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Antibiotics
FromWikipedia,thefreeencyclopedia

Antibiotics,alsocalledantibacterials,areatypeofantimicrobial[1]drugusedinthetreatmentandpreventionofbacterial
infections.[2][3]Theymayeitherkillorinhibitthegrowthofbacteria.Alimitednumberofantibioticsalsopossess
antiprotozoalactivity.[4][5]Antibioticsarenoteffectiveagainstvirusessuchasthecommoncoldorinfluenza,andtheir
inappropriateuseallowstheemergenceofresistantorganisms.[2]In1928,AlexanderFlemingidentifiedpenicillin,thefirst
chemicalcompoundwithantibioticproperties.Flemingwasworkingonacultureofdiseasecausingbacteriawhenhenoticed
thesporesofalittlegreenmold(Penicilliumchrysogenum),inoneofhiscultureplates.Heobservedthatthepresenceofthe
moldkilledorpreventedthegrowthofthebacteria.[6]
Antibioticsrevolutionizedmedicineinthe20thcentury,andhavetogetherwithvaccinationledtotheneareradicationof
diseasessuchastuberculosisinthedevelopedworld.Theireffectivenessandeasyaccessledtooveruse,[7][8][9]especiallyin
livestockraising,promptingbacteriatodevelopresistance.Thishasledtowidespreadproblemswithantimicrobialand
antibioticresistance,somuchastoprompttheWorldHealthOrganizationtoclassifyantimicrobialresistanceasa"serious
threat[that]isnolongerapredictionforthefuture,itishappeningrightnowineveryregionoftheworldandhasthepotential
toaffectanyone,ofanyage,inanycountry".[10]
Theeraofantibacterialtreatmentbeganwiththediscoveryofarsphenamine,firstsynthesizedbyAlfredBertheimandPaul
Ehrlichin1907,andusedtotreatsyphilis.[11][12]Thefirstsystemicallyactiveantibacterialdrug,prontosilwasdiscoveredin
1933byGerhardDomagk,[12][13]forwhichhewasawardedthe1939NobelPrize.[14]Allclassesofantibioticsinusetoday
werefirstdiscoveredpriortothemid1980s.[15]

Testingthesusceptibilityof
Staphylococcusaureusto
antibioticsbytheKirbyBauer
diskdiffusionmethod
antibioticsdiffusefromantibiotic
containingdisksandinhibit
growthofS.aureus,resultingina
zoneofinhibition.

Sometimesthetermantibioticisusedtorefertoanysubstanceusedagainstmicrobes,[16]synonymouswithantimicrobial,[17]leadingtothewidespreadbut
incorrectbeliefthatantibioticscanbeusedagainstviruses.[18]Somesourcesdistinguishbetweenantibacterialandantibioticantibacterialsareusedinsoapsand
cleanersgenerallyandantibioticsareusedasmedicine.[19]

Contents
1 Medicaluses
1.1 Administration
2 Sideeffects
2.1 Obesity
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2.1 Obesity
3 Interactions
3.1 Birthcontrolpills
3.2 Alcohol
4 Pharmacodynamics
4.1 Combinationtherapy
5 Classes
6 Production
7 Resistance
7.1 Misuse
8 History
8.1 Etymology
9 Research
9.1 Alternatives
9.2 Resistancemodifyingagents
9.3 Vaccines
9.4 Phagetherapy
9.5 Supplements
9.6 Developmentofnewantibiotics
10 Seealso
11 References
12 Furtherreading
13 Externallinks

Medicaluses
Antibioticsareusedtotreatorpreventbacterialinfections,[20]andsometimesprotozoaninfections.(Metronidazoleiseffectiveagainstanumberofparasitic
diseases).Whenaninfectionissuspectedofbeingresponsibleforanillnessbuttheresponsiblepathogenhasnotbeenidentified,anempirictherapyisadopted.[21]
Thisinvolvestheadministrationofabroadspectrumantibioticbasedonthesignsandsymptomspresentedandisinitiatedpendinglaboratoryresultsthatcantake
severaldays.[20][21]
Whentheresponsiblepathogenicmicroorganismisalreadyknownorhasbeenidentified,definitivetherapycanbestarted.Thiswillusuallyinvolvetheuseofa
narrowspectrumantibiotic.Thechoiceofantibioticgivenwillalsobebasedonitscost.Identificationiscriticallyimportantasitcanreducethecostandtoxicity
oftheantibiotictherapyandalsoreducethepossibilityoftheemergenceofantimicrobialresistance.[21]Toavoidsurgeryantibioticsmaybegivenfornon
complicatedacuteappendicitis.Effectivetreatmenthasbeenevidenced.[22]
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Antibioticsmaybegivenasapreventivemeasure(prophylactic)andthisisusuallylimitedtoatriskpopulationssuchasthosewithaweakenedimmunesystem
(particularlyinHIVcasestopreventpneumonia),thosetakingimmunosuppressivedrugs,cancerpatientsandthosehavingsurgery.[20]Theiruseinsurgical
proceduresistohelppreventinfectionofincisionsmade.Theyhaveanimportantroleindentalantibioticprophylaxiswheretheirusemaypreventbacteremiaand
consequentinfectiveendocarditis.Antibioticsarealsousedtopreventinfectionincasesofneutropeniaparticularlycancerrelated.[23][24]

Administration
Therearedifferentroutesofadministrationforantibiotictreatment.Antibioticsareusuallytakenbymouth.Inmoreseverecases,particularlydeepseated
systemicinfections,antibioticscanbegivenintravenouslyorbyinjection.[2][21]Wherethesiteofinfectioniseasilyaccessedantibioticsmaybegiventopicallyin
theformofeyedropsontotheconjunctivaforconjunctivitisoreardropsforearinfectionsandacutecasesofswimmer'sear.Topicaluseisalsooneofthe
treatmentoptionsforsomeskinconditionsincludingacneandcellulitis.[25]Advantagesoftopicalapplicationincludeachievinghighandsustainedconcentration
ofantibioticatthesiteofinfectionreducingthepotentialforsystemicabsorptionandtoxicity,andtotalvolumesofantibioticrequiredarereduced,therebyalso
reducingtheriskofantibioticmisuse.[26]However,somesystemicabsorptionoftheantibioticmayoccurthequantityofantibioticappliedisdifficultto
accuratelydose,andthereisalsothepossibilityoflocalhypersensitivityreactionsorcontactdermatitisoccurring.[26]

Sideeffects
Antibioticsarescreenedforanynegativeeffectsbeforetheirapprovalforclinicaluse,andareusuallyconsideredsafeandwelltolerated.However,some
antibioticshavebeenassociatedwithawideextentofadversesideeffectsrangingfrommildtoveryseveredependingonthetypeofantibioticused,themicrobes
targeted,andtheindividualpatient.[27][28]Sideeffectsmayreflectthepharmacologicalortoxicologicalpropertiesoftheantibioticormayinvolvehypersensitivity
orallergicreactions.[5]Adverseeffectsrangefromfeverandnauseatomajorallergicreactions,includingphotodermatitisandanaphylaxis.[29]Safetyprofilesof
newerdrugsareoftennotaswellestablishedasforthosethathavealonghistoryofuse.[27]
Commonsideeffectsincludediarrhea,resultingfromdisruptionofthespeciescompositionintheintestinalflora,resulting,forexample,inovergrowthof
pathogenicbacteria,suchasClostridiumdifficile.[30]Antibacterialscanalsoaffectthevaginalflora,andmayleadtoovergrowthofyeastspeciesofthegenus
Candidainthevulvovaginalarea.[31]Additionalsideeffectscanresultfrominteractionwithotherdrugs,suchasthepossibilityoftendondamagefromthe
administrationofaquinoloneantibioticwithasystemiccorticosteroid.[32]

Obesity
Exposuretoantibioticsearlyinlifeisassociatedwithincreasedbodymassinhumansandmousemodels.[33]Earlylifeisacriticalperiodfortheestablishmentof
theintestinalmicrobiotaandformetabolicdevelopment.[34]Miceexposedtosubtherapeuticantibiotictreatment(STAT)witheitherpenicillin,vancomycin,or
chlortetracyclinehadalteredcompositionofthegutmicrobiotaaswellasitsmetaboliccapabilities.[35]Onestudyhasreportedthatmicegivenlowdosepenicillin
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(1g/gbodyweight)aroundbirthandthroughouttheweaningprocesshadanincreasedbodymassandfatmass,
acceleratedgrowth,andincreasedhepaticexpressionofgenesinvolvedinadipogenesis,comparedtocontrolmice.[36]In
addition,penicillinincombinationwithahighfatdietincreasedfastinginsulinlevelsinmice.[36]However,itisunclear
whetherornotantibioticscauseobesityinhumans.Studieshavefoundacorrelationbetweenearlyexposureofantibiotics
(<6months)andincreasedbodymass(at10and20months).[37]Anotherstudyfoundthatthetypeofantibioticexposure
wasalsosignificantwiththehighestriskofbeingoverweightinthosegivenmacrolidescomparedtopenicillinand
cephalosporin.[38]Therefore,thereiscorrelationbetweenantibioticexposureinearlylifeandobesityinhumans,but
whetherornotthereisacausalrelationshipremainsunclear.Althoughthereisacorrelationbetweenantibioticuseinearly
lifeandobesity,theeffectofantibioticsonobesityinhumansneedstobeweighedagainstthebeneficialeffectsof
clinicallyindicatedtreatmentwithantibioticsininfancy.[34]

Interactions
Birthcontrolpills
Themajorityofstudiesindicateantibioticsdointerferewithbirthcontrolpills,[39]suchasclinicalstudiesthatsuggestthe

Healthadvocacymessagessuchasthis
oneencouragepatientstotalkwith
theirdoctoraboutsafetyinusing
antibiotics.

failurerateofcontraceptivepillscausedbyantibioticsisverylow(about1%).[40]Incaseswhereantibioticshavebeen
suggestedtoaffecttheefficiencyofbirthcontrolpills,suchasforthebroadspectrumantibioticrifampicin,thesecases
maybeduetoanincreaseintheactivitiesofhepaticliverenzymes'causingincreasedbreakdownofthepill'sactive
ingredients.[39]Effectsontheintestinalflora,whichmightresultinreducedabsorptionofestrogensinthecolon,havealsobeensuggested,butsuchsuggestions
havebeeninconclusiveandcontroversial.[41][42]Clinicianshaverecommendedthatextracontraceptivemeasuresbeappliedduringtherapiesusingantibioticsthat
aresuspectedtointeractwithoralcontraceptives.[39]

Alcohol
Interactionsbetweenalcoholandcertainantibioticsmayoccurandmaycausesideeffectsanddecreasedeffectivenessofantibiotictherapy.[43][44]Whilemoderate
alcoholconsumptionisunlikelytointerferewithmanycommonantibiotics,therearespecifictypesofantibioticswithwhichalcoholconsumptionmaycause
serioussideeffects.[45]Therefore,potentialrisksofsideeffectsandeffectivenessdependonthetypeofantibioticadministered.[46]
Antibioticssuchasmetronidazole,tinidazole,cephamandole,latamoxef,cefoperazone,cefmenoxime,andfurazolidone,causeadisulfiramlikechemicalreaction
withalcoholbyinhibitingitsbreakdownbyacetaldehydedehydrogenase,whichmayresultinvomiting,nausea,andshortnessofbreath.[45]Inaddition,the
efficacyofdoxycyclineanderythromycinsuccinatemaybereducedbyalcoholconsumption.[47]Othereffectsofalcoholonantibioticactivityincludealtered
activityoftheliverenzymesthatbreakdowntheantibioticcompound.[48]
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Pharmacodynamics
Thesuccessfuloutcomeofantimicrobialtherapywithantibacterialcompoundsdependsonseveralfactors.Theseincludehostdefensemechanisms,thelocationof
infection,andthepharmacokineticandpharmacodynamicpropertiesoftheantibacterial.[49]Abactericidalactivityofantibacterialsmaydependonthebacterial
growthphase,anditoftenrequiresongoingmetabolicactivityanddivisionofbacterialcells.[50]Thesefindingsarebasedonlaboratorystudies,andinclinical
settingshavealsobeenshowntoeliminatebacterialinfection.[49][51]Sincetheactivityofantibacterialsdependsfrequentlyonitsconcentration,[52]invitro
characterizationofantibacterialactivitycommonlyincludesthedeterminationoftheminimuminhibitoryconcentrationandminimumbactericidalconcentration
ofanantibacterial.[49][53]Topredictclinicaloutcome,theantimicrobialactivityofanantibacterialisusuallycombinedwithitspharmacokineticprofile,and
severalpharmacologicalparametersareusedasmarkersofdrugefficacy.[54]

Combinationtherapy
Inimportantinfectiousdiseases,includingtuberculosis,combinationtherapy(i.e.,theconcurrentapplicationoftwoormoreantibiotics)hasbeenusedtodelayor
preventtheemergenceofresistance.Inacutebacterialinfections,antibioticsaspartofcombinationtherapyareprescribedfortheirsynergisticeffectstoimprove
treatmentoutcomeasthecombinedeffectofbothantibioticsisbetterthantheirindividualeffect.[55][56]MethicillinresistantStaphylococcusaureusinfectionsmay
betreatedwithacombinationtherapyoffusidicacidandrifampin.[55]Antibioticsusedincombinationmayalsobeantagonisticandthecombinedeffectsofthe
twoantibioticsmaybelessthaniftheindividualantibioticwasgivenaspartofamonotherapy.[55]Forexample,Chloramphenicolandtetracyclinesareantagonists
topenicillinsandaminoglycosides.However,thiscanvarydependingonthespeciesofbacteria.[57]Ingeneral,combinationsofabacteriostaticantibioticand
bactericidalantibioticareantagonistic.[55][56]

Classes
Antibioticsarecommonlyclassifiedbasedontheirmechanismofaction,chemicalstructure,orspectrumofactivity.Mosttarget
bacterialfunctionsorgrowthprocesses.[58]Thosethattargetthebacterialcellwall(penicillinsandcephalosporins)orthecell
membrane(polymyxins),orinterferewithessentialbacterialenzymes(rifamycins,lipiarmycins,quinolones,andsulfonamides)have
bactericidalactivities.Thosethattargetproteinsynthesis(macrolides,lincosamidesandtetracyclines)areusuallybacteriostatic(with
theexceptionofbactericidalaminoglycosides).[59]Furthercategorizationisbasedontheirtargetspecificity."Narrowspectrum"
antibioticstargetspecifictypesofbacteria,suchasgramnegativeorgrampositive,whereasbroadspectrumantibioticsaffectawide
rangeofbacteria.Followinga40yearbreakindiscoveringnewclassesofantibacterialcompounds,fournewclassesofantibiotics
havebeenbroughtintoclinicaluseinthelate2000sandearly2010s:cycliclipopeptides(suchasdaptomycin),glycylcyclines(such
astigecycline),oxazolidinones(suchaslinezolid),andlipiarmycins(suchasfidaxomicin).[60][61]

Production
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Moleculartargetsof
antibioticsonthebacteria
cell
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Withadvancesinmedicinalchemistry,mostmodernantibacterialsaresemisyntheticmodificationsofvariousnaturalcompounds.[62]Theseinclude,forexample,
thebetalactamantibiotics,whichincludethepenicillins(producedbyfungiinthegenusPenicillium),thecephalosporins,andthecarbapenems.Compoundsthat
arestillisolatedfromlivingorganismsaretheaminoglycosides,whereasotherantibacterialsforexample,thesulfonamides,thequinolones,andthe
oxazolidinonesareproducedsolelybychemicalsynthesis.[62]Manyantibacterialcompoundsarerelativelysmallmoleculeswithamolecularweightoflessthan
1000daltons.[63]
SincethefirstpioneeringeffortsofFloreyandChainin1939,theimportanceofantibiotics,includingantibacterials,tomedicinehasledtointenseresearchinto
producingantibacterialsatlargescales.Followingscreeningofantibacterialsagainstawiderangeofbacteria,productionoftheactivecompoundsiscarriedout
usingfermentation,usuallyinstronglyaerobicconditions.[64]

Resistance
Theemergenceofresistanceofbacteriatoantibioticsisacommonphenomenon.Emergenceofresistanceoftenreflects
evolutionaryprocessesthattakeplaceduringantibiotictherapy.Theantibiotictreatmentmayselectforbacterialstrains
withphysiologicallyorgeneticallyenhancedcapacitytosurvivehighdosesofantibiotics.Undercertainconditions,itmay
resultinpreferentialgrowthofresistantbacteria,whilegrowthofsusceptiblebacteriaisinhibitedbythedrug.[65]For
example,antibacterialselectionforstrainshavingpreviouslyacquiredantibacterialresistancegeneswasdemonstratedin
1943bytheLuriaDelbrckexperiment.[66]Antibioticssuchaspenicillinanderythromycin,whichusedtohaveahigh
efficacyagainstmanybacterialspeciesandstrains,havebecomelesseffective,duetotheincreasedresistanceofmany
bacterialstrains.[67]
Resistancemaytaketheformofbiodegredationofpharmaceuticals,suchassulfamethazinedegradingsoilbacteria
introducedtosulfamethazinethroughmedicatedpigfeces.[68]Thesurvivalofbacteriaoftenresultsfromaninheritable
resistance,[69]butthegrowthofresistancetoantibacterialsalsooccursthroughhorizontalgenetransfer.Horizontaltransfer
ismorelikelytohappeninlocationsoffrequentantibioticuse.[70]

Scanningelectronmicrographofa
humanneutrophilingesting
methicillinresistantStaphylococcus
aureus(MRSA)

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Antibacterialresistancemayimposeabiologicalcost,therebyreducingfitnessofresistantstrains,whichcanlimitthe
spreadofantibacterialresistantbacteria,forexample,intheabsenceofantibacterialcompounds.Additionalmutations,
however,maycompensateforthisfitnesscostandcanaidthesurvivalofthesebacteria.[71]
Paleontologicaldatashowthatbothantibioticsandantibioticresistanceareancientcompoundsandmechanisms.[72]Useful
antibiotictargetsarethoseforwhichmutationsnegativelyimpactbacterialreproductionorviability.[73]

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Severalmolecularmechanismsofantibacterialresistanceexist.Intrinsicantibacterialresistancemaybepartofthegeneticmakeupofbacterialstrains.[74]For
example,anantibiotictargetmaybeabsentfromthebacterialgenome.Acquiredresistanceresultsfromamutationinthebacterialchromosomeortheacquisition
ofextrachromosomalDNA.[74]Antibacterialproducingbacteriahaveevolvedresistancemechanismsthathavebeenshowntobesimilarto,andmayhavebeen
transferredto,antibacterialresistantstrains.[75][76]Thespreadofantibacterialresistanceoftenoccursthroughverticaltransmissionofmutationsduringgrowthand
bygeneticrecombinationofDNAbyhorizontalgeneticexchange.[69]Forinstance,antibacterialresistancegenescanbeexchangedbetweendifferentbacterial
strainsorspeciesviaplasmidsthatcarrytheseresistancegenes.[69][77]Plasmidsthatcarryseveraldifferentresistancegenescanconferresistancetomultiple
antibacterials.[77]Crossresistancetoseveralantibacterialsmayalsooccurwhenaresistancemechanismencodedbyasinglegeneconveysresistancetomorethan
oneantibacterialcompound.[77]
Antibacterialresistantstrainsandspecies,sometimesreferredtoas"superbugs",nowcontributetotheemergenceofdiseasesthatwereforawhilewellcontrolled.
Forexample,emergentbacterialstrainscausingtuberculosis(TB)thatareresistanttopreviouslyeffectiveantibacterialtreatmentsposemanytherapeutic
challenges.Everyyear,nearlyhalfamillionnewcasesofmultidrugresistanttuberculosis(MDRTB)areestimatedtooccurworldwide.[78]Forexample,NDM1
isanewlyidentifiedenzymeconveyingbacterialresistancetoabroadrangeofbetalactamantibacterials.[79]TheUnitedKingdom'sHealthProtectionAgencyhas
statedthat"mostisolateswithNDM1enzymeareresistanttoallstandardintravenousantibioticsfortreatmentofsevereinfections."[80]OnMay26,2016anE
colibacteria"superbug"wasidentifiedintheUnitedStatesresistanttocolistin,"thelastlineofdefence"antibiotic.[81][82]

Misuse
PertheTheICUBook"Thefirstruleofantibioticsistrynottousethem,andthesecondruleistrynottousetoomanyofthem."[83]Inappropriateantibiotic
treatmentandoveruseofantibioticshavecontributedtotheemergenceofantibioticresistantbacteria.Selfprescriptionofantibioticsisanexampleofmisuse.[84]
Manyantibioticsarefrequentlyprescribedtotreatsymptomsordiseasesthatdonotrespondtoantibioticsorthatarelikelytoresolvewithouttreatment.Also,
incorrectorsuboptimalantibioticsareprescribedforcertainbacterialinfections.[27][84]Theoveruseofantibiotics,likepenicillinanderythromycin,hasbeen
associatedwithemergingantibioticresistancesincethe1950s.[67][85]Widespreadusageofantibioticsinhospitalshasalsobeenassociatedwithincreasesin
bacterialstrainsandspeciesthatnolongerrespondtotreatmentwiththemostcommonantibiotics.[85]
Commonformsofantibioticmisuseincludeexcessiveuseofprophylacticantibioticsintravelersandfailureofmedicalprofessionalstoprescribethecorrect
dosageofantibioticsonthebasisofthepatient'sweightandhistoryofprioruse.Otherformsofmisuseincludefailuretotaketheentireprescribedcourseofthe
antibiotic,incorrectdosageandadministration,orfailuretorestforsufficientrecovery.Inappropriateantibiotictreatment,forexample,istheirprescriptiontotreat
viralinfectionssuchasthecommoncold.Onestudyonrespiratorytractinfectionsfound"physiciansweremorelikelytoprescribeantibioticstopatientswho
appearedtoexpectthem".[86]Multifactorialinterventionsaimedatbothphysiciansandpatientscanreduceinappropriateprescriptionofantibiotics.[87][88]
Severalorganizationsconcernedwithantimicrobialresistancearelobbyingtoeliminatetheunnecessaryuseofantibiotics.[84]Theissuesofmisuseandoveruseof
antibioticshavebeenaddressedbytheformationoftheUSInteragencyTaskForceonAntimicrobialResistance.Thistaskforceaimstoactivelyaddress
antimicrobialresistance,andiscoordinatedbytheUSCentersforDiseaseControlandPrevention,theFoodandDrugAdministration(FDA),andtheNational
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InstitutesofHealth(NIH),aswellasotherUSagencies.[89]AnNGOcampaigngroupisKeepAntibioticsWorking.[90]In
France,an"Antibioticsarenotautomatic"governmentcampaignstartedin2002andledtoamarkedreductionof
unnecessaryantibioticprescriptions,especiallyinchildren.[91]
TheemergenceofantibioticresistancehaspromptedrestrictionsontheiruseintheUKin1970(Swannreport1969),and
theEUhasbannedtheuseofantibioticsasgrowthpromotionalagentssince2003.[92]Moreover,severalorganizations
(includingtheWorldHealthOrganization,theNationalAcademyofSciences,andtheU.S.FoodandDrugAdministration)
haveadvocatedrestrictingtheamountofantibioticuseinfoodanimalproduction.[93]However,commonlytherearedelays
inregulatoryandlegislativeactionstolimittheuseofantibiotics,attributablepartlytoresistanceagainstsuchregulationby
industriesusingorsellingantibiotics,andtothetimerequiredforresearchtotestcausallinksbetweentheiruseand
resistancetothem.Twofederalbills(S.742[94]andH.R.2562[95])aimedatphasingoutnontherapeuticuseofantibioticsin
USfoodanimalswereproposed,buthavenotpassed.[94][95]Thesebillswereendorsedbypublichealthandmedical
organizations,includingtheAmericanHolisticNurses'Association,theAmericanMedicalAssociation,andtheAmerican
PublicHealthAssociation(APHA).[96]
Therehasbeenextensiveuseofantibioticsinanimalhusbandry.IntheUnitedStates,thequestionofemergenceof
antibioticresistantbacterialstrainsduetouseofantibioticsinlivestockwasraisedbytheUSFoodandDrug
Administration(FDA)in1977.InMarch2012,theUnitedStatesDistrictCourtfortheSouthernDistrictofNewYork,
rulinginanactionbroughtbytheNaturalResourcesDefenseCouncilandothers,orderedtheFDAtorevokeapprovalsfor
theuseofantibioticsinlivestock,whichviolatedFDAregulations.[97]

History

ThisposterfromtheUSCentersfor
DiseaseControlandPrevention"Get
Smart"campaign,intendedforusein
doctors'officesandotherhealthcare
facilities,warnsthatantibioticsdonot
workforviralillnessessuchasthe
commoncold.

Beforetheearly20thcentury,treatmentsforinfectionswerebasedprimarilyonmedicinalfolklore.Mixtureswithantimicrobial
propertiesthatwereusedintreatmentsofinfectionsweredescribedover2000yearsago.[98]Manyancientcultures,includingthe
ancientEgyptiansandancientGreeks,usedspeciallyselectedmoldandplantmaterialsandextractstotreatinfections.[99][100]More
recentobservationsmadeinthelaboratoryofantibiosisbetweenmicroorganismsledtothediscoveryofnaturalantibacterials
producedbymicroorganisms.LouisPasteurobserved,"ifwecouldinterveneintheantagonismobservedbetweensomebacteria,it
wouldofferperhapsthegreatesthopesfortherapeutics".[101]Theterm'antibiosis',meaning"againstlife",wasintroducedbythe
Penicillin,thefirstnatural
FrenchbacteriologistJeanPaulVuilleminasadescriptivenameofthephenomenonexhibitedbytheseearlyantibacterial
antibioticdiscoveredby
[58][102][103]
AlexanderFlemingin1928
drugs.
Antibiosiswasfirstdescribedin1877inbacteriawhenLouisPasteurandRobertKochobservedthatanairborne
[102][104]
bacilluscouldinhibitthegrowthofBacillusanthracis.
ThesedrugswerelaterrenamedantibioticsbySelmanWaksman,an
[58][102][105]
Americanmicrobiologist,in1942.
SyntheticantibioticchemotherapyasascienceanddevelopmentofantibacterialsbeganinGermanywithPaul
[58]
Ehrlichinthelate1880s. Ehrlichnotedcertaindyeswouldcolorhuman,animal,orbacterialcells,whereasothersdidnot.Hethenproposedtheideathatit
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mightbepossibletocreatechemicalsthatwouldactasaselectivedrugthatwouldbindtoandkillbacteriawithoutharmingthehumanhost.Afterscreening
hundredsofdyesagainstvariousorganisms,in1907,hediscoveredamedicinallyusefuldrug,thefirstsyntheticantibacterialsalvarsan[58][106][107]nowcalled
arsphenamine.
Theeffectsofsometypesofmoldoninfectionhadbeennoticedmanytimesoverthecourseofhistory(see:Historyofpenicillin).In1928,AlexanderFleming
noticedthesameeffectinaPetridish,whereanumberofdiseasecausingbacteriawerekilledbyafungusofthegenusPenicillium.Flemingpostulatedthatthe
effectismediatedbyanantibacterialcompoundhenamedpenicillin,andthatitsantibacterialpropertiescouldbeexploitedforchemotherapy.Heinitially
characterizedsomeofitsbiologicalproperties,andattemptedtouseacrudepreparationtotreatsomeinfections,buthewasunabletopursueitsfurther
developmentwithouttheaidoftrainedchemists.[108][109]
Thefirstsulfonamideandfirstcommerciallyavailableantibacterial,Prontosil,wasdevelopedbyaresearchteamledby
GerhardDomagkin1932attheBayerLaboratoriesoftheIGFarbenconglomerateinGermany.[107]Domagkreceivedthe
1939NobelPrizeforMedicineforhisefforts.ProntosilhadarelativelybroadeffectagainstGrampositivecocci,butnot
againstenterobacteria.Researchwasstimulatedapacebyitssuccess.Thediscoveryanddevelopmentofthissulfonamide
drugopenedtheeraofantibacterials.[110][111]

AlexanderFleming

In1939,coincidingwiththestartofWorldWarII,ReneDubosreportedthediscoveryofthefirstnaturallyderived
antibiotic,tyrothricin,acompoundof20%gramicidinand80%tyrocidine,fromB.brevis.Itwasoneofthefirst
commerciallymanufacturedantibioticsuniversallyandwasveryeffectiveintreatingwoundsandulcersduringWorldWar
II.[112]Gramicidin,however,couldnotbeusedsystemicallybecauseoftoxicity.Tyrocidinealsoprovedtootoxicfor
systemicusage.ResearchresultsobtainedduringthatperiodwerenotsharedbetweentheAxisandtheAlliedpowers
duringWorldWarIIandlimitedaccessduringtheColdWar.[113]

FloreyandChainsucceededinpurifyingthefirstpenicillin,penicillinG,in1942,butitdidnotbecomewidelyavailableoutsidetheAlliedmilitarybefore1945.
Later,NormanHeatleydevelopedthebackextractiontechniqueforefficientlypurifyingpenicillininbulk.Thechemicalstructureofpenicillinwasdeterminedby
DorothyCrowfootHodgkinin1945.Purifiedpenicillindisplayedpotentantibacterialactivityagainstawiderangeofbacteriaandhadlowtoxicityinhumans.
Furthermore,itsactivitywasnotinhibitedbybiologicalconstituentssuchaspus,unlikethesyntheticsulfonamides.Thediscoveryofsuchapowerfulantibiotic
wasunprecedented,andthedevelopmentofpenicillinledtorenewedinterestinthesearchforantibioticcompoundswithsimilarefficacyandsafety.[114]Fortheir
successfuldevelopmentofpenicillin,whichFleminghadaccidentallydiscoveredbutcouldnotdevelophimself,asatherapeuticdrug,ErnstChainandHoward
Floreysharedthe1945NobelPrizeinMedicinewithFleming.FloreycreditedDuboswithpioneeringtheapproachofdeliberatelyandsystematicallysearching
forantibacterialcompounds,whichhadledtothediscoveryofgramicidinandhadrevivedFlorey'sresearchinpenicillin.[112]

Etymology

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Thetermantibioticwasfirstusedin1942bySelmanWaksmanandhiscollaboratorsinjournalarticlestodescribeanysubstanceproducedbyamicroorganism
thatisantagonistictothegrowthofothermicroorganismsinhighdilution.[102][105]Thisdefinitionexcludedsubstancesthatkillbacteriabutthatarenotproduced
bymicroorganisms(suchasgastricjuicesandhydrogenperoxide).Italsoexcludedsyntheticantibacterialcompoundssuchasthesulfonamides.Incurrentusage,
theterm"antibiotic"isappliedtoanymedicationthatkillsbacteriaorinhibitstheirgrowth,regardlessofwhetherthatmedicationisproducedbyamicroorganism
ornot.[115][116]
Theterm"antibiotic"derivesfromanti+(bitikos),"fitforlife,lively",[117]whichcomesfrom(bisis),"wayoflife",[118]andthatfrom
(bios),"life".[48][119]Theterm"antibacterial"derivesfromGreek(anti),"against"[120]+(baktrion),diminutiveof(baktria),"staff,
cane",[121]becausethefirstonestobediscoveredwererodshaped.[122]

Research
Alternatives
Theincreaseinbacterialstrainsthatareresistanttoconventionalantibacterialtherapieshaspromptedthedevelopmentofbacterialdiseasetreatmentstrategiesthat
arealternativestoconventionalantibacterials,includingphagetherapy.[123]

Resistancemodifyingagents
Onestrategytoaddressbacterialdrugresistanceisthediscoveryandapplicationofcompoundsthatmodifyresistancetocommonantibacterials.Resistance
modifyingagentsarecapableofpartlyorcompletelysuppressingbacterialresistancemechanisms.[124]Forexample,someresistancemodifyingagentsmayinhibit
multidrugresistancemechanisms,suchasdrugeffluxfromthecell,thusincreasingthesusceptibilityofbacteriatoanantibacterial.[124][125]Targetsinclude:
TheeffluxinhibitorPheArgnaphthylamide.[125]
Betalactamaseinhibitors,suchasclavulanicacidandsulbactam[126]
Metabolicstimulisuchassugarcanhelperadicateacertaintypeofantibiotictolerantbacteriabykeepingtheirmetabolismactive.[127]

Vaccines
Vaccinesrelyonimmunemodulationoraugmentation.Vaccinationeitherexcitesorreinforcestheimmunecompetenceofahosttowardoffinfection,leadingto
theactivationofmacrophages,theproductionofantibodies,inflammation,andotherclassicimmunereactions.Antibacterialvaccineshavebeenresponsiblefora
drasticreductioninglobalbacterialdiseases.[128]Vaccinesmadefromattenuatedwholecellsorlysateshavebeenreplacedlargelybylessreactogenic,cellfree

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vaccinesconsistingofpurifiedcomponents,includingcapsularpolysaccharidesandtheirconjugates,toproteincarriers,aswellasinactivatedtoxins(toxoids)and
proteins.[129]

Phagetherapy
Phagetherapyisanothermethodfortreatingantibioticresistantstrainsofbacteria.Phagetherapyinfectspathogenicbacteriawiththeirown
viruses,bacteriophages.Bacteriophages,alsoknownsimplyasphages,infectandcankillbacteria.[130]PhagesinserttheirDNAintothe
bacterium,whereitistranscribedandusedtomakenewphages,afterwhichthecellwilllyse,releasingnewphageabletoinfectanddestroy
furtherbacteriaofthesamestrain.[130]Thehighspecificityofphageprotects"good"bacteriafromdestruction.Whenapplicable,
bacteriophagetherapydefeatsantibioticresistantbacteria.[130]

Supplements

Phageinjecting
itsgenomeinto
bacterialcell

Someantioxidantdietarysupplementscontainpolyphenols,suchasgrapeseedextract,anddemonstrateinvitroantibacterial
properties.[131][132][133]

Developmentofnewantibiotics
InApril2013,theInfectiousDiseaseSocietyofAmerica(IDSA)reportedthattheweakantibioticpipelinedoesnotmatchbacteria'sincreasingabilitytodevelop
resistance.Since2009,only2newantibioticswereapprovedintheUnitedStates.Thenumberofnewantibioticsapprovedformarketingperyeardeclines
continuously.ThereportidentifiedsevenantibioticsagainsttheGramnegativebacilli(GNB)currentlyinphase2orphase3clinicaltrials.However,thesedrugs
donotaddresstheentirespectrumofresistanceofGNB.[134][135]Someoftheseantibioticsarecombinationofexistenttreatments:
Ceftolozane/tazobactam(CXA201CXA
101/tazobactam):Antipseudomonalcephalosporin/
lactamaseinhibitorcombination(cellwallsynthesis
inhibitor).FDAapprovedon12/19/2014.
Ceftazidime/avibactam(ceftazidime/NXL104):
Antipseudomonalcephalosporin/lactamaseinhibitor
combination(cellwallsynthesisinhibitor).Inphase3.
Ceftaroline/avibactam(CPTavibactam
ceftaroline/NXL104):AntiMRSAcephalosporin/
lactamaseinhibitorcombination(cellwallsynthesis
inhibitor)

https://en.wikipedia.org/wiki/Antibiotics

Imipenem/MK7655:Carbapenem/lactamaseinhibitor
combination(cellwallsynthesisinhibitor).Inphase2.
Plazomicin(ACHN490):Aminoglycoside(protein
synthesisinhibitor).Inphase2.
Eravacycline(TP434):Synthetictetracyclinederivative/
proteinsynthesisinhibitortargetingtheribosome.
DevelopmentbyTetraphase,Phase2trialscomplete.[136]
Brilacidin(PMX30063):Peptidedefenseproteinmimetic
(cellmembranedisruption).Inphase2.

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Streptomycesresearchisexpectedtoprovidenewantibiotics,includingtreatmentagainstMRSAandinfectionsresistanttocommonlyusedmedication.Effortsof
JohnInnesCentreanduniversitiesintheUK,supportedbyBBSRC,resultedinthecreationofspinoutcompanies,forexampleNovactaBiosystems(http://www.
novactabio.com),whichhasdesignedthetypeblantibioticbasedcompoundNVB302(inphase1)totreatClostridiumdifficileinfections.[137][138]Possible
improvementsincludeclarificationofclinicaltrialregulationsbyFDA.Furthermore,appropriateeconomicincentivescouldpersuadepharmaceuticalcompanies
toinvestinthisendeavor.[135]IntheUS,theAntibioticDevelopmenttoAdvancePatientTreatment(ADAPT)Actwasintroducedwiththeaimoffasttrackingthe
drugdevelopmentofantibioticstocombatthegrowingthreatof'superbugs'.UnderthisAct,FDAcanapproveantibioticsandantifungalstreatinglifethreatening
infectionsbasedonsmallerclinicaltrials.TheCDCwillmonitortheuseofantibioticsandtheemergingresistance,andpublishthedata.TheFDAantibiotics
labelingprocess,'SusceptibilityTestInterpretiveCriteriaforMicrobialOrganisms'or'breakpoints',willprovideaccuratedatatohealthcareprofessionals.[139][140]
AccordingtoAllanCoukell,seniordirectorforhealthprogramsatThePewCharitableTrusts,"Byallowingdrugdeveloperstorelyonsmallerdatasets,and
clarifyingFDA'sauthoritytotolerateahigherlevelofuncertaintyforthesedrugswhenmakingarisk/benefitcalculation,ADAPTwouldmaketheclinicaltrials
morefeasible."[141]

Seealso
Antiviral
Antifungal
Antiprotozoal
Antimalarial

Antimalarial
Probiotic

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Furtherreading
Davies,JulianDavies,Dorothy(1September2010)."Originsand
EvolutionofAntibioticResistance".MicrobiologyandMolecular
BiologyReviews:MMBR.74(3):417433.doi:10.1128/MMBR.00016
10.ISSN10922172.PMC2937522 .PMID20805405.
"Antibiotics:MedlinePlus".NIH.gov.NationalInstituteofHealth.
Retrieved19July2016.
"WHO'sfirstglobalreportonantibioticresistancerevealsserious,
worldwidethreattopublichealth".WHO.
"Shortcourseversuslongcourseantibiotictreatmentforhospital

"Shortcourseversuslongcourseantibiotictreatmentforhospital
acquiredpneumoniainadultintensivecarepatients|Cochrane".Reviews.
doi:10.1002/14651858.CD007577.pub3.
Giedraitien,AgnVitkauskien,AstraNaginien,RimaPavilonis,
Alvydas(1January2011)."Antibioticresistancemechanismsof
clinicallyimportantbacteria".Medicina(Kaunas,Lithuania).47(3):
137146.ISSN16489144.Retrieved9August2016.

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