Medical Microbiology

ThePrinciplesofAntibioticTherapy 203

&Increasedefflux.Activetransportofanti-infectiveagentsfrominsideto

outsidebymeansofeffluxpumpsinthecytoplasmicmembrane,makingef-

fluxgreaterthaninflux;frequent.

EvolutionofResistancetoAnti-InfectiveAgents.....

Resistancetoanti-infectiveagentsisgeneticallydeterminedbyresistance

genes.Manyresistancedeterminantsarenotnewdevelopmentsinresponse

totheuseofmedicalantibiotics,butdevelopedmillionsofyearsagoinbac-

teriawithnohumanassociations.Theevolutionaryprocessisthereforea

“nonanthropogenic”one.Thedeterminantsthatcodeforresistanceto

anti-infectiveagentsthatarenotantibioticsdiddevelopafterthesubstances

begantobeusedintherapy,hencethisis“anthropogenic”evolution.Factors

contributingtotheresistanceproblemhaveincludedthemolecularmecha-

nismsofgeneticvariability(mutation,homologousrecombination,site-spe-

cificintegration,transposition)andthemechanismsofintercellulargene

transferinbacteria(transformation,transduction,conjugation).

NonanthropogenicandAnthropogenicEvolution

Nonanthropogenicevolution.Theneedforresistancedevelopedparalleltothe

abilitytoproduceantibiotics.Theproducingorganismsprotectthemselvesfrom

theirownproductsbymeansofsuchRmechanisms.Resistancegenesalsoevolved

inbacteriathatsharedthenaturalhabitatoftheantibioticproducers.Theysecured

theirownecologicalnicheinthepresenceoftheproducersbymeansofthechar-

acteristicofresistance.Thegeneticsequencesfromwhichtheresistancegenes

evolvedwerethosethatcodedfortheanabolicorcatabolicmetabolismgenes.

Atalaterpointinevolutionaryhistory,such“nonanthropogenic”geneshaveac-

cidentally,andrarely,foundtheirwayintothegeneticmaterialofhumanpathogen

bacteria.Therefore,whennewantibioticsubstancescometobeusedfortherapeu-

ticpurposes,therearealwaysasmallnumberofbacteriathatalreadyshowresis-

tancetothem.

Anthropogenicevolution.Thistermreferstotheevolutionofresistancegenesin

bacteriaassociatedwithhumansbasedonmutationsinnativegenes.Anexampleis

themutationthatbringsaboutresistanceto4-quinolonesingenegyrA,which

codesforsubunitAoftheDNAgyrase.Aspecialcaseofanthropogenicevolution

isthedevelopmentofnewresistancegenesresultingfrommutationsin“nonan-

thropogenic”resistancegenesalreadyestablishedinhumanpathogenbacteria.

Thebest-knownexampleofthisisprovidedbymutationsinTEMandSHVbetalac-

tamasegenesthatcodeforbetalactamaseswithaverybroadsubstrateprofile(ESBL

=extendedspectrumbetalactamases).

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Kayser, Medical Microbiology © 2005 Thieme