Sethuraman1

KarthikSethuraman EPID516 Spring2013

Examiningthespreadofantibioticresistanceinhospitals
Themathematicalmodel
In2000,Lipsitchetal.publishedaprescriptivestudyofantibioticresistanceinhospitals, examininghownosocomial(hospitalacquired)infectionsarespread,howantibioticresistance canbeacquiredandsubsequentlyproliferated,andhowcertainmeasurescanreducethe prevalenceofantibioticresistance.1 Tomodelagenericnosocomialinfection,theydevelopathreecompartmentsystem.TheS compartmentharborshostswithdrugsensitiveinfection,theXcompartmenthostswithout infection,andtheRcompartmenthostswithdrugresistantinfection.HostsinXcanbecome infectedandmovetoSorRbymassactiontransmissiondependentonthenumberofhostsin SorRandwithaparameter,theinfectioncontactrate,andanadditionalparameterfor resistanttransmissionc,thecostofantibioticresistance.However,thereisnomovement betweentheSandRcompartmentstheonlywayasensitivelyinfectedhostcanbecome resistantlyinfectedistobecomeuninfectedandsubsequentlyreinfectedbyaresistant pathogen.Theyincludeasimplifiedsetoftwotreatmentsforinfection(withtreatmentrates1 and2)andassumethatallhostsaregiventhesetreatmentsasstandardhospitalprocedure hostsinSrespondtobothtreatments,whilehostsinRrespondonlytotreatmenttwo.Hostsin SandRcanselfcureatarate. AconstantinfluxofhostsintotheSandXcompartmentscorrespondstopatientsbeingadmitted tothehospital,eitherwithorwithoutinfectionalreadypresent(mmeasurestheprevalenceof infectioninadmittedhosts).Forsomeubiquitousbacterialinfections,likeE.coli,mmaybeclose to1,whileforothers,itmaybemuchlessthanone.AconstanteffluxofhostsfromtheS,X,and Rcompartmentscorrespondstopatientsleavingthehospital.Overall,rateofadmissionequals rateofdischarge(bothatrate),andthetotalhospitalpopulationisconstant.

Thresholdcriteria
Lipsitchetal.proposethresholdcriteriafordeterminingifresistantinfectionwillpersistat equilibrium,givenasequation1andthesimplifiedequation2ifciszero(nodifferenceinrelative fitness).1Unfortunately,equation1appearstogiveincorrectthresholdpredictions(Fig.1). Varyingand1,settingctozero,andcalculatingthethresholdcriteriawithequation1and equation2givesverydifferentpredictions.Inaddition,anotherpossiblethresholdcriteriahere definedasReq,theequilibriumresistantlyinfectedhostprevalence,iscalculatedandincluded.

Sethuraman2

Becausethetotalpopulationsizeisconstant,theReqcanbeexpressedanalyticallyifitis greaterthanzero,resistancewillpersist[ref].ThisadditionalReqcriteriaagreesonthethreshold valuesofand1abovewhichresistancepersistswithequation2,indicatingthatequation1is incorrect.Thus,insteadofusingthefaultyequation1asthethresholdcriterionorrequiringcto bezeroandusingequation2,equilibriumresistantlyinfectedhostprevalence,Req,shouldbe usedtoevaluatetheeffectofparameterchangesonresistancepersistence.

Simplifyingassumptions
Lipsitchetal.greatlyreducethecomplexityofhospitalinfectionandresistancedynamicsby makingahandfulofsimplifyingassumptions.Foreaseofcalculation,theyassumeaconstant populationwhereinflowandoutflowfromthehospitalareequal.Thisconstantpopulationallows foranalyticcalculationofequilibriumcompartmentalvaluesbutmaycreatebiasinstudyingthe transientdynamicsofthesystem.2Whilethehospitalpopulationmayberoughlystableon moderatelylargetimescalesontheorderofweeksormonths,atsmalltimescalesontheorder ofdays,theinstantaneoushospitalpopulationisfarfromconstant,andatlargetimescaleson theorderofyears,admissionanddischargeratesmaycycleseasonally.35 Similarly,insuchsmalltimescalesandpopulationsasconcernhospitalinfections,respectively ontheorderofmonthsandhundredsofpatients,diseasetransmissiondynamicsareexpected tobehighlystochastic.2,6Whiletheproposedmathematicalmodelcangenericallyassessthe impactofcertaininterventionssuchasreducingtheinfectioncontactrate,itmaylackthe nondeterministicbehaviornecessarytobefittedtospecificscenariosandtosubsequentlybe usedinprognostication. Furthermore,whilepatientscanenterthesensitivelyinfectedanduninfectedcompartments fromoutsidethehospitalpopulation,thereisnoentryintotheresistantlyinfectedcompartment. FindingsonthespreadofadaptedstrainsofMethicillinResistantStaphylococcusAureus (MRSA)fromthecommunityintohospitalssuggeststhatnewentryintoresistantlyinfectedmay significantlyalterthecompartmentallandscape,perhapsevenreplacingmostofthesensitively infectedwithresistantlyinfectedandcausingahigherincidenceofdiseaseoverall.79The communitytohospitaltransitionofMRSAmaybetheresultofavarietyoffactors,includinga poornonresistanttreatmentrate2oranincreasedinfectioncontactrate.Indeed,oneofthe recommendationsforcombatingthespreadofnewMRSAstrainsistooptimizehandwashing proceduresandreducepatienttopatientcontact,therebyreducinganincreased.7,9 Conversely,anadditionalsimplifyingassumptioncanbemadebydisregardingc.Althoughthe modelcurrentlyincludesanonzerocostofantibioticresistance,cisexpectedtobenonzero onlyintheshorttermandtobecomeincreasinglydiminishedinthelongrun.Thisfitnesspenalty maytemporarilybenonzeroandtendtozeroovertimeastheinfectiousagentadaptsto maintainingantibioticresistanceevenintheabsenceofselectivepressure.1011

Sethuraman3

Includingsuperinfections
AnoticeableabsenceintheSXRmodelismovementfromsensitiveinfectiontoresistant infection.Severalothermodelshaveincorporatedsuchdynamicsbypseudosuperinfection transmissionofresistantinfectiontosensitivelyinfectedhosts.1214TheSXRmodelmaybe augmentedbysuchadynamicwherehostsinSmovetoRviamassactiontransmission dependentonRandanadditionalparameter,theresistantsensitivecontactrate.Thisdynamic wouldresemblethemassactioninfectionsofuninfectedhostsbyinfectedones,butitis expectedthatbesignificantlylessthantheinfectioncontactrate.13 Introductionofthisadditionalmassactiontermmakestheequilibriumsituationanalytically unsolvable,butequilibriumvaluessuchasReqcanstillbedeterminednumerically.Thiswas doneusingthenleqslvpackageinR. Varyingfrom0toandtrackingthesensitive,uninfected,andresistantpopulations demonstratesthatasuperinfectiondynamiccannotbeignored(Fig.2).Whenis1,changing from0(nosuperinfection)to(sensitiveresistantcontactratehalfofinfectioncontactrate) causesagreaterthantwofoldincreaseintheproportionofresistantlyinfectedhostsat equilibrium,Req.Sensitivityanalysisonaloneindicates:firstly,superinfectiondynamicsreduce sensitivelyinfectedhostsatamuchhigherratethanuninfectedhosts,andsecondly,increases inresistanceprimarilyhappenbetweenof0and2afterwhichtheproportionofresistantly infectedhostsatequilibriumplateaus(Fig.3).Ajointsensitivityanalysisofanddemonstrates thatwhenthereisahighinfectioncontactrate,evensmallchangesinthesensitiveresistant contactratecancauseamajorchangeintheReq(Fig4).Thus,therealinterplayofinterestis betweenandandcanbesummarizedastheproductofthetwo.Asthisproductincreases,a greaterproportionofhostsatequilibriumwillberesistantlyinfected,andformoderatelylarge valuesof(greaterthan1),changesin(asfrom0to)willcauseconspicuouschangesin Req.

EvaluatingpredictionswiththeSXRmodelaugmentedwithsuperinfections
Lipsitchetal.makethreemainpredictions,thattheuseofatreatmentagainstwhichthereisno resistancewillbepositivelylinkedwithresistantinfectionattheindividuallevelwithresistant infectionandnegativelylinkedatthepopulationlevel,thatdecreasesininfectiontransmissionwill disproportionatelyreduceresistantbacteriaoversensitivebacteria,andthatchangesinthe prevalenceofresistanceaftersuccessfulhospitalinterventionswilloccurontimescalesof months,muchshorterthanthetimenecessaryforstagingsuccessfulcommunitywide interventions.1Becausethefirstpredictioninvolveskeepingtrackoftreatmenthistories,itwillnot beaddressedhere.However,thelattertwopredictionscanbereevaluatedusingtheaugmented SXRmodeltoseeiftheystillhold.

Sethuraman4

Lipsitchetal.examineascenariowherethehospitalhostpopulationshavereachedequilibrium. Onlyonetreatmentisavailableatthistime,withtreatmentrate1,andhostsinRareresistantto it.Toreducetheequilibriumprevalenceofresistantlyinfectedhosts,aseriesofpossible interventionsareproposed:(a)reducetheinfectioncontactrateby30%viabettercontact preventionprotocol,(b)reducetheuseoftheavailabletreatmentby,(c)stoptheuseofthe availabletreatment,(d)replaceoftheavailabletreatmentwithanewtreatment,2,thatisjust aseffectiveandcanalsotreatresistantlyinfectedhosts,and(e)replacealloftheavailable treatmentwiththenewtreatment.Postintervention,theyshowthateveryinterventioncreatesa reductioninthenumberofresistantlyinfectedhostsandthatsuchreductionsoccurover timescalesofweeks.Theyalsonotethatthemosteffectiveinterventionintheendemiccaseis intervention(e)andthattheleasteffectiveinterventionis(a).1 Theinclusionofsuperinfectionsgivesnearlythesameresultsforsmallvaluesof(lessthan 0.15)asseeninFigure5.As,theresistantsensitivecontactrate,increases,superinfection dynamicsdominateandtherelativestandingsoftheinterventionsbecomemuddled(Fig.6). Overthewholerangeoffeasiblevalues,intervention(e)remainsthebestintervention.Onthe otherhand,theworstinterventionisconsistentlyoneoftheinterventions(a),(b),or(c),though whichspecificinterventionistheworstdependsontheparameters.Again,thepresenceor absenceofsuperinfectionsseemstobeanecessarycomponentoftheSXRmodel.Onemight envisionanotherpossibleinterventioninthecaseofsuperinfections:reducing,whereevena smallchangemaygreatlyreducetheresistantlyinfectedhostpopulation.Onepossiblemethod toreduceistoquarantinetheresistantlyinfected(thiswouldalsoreduceforRtoX transmission). Onthewhole,asincreases,superinfectionscausealengtheningofthetimebetweenthestart ofaninterventionandthetimewhenresultsbecomeevident,thoughthetimescalesarestillon theorderofweeks,muchshorterthanforacommunalintervention.Likewise,withincreasing, resistantlyinfectedpopulationsarenotmoredisproportionatelyaffectedbyinterventionsthan sensitivelyinfectedpopulations.However,forsmallvaluesof(lessthan0.15),thepredictions madebyLipsitchetal.stillholdtrue.

Epidemicdynamicswithsuperinfections
Asafinalmeasureofsystembehavior,theepidemicdynamicsoftheSXRmodelaugmented withsuperinfectionsareexamined.Ahospitalsettingcanbeimaginedwhereasingleresistantly infectedhostisintroducedinapopulationofhalfuninfectedandhalfsensitivelyinfectedhosts. Thishostisallowedtospreadtheresistantinfectiontouninfectedhostsnormallyandto sensitivelyinfectedhostsviasuperinfection.Afteraspreadperiodof20days,thepreviously mentionedinterventions(a)(e)areimplementedandevaluated(Fig.7).Heretoointervention (e)isthebestinterventionandtheonlyonethatcausesanimmediateturnaroundinthegrowth oftheresistantlyinfected.Asincreases,thesamemessinesspresentintheendemicsituation

Sethuraman5

alsoarisesintheepidemicsituation,providingmoreevidencethatcannotbeignoredwhen significantlylarge,previouslygivenasgreaterthan0.15.

References
1.Lipsitch,M.,Bergstrom,C.T.,&Levin,B.R.(2000).Theepidemiologyofantibioticresistance inhospitals:paradoxesandprescriptions.ProcNatlAcadSci,97(4),19381943. 2.Keeling,M.J.,&Rohani,P.(2011).Modelinginfectiousdiseasesinhumansandanimals. PrincetonUniversityPress. 3.Atun,R.A.,Samyshkin,Y.A.,Drobniewski,F.,Kuznetsov,S.I.,Fedorin,I.M.,&Coker,R.J. (2005).SeasonalvariationandhospitalutilizationfortuberculosisinRussia:hospitalsas socialcareinstitutions.EurJPublicHealth,15(4),350354. 4.Pace,W.D.,Dickinson,L.M.,&Staton,E.W.(2004).Seasonalvariationindiagnosesand visitstofamilyphysicians.AnnFamMed,2(5),411417. 5.Stott,N.C.H.,&Davis,R.H.(1975).Clinicalandadministrativereviewingeneralpractice.J RColGenPract,25(161),888. 6.Garber,A.M.(1989).Adiscretetimemodeloftheacquisitionofantibioticresistantinfections inhospitalizedpatients.Biometrics,45(3),797816. 7.MCD'Agata,E.,Webb,G.F.,Horn,M.A.,Moellering,R.C.,&Ruan,S.(2009).Modelingthe invasionofcommunityacquiredmethicillinresistantStaphylococcusaureusinto hospitals.ClinInfectDis,48(3),274284. 8.Cooke,F.J.,&Brown,N.M.(2010).Communityassociatedmethicillinresistant Staphylococcusaureusinfections.BritMedBull,94(1),215227. 9.Bootsma,M.C.,&Bonten,M.J.(2013).UnravelingtheDynamicsofCommunityAssociated MethicillinResistantStaphylococcusaureus.ClinInfectDis. 10.Schrag,S.J.,&Perrot,V.(1996).Reducingantibioticresistance.Nature,381(6578),120. 11.Lenski,R.E.(2007).Thecostofantibioticresistancefromtheperspectiveofabacterium. InCibaFoundationSymposium207AntibioticResistance:Origins,Evolution,Selection andSpread(pp.131151).JohnWiley&Sons,Ltd. 12.Levin,S.A.,&Andreasen,V.(1999).Diseasetransmissiondynamicsandtheevolutionof antibioticresistanceinhospitalsandcommunalsettings.ProcNatlAcadSci,96(3), 800801. 13.Austin,D.J.,Kristinsson,K.G.,&Anderson,R.M.(1999).Therelationshipbetweenthe volumeofantimicrobialconsumptioninhumancommunitiesandthefrequencyof resistance.ProcNatlAcadSci,96(3),11521156. 14.Austin,D.J.,Kakehashi,M.,Anderson,R.M.,Austin,D.J.,Kakehashi,M.,&Anderson,R.M. (1997).Thetransmissiondynamicsofantibioticresistantbacteria:therelationship betweenresistanceincommensalorganismsandantibioticconsumption.ProcRSocB, 264(1388),16291638.

Figures

Sethuraman6

Figure1.Thresholdcriteriaevaluation.Theredlinegivespredictionsfromequation1,theblue linefromthesimplificationofequation1,thegreenlinewiththeReqcriteria.Forboth1and,the greenandbluecriteriaintersectat0andgivethesamethresholdvaluesabovewhichresistance willpersist.

Figure2.Theeffectofonhostcompartments.Thegreenlineisuninfectedhostfrequency,the bluesensitivehostfrequency,andtheredresistanthostfrequency.isvariedfrom0to,and theresultingdynamicsareshownwithtimeindays.Increasesincausesignificantdecreases insensitivehostfrequencyandsignificantincreasesinresistanthostfrequencywhileuninfected frequencyisonlyslightlyreduced.

Sethuraman7

Figure3.Sensitivityanalysisof.isvariedfrom0to10andtheresultingequilibrium proportionsofsensitive,uninfected,andresistantpopulationsareshown.Thebluelineis sensitiveequilibriumproportion,thegreenlineuninfected,andtheredlineresistant.

Figure4.Sensitivityanalysisofand.isvariedfrom0to1,gradedfromredatof0to yellowatof1,whileisvariedfrom0to10.Theresultingequilibriumresistanthost frequencies,Req,areshown.

Sethuraman8

Figure5.Endemicinterventiondynamicsforsmall.Superinfectionbehaviorisintroducedat20 daysandhospitalhostpopulationsareallowedtoreachequilibrium.At0days,fivepossible interventionsareproposed:(a)reducetheinfectioncontactrateby30%,(b)reduce1by, (c)reduce1to0,(d)replace1withanewtreatment2,and(e)replaceallof1with2.Blue correspondstointervention(a),green(b),red(c),orange(d),pink(e).Thefirstgraphshows prevalenceofSversustimeindays,thesecondshowsprevalenceofRversustimeindays.

Figure6.Sensitivityanalysisofinterventionsand.Interventions(a)(e)aretestedagainsteach otherasvaluesarevariedfrom0to1.Thegraphdisplaysthepercentofinitialresistantly infectedpopulationremaining80daysintoeachinterventionasvaluesarevariedfrom0to1. Bluecorrespondstointervention(a),green(b),red(c),orange(d),pink(e).Intervention(e)isthe

Sethuraman9

bestovertherangeoftestedsinceithasthelowestpercentinitialremainingeverywhere.

Figure7.Epidemicinterventiondynamicsforsmall.Asingleresistantlyinfectedhostis introducedattime20daysandallowedtospreadinapopulationofhalfSandhalfXhosts.At time0days,thepreviouslymentionedinterventions(a)(e)areimplemented.Bluecorresponds tointervention(a),green(b),red(c),orange(d),pink(e).ThefirstgraphshowsprevalenceofS versustimeindays,thesecondshowsprevalenceofRversustimeindays.