseaandvomitingof 31%[16-19]. SAEsassociatedwithamoxicillinhaveessentiallybeen limitedto sensitivityphenom-ena,althoughpseudomembranouscolitismayalso occur[13].SAEsassociatedwith AVAthat werereportedto VAERSwereevaluatedrecentlyby the AnthraxVaccineExpertCommittee.The committee did not find a high frequencyor an unusualpatternof SAEsassociatedwithAVA[20].A recentreportfromthe Instituteof Medicine of the National Academies(Wash-ington,DC) that evaluatedavailablepublishedreportsof AEs



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afterreceiptof AVAfound no evidencethat SAEs,includinglife-threateningorpermanentlydisablingimmediate-onsetAEs,occurredathigherratesamongAVArecipients,comparedwithratesamongthe generalpopulation[21].Detaileddescriptionsfor all casesand furthercasediscussioncan be found in AppendixA, includedin the online versionof this article in the electronicedition of ClinicalInfectiousDiseases.ThroughSeptember2002, only 1 SAE(case 1) hasbeendeterminedto beprobablyassociatedwiththe individual'sparticipationin the Program(the participantreceivedcipro-floxacinonly; figure3). Aftera renalbiopsywas performed,this participantreceiveda diagnosisof acute renalfailuresec-ondaryto allergicinterstitialnephritisandunderlyingchronichypertensivenephropathy(figure4). TheSAEsof 2 participantswere determinedto be possiblyassociatedwith theirpartici-pationin the Program.In summary,12 participantshave been identifiedwith anAEthat satisfiedthe FDAcriteriafor an SAE.Ofthese,2 SAEswere assessedas possiblyand 1 as probablyassociatedwithtreatmentreceivedin the Program.Follow-upof these3 par-ticipantsby the CDC wasongoingat the time of thiswriting.Activesurveillancebydirecttelephonecontactwithparticipantshasbeen the singlemost importanttool for identifyingSAEsamongparticipantsintheProgram.CDCwillcontinueto mon-itor the healthandsafetyof allProgramparticipantsbyactivesurveillancethroughtelephonefollow-upcalls scheduledat 6,12,and24 monthsafterenrollment.The CDC will use infor-mationcollectedfromtheProgramtobetterrefinefutureemer-gencypublichealthresponsesandprograms.

AcknowledgmentsWe thank Dr. IbikunleKoya (BaltimoreRenalAssociates,Baltimore,MD) and Dr. JosephP. Grande(Departmentof

LaboratoryMedicineand Pathology,MayoClinic, Rochester,MN), fortheir assistancewithcaseinformation;LouisApicellaand KellyBell (Divisionof DataManagement,NationalIm-munizationProgram),for their assistancewith datamanage-ment;and the many peoplewho volunteeredtheir time andeffortto maketheAnthraxVaccineand AntibioticsAvailabilityProgrampossible.References

An additional reference, cited only in Appendix A, appears in theelectronic version of this articleas item 22 in the referencelist.1. Centersfor DiseaseControl and Prevention.Update: investigationofbioterrorism-relatedanthrax-Connecticut, 2001. MMWRMorbMor-tal Wkly Rep 2001;50:1077-9.

2. JerniganDB, RaghunathanPL, Bell BP,et al. Investigationof bioter-rorism-relatedanthrax,United States, 2001: epidemiologic findings.EmergInfect Dis 2002;8:1019-28.3. Centersfor Disease Control and Prevention. Use of anthraxvaccinein response to terrorism:supplementalrecommendationsof the Ad-visory Committee on ImmunizationPractices.MMWR Morb MortalWkly Rep 2002;51:1024-6.4. InglesbyTV,HendersonDA, BartlettJG,et al. Anthraxas a biologicalweapon: medical and public health management.JAMA 1999;281:1735-45.

5. Centersfor Disease Control and Prevention. Use of anthraxvaccinein the United States. MMWR Recomm Rep 2000;49(RR-15):1-20.6. HendersonDW,PeacockS,Belton FC.Observationson theprophylaxisof experimentalpulmonary anthrax in the monkey. J Hyg 1956;54:28-36.7. FriedlanderAM,WelkosSL,PittMLM,et al.Postexposureprophylaxisagainst experimental inhalation anthrax. J Infect Dis 1993;167:1239-42.8. KournikakisB, Armour SJ, Boulet CA, Spence M, BarsonsB. Riskassessment of anthrax threat letters. TR-2001-048.Suffield,Canada:Defense ResearchEstablishmentSuffield,2001.9. Centersfor Disease Control and Prevention.Update:adverseeventsassociated with anthraxprophylaxisamong postal employees-NewJersey,New York,andthe Districtof Columbiametropolitanarea,2001.MMWR Morb MortalWklyRep 2001;50:1051-4.10. ShepardCW,Soriano-GabarroM, Zell ER,et al. Antimicrobialpost-exposureprophylaxisfor anthrax:adverseeventsandadherence.EmergInfectDis 2002;8:1124-32.11. CentersforDiseaseControland Prevention.Notice to readers:Additional

options for preventivetreatmentfor persons exposed to inhalationalanthrax.MMWR Morb MortalWkly Rep 2001;50:1142.Availableat:http://www.cdc.gov/mmwr/preview/mmwrhtmlmm5050a5.htm.12. Expeditedsafetyreportingrequirementsfor humandrugandbiologicalproducts.In: Federalregister.Vol62.Washington,DC: US GovernmentPrintingOffice, 1997.13. In: Physiciansdesk reference.Available(to subscribersonly) at:http://www.pdrel.thomsonhc.com.Accessed 16 December2002.14. SegevS,YanivI, HaverstockD, ReinhartM. Safetyof long-termtherapywith ciprofloxacin:data of controlled clinical trialsand review. ClinInfectDis 1999;28:299-308.15. LomaestroBM.Fluoroquinolone-inducedrenalfailure.DrugSaf2000;22:479-85.

16. BryantSG, FisherS, Kluge RM. Increasedfrequencyof doxycyclineside effects.Pharmacotherapy1987;7:125-9.17. RagnarNS. Atypicalpneumonia in Nordic countries:aetiologyandclinical results of a trialcomparingfleroxacinand doxycycline.JAnti-microb Chemother1997;39:499-508.18. Raoult D, Houpikian P, Tissot Dupont H, Riss JM,Arditi-DjianeJ,BrouquiP. Treatmentof Q fever endocarditis:comparisonof 2 regi-mens containing doxycyclineand 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, GaleAD, LyleJM,Moulton LH,WestDJ.Safetyof anthraxvaccine:a reviewby the AnthraxVaccineExpertCommittee(AVEC)of adverse events reportedto the VaccineAdverseEvent Re-porting System (VAERS).Anthrax VaccineExpertCommittee. Phar-macoepidemiolDrug Saf 2002;11:189-202.21. JoellenbeckLM,ZwanzigerLL,Durch JS,StromBL,eds. Committeeto assessthe safetyandefficacyof anthraxvaccine.Theanthraxvaccine:is it safe? Does it work?Washington,DC: National AcademyPress,2002.

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