lecture3 drug resistance - evolutionary...
TRANSCRIPT
Theevolu)onofdrugresistance
Drugresistancedescribestheabilityofaparasiteorpathogentoovercomeoura9emptsto
controlthem.
Drugresistancehasevolvedtobecomeaworldwidehealththreat.Itistheresultof
evolu)onbynaturalselec)on.
1Lecture“Evolu)onofhost–parasiteinterac)ons”,DieterEbert
Evolu)onofdrugresistance1. Formsofresistance(describingthephenomenon)
– Resistancetodrugs– Resistancetovaccines(e.g.Marek’sdisease)– Resistancetodiagnos)ctests
2. Gene)cmechanismsleadingtodrugresistance– Pointmuta)ons– Copynumbervaria)on– Gene)crecombina)on– Horizontalgenetransfer
3. Doesevolu)onofresistancealwaysoccur?4. Howdoparasitesevolveresistance
– Ageneralmodel
5. Resistanceacquisi)on:Withinandbetweenhostprocessofdrugresistance6. Canwestoptheevolu)onofdrugresistance?(“evolu)onproofing”)
– Resistancevariesinspaceand)me– Uselessdrugs;cyclingandmixing– Reducepopula)onsize(hithardandstrictadherence!)– Combina)ontherapy– Specificsugges)ons
7. Costsofdrugresistance8. Summingitup
2
What’stheproblem?
Whatisthemechanism?
Onemechanismormany?
Doweunderstandtheprocess?
Whatshouldwestopd
oing?
1.Formsofresistance:Resistancetodrugs
Infec)onscausedbyEnterococcusincludeurinarytractinfec)ons,bacteremia,bacterialendocardi)s,diver)culi)s,andmeningi)s.Sensi)vestrainsofthesebacteriacanbetreatedwithvancomycin.
Year
%vancomycinresistant
EnterococcusisolatesinUShospitals
1.Formsofresistance:Resistancetodrugs
Klebsiellapneumoniaecarbapenemase(KPC)-producingKlebsiellapneumoniaeisapathogencausinganepidemicofcarbapenem-resistantEnterobacteriaceae(CRE)inhealthcaresegngsinmanycountries.StatesoftheUSwithKPC-producingCarbapenem-resistantEnterobacteriaceae(CRE)reportedtotheCentersforDiseaseControlandPreven)on(CDC)asofFebruary2015demonstratetherapidspreadofthesebugs.
InJan.2001onlyNorthCarolinareportedCRE!
1.Formsofresistance:ResistancetodrugsManyparasites/pathogensevolveresistancetodrugs
Malaria•chloroquineresistancewasreportedfrom81of92countries
Tuberculosis(TB)•0-17%ofisolatesshowprimarymul)-drugresistance
Gonorrhoea•5-98%penicillinresistanceinNeisseriagonorrhoeae
Pneumoniaandbacterialmeningi9s•0-70%penicillinresistanceinStreptococcuspneumoniae
Diarrhoea:shigellosis•10-90%ampicillinresistance,5-95%cotrimoxazoleresistance
Hospitalinfec9ons•0-70%resistanceofStaphylococcusaureustoallpenicillinsandcephalosporins
Drugresistanceevolu)oncostsabout50Billion$ayearinUSAalone.Wearepugnglessthan1%ofthemoneythatweputintodrugdiscoveryintoresearchonhowtomakethesedrugsmoresustainableinthefaceofevolu)on.
1.Formsofresistance:Resistancetovaccine
6
Step-wiseevolu)onofvirulenceofMarek’sdiseasevirus(MDV).Rela)onshipbetweenthevirulenceincreaseandtheintroduc)onofdifferentvaccinesisshown.HVT,herpesvirusofturkeys;bivalent,HVTandserotype2(SB-1)vaccines;Rispens,CVI988strain.
year
Con)nuumofMDVvirulence.ComparisonofthevirulenceranksofMDVisolates,groupedintovMDV,vvMDVorvv+MDVpathotypes.
Nair2005.TheVeterinaryJournal
1.Formsofresistance:resistancetodiagnos)ctestNewvariantofChlamydiatrachoma9s
Chlamydiatrachoma9sisanobligateintracellularpathogenandcancausesevereinfec)onsinhumans(urethri)s,proc))s(rectaldiseaseandbleeding),trachoma,infer)lity).Itismostlysexuallytransmi9ed.AnewvariantofC.trachoma9s(nvCT)wasdiscoveredinSwedenin2006thathada377-bpdele9oninaplasmid.Thedeletedareaincludedthetargetsequenceusedbygene)ctestsforC.trachoma9smanufacturedbytwocommercialcompanies,Abbo9m2000(Abbo9)andAmplicor/TaqMan48(Roche).Thisdele)onresultedinseveralthousandfalse-nega)veresults,andthepropor)onofnvCTrecordedwasbetween20%and64%inswedishcoun)esusingtestsystemsthatwereunabletodetectnvCTin2006/2007.Adifferentgene)ctestusedinSweden,wastheProbeTecsystemfromBectonDickinson(BD).ThissystemhasalwaysbeenabletodetectnvCT,becauseanothertargetregiononthecryp)cplasmidisused.Thepropor)onofnvCTincoun)esusingBDwasbetween7%and19%duringthesame)meperiod.Themuta)onwhichhadleadtothe377bpdele)onwasadap)veforthebacterium,asitescapeddetec)onandthereforetreatment.Inswedishcoun)eswherediagnos)ctestsfailedtodetectnvCT,prevalenceincreaseddras)cally.
Klintetal2010.ClinicalMicrobiol&Infec9on
1.Formsofresistance:resistancetodiagnos)ctestNewvariantofChlamydiatrachoma9s
%nvCT
year2007 2008 2009
Counties using always
BD test.
Counties using only since end 2007 BD tests.
Aserthenon-func)onaltestswerereplacedinlate2007bynewtests(BectonDickinson=BD)theincidenceofnvCTdeclined.
2.Gene)cmechanismsleadingtodrugresistancePointmuta)ons
9
Muta)onsleadingtoresistancetodrugsusedagainstPlasmodium.
Modifiedfrom:h9p://www.tulane.edu/~wiser/protozoology/notes/drugs.html
2.Gene)cmechanismsleadingtodrugresistancePointmuta)ons
10
Typicalmolecularmechanismsofresistance:
• Altera)on,circumven)onoftargetprotein
• Overexpressionoftargetprotein• Degrada)onofdrug• Effluxpumps
• Changingpermeability
Evolu)onarytheorycanpredictthatevol.ofdrugresistancewilloccur,butcannotpredictthenatureoftheresistancemechanism.
2.Gene)cmechanismsleadingtodrugresistanceCopynumbervaria)on
Nairetal.2008.PLoSGene)cs
Laos:Fansidarhardlyusedun)l2006
Thailand:Fansidarused
intensivelysince1970
IncreasedcopynumberofthegchgeneincreasesresistanceagainstFansidar.
2.Gene)cmechanismsleadingtodrugresistanceGene)crecombina)on
12
Gene)crecombina)onallowsthenewcombina)onofmuta)onsfromdifferentindividuals.Itisdetectablebytheabsenceofcongruenceingenetrees.
Manyvirusesundergofrequentrecombina)on(osencalledre-assortment)e.g.HIV,InfluenzaA
Highrecombina)onrates:noclonalstructuredetectable
e.g.Neisseriagonorrhoeae,Helicobacterpylori
Intermediaterecombina)onrates:clonalstructuredetectablee.g.Neisseriameningi9dis,Staphylococcusaureus,Streptococcuspyogenes,Strep.pneumoniae
No/Verylowratesofrecombina)on:clonalstructurelonglas)ng
e.g.Salmonellaenterica
Feiletal.2001.PNAS
2.Gene)cmechanismsleadingtodrugresistanceHorizontalgenetransfer
13
Resistancetovancomycinwasfirstreportedin1988forEnterococcusfaecium.ResistanceismediatedbyTn1546amobilegene)celements.Highlevelvancomycinresistanceappeared10yearslaterinStaphylococcusaureus.Gene)canalysessuggeststhetransferofvancomycinresistancetoamethicillin-resistantS.aureusoccurredinvivobytransferofTn1546fromEnterococcus.
TheplasmidpLW1043withtheinser)onsiteandgene9celementofTn1546(innercircleinlightgreen).
9genesareencodedontheTn1546transposon.Thevangenesprovidehighlevelvancomycinresistance:ORF1andORF2aretransposaseandresolvaseenzymes,respec)vely,requiredformobiliza)onofthetransposon.
3.Doesevolu)onofresistancealwaysoccur?
14FromJ.Antonovicsetal.(unpublishedmanuscript).
Plasmodiumfalciparumdevelopedresistancetochloroquineinthe1950s.P.vivaxdidnotevolveresistancetochloroquineun)l40yearslaterinspiteofextensiveuse.
Penicillinhasbeenanan)bio)cagainstTreponemapallidum,thebacteriumcausingsyphilis,forover60years,butthereisnorecordthatthebacteriumhasevolvedpenicillinresistance.Ithashoweverevolvedresistancetoothermorerecentlyintroducedan)bio)cs.
WhileTreponemalacksgenesfortheclassicalβ-lactamasesthatgivepenicillinresistanceinotherbacteria,itdoeshaveaprotein,Tp47,thatcleavespenicillin,butitisineffec)vebecausetheproductsofthiscleavageinhibitfurtherenzymeac)vity(Chaetal.2004).WhyTreponemahasnotacquiredmuta)onstoavoidsuchend-productinhibi)onremainsamystery,evenmoresoasthedomainthatisinhibitedisnottheac)vecleavagesite.
Smallpoxwasaninfec)ousdiseaseuniquetohumans,causedbyVariolamajorandVariolaminor.Inthe1970sitwaseradicatedwiththehelpofaworldwidevaccina)oncampaign.
Thereseemtobelimitstoevolu)on!!!
3.Doesevolu)onofresistancealwaysoccur?
Smallpoxisoneoftwoinfec)ousdiseasestohavebeeneradicated,theotherbeingrinderpest,whichwasdeclarederadicatedin2011.Neithervirusevolvedtoovercomethevaccine.
4.Howdoparasitesevolveresistance?
Emergence First appearance of resistant genotype in focal population
Establishment Rise of resistant genotype beyond danger of immediate extinction
Increase Increase of resistant genotype to high levels in population
Equilibrium (extinction) Extinction of sensitive wild-type strain
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
Stochastic process︎Depends on mutation (and immigration) rate and population size. Because of rareness it is sensitive to chance extinction. ︎
Stochastic process︎Depends on selection coefficient, and effective population size. The smaller the selective advantage and the smaller the population size the more likely chance extinction may result. ︎
Deterministic process︎Depends predominantly on selection coefficient. Once the frequency is out of the “danger zone” (i.e. the genotype is frequent enough) it will spread due to selection. ︎ Deterministic process︎
Depends on various factors, such as costs of resistance, alternative resistance mechanisms, migration, etc. ︎
Deterministic process︎Depends on selection coefficient, and effective population size. Faster with stronger selection and smaller pop. size. ︎
ModifiedaserzurWieschetal.2011.LancetInfect.Dis.
Strong immigration may bypass the Emergence and establishment phase︎
4.Howdoparasitesevolveresistance?
Emergence First appearance of resistant genotype in focal population
Stochastic process︎Depends on mutation (and immigration) rate and population size. Because of rareness it is sensitive to chance extinction. ︎
Resistantgenotypesarearesultof1. Muta9on(mostcommon,e.g.M.tuberculosis),2. recombina9on(insomeviruses,e.g.Influenza)or3. horizontalgenetransfer(e.g.S.aureus)
Emergenceofresistancedependsontherateswithwhichresistantgenotypesareproducedandonthepopula)onsizeofthepathogen.
Muta9onrates*
Popula9onsize
HIV 3.5x10-5 107–108inf.cells
Influenza 1x10-5 4x108targetcells
Mycobacteriumtuberculosis 10-6-10-8 108-109
Stapylococcusaureus 10-6-10-10 5x107-4x1010
Plasmodiumfalciparum 10-11-10-20 108-109(1012-1013lethalmalaria)
*Rateofacquiringresistanceperreplica)onModifiedaserzurWieschetal.2011.LancetInfect.Dis.
4.Howdoparasitesevolveresistance?
• Selec)oncoefficients,s,areosenhigh(>0.1)(s=0.1isafitnessadvantageabout10%).
• Popula)onsizesareosenhighenoughtoexcludegene)cdris,exceptinmacroparasites.
Establishmentofanewresistantgenotypedependsonitsfitnessadvantage(selec)oncoefficient)andonthepopula)onsizeofthepathogen.
Establishment Rise of resistant genotype beyond danger of immediate extinction
Stochastic process︎Depends on selection coefficient, and effective population size. The smaller the selective advantage and the smaller the population size the more likely chance extinction may result. ︎
Manybeneficialmuta)onsarelostbychance,sincemutantindividualsmaybychancefailtoreproduce.Haldane(1927)calculatedthatabeneficialmutantinalargepopula)on(nostochas)ceffects)hasonaveragechancetoescapebeinglostofabout2s,wheresistheselec)oncoefficient(thisisanapproxima)on).Example:s=0.1,2s=0.2meansthat20%ofmutantmakeit(80%arelost)s=0.2,2s=0.440%ofmutantsmakeit,60%arelost.
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Generations
Alle
le f
requency
4.Howdoparasitesevolveresistance?
Frequencyofthe
favouredmutantgene
s=0.5
s=0.25s=0.1
s=0.05
s=0
Theselec)oncoefficient,s,hastwomeanings:1. Thestrongertheeffectofamutant(highers)forthedrugexposedcarrier,thequicker
themutantwillspread.2. Thestrongerselec)on(intensityofselec)on),thequickerthemutantwillspread.A
rarelyuseddrugswillnotselectforrapidspreadofresistancemutants.
Increase Increase of resistant genotype to high levels in population
Deterministic process︎Depends predominantly on selection coefficient. Once the frequency is out of the “danger zone” (i.e. the genotype is frequent enough) it will spread due to selection. ︎
Strong immigration may bypass the Emergence and establishment phase︎
Oncethefrequencyofamutantishighenoughtoescapestochas)cprocesses,itwillspreadduetoselec)on.
4.Howdoparasitesevolveresistance?
Equilibrium (extinction) Extinction of sensitive wild-type strain
Deterministic process︎Depends on selection coefficient, and effective population size. Faster with stronger selection and smaller pop. size. ︎
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Generations
Alle
le f
requency
Frequencyofthe
favouredmutantgene
s=0.5
s=0.25s=0.1
s=0.05
s=0
Understrongongoingselec)onthemutantwillreplacethewildtype.
Ex)nc)onofdrugsensi)vewildtypeshasneverbeenobserved.Adrugisconsidereduselessmuchbeforethislevelisreached.
4.Howdoparasitesevolveresistance?
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
Deterministic process︎Depends on various factors, such as costs of resistance, alternative resistance mechanisms, migration, etc. ︎
Resistantanddrugsensi)veformsofpathogensandparasitesarelikelytocoexistforanumberofreasons.
• Costsofresistance.• Imperfectusageofdrugs.• Spa)alvaria)onindrugusageandmigra)on.• Differentwaystoevolveresistance.
4.Howdoparasitesevolveresistance?
Emergence First appearance of resistant genotype in focal population
Establishment Rise of resistant genotype beyond danger of immediate extinction
Increase Increase of resistant genotype to high levels in population
Equilibrium (extinction) Extinction of sensitive wild-type strain
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
• muta)onrate• popula)onsize
• selec)oncoefficient• popula)onsize
• selec)oncoefficient• intensityofselec)on• )me• immigra)on/transmission
5.Resistanceacquisi)onWithinandbetweenhostprocessesofdrugresistance
23
Thefirst)meaparasite/pathogenevolvesresistanceitarisesdenovo.However,lateritmaybeacquiredbytransmissionoftheresistantstraintootherhosts.Thedegreetowhichresistanceevolvesdenovooverandoveragainorisacquiredthroughtransmissionvariesstronglyamongparasites.
Resistanceevolvesosendenovo:HIV,M.tuberculosisResistanceisosenacquiredbyhosttohosttransmission:malaria
Forunderstandingtheevolu)onofdrugresistanceandwhatwecandoagainstit,thisdis)nc)oncanbeveryimportant.Acquiredresistancethroughtransmissionoffersaddi)onalop)onstoreducethelikelihoodforspreadingofdrugresistance.E.g.minimizetransmissionfromtreatedpa)ents.
5.Resistanceacquisi)onWithinandbetweenhostprocessesofdrugresistance
24
Mul)pleOriginsandRegionalDispersalofResistantdhpsinPlasmodiumfalciparumMalaria.5independent“de-novo”originsofan)folateresistancemuta)onsinthedihydropteroatesynthase(dhps)genewithuniquegeographicaldistrribu)ons.
Pearceetal.(2009)PLoSMedicine
sulfadoxine-resistance
6.Canwestoptheevolu)onofdrugresistance?
No,butmaybewecanslowitdown!
Thescienceof“evolu9on-proofing”!
Resistancevariesinspaceand9meSpa)alandtemporalvaria)oninlevelsofdrugresistancetes)fiesthatdrugresistanceworksbylocaladapta9on.Bystudyinglocaldifferenceswecanlearnaboutthefactorswhichmightpromoteorslowdowndrugresistanceevolu9on.Understandingthesefactorsisdifficult.Italsoshowsthatsolu)onstotheproblemarenotglobal,butcanbeimplementedlocally.Ontheposi)veside,despiteofglobaltrafficandmigra)on,localsolu)onshavebeenshowntobehighlyeffec)ve.
6.Canwestoptheevolu)onofdrugresistance?
Emergence First appearance of resistant genotype in focal population
Establishment Rise of resistant genotype beyond danger of immediate extinction
Increase Increase of resistant genotype to high levels in population
Equilibrium (extinction) Extinction of sensitive wild-type strain
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
• muta)onrate• popula)onsize
• popula)onsize• selec)oncoefficient
• selec)oncoefficient• intensityofselec)on• )me• immigra)on/transmission
Reducepopula)onsize!
Reduceintensityofselec)on!
Reducetransmission!
Reduceselec)oncoefficient!
6.Canwestoptheevolu)onofdrugresistance?Uselessdrugs
Reduceinten
sityofselec)
on!
Thelessdrugsareused,thelowertheintensityof
selec)on.
PenicillinresistanceofStreptococcuspneumoniae(causespneumoniaand
bacterialmeningi)s)ishighestwereitismostosenused
WHOPolicyPerspec)vesonMedicines,No.010,April2005
Totalan9bio9cuse(DDD/1000popula9on/day)
PenicillinresistantS.pne
umioniae(%
)
6.Canwestoptheevolu)onofdrugresistance?Uselessdrugs
Totalan9bio9cuse(DDD/1000popula9on/day)bycountry
Reduceinten
sityofselec)
on!
Outpa)entan)bio)cusepercountry
6.Canwestoptheevolu)onofdrugresistance?Reducedrugsintheenvironment
Reduceinten
sityofselec)
on!
Examplesoffluoroquinolone*concentra)onsinvariousenvironments
*Fluoroquinolonesarebroad-spectruman)bio)cs(effec)veforbothgram-nega)veandgram-posi)vebacteria)thatplayanimportantroleintreatmentofseriousbacterialinfec)ons,especiallyhospital-acquiredinfec)onsandothersinwhichresistancetoolderan)bacterialclassesissuspected.
6.Canwestoptheevolu)onofdrugresistance?Uselessdrugs:mixingandcyclingofdrugs
Reduceinten
sityofselec)
on!
Whenusingdifferentdrugsagainstthesameparasitetheintensityofselec)onbyeachdrugisreduced.Twomethodsweresuggestedtoincreasetheenvironmentalheterogeneityfortheparasite:Cycling:thescheduledchangesofthepredominantdruginahospital(e.g.weeklyormonthlyaltera)ons)Mixing:assignmentofconsecu)vepa)entstodifferentdrugs.Mixingproducesheterogeneityonafinerscaleandwasthereforesuggestedtobethebe9ermethodforendemicparasites.Forepidemicparasites(e.g.influenza)cyclingmaybebe9er.However,mathema)calmodelsarenotfullyworkedoutandgoodempiricaldataarescarce.
6.Canwestoptheevolu)onofdrugresistance?
Emergence First appearance of resistant genotype in focal population
Establishment Rise of resistant genotype beyond danger of immediate extinction
Increase Increase of resistant genotype to high levels in population
Equilibrium (extinction) Extinction of sensitive wild-type strain
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
• muta)onrate• popula)onsize
• popula)onsize• selec)oncoefficient
• selec)oncoefficient• intensityofselec)on• )me• immigra)on/transmission
Reducepopula)onsize!
Reduceintensityofselec)on!
Reducetransmission!
Reduceselec)oncoefficient!
6. Can we stop the evolution of drug resistance? Reducepopula)onsize
Reducepopula
)onsize!
Thelikelihoodofbeneficialmutantsarisingispropor)onaltotheparasitepopula)onsize.Reducingthepopula)onsizefastandtoverylowlevelsslowsdowntheevolu)onofdrugresistance.Thisisinpar)cularimportantincasesofde-novoevolu)onofresistance.Hit-hard:Ahighdrugdosewillreducetheparasitepopula)onfastandtoverydeeplevel.Sub-op)maldrugdosagesreducepopula)onsizenotfastandstrongenoughandmayallowtheoutgrowthofresistantmutants.Non-adherence:Missingadoseofthedrugcanleadtohigherpopula)onsizesandfasterevo.ofresistance,especiallyearlyintreatment.Itisthereforeimportanttofollowtherecommendedtreatmentintervalandtreatmentdura)on.
6.Canwestoptheevolu)onofdrugresistance?
Emergence First appearance of resistant genotype in focal population
Establishment Rise of resistant genotype beyond danger of immediate extinction
Increase Increase of resistant genotype to high levels in population
Equilibrium (extinction) Extinction of sensitive wild-type strain
Equilibrium (coexistence) Long-term coexistence of resistant and wild-type strains
• muta)onrate• popula)onsize
• popula)onsize• selec)oncoefficient
• selec)oncoefficient• intensityofselec)on• )me• immigra)on/transmission
Reducepopula)onsize!
Reduceintensityofselec)on!
Reducetransmission!
Reduceselec)oncoefficient!
6. Can we stop the evolution of drug resistance? Combina)ontherapy
Ifresistancetotwo(ormore)drugsisacquiredindependently,combina)ontherapydecreasestheprobabilityofde-novoacquisi)onofresistance,becauseofpathogenwithtwo(ormore)appropriatemuta)onsisunlikelytoexistintheini)alpopula)onandunlikelytoarisespontaneously.Itisimportantthatthedifferentdrugsactatthesame)meandthesameloca)ons.Combina)ontherapyisrecommendasthestandardtreatmentfortuberculosis,HIVandmalaria.
Reduceselec)
oncoefficient!
Combina)ontherapydoesnotaltermuta)onrates,butreducestherela)vebeneficialeffectofmuta)onsthatprovideabenefittoonlyoneofthedrugs.
6.Canwestoptheevolu)onofdrugresistance?Specificsugges)onsforspecificcases
35
2examples:Plasmodium(causingmalaria)isosencontrolledbykillingitsvector.Plasmodiumtakesalong)metocompleteitsvectorstagepartofthelifecycle.Thus,onlyoldmosquitoscantransmitmalaria.Ifwetargetoldmosquitoswithdrugsorinsec)cidesthechancesthatresistanceevolvesisstronglyreduced.Thisisbecausetheforceofselec)onisweakinoldorganisms.Usebiologicalcontroltoreducevectors.Thecontrolagentwillco-evolvewiththevectorandremaineffec)ve.
7. Costs of drug resistance
Ifmutantsconferringdrugresistanceproduceacostfortheparasite(costofresistance),thefrequencyofthesemuta)onsisexpectedtodeclineaserthedrugisnotusedanymore.ThiswasthecaseinMalawiaserchloroquine(CQ)wasreplacedbysulphadoxine/pyrimethamineasfirstlinedrugin1993.
1990 1995 2000
100
75
50
25
0
Frequency of the CQ resistance pfcrt K76T mutation
(Kublinetal.,2003)
(Mitaetal.,2003)
These2studiessuggestthatthepfcrtK76Tmuta)onisabout5%lessfitthanthenormaltypes(assumingfivemalariagenera)onsperyear,andthatnoparasitemigra)onwasoccurring(Has)ngs&Donnelly2005)
Note:Itisunclearifthisisgenerallylikethis.Therearehardlydataoncostsofresistanceinothercases.
Summingup
1. Evolu)onofdrug/vaccine/diagnos)csresistanceisbasedonnaturalselec)onontheparasite/pathogenpopula)on.Itisanadap)veprocess.
2. Resistancevariesgeographicallysugges)nglocaladapta)on.3. Thereissomeevidenceforacostofresistance.4. Wecannotpreventtheevolu)onofresistance,butwemay
slowitdown.Thecrucialpopula)ongene)cmechanismstobeappliedarereducingpopula)onsize,reducingselec)onintensityandreducingselec)oncoefficients.
5. Imperfectvaccinesmaycauseevolu)onofhighervirulence.
Evolu)on-proofing
safeslife!
38
Downloadat:h9p://www.who.int/pa)entsafety/implementa)on/amr/publica)on/en/index.html
Publica9ondate:2012Languages:EnglishISBN:9789241503181
ZurWieschetal.2011.LancetInfect.Dis.Vol.11:236-247.
Furtherreading