The Drugs Don't Work (Penguin) - Final Files

The Drugs Dont Work
lroessor Dame Sally C. Davies is the Chie Medical

Omcer or Lngland and the nrst woman to hold the
post. As CMO she is the independent advisor to the
Governmentonmedicalmatterswithparticularinter-
est in lublic lealth and Research. She developed the
National lnstitute or lealth Research in zooo. She
holdsanumbero internationaladvisorypositionsand
isanLmerituslroessoratlmperialCollege.
Dr}onathanGrantisalrincipalResearchIellowandor-
mer lresident at RAND Lurope, a not-or-pront public
policyresearchinstitute.lismainresearchinterestsare
onhealthR&Dpolicy,andtheuseo researchandevi-
denceinpolicymaking.lewasormerlyleado lolicy
at 1he Vellcome 1rust. le received his lhD rom the
Iacultyo Medicine,Lniversityo London,andhislSc
(Lcon,romtheLondonSchoolo Lconomics.
lroessor Mike Catchpole is an internationally recog-
nized expert in inectious diseases and the Director o
lnectious Disease Surveillance and Control at lublic
lealth Lngland, the government agency charged with
protecting and improving health. le has coordinated
many nationalinectiousdiseaseoutbreakinvestigations
and is an advisor to the Luropean Centre or Disease
lreventionandControl.leisalsoavisitingproessorat
lmperialCollege.
9780241969199_TheDrugsDontWork_PRE.indd 1 05/09/13 5:38 PM
The Drugs Dont Work
A Global Threat
Professor Dame Sally C. Davies, Dr Jonathan
Grant and Professor Mike Catchpole
Vl Kl NG
an imprint of
Vl Kl NG
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Contents
Introduction vii
+. Man,MicrobesandMicrobiomes +
a. 1heIallandRiseo lnection a,
,. MakingtheDrugsVorkAgain o
Conclusion ,,
Appendix: Major classes of antibacterial
agents and their use ,,
Further Reading and Websites s
Acknowledgements ,
vii
Introduction
ltisadark}ulyday.MrsXuhasnotbeencounting,
butitisthenteenthdayo herisolation.ltstarted
with a wheeze a week ater her sons birthday.
She hadtaken}oshtothethemeparkwithacouple
o hisschoolriends.Shekeepsongoingbacktothat
dayinhermind itwasullo energyandlaughter.
1hewheezeturnedintoacough,thecoughinto
a sore throat. ler husband, }on, gave her that
look concernedbutdistant,scaredo whatwas
coming. le knew. lt had happened to one o his
colleaguesatwork.lewasalreadythinkingabout
what it would mean. low would he look ater
}osh.Vouldhecope:
Vhen}oshwasbornsixteenyearsago,thecrisis
wasbeginningtotakehold.lnthennalmonthso
herpregnancy,MrsXuwasadvisedtostayindoors
to separate hersel rom her riends and amily.
Vhen}oshwenttonursery,sheand}onwerelec-
turedbytheleadabouthowirresponsibleitwas
to send a child into public with even mild symp-
toms. 1hey were given a home testing kit. }osh
had tospitonastripo paper.l itturnedgreenhe
could attend, i it was red he must stay at home.
viii
Introduction
1heycalledittheredspot.}onsmumlikenedit
toapregnancytest.
A ew years later, shortly ater }osh joined pri-
mary school, the government passed new laws
makingitacriminalonenceortheinectedtobe
inpublic.1hereweretalkso randomtestsinthe
street.l youwerecontagious,youwouldbecom-
mitted to one o the isolation sanatoriums that
were being built on the edge o all major towns.
1hiswasadeathpenalty.1heywerereerredtoas
colonies.
MrsXuwantstodieathome.Shehasspenttwo
weeksinherroomonherown.}onand}oshleave
her ood and medication in the sealed space
betweenthetwodoors.1heyusetheouterdoor,
sheopenstheinnerdoor.Shespeakstothedoctor.
le provides her with ever-reducing medicine,
painkillers and something to help at the end. le
also notines the authorities. 1heir home is now
identinedasaninectionspot.
1heyeariszo,.
As Chie Medical Omcer l am the LK govern-
ments most senior advisor on health issues. 1he
role dates back to ss,, and l am the sixteenth
holder o the post and the nrst woman, some-
thingthatlamimmenselyproudo.Lveryyearl
publish my assessment o the publics health and
advisethegovernmentonwhereactionisrequired.
ix
Introduction
lnzoszldecidedtoocusmynrstin-depthreport
oninectiousdiseases partlyasitseemedtobean
uncontroversialtopic.lwaswrong.lamnoteasily
rattled,butwhatllearntscaredme notjustasa
doctor,butasamother,awieandariend.lreaking
romtradition,lengagedtheexpertiseo abroad
rangeo leadingclinicians,academics,researchers
andpolicymakers.Ournndingsweresimple.
Vearelosingthebattleagainstinectious
diseases.
lacteriaarenghtingbackandarebecoming
resistanttomodernmedicine.
lnshort,thedrugsdontwork.
Since the manuacture o penicillin in s,,
almostallo ushavebenentedromthemedicinal
enectso antimicrobialdrugs whatweotencol-
loquiallyand,aswewillsee,inappropriatelyreer
toasantibiotics.1hesewonderdrugshavestopped
us dying rom mundane inections such as a sore
throat and have allowed us to routinely survive
extraordinary operations, rom hip replacements to
hearttransplants.lndeed,theVorldlealthOrgan-
izationestimatesthatantimicrobialsadd,onaverage,
twenty years to everyones lives. 1hink about the
timeyourthree-year-oldchildhadearache.Asan
anxious parent you try to console her, but in the
early hours o the morning you are at your wits
end and take her to the night clinic, earing the
x
Introduction
worst but clinging to the rational best. A nve-
minuteconsultation,aprescription,ahuntorthe
openpharmacyandyouarehomewithanuores-
cent yellow medicine. 1wenty-our hours later
yourlovedoneisplayinginthegardenobliviousto
thedramao thenightbeore.
1he story o Mrs Xu may read like science nc-
tion,orascenarioromWorld War Z,buti wedo
notchangethecourseo history,andi weallow
resistance to increase, in a ew decades we may
start dying rom the most commonplace o ail-
ments that can today be treated easily. Ve will
regresstothepointwhere,intwentyyearstime,
whenlneedahipreplacement,theoperationmay
bedeemedtoodangeroustoevenattemptdueto
therisko catchinganuntreatableinection.
Antimicrobial drugs have been important to
me.lnthelates,os,myhusband,lhilip,wasdiag-
nosed with chronic myeloid leukaemia (CML,.
1heonlytreatmentavailableorCMLatthattime
wassymptomatic,butcolleagueshaddevelopeda
newwayo extendinglie.theycollectedthestem
cellscirculatinginhisbloodearlyinhisdiseaseand
rozethem.lnthisway,theycouldbegivenback
to him when, as always happens, his chronic leu-
kaemiadevelopedintothelethal,acuteorm.
ln sso, lhilips CML transormed into acute
leukaemia his death sentence. Naturally, we
wanted more time together. le was given very
xi
Introduction
high doses o chemotherapy to kill the leukaemia
cells,andbeganthestemcelltransusion.1hehope
was that the stem cells (or bone marrow, would
producebothCMLandnormalbloodcells.Vith
a transplant o this kind, the bone marrow can
takedaysorweekstoregenerateandthentotake
enect. ln the intervening period, patients have to
be supported with red blood cell transusions,
platelets to prevent bleeding and antimicrobial
drugstothwartandtreatinection.1hisisanawul
time or everyone. there was a chance that lhilip
coulddieo bleedingorinectionbeorehistrans-
usedcellssettledinandgrewback.Lverydaywe
anxiously checked or bruises indicating bleeding
and his temperature chart or inection. le was
assaultedwithswabsandneedlesatthewhino a
riseintemperature,thebestcarehecouldreceive,
butextremelystressul.
1he nrst time lhilip received this course o
treatmenthelastedthreemonthsbeoretheacute
leukaemia returned. 1he second time was even
shorter,andaterthethirdtimethesevereormo
the disease was detected in his blood at the same
timeasthenormalbloodcellswerereturning.le
declinedurthertreatments,butthankstoacom-
binationo stemcellrescueandantimicrobialshe
was granted nearly an extra year o lie with me.
1hiswasveryspecialorbotho us.
latientswithloworabsentwhitecells,orpoor
xii
Introduction
immunity,suchaslhiliporpeoplereceivingstrong
anti-cancer treatment, receive essential intraven-
ous antimicrobial drugs as lie-saving measures.
1heyaresupportedbyanumbero othermeasures
to prevent the introduction o inectious agents,
including staying in an isolation room, very strict
hand-washing,disinectionandmeticulousmouth
care, including rather horrid-tasting antiseptic
mouthwashes. lt is clear, however, that none o
thesetreatmentswouldbesuccessulwithoutanti-
bacterials,antiungalsandantivirals,usedbothto
prevent inection and to treat inections as they
occur. My mother, during treatment or ovarian
cancer,dependedonantimicrobialstoendureher
strongertreatments.
lutthepowero thesedrugsmaybecomingto
anend.Vehavetakenantibacterialandotheranti-
microbialdrugsorgrantedortoolong.Vehave
misusedthemthroughoveruseandalseprescrip-
tion, and as a result the bugs are growing in
resistanceandnghtingback.Vearealsonotdevel-
opingnewdrugsastenough.1hisisnotadistant
threat. already, resistant bugs are killing z,,ooo
people a year across Lurope. 1hat is almost the
samenumberasdieinroadtramcaccidents.
Myintentioninthisbookistodrawattentionto
this potentially devastating story. l am joined in
thisendeavourbymytwocolleagues.apolicyand
researchexpert,Dr}onathanGrant,andaninectious
Introduction
diseaseepidemiologist,lroessorMikeCatchpole.
}onathan is a long-time and trusted advisor and
esteemed analyst who works at RAND Lurope, a
researchorganizationthataimstoimprovepublic
policy.Mikeisaninternationallyrecognizedexpert
ininectiousdiseasesandtheDirectoro theCentre
orlnectiousDiseaseSurveillanceandControlat
lublic lealth Lngland, the government agency
chargedwithprotectingandimprovingourhealth.
lntheollowingchaptersweattempttoprovide
ascientincoverviewo microbesandhowtheycan
causehumandisease.Veidentiydinerenttreatment
options and examine how the rules o evolution
mean the bugs are constantly adapting to those
treatments.lutmoreimportantlyweexplainwhat
can be done about it, rom changes in personal
hygienetodevelopingnewdrugs.
Our response needs to be global and multia-
ceted, but i we do work together, bringing the
ingenuity o humanity to this real, growing and
otenorgottenglobalthreat,wecanmanageand
mitigatetherisko antimicrobialresistance,which
is just as important and deadly as climate change
andinternationalterrorism.
s
s.
Man, Microbes and Microbiomes
l itisaterriyingthoughtthatlieisatthemercyo
themultiplicationo theseminutebodies,itisa
consolinghopethatsciencewillnotalwaysremain
powerlessbeoresuchenemies ...
Louislasteur,
paperreadtotheIrenchAcademyo Sciences,ss,s
lnections have dominated the history o human
disease,andattimestheyhavedominatedhistory
itsel. 1he llack Death swept across the world in
theourteenthcentury,romitsprobableoriginsin
ChinatoitspeakinLurope,whereitreducedthe
populationbyanestimated,ooopercent.lnsss
theinnuenzapandemic,sometimesreerredtoas
theSpanishnu,isestimatedtohavekilledatleast
,omillionpeopleworldwide.ltisthispotentialor
inectiousdiseasestospreadrapidlyromhuman,
animalorenvironmentalsources,andtherebygive
rise to outbreaks, epidemics or even pandemics
9780241969199_TheDrugsDontWork_TXT.indd 1 05/09/13 5:46 PM
z
The Drugs Dont Work
that circle the globe, that makes them a unique
threat. On a global scale, inections are still the
leading cause o human morbidity and mortality,
particularly because o their impact on lower-
incomecountriessuchasinAricaandSouthLast
Asia, but also because o the long-term disability
that they can cause in richer countries, through
healthcare-associated inections and the conse-
quenceso viralinectionssuchashepatitisCand
llV.
Antimicrobials are a group o drugs that pro-
vide us with the weapons to nght these (still,
important causes o disease, disability and death.
1heir discovery and use through the second hal
o thetwentiethcenturyhashadaprooundenect
onhumanhealthandhasbeenessentialtomodern
medicaladvancessuchasthetreatmento cancer.
Vearenow,however,atacrossroadsinthejour-
ney towards the deeat o inection as a cause o
disease, as our use o these valuable drugs is not
onlybecomingthreatenedbythespectreo resist-
ance among the bugs they are used to treat, but
alsoaswerecognizethattheirinjudicioususecan
causeharminitsownright.
lnectiousdiseasesarecausedbyminuteorgan-
isms that can be ound living in or on plants and
animals, and also in the inanimate environment,
suchasinwaterandsoil.1heseminuteorganisms
,
rangeromvirusesandbacteria,toungiandpro-
tozoans (and inections may also be caused by
larger multicellular organisms such as parasitic
worms,.Althoughthemajorityo thesemicrobes
are too small to be seen with the naked eye, and
theylackthecomplexityo higherlieorms,they
neverthelesssharewithhumansandotheranimals
many o the building blocks or lie, such as
ribonucleic acid (RNA, or deoxyribonucleic acid
(DNA,orcodingo geneticinormationandpro-
tein-basedstructuralandunctionalelements.1his
sharingo buildingblockslimitstheopportunities
ortreatment,sincetreatmentsneedtobeableto
kill the microbes by interering with their struc-
ture or metabolism, but not with the cells o the
human(oranimal,nsh,insect,plant,etc.,thatthey
areinecting.
1he relationship between man and microbes,
particularly bacteria, is complex. Vhile bacteria
are an important cause o inectious disease, the
great majority o the enormous number o bac-
teria that we carry around with us as normal
healthyindividualsareharmlesspassengers(com-
mensals,, or even benent the hosts that harbour
them,aslongastheyremainwheretheyarenor-
mallyound,whichismainlyinthegutandonthe
skin.1hesecommensalbacteriahelptokeepour
bodieshealthybyaidinginthedigestiono oods
The Drugs Dont Work

andbyproducingvitaminslandK,whichwecan
absorb.1heyalsoplayaroleinthedevelopmento
the immune system and inhibit the growth o
harmul bacteria that can cause disease, by com-
petingwiththem.1hebenencialroleso bacteria
that occur naturally as part o the human biome
(good bacteria, are oten given as the rationale
or the use o probiotics. 1hese are live microbes
thatarethesameas,orsimilarto,thoseoundnat-
urally in the human body. lrobiotics are oten
ound in products such as dietary supplements,
yoghurts and suppositories. A zoos overview o
clinical applications o probiotics published in
the journal Clinical Infectious Diseases concluded
thatstrongevidenceexistsortheirbenentinthe
managemento acuteandantibacterial-associated
diarrhoea,andsubstantialevidenceexistsortheir
havingabenencialenectinatopiceczema(askin
conditionmostcommonlyseenininants,.Com-
mensalbacteriainthevaginaarealsoimportantin
inhibiting the growth o bacteria that can cause
inectiono thenewbornbabyasitpassesthrough
thebirthcanal.
1he term given to describe the entirety o
microorganisms that reside in or on the human
body is the human microbiome. lt has been esti-
mated that the microorganisms in the human
microbiomeoutnumberthecellsthatmakeupthe
,
human body by so to s, and that as such each
human carries around soo trillion (so`, micro-
organisms. Some o the microorganisms cause
illnesses,butmanyarenecessaryorgoodhealth.
Researchersnowcalculatethatarounds,ooodiner-
ent bacterial species can be ound within the
human intestine alone, and that the total weight
o bacteriawithinthehumangutcanbeasmuch
aszkg.
Large as it may be, the human microbiome is
onlyasmallparto thetotalo allmicroorganisms
that live on the Larth. 1here are approximately
,so bacteria on Larth, making up a biomass
that equals or exceeds that o all plants and ani-
mals on Larth, and containing ten times the
quantityo nutrientsoundinplantsandanimals.
Mosto thesemicroorganismsliveinthesoil,the
openoceanandontheoceannoor.1herearetyp-
icallyomillionbacterialcellsinagramo soiland
amillionbacterialcellsinamillilitreo reshwater.
1hetimethatittakesorbacterialcells(orpopu-
lations, to divide, and thereore spread, is called
thegenerationtime.1histimevariesconsiderably
between bacterial species and according to the
environmentwithinwhichthebacteriaaregrow-
ing.1herateo cellreplicationorallprokaryotes
(all bacteria and other organisms that lack a
nucleus, on Larth is estimated at s.,so cells
o
The Drugs Dont Work
everyyear.1heenormoussizeo thispopulation
and the speed with which its members replicate
provide a huge capacity or genetic diversity. 1he
generationtimeoraprokaryotesuchasEscherichia
coli(L.coli,intheintestinaltractisestimatedtobe
twelvetotwenty-ourhours,althoughunderopti-
malconditionsinalaboratoryitcanbeasshortas
nteen to twenty minutes (compared to a gener-
ationtimeo betweentwentyandthirtyyearsor
most human populations, i.e. the mean age o
mothersatnrstchildbirth,.
Microbesandmicrobialdisease
Microbes can cause a wide range o diseases,
renecting the many dinerent ways in which they
interactwithandanectthehosttheyareinecting.
Disease may stem rom the direct action o the
microbe on the hosts cells, or rom the inerred
action o toxins released by the microbe. lt may
alsobecausedbythehostsownimmuneresponse
totheinection(1ables,.
,
1ables.Dinerentwaysmicrobescancausediseases
xtcnaisxoracrio txaxrits
Killingo thehostscells
byinvadingmicrobes
Killingo cellsinthehosts
respiratorysystembyinnu-
enza,leadingtonuand
pneumonia
Killingo cellsinthehosts
centralnervoussystemby
poliovirus,leadingtoparalysis
lntererencewithhost
cellunctionsbymicro-
bialtoxins
1etanusandbotulismbacteria
bothcausediseasebythe
releaseo toxinsthatinterere
withthenervoussystem
controlo muscles
Cholerabacteriumcausesthe
releaseo toxinsthatpromote
excessivesecretiono nuidsby
thecellso thegut
Modincationo hostcell
behaviour
1hehumanpapillomavirus
inhibitstumoursuppressor
pathwaysininectedhostcells,
causingcancer
Diseasesymptomsand
signscausedbythehosts
immuneresponse
Celldamagecausedbythe
hostsimmuneresponse
to tuberculosisandhepatitisA
Anunderstandingo thestructureandunction-
ing o microbes is critically important to our
understandingo howtheycaninecthumans(and
otheranimals,andcausedisease,andalsotohow
s
The Drugs Dont Work
drugscanbedevelopedandusedtotreatthediseases
thattheycause.1hisnextsectionprovidesabrie
descriptiono themaintypeso microbethatthis
bookwillocusupon,beorewegoontodescribe
how we can use drugs to treat the inections that
theycause.
Viruses are the smallest o the microbial lie
orms, and have a relatively simple structure that
consists mainly o a genome (the genetic code,
made up o either DNA or RNA, which is con-
tained within an outer coat made up o proteins,
andsometimesalsoatmolecules(knownaslipids,.
1hegenomecarriesthecodethatallowsthevirus
to replicate and multiply once it has invaded a
hosts cell, while the outer coat protects the gen-
ome rom the surrounding environment and
enables the virus to bind to the walls o the cells
that they inect. Viruses may also contain other
proteins(enzymes,thatarerequiredortheinitial
steps in replication o the virus when it inects a
cell.Vhilesomevirusescansurviveintheenvir-
onment,sometimesinrelativelyharshconditions,
allvirusescanreplicateonlywithinthelivingcells
o ahostorganismthattheyhaveinected,making
useo thehostcellssystemstoproducecopieso
themselves.1heactthatvirusescannotreplicate
otherthanbyusingthemachineryo thecellso
theanimal,orplant,thattheyinectnotonlychal-
lengesourconceptso whatconstitutesalieorm,

butalsolimitsthetargetsthatwecandirectdrugs
against. Nonetheless, viruses have the essential
characteristics o being able to invade cells, to
reproduceandrespondtoevolutionarypressures,
and the limited structural components that they
needinordertoachievethosebasicbehaviourscan
beexploitedastargetsordrugtreatment.
lacteria are single-celled microorganisms that
are typically about one-tenth the size o the cells
that make up most o the human body. lacteria
consist o a chromosome made o DNA that is
enclosed, along with other intracellular compo-
nents,withinamembranethatismadeupo lipids
and proteins. lacteria may also contain genetic
codeinplasmids,whichareusuallysmall,circular
loops o DNA that can be ound noating ree in
theinterioro bacteria,butareseparateromthe
mainbacterialchromosome,andmaycarrygenes
thatareimportanttotheabilityo thebacteriato
cause disease or to survive under hostile condi-
tions.llasmidsareimportantbecausetheycanbe
transerred between bacteria o dinerent species,
as well as between bacteria o the same species.
Lnlike viruses, bacteria also possess a range o
other structural and unctional components that
areimportanttotheirsurvivalandtheirabilityto
replicate, which oner potential targets or anti-
microbial drugs. 1he great majority o bacteria
alsohaveacellwall,madeupo sugarsandamino
so
The Drugs Dont Work
acids, that is located outside the cell membrane
and provides structural support and protection.
1he cell wall, which is not ound in humans or
otheranimals,isessentialtothesurvivalo many
bacteria, and dinerences in the detailed structure
o the cell wall can have an important enect on
howsusceptiblebacteriaaretoantibacterialdrugs.
lacteria are oten classined broadly according to
how their cell wall reacts to a particular staining
agent (the Gram stain, when viewed under a
microscope, with Gram-positive bacteria staining
blueandexhibitingdinerentsusceptibilitiestocer-
taincommonantibacterialsthantheGram-negative
bacteria, which appear red, as a result o picking
upacounter-stain.
Iungiarealargegroupo organismsthatarecon-
sidered to be distinct rom animals and plants (and
rom viruses and bacteria,. 1hey range rom large
structures,suchasmushrooms,tomicroscopicstruc-
tures,whichincludemicroorganismsthatcaninect
humans suchasathletesoot otheranimalsand
plants. Iungi possess chromosomes that are com-
posed o DNA located within a distinct nucleus
withintheungalcell,andmayreplicatethroughsex-
ualorasexualreproduction.Iungi,likebacteria(and
plants,,possessacellwall,althoughitscompositionis
dinerentromthato bacteria.
ss
Antimicrobialsandantimicrobialtreatment
Ournrstlineo deencesagainstinectionarethe
physical barriers that the body has to prevent
microbialinvasion.1heseincludeanintactcover-
ingo skin,theacidthatwehaveinourstomachs,
andthemicroscopichair-likestructuresinourair-
ways that push any potential invading organisms
outo ourlungs.
Vhen these natural deences are breached,
because the invading microorganism is particu-
larlyvirulentorourdeenceshavebeenweakened
by disease, injury or medical treatment, we have
another line o deence at the ready. Many inec-
tions, particularly viral ones, are enectively dealt
with by the bodys chemical deence systems
suchaslysozyme,oundintearsandsaliva which
attackthecellwallo bacteria,andspecializedpro-
teinsintheblood(thecomplementsystem,that
can attack microbes and attract immune cells.
1hese immune cells not only help to deend the
bodyagainstcurrentinection,butalsootenprovide
uswithlong-termimmunitytoutureinectionby
thesamestraino microbe.lowever,insomecir-
cumstancesantimicrobialdrugsmayberequired.
Drugsthatkillorinhibitthegrowtho microbes
have been the mainstay o therapy or inectious
disease since the introduction o penicillin or
sz
The Drugs Dont Work
treating inection in the sos. lt is astonishing to
think that the discovery o this wonder drug was
accidental.Vhenwasthelasttimeyouwenttothe
kitchenorasliceo toastandnoticedanumbero
smalluzzyspotso mouldonyourbread:Chances
areyouhadbeenawayoraewdaysandorgotto
givethebreadandotherperishablestoyourneigh-
bours or riends beore you let. lt happens to us
all,butwedontwinNobelprizesonthebacko
such mistakes. Alexander Ileming did. lorn in
ssss in Ayrshire, Scotland, he had moved to Lon-
don when he was sixteen and ended up studying
medicineatStMaryslospitalateraewclerical
jobsandagenerousinheritance.Atmedicalschool
he was a couple o years older than his contem-
poraries,andaidedbythismaturityandhissharp
intellecthewonmanystudentprizes.Onthesur-
ace Ileming was dour and unassuming, but his
interests pointed to a more complex personality.
he was a Ireemason, a member o the Chelsea
Arts Club, a private in the London Scottish Regi-
ment and a nrst-rate shot or St Marys lospital
rineclub.lartlyinnuencedbyconcernsthatIlem-
ingcouldendupshootingorarivalhospitalteam,
he was onered a job as an assistant in St Marys
lnoculationDepartmentinsoo.lequalinedasa
doctor a ew years later and began to develop a
reputationasapoxdoctor,treatingsexuallytrans-
s,
mitted diseases both in the poorhouses o Vest
London and through a lucrative private practice.
lut the outbreak o war was to change that. ln
October ss Ileming joined colleagues rom the
lnoculation Department in establishing an army
laboratory or the study o wound inections at
loulogne,Irance.Gangreneandtetanuswouldbe
responsibleornearlyatentho alldeathsinneld
hospitals during the Iirst Vorld Var. Ileming
wanted to understand the cause o these inec-
tions, and ound that the majority o them were
comingromthesoldiersownclothing.leinves-
tigated the enects o antiseptic washing, which
wasthestandardtreatmentatthetime,andound
it to be potentially counterproductive, especially
orthedeepwoundstypicallyinnictedinwar.lac-
teria arising rom a wound were attacked by the
bodys own white bloods cells (phagocytes,, but
theythemselveswerebeingkilledonbytheanti-
septics,allowingthebacteriatonourish.
Ilem ashiscolleaguescalledhim wasdemo-
bilized in ss and returned to the lnoculation
Department at St Marys as an acknowledged
expert on wound inection. lis research interests
overthenexttenyearswerelargelyocusedaround
lysozyme a natural enzyme that acts like an
antiseptic,providingprotectionromsomebacteria
whichhediscoveredinszs.
s
The Drugs Dont Work
ln the summer o szs, Ileming went on holi-
day with his wie Sareen and our-year-old son,
Robert. 1hey had bought a country home, 1he
Dhoon, in the picturesque Sunolk village o lar-
ton Mill in szs, and spent most o their holidays
and weekends there. On returning to his labora-
toryinLondonatthebeginningo Septemberhe
discovered that the letri dishes he had let on his
benchhadgonemouldy.lewasinvestigatingthe
propertieso Staphylococcus aureus,acommonbac-
teriumthatcancauseskininectionssuchasboils.
As was typical o Ileming, he had not cleaned or
tidiedhislabbeoregoingonholiday,creatingan
ideal environment or the mould to ester. Vhat
perplexed Ileming was not the growth o the
mould but that the mould seemed to have killed
on the bacteria that he was growing in the cul-
tures. lntrigued by this observation, he set about
identiyingthemouldanddiscovereditwasPenicil-
lium,acommonandnaturallyoccurringgenuso
ungithathadnrstbeendescribedatthebeginning
o the nineteenth century. le managed to puriy
the mould juice and test it against a number o
knownbacteriathatcausecommondiseasessuch
as diphtheria,pneumoniaandmeningitis.Ileming
reproduced the results o the accidental experi-
ment and called the antibacterial penicillin,
publishinghisnndingsintheJournal of Experimental
Pathologyinsz.
s,
Convinced that he had discovered one o the
worldsoremostblockbusterdrugs,Ilemingspent
subsequent years trying to puriy and isolate the
antibacterial properties o penicillin and demon-
strateitsclinicalvalue.leailedandhadgivenup
when two Oxord chemists Lrnst Chain and
lowardIlorey tookupthischallengeinthelate
s,os.Atthetimetheirinterestwasacademic.1he
possibility that penicillin could have practical use
inclinicalmedicinedidnotenterourmindswhen
westartedthework,Chainsaidlaterinlie.1hey
succeeded in developing a way to isolate, puriy
andproducesmallquantitieso penicillin.lnMay
so they tested the drug on eight white mice by
injectingthemwithlargeamountso streptococci.
Iourmicewereletuntreated.thecontrolgroup,
andtheotherourinjectedwithdinerentdoseso
penicillin. 1he mice in the control group died
within a couple o hours, while the treated mice
survived. 1hey had managed to demonstrate the
potential clinical application o penicillin when
war was beginning to rage around Lurope. 1he
animal experiment was ollowed by a successul
toxicologytestinahealthyvolunteerinssanda
serieso clinicaltrials,sothatinsztheGeneral
lenicillin Committee was set up to coordinate
commercial production as part o the war enort.
Glaxo, a drug company, established a penicillin
productionplantinlritaininDecembersz,but
so
The Drugs Dont Work
it was dimcult or the lritish companies to ramp
up production given their existing commitments
or other medicines. Ilorey managed to persuade
the LS government to und the equipment or
drug companies to mass-produce penicillin in
America.lystherewasenoughpenicillintobe
givenroutinelytoallwoundedsoldiers,anditwas
seenastheoriginalwonderdrugatatimewhen
goodnewswasrare.lnrecognitionorthediscov-
ery o penicillin and its curative enect in various
inectious diseases, Ileming, Chain and Ilorey
jointlywontheNobellrizeinlhysiologyorMedi-
cineins,.
1hereisotenconusionaboutthetermsusedto
describedrugsthatareenectiveagainstmicrobes.
1he common uniying term or all these drugs is
antimicrobials(althoughantibioticisotenused
asthecolloquialequivalent,.1hetermantibiotic
was nrst used in sz to describe substances that
are produced naturally by microbes and that
inhibit the growth o, or kill, other microbes.
1hese substances provide the microbes that pro-
duce them with a competitive advantage, and
hence enable them to nourish, over the microbes
thattheyinhibitorkillthroughthereleaseo anti-
biotic substances. ln strict scientinc terms, this
means that we should not describe as antibiotics
themanydrugsthatarepartiallyorwhollymanu-
actured through man-made chemical processes,
s,
andthatwenowusetotreatinections,astheyare
notproducedbymicrobes.1helanguageo drug
treatmentorinectionsisurthercomplicatedby
the act that the great majority o such drugs are
activeonlyagainstviruses,orbacteria,orungi(or
othercauseso inection,.1hisleadstotheuseo
terms such as antiviral, antibacterial and anti-
ungal or the dinerent classes o drug that we
use.
Vewilluseantimicrobialasthegeneralterm
to describe all drugs that are used to treat micro-
bial inections, and antibacterial, antiviral and
antiungalwhenwearediscussingdrugsthatare
used primarily to treat orms o inection caused
by bacteria, viruses or ungi respectively. Vithin
those groupings, the drugs may also be classined
according to their underlying mode o action or
their enect on the microorganism they are being
used against, or example bacteriostatic (only
inhibitbacterialgrowth,orbacteriocidal(killbac-
teria,.Dinerenttypeso viruses,bacteriaandungi
are susceptible to dinerent types o antimicrobial
drug, and dinerent strains o the same type o
virus, bacteria or ungi can diner in which drugs
they are susceptible to (because they can acquire
resistance,.Aswithanydrug,antimicrobialdrugs
cangiverisetoadversereactions(sometimescalled
sideenects,,whichinrarecasescanbesevere.Ior
thisreason,andbecauseo theriskso promoting
ss
The Drugs Dont Work
antimicrobialresistancethroughinappropriateuse
o drugs, it is important that antimicrobials are
onlyusedwhentheyarelikelytobeo benentin
thetreatmento aninection,whichmeansknow-
ingwhichinectionandwhichantimicrobialsthat
straino inectionislikelytobesusceptibleto.
Lnortunately,itisotennotpossibletobecer-
tainwhethertheillnessinapatientwithinectious
diseaseisviral,bacterial,orduetoanotherormo
microbe, without undertaking laboratory tests.
1hus,inthemajorityo cases,itisnotpossibleor
adoctortoknowwithcertaintywhetherapatient
withasorethroathasabacterialormo inection
that might benent rom antibacterial treatment,
let alone which orm o bacterial inection and
hence which type o antibacterial drug would be
o benent.lndeed,i thepatienthasaviralormo
inection then antibacterial treatment would be
o nohelpwhatsoever.lnmostcauseso viralsore
throat, antiviral treatment would not be o use
either,ascurrentlyavailableantiviraldrugsarenot
enectiveagainstthemajorityo commoncauseso
the ailment. Iurthermore, these common causes
o viral throat inection are enectively eliminated
overtimebyanormalbodysimmunesystem.
Antimicrobial treatment, particularly repeated
courses and treatment with broad-spectrum anti-
bacterials, can, in addition to eliminating the
harmulbacteriacausingdisease,alsosubstantially
s
reducethenumbero thecommensalbacteriathat
liveinandonourbodies.lnthecaseo thecom-
mensalsthatliveinourintestines,thiscanleadto
the gut being colonized with harmul bacteria in
their place. lndeed, the use o broad-spectrum
antimicrobialsisnowrecognizedasamajoractor
behindtheriseinaseriousormo inectiono the
intestine called Clostridium difcile, towards the
end o thetwentiethcenturyandthebeginningo
thisone.Aswewillsee,thishasbecomeoneo the
most important causes o inection anecting
patientsinhospital,andinzossClostridium difcile
was mentioned on the death certincates o just
overz,,oopeopleintheLK.1hegoodnewsisthat
thenumbero casesanddeathsduetothisinec-
tion has declined dramatically as a result o the
introduction o strict controls on the use o anti-
microbials in hospital and the reintroduction o
stronginectioncontrolmeasuresincludinghand-
washing.
1hechallengeindevelopingnewdrugsorsys-
temic use is to nnd substances that are active
against microbial cell structures and metabolic
processesbutnotagainststructuresandprocesses
inthecellso thehumanpatientwhoistoreceive
thetreatment.1hisiswhymanyo thedrugswe
use today to treat bacterial inections target the
cell wall, which exists in most bacteria but not in
humans. Lxamples o such drugs include the
zo
The Drugs Dont Work
penicillins,aslistedintheAppendix.Othertargets
or antibacterial drugs include the bacterial cell
membrane,bacterialproteinproduction,andbac-
terialDNAreplicationandortranscription.Some
antibacterialdrugsareactiveagainstawiderange
o bacteria, such as the carbapenems and tetra-
cyclines, whereas others have a much narrower
spectrumo activity,suchasvancomycin,whichis
only enective at killing sensitive Gram-positive
bacteria. Metronidazole, which acts by inactivat-
ing a wide range o enzymes, is active against a
rangeo bacteriaandalsoagainstprotozoalinec-
tions (which, or example, can cause amoebic
dysentery,.
Most o todays antibacterial drugs are man-
made (semi-synthetic, modincations o naturally
occurringcompounds.1heseinclude,orexample,
thepenicillins(whichwereoriginallyidentinedas
acompoundproducedbyPenicilliumungi,.Some
antibacterialcompoundsarestillisolatedromliv-
ingorganisms,suchasthegroupo antibioticsthat
arecalledaminoglycosides,whichareusuallyused
only or treating severe inections in hospitalized
patientsastheirbloodlevelsneedtobemonitored
closely to avoid the hearing and kidney damage
that can be caused i levels become too high.
Others, such as the sulphonamides, are produced
solelybychemicalsynthesis.
As with antibacterial drugs, antiviral drugs tar-
zs
get viral components or processes that are as
distinct as possible rom human cell components
andprocesses.1heearliestantiviraldrugsinwide
usewerethosedevelopedagainstinnuenza(aman-
tadine, and herpes viruses (acyclovir,, although
the major ocus o antiviral drug development in
more recent years has been with respect to llV
inection. Antiviral drugs work by targeting key
stepsinthestageso invasiono thehostcell,rep-
lication o the viral genome, and assembly and
releaseo thenewvirusoncethegenomehasbeen
replicated.Iorexample,amantadine,whichisused
inthetreatmento innuenza,inhibitsthestepo
uncoating the viral genome that is necessary or
the viruss genetic code to be inserted into the
hosts cells so that it can be replicated. Acyclovir,
usedorthetreatmento herpesvirusinections,
manyo thedrugsusedorthetreatmento llV
inection, and lamivudine, used or the treatment
o hepatitisl,allworkbyinhibitingthereplication
o the virus ater invasion o the host cell. Osel-
tamivir, another drug used or the treatment o
innuenza, works by inhibiting the release o the
virusromthehostcellaterithasbeenreplicated.
1here are greater similarities between ungal
andhumancellsatthemolecularlevelthanthere
arebetweenhumancellsandeithervirusesorbac-
terial cells. As a consequence, identiying targets
ordrugsinthetreatmento ungalinectionshas
The Drugs Dont Work
proved more dimcult, and side enects rom sys-
temicanti-ungaldrugsaremorecommon.Many
o the drugs used or treating systemic ungal
inectionstargetthecellmembrane,whichcontains
ergosterol in place o the cholesterol component
oundinhumancellmembranes.
z,
z.
The Fall and Rise of Infection
1hetimemaycomewhenpenicillincanbeboughtby
anyoneintheshops.1henthereisthedangerthatthe
ignorant man may easily underdose himsel and by
exposing his microbes to non-lethal quantities o the
drugmakethemresistant.lereisahypotheticalillus-
tration.MrXhasasorethroat.lebuyssomepenicillin
and gives himsel, not enough to kill the streptococci
but enough to educate them to resist penicillin. le
then inects his wie. Mrs X gets pneumonia and is
treated with penicillin. As the streptococci are now
resistant to penicillin the treatment ails. Mrs X dies.
VhoisprimarilyresponsibleorMrsXsdeath:
SirAlexanderIleming,
NobelLecture,s,
Iromhappyaccidenttoglobalblockbuster
SixteenyearspassedbetweenSirAlexanderIlem-
ings accidental discovery o pencillin in szs and
z
The Drugs Dont Work
itsmassproductionins,.lenicillinbecamealie
saverintheSecondVorldVarbecauseSirloward
Ilorey and Sir Lrnst Chain helped turn it into a
useabledrug.lutitwastheexpertiseo American
drugcompaniesthatallowedthewonderdrugto
be mass-produced. 1hey succeeded in making
large quantities o penicillin using a technique
knownasdeep-tankermentation,wheretheanti-
bacterialdrugwasgrowninlargequantitiesinan
aerobic mixture o corn steep liquor, milk sugar,
salts and minerals, which controlled or pl and
the sterility o the air. Due to these changes in
manuacturingtechniques,outputincreasedexpo-
nentiallyromzsbillionOxordunitsins,too.s
trillion in s,. (An Oxord unit is the minimum
amounto penicillinthatwillpreventthegrowth
o Staphylococcus aureus over an area an inch in
diameter in a standard culture medium and is
equivalenttoo.ooomicrogramso thecrystalline
compound atypicaldoseo benzylpenicillinor
anadultwithathroatorskininectioncausedby
sensitive Gram-positive bacteria today would be
tosmillionunitsperday.,1heAmericangovern-
ment was able to remove all restrictions on
penicillin in s,, and in the LK it nrst became
available to the general public as a prescription
drugayearlater.
1oday over ,, million courses o antimicrobial
drugsareprescribedbyamilydoctorsinLngland
z,
eachyear thatsmorethanoneprescriptionper
household per year. Millions o doses o anti-
microbials are given in hospitals each day, with
prophylactic use o antibacterials beore surgery
now a routine precaution or many types o
operation. Vhen compared to other Luropean
countries, the LK is not a major consumer o
antimicrobial drugs. Luropean Surveillance o
Antimicrobial Consumption is an international
networkthatcollectscomparableandreliableuse
data.1heyestimatethedenneddailydose(DDD,
pers,ooopeopleorantimicrobialdrugs.1heDDD
isaninternationalacceptedstatisticalmeasurethat
helps to make comparisons between countries.
Actual doses or individual patients and patient
groups will oten diner rom the DDD. ln zoo,
thelatestthedataareavailable,theDDDorout-
patientantimicrobialconsumptionintheLKwas
s,oreverys,ooopeople,whichwasaboutaverage
orLurope.lycomparison,theDDDorGreece
wasnearlytwicethat,at,s.Cyprus,Irance,ltaly,
Luxembourg and lelgium all had comparatively
high rates o antimicrobial consumption. One o
thereasonsortheselargedinerencesinprescrib-
ing practice is the availability o antimicrobial
drugs rom pharmacists. ly contrast to the LK,
where the availability o antimicrobial drugs is
strictlycontrolledthroughtheneedoraprescrip-
tion rom a qualined doctor or a pharmacist, in
zo
The Drugs Dont Work
somecountriesyoucanbuythemoverthecounter.
(1heonlyexceptionintheLKisortheissuingo
single doses o azithromycin by pharmacists or
the treatment o a laboratory-connrmed chla-
mydiainection,andtheover-the-counteravailability
o twoo theantimicrobialsusedasprophylactics
againstmalaria.,
Researchers in Catalonia, Spain, asked two
actors to visit nearly zoo pharmacies. 1he actors
pretended they had either a sore throat, acute
bronchitisoraurinarytractinection.Antibacter-
ialdrugsweresoldwithoutprescriptioninnearly
hal o the cases, although it did depend a bit on
thecondition,rangingromarounds,percentor
thesorethroattosopercentortheurinarytract
inection. Another study in the LK ound that
nearlyopercento householdshadantimicrobial
drugsintheirmedicinecabinets,unusedromapre-
vious prescription. lal o these households had
kept them in case o uture illness. 1his is doubly
worrying, as it indicates that people may not be
completing their prescription and that they plan
to sel-medicate with a likely incomplete course
o medication both o which increase the risk
o colonization and inection with drug-resistant
organisms.
luttheuseandmisuseo antimicrobialdrugsis
notrestrictedtohumans.Globallythevastmajor-
ity o antimicrobial drugs are given to armed
z,
animals,includingcattle,sheep,chickensandpigs.
Like humans, sick animals can be treated with
the drugs, but they are also used prophylactically
in animals at high risk, such as those intensively
armed. ln the LK, a total o , tonnes o anti-
microbials were sold or animal use in zoso, o
which s, per cent were purchased or prophy-
laxisandtreatmento inectionsinood-producing
animals. More controversially, antimicrobials are
sometimesusedtoattenthemuporslaughter a
sideenecto antimicrobialuse.1heyarealsorou-
tinely used in plant agriculture or example in
spraying ruit and even as antiungal paints on
ships,oilpipesandorotherindustrialuses.
1heallo inection
lnzoss,,,millionpeoplediedouto aglobalpopu-
lation o o. billion. About so million, roughly a
nth,o thesedeathswererominectiousdiseases.
.,millionromlow-andmiddle-incomecountries
andhal amillionromhigh-incomecountries.lut
another way, o per cent o all deaths in low-
income countries were a result o inectious
diseases,comparedtoaround,percentintheLK
and other high-income countries. l you include
illness in these estimates, then inections resulted
in the loss o ,o million disability-adjusted lie
zs
The Drugs Dont Work
years in zoso, just under a quarter o the global
burdeno disease.Adisability-adjustedlieyear(or
DALY,isacompositemeasurethatcombinesthe
timelostduetoprematuredeathwiththetimeo
healthy lie lost due to illness. ln high-income
countries the burden o inectious diseases is
relatively low at less than one-twentieth o all
DALYs butinlow-incomecountries(particularly
those in sub-Saharan Arica,, by contrast, inec-
tious diseases account or at least one-third o
DALYs.
Over the past soo years, many high-income
countrieshaveexperiencedasignincantdeclinein
death rates. Lie expectancy has rapidly increased
during this time. Ior instance, lie expectancy at
birthintheLKwasjustbelowntyyearsinsoo,
sixty-eightyearsins,oandeightyyearsinzoso.As
illustrated in Iigure s (below,, death rates ell
three-old, rom so,,s deaths or every million
people in the LK in sos to around ,,,s in s,s
(thesenguresarestandardizedorageandsex,so
theyarenotdistortedbychangesintheagestruc-
ture o the population,. About three-quarters
o this decline is due to a drop in inectious dis-
eases. the death rate or inectious diseases ell
nine-old, rom ,,o to s,sss deaths or every mil-
lionpeoplebetweensosands,s.
l youlookatspecinccauseso death,thenthe
statistics are more dramatic. Deaths rom puer-
z
peral ever (inection ater childbirth, in the early
s,os were s,ooos,zoo deaths per s,ooo,ooo live
births, despite rigorous hygienic precautions, but
withintenyearso theintroductiono sulphona-
mides in the s,os, and subsequently o penicillin
inthesos,thisrateelltoalmostzero.Likewise,
deaths rom syphilis all but disappeared in the
twentieth century. Although these declines in
mortalitycoincidedwiththeintroductiono anti-
microbialdrugs,itwouldbewrongtoattributeall
oreventhemajorityo thishealthgaintothewon-
der drugs. Almost without exception, the decline
indeathsromthebiggestkillersatthebeginning
o thetwentiethcenturypredatestheintroduction
o antimicrobial drugs or civilian use at the
end o theSecondVorldVar.}ustoverhal o the
decline in inectious diseases had occurred beore
s,s.1hemaininnuencesonthedeclineinmortal-
ity were better nutrition, improved hygiene and
sanitation,andlessdensehousing,whichallhelped
topreventandtoreducetransmissiono inectious
diseases.
1hesebroaderenvironmentalinnuenceso poor
sanitation, overcrowding and malnutrition partly
explainwhyinectiousdiseaseisstillamajorcause
o death and illness in low- and middle-income
countries. Ior low-income countries, lie expect-
ancyiscurrentlyaboutsixtyyears.lneumoniaand
diarrhoealdiseasescurrentlyaccountorathirdo
,o
The Drugs Dont Work
alldeathstochildrenundertheageo nve,withthe
highest burden occurring in Arica and South Last
Asia. lut there is a glimmer o hope that inec-
tious disease in the worlds poorer countries is
beginningtobecontrolled.Iorexample,childhood
immunization against measles has increased. ln so
about three-quarters o all children globally had
received a vaccination, by zoo, coverage was s, per
cent, with low-income countries experiencing the
highestincrease.Likewise,anumberocountrieshave
recordeddecreasesinthenumberoconnrmedcases
o malariasincezooo.Globallytheestimatednumber
o deathsrommalariaellromalmostsmillionin
18,000
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
D
e
a
t
h

r
a
t
e
s
(
p
e
r
s
o
n
s

p
e
r

m
i
l
l
i
o
n
,

s
t
a
n
d
a
r
d
i
z
e
d

f
o
r

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e

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o

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e

1
9
0
1

p
o
p
u
l
a
t
i
o
n
)
0
1901 1911 1921 1931 1941 1951 1961 1971
Deaths from infectious diseases
Deaths from non-infectious diseases
Total deaths
Iigures.Age-standardizeddeathratesbycauseo death,
LnglandandVales,soss,s
Source.McKeownetal.,s,,
,s
zoooto,ss,oooinzoo.lnAricatherewasareduc-
tion o more than ,o per cent in either connrmed
malariacasesormalariaadmissionsanddeathsover
thesameperiod.lowever,thenumbero peopleliv-
ingwithllVworldwidecontinuestogrow,reaching
anestimated,,.,millionpeopleinzoo z,percent
higherthanins.1hatsaid,theoverallgrowtho
the global epidemic appears to have stabilized, in
zoo, the estimated number o new llV inections
was s per cent lower than in s. 1he increasing
numbero peoplelivingwithllVrenectsinpartthe
lie-prolonging enects o antiretroviral therapy.
According to the Vorld lealth Organization, as o
December zoo, antiretroviral therapy was avail-
able to more than , million people in low-income
and middle-income countries, although coverage
remained low, with only one-third o people with
llVreceivingthistreatment.
Ior over three generations, Lurope and North
America have experienced an extraordinary and
unprecedented decline in mortality. 1he worlds
poorer regions are beginning to experience this
demographictransitionbutstillhaveunacceptably
high levels o avoidable death and illness. 1he
cause o the decline in the worlds rich countries
andthepersistentinequityinpoorcountriesisdue
to a combination o economic development and
accesstomodernmedicine.Vehavethetoolstowin
thebattleagainstinectiousdiseases.Lnortunately,
,z
The Drugs Dont Work
these actual and potential gains are under threat.
1heantimicrobialdrugsthathavehelpedcombat
inectious diseases are becoming less and less
enective.
1heriseo theresistantbug
1hesamebacteriathatIlemingwasinvestigating
when he discovered penicillin Staphylococcus
aureus becameresistanttothedruginthes,os.
Staphylococcus aureus is a common cause o skin
inection,respiratorydiseasesandoodpoisoning.
1o address the penicillin-resistant Staphylococcus
aureus, methicillin a new class o antimicrobial
drugs was developed in the soos. Methicillin-
resistant Staphylococcus aureus (MRSA, emerged
quite quickly but became headline news in the
sosollowinganumbero high-pronlecaseso
peoplecatchingtheinectioninhospitals.
lacteriacanbeconsideredpromiscuousinthat
theyhavedevelopedseveraldinerentwayso shar-
ingtheirgeneticmaterial,acilitatingtheeaseand
speed o evolution o drug-resistant strains. 1he
mostcommonisbypassinggenesrommotherto
daughter,aswealldothroughouramilylineage.
Secondly,bacteriaarealsoabletoexchangegenetic
material in the orm o plasmid DNA that exists
separatelyromthemainchromosomalDNA,and
,,
whichmayincludethegeneticcodeorantimicro-
bial resistance. llasmids may be exchanged not
only vertically, to daughter bacteria, through
theprocesso bacterialreplicationbydivision,but
also horizontally, through contact with other
bacteria.lmportantly,thisexchangecanoccurnot
onlybetweenmemberso thesamebacterialspe-
cies,butalsobetweendinerentbacterialspecies.ln
this way resistance that has been developed or
acquiredbyonestraino bacteria,includingstrains
that are ound as normal commensals in the
human gut,canbespreadtootherstrainsorspe-
cies, including strains and species that can cause
severe disease. (ln some cases the plasmid DNA
can become incorporated into the main bacterial
chromosomal DNA., 1hirdly, bacteria can also
acquire new genetic material, including genes or
antimicrobial resistance, by taking up exogenous
DNA rom their environment, in a process called
transormation,orasaresulto beinginectedbya
ormo virusthatiscalledabacteriophage,which
canintroduceoreignDNAintothechromosome.
Genes or resistance can exert their enect
through any o nve broad types o mechanism.
(i, the bacteria can inactivate the drug beore it
reaches its target within the bacterial cell, (ii, the
outer layers o the cell can be impermeable, and
preventthedrugromentering,(iii,thedrugcan
enterbutisthenpumpedbackoutagain(emux,,
,
The Drugs Dont Work
(iv,thetargetcanbealteredsothatitisnolonger
recognizedbytheantibacterial,or(v,thebacteria
can acquire an alternative metabolic pathway
that renders the antibacterials target redundant
(bypass,.Althoughsomehundredso resistances
areknown,virtuallyallcanbeascribedtooneo
thesenvebroadtypeso mechanism.
1here are now examples o drug-resistant
strains in all types o microorganisms, including
bacteria (e.g. Staphylococcus aureus,, viruses (llV
and hepatitis l,, ungi and parasites (malaria,.
Antimicrobial resistance in hospitals and other
healthcare settings presents a particular threat.
1hisisbecauseo theinevitablyhighuseo anti-
microbialdrugsinhealthcaresettingsandtheease
o patient-to-patient transmission. lt is estimated
thataboutmillionpatientsacquireahealthcare-
associated inection in the Luropean Lnion every
year. Drug-resistant bacteria are responsible or
about z,,ooo deaths a year, which translate into
healthcarecostsandproductivitylosseso s.,bil-
lionannuallyintheLL.lnLnglandinzoss,there
were s,ss, reported cases o MRSA, but this had
declinedromapeako ,,,oocaseseightyearsearl-
ier. 1his success was largely due to public and
political pressure in improving hospital inection
control, including mandatory reporting, inection
reduction targets and deep cleans o inected
wards.
,,
AsweperhapsbegintogettogripswithMRSA,
newchallengesbegintoemerge,suchasEscherichia
coli(L.coli,.L.coliisabacteriumthatisoundin
large numbers in the lower intestine and is nor-
mallyharmless,butcertaintypescancauseserious
oodpoisoninganditisthemostrequentcauseo
bloodstream inection in Luropean hospitals. ln
theLKinzoss,oversoo,ooocaseso bloodstream
inection were reported to the lealth lrotection
Agency.L.colialoneaccountedoraround,oper
cent o these, compared with ss per cent or
Staphylococcus aureus (o which just s.o per cent
were due to MRSA,. Recent Luropean data sug-
gest a ,o per cent mortality or patients with
septicaemia due to multi-resistant L. coli, com-
pared with s, per cent or those with susceptible
L. coli.
luthealthcare-acquiredinectionsarenotarich-
country problem. Recent analysis by the Vorld
lealthOrganizationoundthathealthcare-associated
inections are more requent in resource-limited
settingsthanindevelopedcountries.Ioreverysoo
hospitalizedpatients,aroundsowillcatchaninec-
tionindevelopingcountries,comparedtoaround
, in high-income countries. About one-third o
operatedpatientswillcatchaninectionollowing
surgery, which is nine times higher than in
developedcountries.lealthcareacilitiesindevel-
oping countries provide the perect environment
,o
The Drugs Dont Work
or the transmission o resistant bugs. ln add-
ition to those actors evident in developed
countries Darwinian selection and patient-to-
patienttransmission thereisalimitedspectrum
o antimicrobialdrugsavailable,andthisshortage
o drugscanleadtounder-dosing.
Although antimicrobial resistance is a current
and serious problem in healthcare settings, this is
only the tip o the iceberg. Ve are beginning to
witness resistance to community-acquired inec-
tions.Streptococcus pneumoniaeisoneo themore
commoncommunity-acquiredbacteria,causinga
range o diseases including pneumonia, meningi-
tis, otitis media and sinusitis. ln the LS, about s,
percento pneumococcalisolatesareresistantto
penicillin.Ratesarelowerincountrieswhichhave
traditionally been conservative with their anti-
microbial use, such as the Netherlands and
Germany, and higher in countries that have been
moreliberal,suchasIranceandGreece.lnSpain,
resistancerateso ,percenthavebeenreported.
Iluoroquinolones are another group o anti-
bacterial drugs that are used or a number o
common inections, including bacterial gastro-
enteritisandurinarytractinection.Resistanceto
nuoroquinolones by campylobacter a cause o
gastroenteritis is being reported worldwide,
including examples o treatment ailure. ln the
Netherlands, or example, the examination o
,,
humanaecesreportedathree-oldincreaserom
around so to ,o per cent over a twelve-month
period. lnection with L. coli is responsible or
more than so per cent o cases o urinary tract
inection in young women, with several studies
reportingresistancetonuoroquinolonesasanrst-
linetreatment.
lncreased international travel means that indi-
viduals inected with resistant microbes in one
countrycanspreadthemtoanothercountryvery
quickly.1heinternationalspreado antimicrobial
resistance is renected in the recent convention
o naming new types o antibacterial-destroying
enzymeso aparticularclass,knownasthemetallo
beta-lactamases,whicharecapableo destroyinga
widerangeo antimicrobials,atertheplacewhere
they are nrst identined. 1hese enzymes coner
resistance against the powerul carbapenems,
among others, which represent one o our last
enectivedeencesagainstmulti-resistantstrainso
bacterialikeKlebsiella pneumoniaeandL.coli.1hese
enzymescanbespreadbetweendinerenttypeso
bacteria, because the genes that allow bacteria to
producethemarecontainedonplasmids.Recently
identined orms o this type o resistance include
New-Delhi metallo beta-lactamase (NDM-s,, Sao
laulo metallo beta-lactamase (SlM, and Verona
lmipenemase (VlM,. 1he LK patient in whom
NDM-s resistance was nrst identined contracted
,s
The Drugs Dont Work
the resistant strain through travel to New Delhi,
wherehewashospitalizedandnrststartedshow-
ing symptoms. 1here is separate evidence that
the NDM-s resistance was already circulating in
lndia in zoo,. 1he NDM enzyme has now also
been reported in Australia, the LSA, the Nether-
lands, Irance, Sweden and Canada, with most
patients having had prior hospital contact in the
lndiansubcontinent.
lnappropriate or suboptimal use o antimicro-
bials,suchastheuseo drugsthatarenotenective
against the microbes causing disease, or patients
not completing or missing doses, can promote
the development o resistant microbes. Likewise,
countereit medicines that contain low doses o
antimicrobialsarealsoamajorcauseo resistance.
l anantimicrobialisinenectiveagainstaparticu-
larbacteriumorisonlypresentatlevelsthatdonot
kill or prevent the growth o the bacteria, those
bacteriacancontinuetomultiply,withthechance
thattherandommutationsthatcanoccurateach
celldivisionwillmakethebacteriumresistantand
asaresultthoseparticularbacteriawillgrowaster
thanotherswhiletheantimicrobialdrugisstillin
thepatientstissues.
1herapidrateo multiplicationamongbacteria
contributessignincantlytothespeedo thedevel-
opment o antibacterial resistance, since each
division represents an opportunity or mutations
,
to occur in its genetic code. 1he result o which
couldbethedevelopmento resistancetoananti-
microbial drug. Vhen such mutations occur, the
bacterium, and the generations that it then gives
rise to, have an enormous competitive advantage
i exposed to antimicrobial treatment. 1hey will
rapidly replace the susceptible strains to become
thepredominantormwithintheoverallbacterial
population. 1his is a classic example o natural
selection o the nttest members o the popula-
tion, as described by Darwin in his theory o
evolution.
Repeated use o antimicrobials also increases
thechancesthatsomeo themanyharmlessbac-
teria that we carry around with us will develop
resistance as a result o random mutations. Once
resistance hasdevelopedin thisway, therepeated
useo theseantimicrobialdrugsexertsaselective
pressure that avours the survival o the resistant
bacteriaoverthosethataresusceptibletotheanti-
microbial. Repeated courses o antimicrobial
therapy will also avour the nourishing o com-
mensals(healthybacteriawhichliveinthebody,
thatmightalreadycarryplasmidswithgenesthat
coner resistance. Lnder the selective pressure o
repeated courses o antimicrobial drugs, these
resistant strains become dominant in the micro-
norathatwecarry,posingasignincantthreat.1his
threatcanberealizedthroughthespreado these
o
The Drugs Dont Work
bacteriatopartso thebodywheretheycancause
disease,suchascanoccuratersurgeryorserious
injury, when the bodys normal barriers to the
spreado microbesarebreached.luttheycanalso
arisewhenthebodysnormalimmunityisreduced
asaresulto disease(e.g.certainormso cancer
anddiabetes,ormedicaltreatment(e.g.highdoses
o steroids,, or when the resistance is transerred
tomoreharmulbacteriathroughtheexchangeo
plasmids.
1heconsequenceso thisorhumanhealthare
notonlythattheinectioninthepersonreceiving
treatment will persist, but also that they pose a
risk to others or developing resistant inection,
particularly i the orm o disease gives rise to
symptomssuchascoughingordiarrhoea.1aking
an average generation time o twelve to twenty-
ourhours,anysinglebacteriumthatispresentat
thebeginningo aseven-daycourseo antimicro-
bial treatment has the potential to give rise to as
many as so,ooo potential mutation events or, i
alreadyresistant,so,oooresistantonspringduring
that course o treatment. 1his many bacteria
would pose a signincant threat to others i the
patienthadsymptomssuchasdiarrhoea,withan
associatedoutpouringo themicrobecausingthe
symptoms.
Many o the antimicrobials employed in arm-
ing and other non-human uses can also promote
s
resistance in bacteria common to both humans
and animals. lacteria ound in animals, including
bacteriathatcausenosignincantillnessintheani-
malsthatharbourthem,cangiverisetodiseasein
humans.Lxamplesincludesalmonellasandstrains
o L. coli that can cause severe bloody diarrhoea
and renal ailure in humans (verocytotoxin-pro-
ducingL.coli,.1heuseo antimicrobialstotreat
animal inections, or as growth promoters, can
giverisetoresistanceinthebacteriainthoseani-
malsthatcanthenbespreadtohumans.
1hereareclearlinksbetweenthedevelopment
o resistance in bacteria causing inection in ani-
malsandtheemergenceo thosestrainsasacause
o inections in humans. 1here is evidence that
occupational exposure to animals is associated
with an increased risk o carrying MRSA on the
skinorotherpartso thebody,withstudiesshow-
ing that MRSA can be ound on so per cent o
equine veterinarians and ss per cent o small-
animalhospitalpersonnel,comparedwithupto,
percentinthegeneralpopulation.ltisalsoknown
thatdogsandcatscancarryMRSA,andthatinthe
LKthemajorityo MRSAstrainsidentinedincats
and dogs are those that are commonly associated
withhumaninection.1hisraisesthequestiono
whetherweshouldtreatcompanionanimalsatthe
same time as their owners when the latter are
oundtohaveMRSA-relateddisease.
z
The Drugs Dont Work
Iurtherevidenceorthelinkbetweenbacterial
resistanceinanimalsandhumanscomesromthe
Netherlands.Sincethediscoveryo anewstraino
MRSA(S1,s,inpigsintheNetherlandsinzoo,,
the Dutch authorities have carried out screening
o individualsinclosecontactwithpigsandcattle,
andthroughthishaveoundcarriagelevelso the
pig-associatedMRSAstrainrisingromopercent
to ,, per cent o all reported MRSA cases in the
human population between zoo, and early zoo,,
particularlyamongstanworkinginclosecontact
with pigs and cattle, such as armers. 1he pig-
associated strain has not yet been encountered in
the LK, other than a very ew sporadic isolated
cases, or which there was no apparent contact
withlivestockanimals.
Vorryingly, the threat o resistance might not
only come rom the use o antimicrobials in
humans and animals. 1he Luropean Centre or
DiseaselreventionandControl(LCDC,recently
publishedathreatassessmentthathighlightedpos-
siblelinksbetweentheuseo ungicidestoprevent
the development o moulds on crops and stored
cereals and the increase in a particular orm o
antimicrobial resistance in a ungus (Aspergillus,
thatcangiverisetoseriousinectionsinhumans.
AzoleungicidesarewidelyusedinLuropetopro-
tectcropsromdisease,ensureyieldsandprevent
ungal contamination o produce, or example in
,
cereals and soybean crops. Although there is no
dennitiveevidencethatresistanceinhumanstrains
hasderiveddirectlyromplantstrains,theLCDC
reportconcludesthatGiventhehighrequencies
o allergiesandasthma,theagingpopulation,the
attendant increase in cancers and their treatment
andtheexpandingindicationsortransplantation,
the numbers o patients at risk o developing
aspergillosislookssettoriserelentlessly.Although
the threat is evident, at the moment we can only
provideaneducatedguessastotheextento the
dangerinvolved.lardactsarerequired ...
lutitisthere-emergenceintheVesto classic
diseases such as tuberculosis (1l, that ore-
shadowstheglobalthreato antimicrobialresistance.
As in many developed countries, in the LK 1l
was a major cause o morbidity and mortality
throughouttheeighteenthandnineteenthcentur-
ies and declined during the twentieth century
untilthelatessos.Sincethen,incidencehasbeen
on the rise. letween zooo and zoss, over so,ooo
individuals were diagnosed with tuberculosis in
the LK. 1he majority o cases come rom the
more deprived communities within the LK, with
the highest burden on migrants coming rom
SouthAsiaandsub-SaharanArica.1listypically
treated with a six-month course o dinerent
antibacterialdrugs.Duetothelengtho thetreat-
mentandthecombinationo dinerentdrugs,itis
The Drugs Dont Work

relativelyeasyortreatmentnottobecompleted.
Lnortunately, 1l bacteria that have acquired
resistance to the antibacterials used in its treat-
ment are now globally widespread and are being
spreadrompersontopersoninthesamewayas
drug-sensitive1l.lnotherwords,thedrugsdont
work.lntheLK,caseso 1lthataremultidrug-
resistant increased rom thirty in zooo to over
eightyinzossand,todate,therehavebeentwenty-
our cases with extensive drug resistance. A
multi-resistant strain o 1l is immune to two o
the our most powerul anti-1l drugs, isoniazid
and riampicin. Lxtensive drug resistance occurs
whenthereisalsoresistancetoanyo thenuoro-
quinolones(suchasonoxacinormoxinoxacin,and
toatleastoneo threeinjectablesecond-linedrugs
(amikacin,capreomycinorkanamycin,.Multi-and
extensively drug-resistant strains o 1l take sub-
stantially longer to treat than the ordinary
(drug-susceptible, strain, and require the use o
second-lineanti-1ldrugs,whicharemoreexpen-
sive and have more side enects than the nrst-line
drugsusedordrug-susceptible1l.
1heriseo multi-andextensivelydrug-resistant
1lisaglobalissue.Vorldwide,inzoso,oversmil-
lion people died o 1l. 1he global incidence o
multidrug-resistant1lwasestimatedtobeabout
hal amillionpeopleinzoo, accountingorabout
sinzonewcases.Soar,extensivelydrug-resistant
1l is rare. Although it is dimcult to be sure, the
Vorld lealth Organization estimates that about
so per cent o drug-resistant 1l cases are o the
extensiveorm.Aboutoopercento drug-resistant
1lcasesoccurredinlrazil,China,lndia,theRus-
sian Iederation and South Arica. ln New York
Citythenumbero patientswith1lnearlytripled
between s,s and sz, with a doubling in the
proportionwithdrug-resistantisolateso Mycobac-
terium tuberculosis. About hal o patients with
multidrug-resistant 1l are successully treated,
mainlythroughdirectlyobservedtherapyinwhich
healthcare workers watch patients take their
medication.
o
,.
Making the Drugs Work Again
ltiseasytoeeloverwhelmedandpowerless sceptical
thatindividualenortscanreallyhaveanimpact.lutwe
needtoresistthatresponse,becausethiscrisiswillget
resolvedonlyi weasindividualstakeresponsibilityor
it.lyeducatingourselvesandothers,bydoingour
part ...eacho uscanmakeadinerence.
AlGore,An Inconvenient Truth(zooo,
Antimicrobial resistance is like climate change in
manyways.wearevictimso ourownsuccess,the
science is complicated but compelling, the inter-
nationalpoliticsareraughtwithairness,thereisa
senseo helplessness,butimportantlywecanand
mustdosomethingaboutit,startingnow.
Changingourbehaviour
Let us begin with the baby steps. 1he nrst pre-
ventive measure is to help control the spread o
,
inection.Atitssimplest,thiscouldmeanimproved
hand-washing. lroper hand-washing with soap
and water is the single most important thing you
candotohelpreducethespreado inectionsand
help protect you, your amily and those around
you.1hemostcommonwayorspreadingbugsis
byyourhands.wehavebetweenzandsomillion
bacteriabetweennngertipandelbow.Aswehave
seen, most o these bugs are harmless, but some
cancauseseriousillness.Vemaybeinadvertently
carrying the bugs that cause diseases such as sal-
monellosis, MRSA and impetigo diseases that
can be lie-threatening, especially or the young
andtheold.Giventhat,itisappallingthatonlysin
zopeoplewashtheirhandslongenoughtokillon
allinectiousbugsatergoingtothetoilet.1hisis
what researchers rom Michigan State Lniversity
in the LS recently ound out by watching more
than,,,oopeoplewashingtheirhandsinbars,res-
taurants and other public establishments. 1hey
alsooundthatsopercento peopledidnotwash
theirhandsandathirddidnotusesoap.lnorder
to killonthebugs,allittakesisnteentotwenty
secondso vigoroushand-washingwithsoapand
water this is about how long it takes to sing
lappylirthdaytoYoutwicethrough.
1he second action we can take is to stop
demanding antimicrobial medicines, especially
antibacterial drugs, rom our doctors when we
s
The Drugs Dont Work
have a viral inection. Vorryingly, one in two
Luropeansbelievesthatantibacterialssuchaspeni-
cillin are enective against colds and nu. 1hey are
not.AsimilarpollintheLSrevealsthesamelevel
o misunderstanding.Veneedtotacklethesemis-
conceptions surrounding antimicrobials. 1he LS
Centers or Disease Control and lrevention have
been running the annual campaign Get Smart.
KnowVhenAntibioticsVorksinces,withthe
aimo decreasingdemandorantimicrobialsamong
healthyadultsandparentso youngchildren.Simi-
larly, in Lurope public health advocates have
successully run a number o campaigns to try to
reduce the use and misuse o antimicrobials. Since
zooztheIrenchhaverunthecampaignAntibiotiques,
cest pas automatique(Antibioticsarenotautomatic,.
ltisaimedatdoctorsandthepublic,andhasincluded
adverts, lnternet campaigns and travelling exhib-
itions.Asaresult,therewasadropo aboutaquarter
inthenumbero antibacterialdrugsthatwerepre-
scribedbetweenzoozandzoo,,withthebiggestall
inchildren.e-lugisaLuropean-widelnternet-based
campaign that aims to educate children o all ages
about microbiology, hygiene and the spread, treat-
ment and prevention o disease, including prudent
antimicrobial use and how inappropriate use can
haveanadverseenectonantimicrobialresistancein
the community. lts website contains some educa-
tional games, including lody lusters, where you

win by collecting antibacterial drugs to kill on the
bacteriabutlosei youusethemagainsttheviruses.
1he threat o antimicrobial resistance is well
knowntomanyscientists,doctorsandhealthcare
proessionals. lut that inormation has yet to
becomecommonknowledgeorbetranslatedinto
meaningul action by us as a society. lart o the
reason we dont take the antimicrobial resistance
threat seriously is that estimates o current costs
arerelativelylowanduturecosts,whilelikelyto
be high, are hard to predict. lt is considered as
tomorrowsproblem.lowever,arecentreviewin
theBritish Medical Journalarguedthatcurrentcosts
o antimicrobialresistancearemisleadingandthat
uturecostsmayhavebeensignincantlyunderesti-
mated.Mosto thestudiesexamineddidnottake
intoaccountaworldwheretherearenoenective
antimicrobials. 1his included the study with the
highestestimatedcosto antimicrobialresistance
s,,billionperyearortheLS whichonlylooked
at the cost o resistance to the health service and
lost productivity. 1he apparent low cost o using
antimicrobial drugs today gives us immediate
benent,controllingtheirusewilldelaythatbenent
or tomorrow. 1his is what economists call a
hyperbolic discounting. As a result, an inherent
connict between generations arises. l we con-
tinue to misuse antimicrobial drugs, then our
children and grandchildren will not benent rom
,o
The Drugs Dont Work
them. 1he drugs will not work. So in addition to
improving our personal hygiene, and stopping
demanding antimicrobials rom our doctors or
thecommoncold,weallneedtoraiseawareness
o thethreato antimicrobialresistance.Allo us
need to learn about it, explain the threat to our
riendsandcolleagues,andgetthemtolearnabout
itandexplainittotheirriends.lnthisway,wecan
all help to put antimicrobial resistance into the
publicconsciousnessandstopthisunairintergen-
erationalprobleminitstracks.
Keeponinventing
Onesolutiontocontrolthethreato antimicrobial
resistance is through scientinc discovery. An area
thatisprovidingsomehopeisrecentadvancesin the
rapid diagnostics o microbes. lt is oten the case
that a doctor will not know the nature o the bug
that is causing an inection. ln non-lie-threatening
situations suchasalittlegirlwhohasearache this
doesnotmattertoomuch.1hedoctordrawsonher
experience as to what the underlying inection is
likelytobe,andmakesabestguessaboutthemost
appropriate antimicrobial to use. l the inection
doesnotsubsideintwodays,shemaytryadinerent
antimicrobial drug. lut in a lie-threatening situ-
ationaprocesso trialanderrorisnotgoodenough.
,s
Considerayoungbabyboywhoisacoupleo weeks
old. le was born without complications and had
been doing well, but suddenly becomes irritable
with ever. lis parents rush him to Accident and
Lmergency early one evening. 1he duty doctors
agreethatthebabyisunwell,heissluggishandnot
quiteright.Astheyarenotsurewhatiswrongwith
him, they suggest that he spends the night in the
babyward,andtakesomesamplesthataresentto
thehospitallaboratoryortesting.Asaprecaution-
arymeasurethedoctorprescribesceotaxime,which
is a broad-spectrum antibacterial, she is concerned
theremaybeaseriousunderlyinginectionbutcan-
not be sure o what is causing it. Lsing similar
techniquestothoseAlexanderIlemingusedeighty
years ago, the technicians grow some cultures and
two days later identiy Group l streptococcus
(sometimescalledGlS, ittakesonedaytogrow
the culture bacteria and another to identiy them.
1he doctor prescribes penicillin or the baby, who
recovers with no long-term complications. le is
lucky.lntheLKaround,oobabiesayearareinected
byGlSandaround,oo themdie,andaboutsins
have longer-term complications. le is also lucky
thathisdoctorsmadesurethathewasswitchedto
anantibacterialthatwaslikelytobemoreenective
in treating his GlS inection and that would have
lesso anenectonhishelpulcommensalbacteria
oncetheyknewthecauseo theinection.
,z
The Drugs Dont Work
l techniquescanbedevelopedtospeedupthe
diagnosis o GlS and other inections, then this
will cut the time it takes or our doctors to pre-
scribe the correct or most appropriate medicine.
1his in turn will save lives and reduce the risk o
urther complications. Recent advances in the
machines used to sequence DNA mean that it is
possible to break the code o bacterial or virus
genomesorlessthan_soo.1hepotentialo rapid
whole-genome sequencing was illustrated in zosz
byscientistsworkingattheworld-amousSanger
lnstitute in the LK. 1hey used ast genome-
sequencing technology to identiy, analyse and
stopthespreado MRSAinababywardatAdden-
brookes lospital in Cambridge. MRSA is a
drug-resistantbugthatwasinvolvedin,ssands,
deaths in Lngland and Vales in zoo and zoso
respectively. A study undertaken in Lngland in
zoo, ound that patients with a bloodstream
inectioncausedbyMRSAhadagreaterthansin
, chance o dying, rom any cause, within thirty
days o their inection being detected. Lsing rou-
tinescreening,stanidentinedanumbero inants
whowerecarryingMRSA,buttheywerenotsure
whether they were connected. 1he Sanger team
analysedthegenomeso theMRSAsamplesand
ound that they were closely related, alerting the
authorities to an outbreak that had originated in
the baby ward. Although it is still early days and
,,
thisisverymuchatthecuttingedgeo technological
development,itislikelythatinthenearuturethe
immediate identincation o pathogens through
rapid whole-genome sequencing and other tech-
nologies will cut the time it takes to diagnose a
microbialinection.1hishastwobenents.doctors
willbeabletoprescribethemostappropriatedrugs,
andtheywillbeabletodosomorequickly.
1heotherareawhereresearchwillmatterisin
thesearchornewantimicrobialdrugs.1hereare
currentlythreestrategiesordiscoveringnewanti-
microbialdrugs.
s. Systematictestingo theimpacto
dinerentsyntheticandnaturalsubstances
onthegrowtho microbes(whole-cell
screening,.
z. ldentiyingspecinctargetsordrugs
withinamicrobe,particularlythroughthe
analysiso thewholemicrobegenome
(target-basedscreening,.
,. Llucidatingthethree-dimensional
structureo potentialtargetsinamicrobe
(targetsidentinedthroughgenome
analysisoridentincationo existingdrug
treatmenttargets,andthedevelopment
o compoundsthatmightbindand
intererewiththosestructuraltargets
(structure-baseddrugdiscovery,.
,
The Drugs Dont Work
Much o the history o antimicrobial drug dis-
covery, particularly during the nrst hal o the
twentieth century, is one o whole-cell screening,
withthenrstantimicrobialdrugsbeingdiscovered
through the observation o the inhibiting enect
that man-made substances (sulphonamides, and
naturally occurring substances (penicillin, had on
thegrowtho bacteriainthelaboratory.
1he earliest antimicrobial drugs to be used
widelywerethesulphonamides,whichareagroup
o chemicalcompoundsderivedromdyesthatare
manuacturedromcoal-tar.1hediscoveryo sul-
phonamides took many years o research by
chemists, working in the layer company in Ger-
many,whobelievedthatthesecompounds,which
had been shown to be able to bind to bacteria,
might be developed to treat inectious disease.
Ater several years o ruitless experiments, the
scientists in Germany ound a red dye that was
enective in treating certain types o bacterial
inection in mice. 1his chemical substance was
marketed as lrontosil in the early s,os, and pro-
vided, or the nrst time, an enective treatment
againstinectionscausedbystreptococcalbacteria.
1hiswasanenormousadvanceincombatingthis
group o inectious diseases, which included
lie-threateningbloodstreaminectionsandwerea
signincant cause o maternal death due to puer-
peralever.
,,
lt was not until sometime ater lrontosil had
beenoundtobeasuccessultreatmentorinec-
tions that it was discovered it was not in act the
dye molecule itsel that was enective against the
bacteria, but rather a small compound called sul-
phanilamide, created as a result o the patients
bodybreakingthedyemoleculedown.Oncethis
had been recognized, the chase was on among
othermanuacturerstonndothersulpha-contain-
ingcompoundsthatcouldalsobeusedasdrugsto
treatinectiousdisease.
As described earlier, the story o the discovery
o penicillinisoneo themostamousandsignin-
cantaccountsinthehistoryo medicine.Iorallits
signincance,andnotwithstandingthebrillianceo
AlexanderIleminginrecognizingtheimportance
o what he observed, this discovery was at heart
a happy accident. Since this discovery about
naturally occurring substances, particularly those
produced by microbes themselves as they wage
waragainsteachotherintheircompetitionorsur-
vival, the search or other naturally occurring
substances that can selectively inhibit the growth
o microbes has been an important part o the
strategyornndingnewantimicrobialdrugs.
lnrecentdecadesthesearchornewmedicines
bytestingtheimpacto dinerentsubstancesonthe
growtho microbeshasocusedonlargelibraries
o synthetic chemical compounds rather than on
,o
The Drugs Dont Work
testingsubstancesproducednaturallybymicrobes,
plants or animals. 1his is, in part, because o a
belie that emerged in the ssos that bacterial
resistance might develop less readily to synthetic
compounds than to naturally occurring sub-
stances. 1here are also important pragmatic
advantagesinocusingonsyntheticcompounds,in
that they can oten be more readily produced in
signincant quantities or testing purposes, and
their synthesis can be more readily controlled, so
that they are less susceptible to being contamin-
atedbyotherunrecognizedsubstances.
Vith the ailure o screening libraries o syn-
thetic compounds, many o which are now
thought to have been unsuitable as sources o
compoundswithantimicrobialactivity,thesearch
is now turning back to naturally occurring sub-
stances. Vith a global microbiome that includes
anestimated,sobacteria,thescopeordiscov-
eringnewsubstancesisconsiderable,aslongasthe
nnancial and logistical challenges o harvesting
thesemicrobesromhabitatsthatincludetheopen
oceanandthedeepestoceannoorscanbemet.
1he development o techniques that allow the
reading o the entire genome (genetic code, o
microbes,plantsandanimalsprovidesnewinsights
into how microbes are made and unction, with
the potential o identiying new targets or anti-
microbial drugs to act against. 1his genetic
,,
inormation also provides insights into how
microbes diner rom humans and other animals,
whichisall-importantinthedevelopmento drugs
thatcankillmicrobesbutnotharmthecellso the
hoststheyinect.1henrstree-livingorganismto
haveitsentiregenomemapped,ins,,wasHaemo-
philus,abacteriumthatwasasignincantcauseo
meningitisbeoretheintroductiono anenective
vaccine against it in sz. Since this landmark
event,manyotherimportantbacteriacausingdis-
ease in humans have had their entire genomes
sequenced, and as a result over s,o bacterial
enzymesthatcouldbeexploitedbyantimicrobial
drugshavebeenidentined.Vhileitisencouraging
that o these s,o or more potential targets only a
smallproportionaretargetedbyexistingdrugs,it
isnoeasytasknndingdrugsthatcansaelyexploit
the as yet unused targets, and there is a growing
sense that the genomic revolution has still to
deliveronitsearlypromise.lywayo illustration
o the problem, over a period o seven years one
major pharmaceutical company assessed over
,oo,ooo compounds in sixty-seven screening pro-
grammesagainstpotentialbacterialtargets,atthe
end o which results or only nve o the targets
appeared to show any promise, and none o the
compoundstestedmadeitasarasbeingassessed
inaclinicaltrial.
1he last, and the newest, o the strategic
,s
The Drugs Dont Work
approachestodevelopingnewantimicrobialdrugs
isthato developingdesignermoleculesthatcan
bindtostructureswithinthemicrobeoritsouter
wallorcoatingandasaresultinhibitthedevelop-
mentorsurvivalo themicrobe.1hisstrategyhas
beenmadepossiblebycomputerapplicationsthat
enable the three-dimensional structure o micro-
bial cell components to be visualized. Once the
structureisunderstoodinthisway,itispossibleto
designmoleculesthatwillbindtothosestructures
andsopotentiallyintererewiththeirnormalunc-
tioning.1odate,thestructureso overooobacterial
proteins have been revealed through this orm o
computeranalysis,openingupnewopportunities
or drug design, although there are many chal-
lenges in moving rom an understanding o the
three-dimensional structure o a potential target
toproducingasaeandenectivedrugthatisbased
on that understanding. A particular challenge is
proving to be that o nnding antimicrobial mol-
eculesthatcancrossthemicrobeswallandremain
there in high enough concentrations to have the
desiredenect.Vhilestrategiesordesigningmol-
eculestoimproveuptakeandretentionareknown,
thechemicalcharacteristicsthathelpwiththiscan,
unortunately, reduce that molecules ability to
bind to the target through which it will exert its
enect. 1his is still a developing science, and one
that may lead to the development o new drugs,
,
but the technical challenges, on top o the chal-
lenges o taking any new drug to market, do not
augurwellorarapidresult.
Despite these opportunities, as we have seen
in the Appendix no new class o antibacterial has
beendiscoveredsincess,.1helacko newdrug
development is partly because companies can no
longermakeenoughmoneyouto antimicrobials
to justiy investing in the research needed. lt can
cost over _s billion to develop a new medicine,
meaning that drug companies are very careul
aboutwhatareastoresearch.Currentlythereturn
oninvestmentislikelytobemuchhigherorother
therapeuticareas,suchascancer,arthritis,diabetes
and other chronic diseases. 1his is because treat-
ment or chronic diseases can last or months or
years as opposed to relatively short courses
or antimicrobials makingitmoreprontableor
companiestoinvestinthesenewdrugs.Asasenior
executive rom a pharmaceutical company put it,
Vithout a reliable arsenal o enective antimicro-
bials, modern medical care will no longer be
possible.Vhilethedesiretocareullymanagethe
uptake o new drugs is entirely correct, doing so
makes it dimcult to justiy the increasingly high
developmentcoststhatotenrunintohundredso
millionso dollars.Companiesarealsoawarethat
any new drugs they develop are likely to have a
shortened shel-lie as they may be misused and
oo
The Drugs Dont Work
become useless, or that governments will put
restrictionontheiruseasaprotectionagainstanti-
microbialresistance.lnshortwewantnewdrugs,
butwedontwanttousethem.
1he lack o new antibacterial drugs and other
antimicrobialsisthoughtbymanytobeanexample
o a market ailure. Governments oten attempt
tocorrectinstitutionalailurethroughinvestment
and the creation o new incentives, and the same
casecanbemadeorthedevelopmento newanti-
microbialdrugs.1hereareanumbero waysthat
thepublicandprivatesectorscouldworktogether
tomakethisdruginnovationnnanciallyattractive.
1hese could be structured around partnership,
prizes,pricesandpatents.
Governments, donors and the private sector
already work in partnership to develop new anti-
microbialdrugsinanumbero areas.Iorexample,
attheturno thecenturythepipelineorantimal-
arial drugs was non-existent and the old drugs
werenolongerworkingduetoresistance.Malaria
is a mosquito-borne disease caused by a parasite,
andwaskillingszmillionpeopleayear,mosto
them children. Antimicrobial resistance was con-
nrmedintwoo theourhumanmalariaparasite
species, Plasmodium falciparum and Plasmodium
vivax. lut it made no commercial sense or drug
companiestoinvestinnewdrugssincemalariaisa
diseasemostcommonintheworldspoorestcoun-
os
tries, whose citizens would not be able to anord
the medication. Motivated by this inequity, the
Swiss, LK and Dutch governments joined orces
withtheVorldlankandtheRockeellerIounda-
tiontoestablishtheMedicinesorMalariaVenture,
anexampleo alroductDevelopmentlartnership.
1heMMVworkslikeanon-prontpharmaceutical
company.undertakingdiscoveryandearlyclinical
research. lut it does so in collaboration with or-
prontcompanies.lnzooMMVandNovartis a
drugs company launched a medicine especially
madeorchildren.lytheendo zosz,overs,smil-
lion treatments o this lie-saving therapy had
been delivered to more than thirty malaria-
endemic countries. 1he MMV and other similar
partnerships oner a potentially new business
model or addressing antimicrobial resistance. As
the senior pharmaceutical executive suggested,
1oaddresstherisingthreato antimicrobialresist-
anceitsvitalthatindustryandgovernmentwork
together to develop new business models or
pathogen- targetedantimicrobialsthatwillencourage
investment,rewardinnovationandcreateadiverse
androbustpipelineo theselie-savingmedicines.
lns,,NapoleonsSocietyortheLncouragement
o lndustryoneredaprizeo sz,ooorancstothe
nrstpersonwhocameupwithamethodo ood
preservationusablebytheIrenchmilitary.ltwas
awardedinsssotoNicolasAppert,theinventoro
oz
The Drugs Dont Work
oodcanning.1heprocessutilizedheattreatment
o ood in sealed champagne bottles. ln recent
years,prizeshavebeenundergoingarenaissance,
ranging rom a growing number o cash rewards
o sso million or more to an increasingly popular
variety o online contests at values o sso,ooo or
less. 1he sso million Ansari XlRlZL was created
in so to stimulate a new generation o launch
vehicles to carry passengers into space. Mean-
while, only last year, the Automated Student
Assessment lrize demonstrated that computers
cangradestudentsessaysasaccuratelyastrained
human experts. 1he Vorld lealth Organization
and the Vorld lank have proposed the use o
prizes or vaccines that would otherwise not be
developed or distributed widely enough. A _,o
million prize or anyone or any organization that
candiscoveranddevelopanewclasso antimicro-
bialdrugscouldshakeupresearchandinnovation
intheneld.Suchaprizecouldbeundedbyacoali-
tion o governments, oundations and private
donors, and would mobilize and ocus global tal-
ent on a global problem. 1hey would reward the
winnerbybringingorwardandaddingtotherev-
enuesthatthedrugswouldgenerate.
1hethirdlisorprices.Drugcompaniesmay
be tempted to undertake research and develop-
ment i they were onered an advanced price or
market commitment (AMC, or a new type o
o,
antimicrobial. Lnder this approach, the govern-
ments or oundations would promise to buy the
newdrugatacertainpriceandoracertainnum-
bero doses.lnexchange,nrmswouldcommitto
try and develop new drugs, but i they were not
successulthenclearlytheywouldnotgetpaid.An
exampleisthelneumococcalAMC,apartnership
established in zoo between the governments o
ltaly,theLK,Canada,Norway,theRussianIeder-
ation,thelillandMelindaGatesIoundationand
theGlobalAllianceorVaccinesandlmmunisation
(GAVlAlliance,.Streptococcus pneumoniaeisabac-
terium that causes a broad range o inections,
includingpneumoniaandmeningitis.ltisalsothe
leadingvaccine-preventablecauseo deathinchil-
dren aged under nve worldwide. Nearly s million
children a year die rom pneumococcal inection,
themajorityoccurringindevelopingcountries.ln
the Vest a vaccine is widely used, in the LK, or
example,itisgiventoallchildrenundertheageo
twoasparto thenationalchildhoodvaccination
programme.lowever,thisvaccineisnotoptimal
in developing countries because there are many
dinerent strains o the bacteria and specinc vac-
cinesneedtobetailor-madeordinerentcountries.
Lnder the lneumococcal AMC, the partners
pooledundso overss.,billionandguaranteedto
buyappropriatevaccinesats,.,oeachortenyears.
1his created an incentive or pharmaceutical
o
The Drugs Dont Work
companiestoinvestinvaccineresearchanddevel-
opmentandtoexpandmanuacturingcapacityas
needed.Althoughitistooearlytoassesswhether
this approach has worked, it provides an interest-
ingmodelorotherantimicrobialdrugs.
1he nnal l is or patents. latents provide an
inventorwithexclusiverightstotheirproduct,typ-
ically or twenty years. Vhen a drug company
believesithasdevelopedtheactiveingredientora
newmedicine,itwillapplyorapatent.l granted,
thiswillthenallowthatcompanytourtherdevelop
the medicine or the market. 1his is particularly
important in the pharmaceutical industry, given
thatittakesabouttwentyyearsandabout_sbillion
to develop a drug. 1he development time and the
patent period will inevitably overlap, giving the
companyanenectivemonopolyinsellingthenew
medicine o around eight to twelve years. ln this
time it is able to recoup its research and develop-
mentcostsandbegintomakeaprontromitsinitial
investment. Vithout the exclusive rights provided
byapatenttosellanewdrug,companieswouldnot
makenewmedicines.Oneapproachthatmayhelp
persuade companies to develop new antimicrobial
drugs would be to extend the patent period rom
twenty years to, say, twenty-nve years. 1his would
actinasimilarwayasguaranteedprices,asitwould
securearevenuestreamorthenrm thistimeora
longerperiodo timeasopposedtoagivenprice.
o,
Conservingourmicrobialheritage
Lven with better hygiene and new and improved
drugsweareonlybuyingtime.l wedontmanage
thestocko existingandnewantimicrobialdrugs
well,thentheproblemo resistancewilljustkeep
onrepeatingitsel.Veneedtorecalibrateourrela-
tionshiptoantimicrobials,andweneedtodothis
atagloballevel.l wedonotaddressthisplanetary
threat, then within a generation we will ace an
apocalypticscenariowherepeoplewilldieo rou-
tine inections because we have run out o
antimicrobial drugs. 1o avoid going back to the
uture we must work towards an international
rameworkthatwouldideally.
s. Agree to control the use of antimicrobial
drugs globally.1hiswouldrequiretheend
o over-the-countersales,thebano the
non-therapeuticuseinanimals,especially
inanimaleed,andtheprohibitiono
antimicrobialsornon-healthreasons.
z. Provide technical and fnancial assistance
to developing countries in balancing
access to essential drugs with action to
curb resistance.1hiswouldneedto
reducethecurrenthighlevelso inectious
diseasesindevelopingcountriesand
oo
The Drugs Dont Work
providesupportincontrollingand
conservingtheuseo antimicrobialdrugs.
,. Establish a system to ensure compliance
with the agreement.1hiswould
monitor,veriyandenorceanagreedset
o rules,butalsoprovideearlywarnings
o resistantstrainso bacteriaandother
microbesandhelpdetercountereitedand
substandarddrugs.
Veneedtobeginwithinternationalagreement
thatantimicrobialdrugsareacommongoodthat
mustbeconserved similartonshstocksandpub-
lic waterways. }ust as we look ater old churches,
beautiul landscapes and endangered animals, we
needtolookaterourbugs.lutasthereisnopoint
in one country or one person doing this on their
own, we need to agree a set o rules to manage
this hidden heritage. 1here are a number o
approachesthatcouldbeadopted,rangingroma
communique o signatory countries, a code o
practice sponsored by an existing international
agencysuchastheLnitedNations,tomoreormal
conventions with legal sanction. 1here are two
broad ways or conserving antimicrobials. limit
theuseo microbialdrugsthroughquotasorintro-
duce a price or tax on consumption. loth sound
draconian,butarealreadywidelyusedinthecon-
textslistedin1ablez.Noneo theseschemesare
o,
withouttheircontroversies,buttheydoprovidea
blueprintoraMicrobialManiesto.Vithpublic
goodwillandthecommitmento ourleaders,itis
possibletoseehowtheseschemescouldbeusedto
conserve our antimicrobials. A Vorld lealth
Organization agreement could limit the use o
existing and new antimicrobial drugs or certain
diseasesandbantheiruseinagriculturalandother
products.
1ablez.Lxampleso internationalagreements
The UN Framework Convention on Climate Change
wasoriginallyestablishedinsztocooperativelyconsider
whatmemberstatescoulddotolimitaverageglobaltem-
perature increases and the resulting climate change. 1he
global response was strengthened in s, through the
adoption o the Kyoto Protocol, which legally binds
developed countries to emission-reduction targets. 1here
areszpartiestotheKyotolrotocol.
TheWHOFramework Convention on Tobacco Control
isasupranationalagreementthatseekstoprotectpresent
anduturegenerationsromthedevastatinghealth,social,
environmental and economic consequences o tobacco
consumptionandexposuretotobaccosmokebyenacting
aseto universalstandardsstatingthedangerso tobacco
and limiting its use in all orms worldwide. lt came into
orceinzoo,.1hetreatysprovisionsincluderulesthatgov-
ern the production, sale, distribution, advertisement and
taxationo tobacco.
os
The Drugs Dont Work
1ablez.Lxampleso internationalagreements
The Convention on the Prohibition of the Develop-
ment, Production, Stockpiling and Use of Chemical
Weapons and on Their Destruction came into orce in
sz.lyzos,thereweresssignatories.1hemainobliga-
tionundertheconventionistheprohibitiono theuseand
productiono chemicalweapons,aswellasthedestruction
o all chemical weapons. 1he convention is administered
by the independent Organisation or the lrohibition o
Chemical Veapons (OlCV,. 1he destruction activities
are verined by the OlCV. As o }anuary zos,, around
three-quarters o the declared stockpile o chemical
weaponshadbeendestroyed.
The European Commissions Common Fisheries Policy
(CIl,setstheamounto eachtypeo nshmemberstates
areallowedtocatchinacertainarea,i.e.thetotalallowable
catch(1AC,.1heCIlwascreatedinss,butdatesback
tos,,whenthe1reatyo Romestatedthatthereshould
beacommonpolicyornsheries.1heCIlisenorcedby
memberstatesbutoverseenbyLCinspectors.
Gs Gleneagles Communiqu. ln zoo, members o the
Group o Light richest countries in the world agreed to
doubleaidtoAricaandtoeliminateoutstandingdebtso
thepoorestcountries.1hisdecisionwasnotlegallybinding,
butwasaverypublicpoliticalcommitmentwithoversight
providedthroughcontinuedpressurerom society.
1hemaindeal-breakertothesetypeso agree-
ments will happen when the worlds poorer
countries point out that the Vest has benented
o
romthereeandlargelyunregulateduseo anti-
microbial drugs or nearly a century. 1hey are
likely to suggest that, as with ossil uel, this key
developmental technology is being withheld at
the point that their economies are beginning to
emerge on the international stage. 1his is an
entirelyairpointthatshouldnotbecontested.As
Ministero lealthorlndia,GhulumNabiAzad,
recently said, lndia is a vast country our prob-
lems are dinerent, when expressing concerns
that curbsonthesaleo antimicrobialscouldhurt
vastsectionso lndiasruralpopulationswhodont
haveaccesstodoctorstoprescribemedicines.lut
no action will also hurt these people. Developing
countriesacethedoublewhammyo unnecessary
deathsrominectionsandgrowingantimicrobial
resistance. Again, in the past, the international
community has provided technical and nnancial
assistancewhenthinkingaboutthesetypeso glo-
bal issues. More analogous to the debate on
antimicrobialresistanceistheVorldlealthOrgan-
izations Iramework Convention on 1obacco
Control.1heconventionprovidesassistancetoall
signatories, but in particular to developing coun-
tries,instrengtheningnationallegislationstoalign
withaseto agreedrulesthatgoverntheproduc-
tion,sale,distribution,advertisingandtaxationo
tobacco. 1he convention was signed in zoo,, and
six years later the s,o countries had established
,o
The Drugs Dont Work
nationalprogrammesortheregulationo tobacco,
with VlO providing assistance to those coun-
tries that could not anord or did not have the
experienceinimplementingsuchpolicies.
1he existence o suitable monitoring and
enorcementmechanismswillbecrucialtothesuc-
cess o global strategies to contain antimicrobial
resistance. Non-compliance in one country will
underminetheenortsmadeinothercountries.lut
monitoring is not just about enorcement, it will
alsoneedtoidentiybugsthatarebecomingresist-
anttoourexistingdrugsandocusontheincreasing
problem o raudulent or substandard drugs. 1he
compliance element will need to involve an inde-
pendent organization that audits how countries
implement the agreement, but also provides help
and support in that implementation. As such, it
will need to act as both a guide dog (helping,
and a guard dog (enorcing,. Again there are
lessons rom other treaties. 1he Organization or
SecurityandCo-operationinLuropeobservesand
assesses elections, but crucially it also engages in
theimplementationo itsownrecommendations.
Although it has no ormal enorcement mech-
anisms, the combination o openly critical review
ollowed by practical help provides an attractive
modeloraMicrobialManiesto.ltwillbeimport-
ant that the remit o a monitoring unction is
extended to cover the surveillance o emerging
,s
strainso drug-resistantinections.1hiswillrequire
a global network that piggybacks on existing
nationalnetworks,eitherorcollatinginormation
oninectiousdiseasesortoexpandonactivitiesthat
havebeensetupordrug-resistanttuberculosis.At
the same time, and as discussed earlier, there will
beaneedorrapidsimplediagnosticteststoiden-
tiyresistantorganismsinanimalsandhumans.
Another important unction o a monitoring
systemcouldbeveriyingthequalityo drugpro-
duction. Countereit and substandard antimicrobial
drugs are dangerous as they do not work and
increase resistance. Countereit drugs are deliber-
ately raudulent as they are mislabelled, and have
no active ingredient. Substandard drugs are real
butdonotmeetthequalitystandardssetorthem.
Although we dont know or sure, it is likely that
both countereit and substandard drugs are more
common in low- and middle-income countries
withweakornodrugregulation.Anythingthatis
donetoreducetheamounto akedrugsincircu-
lation should help to cut the number o people
who are ill or dying rom inectious diseases. A
rangeo approacheshavebeendevelopedtotackle
countereitandsubstandarddrugs,includingsup-
portorimprovedmanuacturingpractices,robust
actoryinspections,theuseo barcodes,electronic
tags and other orms o technology to veriy a
drugsorigins,andregulationo on-linesales.
The Drugs Dont Work
Noneo thesesolutionswilltackletheproblem
on its own, but, as with much o the story about
theglobalthreato antimicrobialresistance,each
islikelytobenentrominternationalcooperation.
1his is currently not occurring as countries are
hesitant about curbing the use o antimicrobial
drugsontheirown.lnpursuito perceivednational
interest,wemayallinadvertentlybecomeglobally
worse on. Not only does antimicrobial resistance
illustrate the connict between generations, but
also one between individual countries and the
internationalcommunity.lntheimmediateuture
the benent or a country not to address the issue
may seem greater than the eventual return to all
countries in jointly implementing a Microbial
Maniesto. lut as we have seen, this is not the
case. l we dont take collective action, then we
will all be responsible or increased disease and
death in our children and grandchildrens gener-
ations. Ve know how to nx the global threat o
antimicrobialresistance,nowisthetimetodoso
byworkingtogether.
,,
Conclusion
Onegenerationplantsthetrees,anotherenjoys
the shade.
Chineselroverb
ltisabright}ulyday.MrsXuhasnotbeencount-
ing, but it is her nteenth day o treatment. lt
startedwithawheezeaweekaterhersonsbirth-
day. She had taken }osh to the theme park with a
couple o his school riends. She keeps on going
backtothatdayinhermind itwasullo energy
andlaughter.
1hewheezeturnedintoacough,thecoughinto
a sore throat. ler husband, }on, gave her that
look concernedbutuntroubled.lthappenedall
thetime.
Vhen}oshwasbornsixteenyearsagoitwasnt
always this way. ln the nnal months o her preg-
nancy, Mrs Xu was advised to stay indoors to
separatehersel romherriendsandamily.Vhen
}oshwenttonursery,sheand}onwerelecturedby
theleadabouthowirresponsibleitwastosenda
Conclusion
childintopublicwithevenmildsymptoms.1hey
weregivenahometestingkit.lespatonastripo
paper.l itturnedgreenhecouldattend,i itwas
redhemuststayathome.1heycalledthetestthe
redspot.}onsmumlikenedittoapregnancytest.
A ew years later, shortly ater }osh joined pri-
maryschool,theglobalthreatwasover.lnectious
diseases were declining, poor personal hygiene
became a thing o the past. 1he wonder drugs
workedagain.lutthistime,everyoneunderstood
themiracle.
Mrs Xu recuperated at home. She spent two
weeks with her amily. }on and }osh cooked her
mealseverydayandtheyatetogetherintheeven-
ings.
She speaks to the doctor. le says she can stop
takingthemedication.Sheiswell.
1heyeariszo,.
,,
Appendix
Major classes of antibacterial agents and their use
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Sulphonamides
sulphamethoxazole
sulphadiazine
s,z Videspread
developmento
resistancemeans
thatuseisnow
limitedtocaseso
urinarytract
inectionand
exacerbationso
chronicbronchitis
wherethereisgood
laboratoryevidence
thatthebacterial
causeissensitive.
1heyalsoremain
thedrugo choice
(incombination
withtrimethoprim
seebelow,or
treatingpneumo-
cystispneumonia.
(continued,
,o
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Penicillins susceptible
to b-lactamases
penicillinG
penicillinV
ampicillin
amoxycillin
ticarcillin
piperacillin
s Muchresistancehas
accumulated,due
largelyto
-lactamases.
Someresistance
overcomeby
protectingwith
-lactamaseinhibitors.
Nonewpenicillin
or,oyears.
Tetracyclines
oxytetracycline
tigecycline
s, Lsedtotreat
inectionscausedby
awiderangeo
organisms,buttheir
useisdecreasing
becauseresistance
hasbecomerequent
inmanyorganisms.
Newanalogues
(e.g.tigecycline,
designedto
,,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
overcomethis
resistanceareused
againsthighly
multi-resistant
Gram-negative
bacteriawhere
treatmentoptions
arelimited.
Resistancehasbeen
reportedbutis
uncommon.
Chloramphenicol s, Canbeusedtotreat
awiderangeo
inections,butitsuse
isdiscouraged
becauseo its
toxicityorhumans.
Nonewanalogues
havebeenintro-
ducedsincethe
s,os.
(continued,
,s
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Aminoglycosides
streptomycin
gentamicin
amikacin
s, Lsedtotreat
inectionscausedby
Gram-negative
opportunist
organisms.Anew
resistance,which
conersresistanceto
allaminoglycosides,
wasidentinedin
zooz.Aminoglyco-
sidesaretoxicto
humansandserum
levelsmustbe
monitoredcareully.
Nonewanalogues
havebeenintro-
ducedsincethe
earlys,os.
Isoniazid s,z Lsedtotreat
tuberculosis.
Resistancehasbeen
increasinginLK(,.,
percento 1l
casesinzoss,,andis
commoner
elsewhere.
,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Macrolides
erythromycin
azithromycin
clarithromycin
roxithromycin
ndaxomicin
s,z 1heseareused
mainlyinprimary
caretotreat
respiratorytract
inections.Resist-
anceiswidespread
inStreptococcus
pneumoniae,andis
alsoseeninGroup
Astreptococci,a
commonbacterial
causeo asore
throat.Iidaxomicin,
introducedinzosz,
isusedorthe
treatmento
Clostridium difcile
inection.Clinical
activityiscompar-
abletothato
vancomycin,but
rateo recurrenceis
muchlower.
Resistancehasnot
beenseentodate.
(continued,
so
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Glycopeptides
vancomycin
teicoplanin
s,o 1hesehadbeenthe
drugso lastresort
ormanyyearsor
treatinginections
causedbyGram-
positivebacteria
includingstaphylo-
cocci,streptococci
andenterococcithat
areresistanttoall
otherantibacterial
agents.Resistance
wasthoughttobe
impossible,buthas
emergedandspread
inenterococci,and
hasalsobeenound
inStaphylococcus
aureus(including
MRSAstrains,.
ss
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Penicillin resistant to
b-lactamase
methicillinnucloxacil-
lin
soo Lsedtotreat
staphylococcal
inections,but
methicillin-resistant
Staphylococcus aureus
(MRSA,isnot
sensitivetoitand
increasedsteadily
duringthelasttwo
decadeso the
twentiethcentury.
Metronidazole soo Lsedtotreat
inectionscausedby
anaerobicbacteria.
Iewreportso
resistance,except
withHelicobacter
pylori.
(continued,
sz
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Rifampicin sos Lsedtotreat
inectionscausedby
Gram-positive
bacteriaand
mycobacteria.
lrimaryresistance
israre,butemerges
readilybymutation
duringclinicaluse.
Nonewanalogues.
Cephalosporins
(generation)
cephalexin(sst,
ceuroxime(znd,
ceotaxime(,rd,
cetazidime(,rd,
cepirome(th,
soz lugeamily.
Successivegener-
ationswere
developedto
overcomeresistance
toprevious
generations,but
resistanceisnow
accumulatingto
ourth-generation
drugs.
s,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Fusidic acid soz Lsedtotreat
staphylococcal
inections.lrimary
resistanceisrare,but
resistancedueto
mutationisacquired
readilyinclinicaluse.
Nonewanalogues
havebeenintro-
ducedsincethelate
soos.
Trimethoprim so Lsedmainlytotreat
urinarytract
inectionswhichare
mostlycausedby
Escherichia coli.
Resistanceis
common.
Nonewanalogues.
(continued,
s
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Carbapenems
meropenem
imipenem
ertapenem
s,, 1hesearethemost
powerul-lactams,
andthemostrecent
o thedrugso last
resortortreating
Gram-negative
bacteria,particu-
larlythoseacquired
inhospital,andthat
areresistantto
cephalosporins.
Morerecently
produceddrugs
(e.g.ertapenem,are
usedorserious
community-
acquiredinections,
includingthose
causedbyLSlL-
producing
Enterobacteriaceae,
butnotor
s,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
hospital-acquired
inectionsasthey
arenotactive
againstPseudomonas
aeruginosa.Resist-
anceisemerging
andincreasing.
Penicillins combined
with an inhibitor
amoxycillin
clavulanate
piperacillin
tazobactam
s,o -lactamasesarethe
maincauseo
resistanceto
-lactams,especially
penicillins.lnhibi-
torsovercome
some,butnotall
thisresistance.
(continued,
so
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Fluoroquinolones
cipronoxacin
nornoxacin
ssz Derivativeso
nalidixicacid.1hey
havegoodactivity
againstGram-nega-
tivebacteria,but
resistancehasbeen
risingsharplyinL.
colisincezooo,and
isalsoincreasing
amongcaseso
gonorrhoea.
Resistanceis
commoninMRSA.
Mupirocin ss, Lsedtopicallyto
treatthecarriageo
MRSA.Resistance
isincreasing.
Nonewanalogues.
s,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Lipopeptides
daptomycin
ss(but only
introducedinto
clinicaluse
inzooo,
Activeonlyagainst
Gram-positive
bacteriaandused
mainlytotreat
staphylococci
(includingMRSA,.
Resistancehasbeen
reportedin
staphylococciand
enterococcibut
remainsuncom-
mon.Now,along
withtheoxazolid-
inines,thedrugso
lastresortor
Gram-positive
inectionsthatare
resistanttoallother
antimicrobials.
(continued,
Appendix
aritacrtriai
ciassan
xajortxaxrits
tar
irronuctn
ustansrarus
orrtsisract
Oxazolidinines
linezolid
ss,
(butonly
introducedinto
clinicaluse
inzoos,
Activeonlyagainst
Gram-positive
bacteriaandusedto
treatstaphylococci
(includingMRSA,
andenterococci
(includingVRL,.
Resistancereported
inenterococciand
staphylococci,but
remainslow.
Lpdated rom. The Path of Least Resistance, Standing Medical
AdvisoryCommittee,Departmento lealth,ss
s
Further Reading and Websites
Selected source books, reports and papers
lorchgrevink,C.l.,Cha,}.,andKimS.,landwashing
practicesinacollegetownenvironment,Journal of
Environmental Health (zos,,, ,,(s,, ssz. Lsing neld
observations o ,,, people, the research identines
potential predictors o hand-washing compliance
andsuggeststhatproperhand-washingpracticesare
notbeingcarriedout.
lrown, K., Penicillin Man: Alexander Fleming and the
Antibiotic Revolution(Stroud.Suttonlublishing,zoo,.
liographyo Ilemingbythecuratoro theAlexan-
der Ileming Laboratory Museum at St Marys
lospitalNlS1rust,London.
Davies,S.C.,Annual Report of the Chief Medical Ofcer,
Volume 1wo, zoss, lnections and the Rise o anti-
microbialresistance(London.Departmento lealth,
zos,,. Available rom. http.www.dh.gov.ukcmo.
ln-depthreviewo inectiousdiseasesandantimicrobial
resistancebytheLKgovernmentsprincipalmedical
advisorandtheproessionalheado alldirectorso
publichealthinlocalgovernment.
o
Luropean Commission, Communication from the Com-
mission to the European Parliament and the Council:
Action Plan against the Rising Threats from Antimicro-
bial Resistance, COM (zoss, ,s (lrussels. LC, zoss,.
Available at. http.ec.europa.eudgshealth_
consumerdocscommunication_amr_zoss_,s_
en.pd.1heLuropeanCommissionspolicyonanti-
microbialresistance.
Goldin,l.R.,andGorbach,S.L.,Clinicalindications
orprobiotics.anoverview,Clinical Infectious Diseases
(zoos,, o, Sosoo. Available at. http.cid.oxord-
journals.orgcontentoSupplement_zSo.ull.
Review o scientinc studies that concludes there is
strongevidencethatprobioticsbenentthemanage-
mento acuteandantibacterial-associateddiarrhoea,
and substantial evidence exists or their having a
benencialenectinatopiceczema.
Goossens, l., and Sprenger, M. }. V., Community
acquired inections and bacterial resistance, BMJ
(ss,,,s,,o,,.Availableat.http.www.ncbi.nlm.
nih.govpmcarticleslMCsss,s,,pdo,.pd.
Reviewpaperontherequencyo resistancetoanti-
microbials among community-acquired pathogens
andthenumbero drugstowhichtheyareresistant.
Gore,A.,An Inconvenient Truth: The Planetary Emergency
of Global Warming and What We Can Do About It
(London. lloomsbury lublishing, zooo,. lased on
theormerLSVicelresidentslecturetouronglo-
s
bal warming and released in conjunction with the
Oscar-winningnlmo thesametitle.
Guarner, I., and Malagelada, }-R., Gut nora in health
anddisease,Lancet(zoo,,,,os,,szs.Reviewo the
scientincevidenceo themajorunctionso thegut
micronora.Concludesthatprobioticsandprebiotics
areknowntohavearoleinthepreventionortreat-
mento somediseases.
laensch, S., lianucci, R., Signoli, M., et al., Distinct
cloneso Yersiniapestiscausedtheblackdeath,PLoS
Pathogens(zoso,,o(so,.esooss,.Availableat.http.
www.ncbi.nlm.nih.govpmcarticleslMCz,s,,.
ly combining ancient DNA analyses and protein-
specinc detection, the authors demonstrate unam-
biguouslythatY. pestiscausedthellackDeath.
lonman,S.}.,andRottingen,}-A.,Assessingimplemen-
tation mechanisms or an international agreement
on research and development or health products,
Bulletin of the World Health Organization (zosz,, o,
s,o,.Areviewo internationalagreementsusedto
make commitments, administer activities, manage
nnancialcontributions,makedecisionsandmonitor
compliance.
louse o Lords Select Committee on Science and
1echnology,Seventh Report, Sessions,s: Resistance
to Antibiotics and Other Antimicrobial Agents(London.
louse o Lords, ss,. Lnquiry by their Lordships
that concludes that resistance to antibacterial and
z
otheranti-inectiveagentsconstitutesamajorthreat
topublichealth,andoughttoberecognizedassuch.
lnstitute or lealth Metrics and Lvaluation (llML,,
The Global Burden of Disease: Generating Evidence,
Guiding Policy (Seattle. llML, zos,,. Available at.
http.www.healthmetricsandevaluation.orggbd.
1hisreportwasbasedonsevenpaperspublishedin
the Lancet, s, December zosz, p. ,so, available at.
http.www.thelancet.comthemedglobal-burden-
o-disease. 1he global burden o disease (GlD,
enterprisedatesbacktotheearlysosandthemost
recent iteration o the project is published by the
lnstitute or lealth Metrics and Lvaluation. See
VlO(zoos,orearlieriteration.
Kramer,A.,Kretzschmar,M.,andKrickeberg,K.,Mod-
ern Infectious Disease Epidemiology: Concepts, Methods,
Mathematical Models and Public Health (New York.
London,zoso,.Availableat.http.link.springer.com
bookso.soo,,s-o-,s,-,s,,-opages. 1extbook
oninectiousdiseasesthatprovidescontextandgen-
eralmethodsorstudyinginectiousdiseasesaswell
asdetailso transmissionroutesorspecincdiseases.
Llor,C.,andCots,}.M.,1hesaleo antibioticswithout
prescription in pharmacies in Catalonia, Spain,
Clinical Infectious Diseases (zoo,, s, s,,. lnnova-
tivepaperthatusesactorstoassessnon-prescription
saleo antibacterialsinSpain.
McKeown,1.,Record,R.G.,and1urner,D.,Aninter-
pretationo thedeclineo mortalityinLnglandand
,
Vales during the twentieth century, Population
Studies (s,,,, z(,,, ,szz. An assessment o the
contribution that dinerent causes o death make to
themortalitydeclinebetweensosands,s.
McNulty, C. A. M., loyle, l., Nichols, 1., Clappison,
D. l,andDavey,l.,Antimicrobialdrugsinthehome,
LnitedKingdom,Emerging Infectious Diseases(zooo,,
sz(so,, s,z,o. Available at. http.www.ncbi.nlm.
nih.govpmcarticleslMC,zo,o. A representa-
tivesurveyo LKhouseholdsthatshowedthatoper
centhadletoverantimicrobialdrugsandpercent
hadstandbyantimicrobialdrugs.
Mahoney, R., lroduct Development lartnerships.
Casestudieso anewmechanismorhealthtechnol-
ogy innovation, Health Research Policy and Systems
(zoss,,,,,.Availableat.http.www.health-policy-
systems.comcontents,,. lDls are a orm o
publicprivate partnerships that ocus on health
technology development. 1he paper examines our
case studies o lDls and shows how they have
addressedthesixdeterminantstoachievesuccess.
Mestre-Ierrandiz,}.,Sussex,}.,and1owse,A.,The R&D
Costs of a New Medicine (London. Omce o lealth
Lconomics,zosz,.Availableat.http.www.ohe.org
publications.Acomprehensivereviewo howmuch
itcostsandthetimeittakestoresearchanddevelop
asuccessulnewmedicine.
Sharma,l.,and1owse,A.,New drugs to Tackle Antimicro-
bial Resistance: Analysis ofLLPolicy Options(London.

Omce o lealth Lconomics, zosz,. Available at.
http.www.ohe.orgpublications. An assessment
o thewaysinwhichmarketailurecanbeaddressed,
including examination o the economic impact o
dinerentpush-and-pullincentivesonthenetpresent
valueo antibacterialRoD.
Standing Medical Advisory Committee, Sub Group on
Antimicrobial Resistance,The Path of Least Resistance
(London. Department o lealth, ss,. Available at.
http.antibiotic-action.comwp-contentuploads
zosso,Standing-Medical-Advisory-Committee-
1he-path-o-least-resistance-ss.pd. A review
commissionedbyapreviouschie medicalomcer,Sir
KennethCalman,ontheissueo antimicrobialresist-
anceinrelationtoclinicalprescribingpractice.
1aubenberger,}.K.,andMorens,D.M.,sssinnuenza.
1hemothero allpandemics,Emerging Infectious Dis-
eases (zooo,, sz (s,, s,zz. Available at. http.www.
cdc.goveidarticleszspdso,-o,.pd. Review
o theSpanishinnuenzapandemico ssss,which
caused approximately ,o million deaths worldwide
andremainsanominouswarningtopublichealth.
Vhitman V. l., Coleman, D. C., and Viebe V. }.,
lrokaryotes. 1he unseen majority, Proceedings of
the National Academy of Science (ss,, ,, o,,ss,.
Available at. http.www.pnas.orgcontent,sz
o,,s.ull. An attempt to estimate the number o
prokaryotes on Larth through the examination o
severalrepresentativehabitats.
,
VorldlealthOrganization(VlO,,The Global Burden
of Disease: zoo Update (Geneva. Vorld lealth
Organization,zoos,.Availableat.http.www.who.
inttopicsglobal_burden_o_disease. 1he VlO
globalburdeno disease(GlD,measuresburdeno
diseaseusingthedisability-adjustedlieyear(DALY,.
1he DALY metric was developed in the original
GlDsostudytoassesstheburdeno diseasecon-
sistentlyacrossdiseases,riskactorsandregions.See
llML(zos,,orsubsequentiteration.
Vorld lealth Organization (VlO,, World Health
Statistics,zoss(Geneva.VorldlealthOrganization,
zoss,. Available at. http.www.who.intwhosis
whostatzossen.1heVlOsannualcompilation
o health-related data or its s, member states,
includingasummaryo theprogressmadetowards
achieving the health-related Millennium Develop-
mentGoals(MDGs,andassociatedtargets.
Useful websites
e-Bug is a ree educational resource or classroom and
home use, and makes learning about microorgan-
isms, and the spread, prevention and treatment o
inection,unandaccessibleorallstudents.http.
www.e-bug.eu
Wash Your Hands . . . Give Soap a Chance is a NlS
hand-washing campaign that aims to improve hand
hygiene.http.www.wash-hands.com
European Surveillance of Antimicrobial Consump-
tion Network (LSAC-Net,isaLurope-widenetwork
o national surveillance systems, providing Luro-
pean reerence data on antimicrobial consumption.
LSAC-Netcollectsandanalysesdataonantimicrobial
consumption rom LL and LLALI1A countries,
both in the community and in the hospital sector.
http.www.ecdc.europa.euenactivitiessurveil
lanceesac-netpagesindex.aspx
Multidrug-resistant tuberculosis (MDR-TB) is a
website maintained by the Vorld lealth Organiza-
tion(VlO,thatprovidesinormationonthemajor
publichealthproblemthatthreatensprogressmade
in 1l care and control worldwide. http.www.
who.inttbchallengesmdrenindex.html
,
Acknowledgements
Ve would like to thank and acknowledge every-
one who has supported us in writing this book.
Needlesstosay,theirinput,adviceandcomments
have been essential to this endeavour, but any
errors or misunderstandings are solely ours. Ve
areparticularlygrateultotheassistancegivenby.
lenlrusey,}oannaChataway,}eremyGrant,Sarah
lopwood,Simonloward,Deepa}ahagirdar,Alan
}ohnson, }orge Mestre-Ierrandiz, Lllen Nolte,
Maaldalardal,Lmmalitchorth,}ennierRubin,
LucilaSanzand}irka1aylor.

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The Drugs Dont Work

lroessor Dame Sally C. Davies is the Chie Medical