M ay 20 15
N o.233
‘C A S T B A C K IN TO TH E D A RK A GE S O F M E D IC IN E ’?
TH E C H A L L E N GE O F A N TIM IC RO B IA L RE S IS TA N C E
C ormac Ó Grád a
W O RKIN G P A P E R S E RIE S
C entre forC ompetitive A d vantage in the GlobalE conomy
D epartmentof E conomics
A bstract
A ntimicrobialresistance (A M R)is cu rrently the focu s of mu chmed iaattention and policy
d iscu ssion.A historicalperspective on A M R su ggests thatalthou ghthe challenge of A M R is
real,the d oomsd ay tone of mostcommentary is u nwarranted .Thatis partly becau se mostof
the gains in life ex pectancy now d eemed u nd erthreatpreced ed the antibiotics revolu tion.A
combination of pu blic healthmeasu res,risinglivingstand ard s,and new med icalknowled ge
allplayed theirpartin this.E ven if A M R increases,the continu ingeffectof these factors and
of new pu blic healthmeasu res can limitthe negative consequ ences.M oreover,recent
d evelopments su ggestthatthe su pply pipeline of new d ru gs is notqu ite as d ry as u su ally
claimed .The problem fornow is notso mu chM RSA ormalariabu tcarbapenem‐resistant
gram‐negative bacteria,whichpose an u rgentthreatand on whichpu blic fu nd ingforresearch
on effective new therapies shou ld concentrate.
Keyword s:infectiou s d isease,health,antimicrobialresistance,economic history
J
E L C lassification N u mbers:I15,I18 ,N 30
‘
CAST BACK IN T O T H E DARK AGESO F M EDICIN E’?
T H E CH ALLEN GE O F AN TIM ICRO BIALRESIST AN CE 1
Corm ac Ó Gráda
U nivers ity College Du b lin and CAGE,U nivers ity ofW arw ick
Contents
1 . Introdu ction
2 . W hat H is tory Says
2 .1 . The Glob alSu rge in Life Ex p ectancy Since c. 1 9 5 0
3 . W elfare Im p lications
3 .1 . M alaria in India and China:A Cas e Stu dy
3 .2 . A Clos er Look at T u b ercu los is
4 . Su p p ly:the Pip eline
4 .1 . M RSA
4 .2 . M alaria
4 .3 . M DR-TB
4 .4 . CRGM Bs
5 . Dem and Als o M atters
6 . Conclu ding Rem arks
1
1 .Introdu ction
T oday p eop le in high-incom e cou ntries can ex p ect to live ab ou t tw ice as long as
their foreb ears a centu ry ago. This hu ge increas e in life ex p ectancy is du e in large p art
to the eradication or near-eradication ofa w hole range ofp otentially fatalinfectiou s
dis eas es . In the U K c. 1 9 0 0 one s u ch dis eas e,tu b ercu los is ,w as res p ons ib le for one
death in ten;it cu t s hort the lives ofEm ily Brontë (1 8 4 8 ,aged 3 0 ),Au b rey Beards ley
(1 8 9 8 ,aged 2 6 ),D. H . Law rence (1 9 3 0 ,aged 4 5 ),George O rw ell(1 9 5 0 ,aged 4 6 ),and
m yriad others . M eas les ,s carlet fever,dip htheria,and w hoop ing cou gh accou nted for
another 6 .5 p er cent ofBritis h deaths ,and diarrhoea and typ hu s carried offanother 5
p er cent.2 Today thos e dis eas es killvirtu ally no one in high-incom e cou ntries .
T he s hare ofalldeaths in England and W ales du e to infectiou s dis eas es
drop p ed from nearly halfin 1 8 5 0 to one-third in 1 9 0 0 ,w hereas today they accou nt for
ab ou t 7 p er cent,m ainly elderly p eop le s u ccu m b ing to p neu m onia or acu te b ronchitis .
In high-incom e cou ntries like the U K m os t ofu s can ex p ect to s u ccu m b ,not to
infectiou s dis eas es ,b u t to cancer,heart dis eas e,and other non-contagiou s cau s es and
illnes s es .3
Low -incom e cou ntries ,w here infectiou s dis eas es s tillaccou nt for nearly halfof
alldeaths ,s tillhave a long w ay to go. Bu t they have b een doing b etter too. Take
N iger,p erhap s the p oores t p lace in the w orld today 4 ,w here the s hare ofinfectiou s
dis eas es has drop p ed from 6 8 to 5 0 p er cent b etw een 2 0 0 0 and 2 0 1 2 ;or neighb ou ring
M ali,w here the drop w as from 4 8 to 3 7 p er cent.5 Indeed,life ex p ectancy today even
in the p oores t oflow -incom e cou ntries is higher than anyw here b efore the revolu tions
in p u b lic health and m edicaltechnology that follow ed the w ork ofLou is Pas teu r (1 8 2 2 9 5 )and his rivalRob ert Koch (1 8 4 3 -1 9 1 0 )(Tab le 1 ).
2
[Tab le 1 ab ou t here]
In dem ograp hic term s ,thes e gains are u np recedented. And not only do w e live
longer:the q u ality oflife has ris en in tandem w ith the q u antity oflife. In term s of
hu m an w ellb eing,as dis cu s s ed b elow ,the gains are enorm ou s . W hat ifthos e gains
w ere los t in p art du e to increas ing antim icrob ialres is tance (AM R),i.e. the ab ility of
m icroorganis m s to res is t the antim icrob ialagent once cap ab le ofkilling or inhib iting
the grow th ofthes e s elfs am e m icrob es ? The q u es tion is b y no m eans a new one,b u t
in the las t few years it has taken on a new u rgency,w ith the W orld H ealth
O rganis ation w arning of‘
a p os t-antib iotic era,in w hich m any com m on infections w ill
no longer have a cu re and,once again,killu nab ated’6 and,clos er to hom e,the U K’s
ChiefM edicalO fficer,Dam e Sally Davies ,recently cau tioning ofthe danger of‘
finding
ou rs elves in a health s ys tem not dis s im ilar to the early 1 9 th centu ry at s om e p oint’.
T here is no denying that res is tance to s everalkey antim icrob ialdru gs is
increas ing. Althou gh M ethicillin-Res is tant Stap hylococcu s au reu s (M RSA),a hos p ital
acq u ired infection,has hogged the headlines ,m ore and m ore m icrob es are b ecom ing
res is tant to m ore and m ore antib iotics . The greates t w orry now is the s p read of
carb ap enem -res is tant Enterob acteriaceae (CREs )s u ch as Kleb s iella p neu m oniae,
Es cherichia coli,Enterob acter s p p .,and Acinetob acter b au m annii. Thos e are the
p athogens ;an added w orry is enzym es s u ch as N ew Delhim etallo-b eta-lactam as e
(N DM )that confer res is tance to carb ap enem s .7 Initially the concern w as that b acteria
w ere acq u iring res is tance to anitib iotics ,b u t other p athogenic m icrob es s u ch as
viru s es ,p rotozoa,and fu ngiare als o develop ing res is tance to the com p ou nds b eing
u s ed to treat them ,redu cing the therap eu tic op tions availab le to the m edical
3
p rofes s ionals . Bu t does this ju s tify Prim e M inis ter David Cam eron’s claim ing las t Ju ly
that AM Rcou ld ‘
cas t the w orld b ack into the dark ages ofm edicine’?8 Cou ld
infectiou s dis eas es again as s u m e the s inis ter role they p layed in the p as t?
2 .W hat H is tory Says
H is tory and econom ics have an im p ortant p art to p lay in telling u s how far w e
have com e and how m u ch w e ris k los ing. Let u s b egin w ith tw o key his toricalp oints .
Firs t,m os t ofthe gains in life ex p ectancy du e to the eradication ofinfectiou s dis eas es
p receded the antib iotic revolu tion linked to s u lfa dru gs ,p enicillin,and s trep tom ycin
b y centu ries . The s tory b egins w ith the dis ap p earance ofp lagu e,w hich in England is
u s u ally dated b ack to 1 6 6 5 . The firs t attack ofp lagu e in the m id-fou rteenth centu ry
cu t England’s p op u lation b y half,and s u b s eq u ent ep idem ics kep t nu m b ers dow n for a
centu ry or m ore. Then gradu ally the ravages ofthe Black Death dim inis hed.
N evertheles s ,b etw een the 1 5 6 0 s and the 1 6 6 0 s it w as res p ons ib le for ab ou t one death
in every five in London. W hy did it then dis ap p ear? W e are s tillnot q u ite s u re,b u t
Pau lSlack’s cas e for effective q u arantining,b oth at hom e and fu rther afield,is the
m os t p ers u as ive.9
W e know m ore ab ou t s m allp ox ,w hich p reventive m edicine in the form of
variolation (introdu ced to the w es t b y Lady M ary M ontagu in the early eighteenth
centu ry)and vaccination (Edw ard Jenner,1 7 9 8 ),redu ced from b eing the s ingle b igges t
killer in eighteenth-centu ry Britain to a m inor cau s e ofdeath b y the m id-nineteenth
centu ry.
And one cou ld continu e at s om e length des crib ing Britain’s victories over a
litany ofinfectiou s dis eas es — cholera,typ hoid fever,m eas les ,dip htheria,and
4
tu b ercu los is — alldu e to a com b ination ofp u b lic action (p articu larly in the p rovis ion
ofclean w ater and b etter s ew age dis p os al),b etter living conditions ,and p reventive
m edicine (s ee Figu re 3 ). This w as allin an era b efore any antib iotics .
Second,the gains in life ex p ectancy in the p re-antib iotics era far ou tw eighed
thos e that follow ed. T his is im p ortant:althou gh hailed as w onder dru gs ,the direct
im p act ofantim icrob ialtechnologies on his toricaltrends in m ortality w as s u rp ris ingly
s light. In England infectiou s dis eas es w ere already u nder controlto a great ex tent b y
1 9 4 0 u s ing m ethods that p revented trans m is s ion or increas ed res is tance (rather than
cu red infections ,as antib iotics do).
[Tab le 2 ab ou t here]
In Britain,p u b lic health m eas u res s u ch as is olation and im p roved s anitation
w ere m ainly res p ons ib le for the victories over cholera and typ hoid fever. Thes e older
m ethods ofdis eas e controlw ere fu rther enhanced in the s econd halfofthe tw entieth
centu ry b y new vaccines agains t a range ofinfectiou s dis eas es (Tab le 2 ). Vaccines
alone w ere res p ons ib le for the eradication ofp oliom yelitis and the near-eradication of
m eas les . T he BCG vaccine agains t tu b ercu los is w as develop ed in the 1 9 2 0 s ,b u t only
b rou ght into rou tine u s e in Britain in 1 9 5 3 . BCG im m u nis ation w as dis continu ed in
Britain in 2 0 0 5 b u t rem ains rou tine acros s m os t ofthe glob e1 0 ,and has b een
reintrodu ced in high-ris k areas ofLondon,w ith a s hift in the very recent p as t tow ards
u nivers alBCG im m u nis ation for infants .1 1
In s u m ,his tory tells u s that m any factors contrib u ted to redu cing the
m ortality from infectiou s dis eas es in develop ed cou ntries ,inclu ding b etter s anitation,
b etter nu trition and vaccination s trategies . Therefore los ing s everalantib iotics allofa
5
s u dden w ou ld not hu rlu s b ack into the m edicaldark ages ;nor w ou ld it force u s allthe
w ay b ack to the m id-tw entieth centu ry,w hen the age ofantib iotics b egan. That is
b ecau s e factors w hich help ed redu ce infectiou s dis eas e b efore antib iotics — m edical,
ins titu tional,and econom ic— are likely to b e m u ch m ore p ow erfu lnow than they w ere
then.
Bu t this is not to deny that the hu ge dep endence ofm any m odern m edical
technologies on p rop hylactic or cu rative antib iotics for their s u cces s . Before c. 1 9 5 0
s u rgery rem ained a dangerou s p rocedu re,des p ite s ignificant develop m ents in s terile
p rocedu res and w ou nd treatm ent. M any ofthe gains in s u rvivalfrom heart dis eas e
and cancers in the las t half-centu ry dep ended and continu e to dep end on s u rgical
interventions that w ou ld have involved s u b s tantialris k b efore the advent ofp enicillin.
Chem otherap y als o relies on antib iotics in the event ofop p ortu nis tic infections ,as
does organ trans p lant technology. H ip and knee joint rep lacem ents ,ofw hich there
are now ab ou t 1 6 0 ,0 0 0 annu ally in the U K,w ou ld b ecom e m u ch ris kier w ithou t
antib iotics and b lood anticoagu lants . Today infection rates are very low ,and the
infections can b e s u cces s fu lly treated. Bu t w ithou t antib iotics ,they w ou ld b e m u ch
higher and a s ignificant p rop ortion ofthos e infected w ou ld not s u rvive.1 2 Given the
odds p res u m ab ly m any,ifnot m os t s u fferers w ou ld b e forced to live w ith the p ain.
2 .1 .The Glob alSu rge in Life Ex p ectancy Since c.1 9 5 0
W hile the health gap b etw een rich and p oor nations rem ains very w ide,it has
narrow ed cons iderab ly over the las t centu ry,as has the gap in life ex p ectancies (Figu re
1 ).1 3 Figu re 2 com p ares trends in the log valu es ofincom e p er head and life ex p ectancy
at b irth (a com m on p rox y for a com m u nity’s health)in India,rep res enting low -incom e
6
cou ntries ,and Sw eden,rep res enting high-incom e cou ntries ,s ince 1 9 0 0 . N ote that
w hile the p rop ortionate gap in incom e p er head is w ider now than a centu ry ago,the
gap in life ex p ectancy has narrow ed s ignificantly. That narrow ing ofthe health gap
has b een m ainly du e to the radicalredu ction in India ofdeaths from fam ine,b u b onic
p lagu e and s m allp ox .1 4 This narrow ing als o ex p lains w hy m eas u res ofhu m an
w ellb eing that incorp orate health im p ly les s ineq u ality than thos e relying on incom e
alone.
In develop ing cou ntries the p roces s ofinfectiou s dis eas e control,s o draw n ou t
in England,w as com p res s ed into the tw entieth centu ry and enorm ou s ly accelerated
b y the availab ility ofm edicaland p u b lic health technologies . U nfortu nately w e have
relatively little ins ight into m ortality trends in m os t cou ntries b efore the 1 9 5 0 s at the
earlies t. H ow ever,it is clear from the very rap id rates ofp op u lation grow th already
evident b y the m id-tw entieth centu ry that there m u s t have b een s ignificant falls in
m ortality b efore 1 9 5 0 .
M ortality declines from the m id-tw entieth centu ry (w hen the U .N . b egan to
p u b lis h s ys tem atic cou ntry-leveldata)are m u ch b etter docu m ented. Gains w ere
p articu larly rap id alm os t everyw here in the 1 9 5 0 s and 1 9 6 0 s . Severalfactors p layed a
role,inclu ding im p roved food s u p p lies ,the s p read ofim m u nis ation p rogram m es
es p ecially agains t s m allp ox ,typ hoid and yellow fever,controlofp lagu e,im p roved
s anitation,and the advent ofDDT in ins ect control. Ris ing edu cationallevels and
changes in the s tatu s ofw om en als o m attered.1 5 The res u lt w as a rap id increas e in life
ex p ectancy glob ally,and a s harp convergence in life ex p ectancies 1 6 (Figu re 2 ).
[Figu res 1 ,2 ab ou t here]
7
In low -incom e cou ntries ,how ever,low er res p iratory infections (es p ecially
p neu m onia)and acu te diarrhoealinfections are s tillleading cau s es ofdeath. Deaths
from thes e dis eas es w ere s u b s tantially redu ced in afflu ent p op u lations w ellb efore
antib iotics . Their p ers is tence in p oorer p op u lations indicates b oth p oor nu tritional
s tatu s and living conditions and the incom p lete p enetration ofantib iotics to treat
them ,des p ite the relatively high and increas ing p er cap ita cons u m p tion ofantib iotics
in m any develop ing cou ntries . The contrib u tion ofantim icrob ialdru gs is m os t
evident in the s u cces s ofanti-m alarialtreatm ents and m ore recently anti-retroviral
therap y (ART)in redu cing H IV trans m is s ion and m ortality. By the end of2 0 1 3 ,thanks
to a com b ination ofcom p etition,technologicalp rogres s ,and activis m ,1 3 m illion
p eop le,m os tly in Africa,w ere receiving ART at a fraction ofits originalcos t in the
1 9 9 0 s 1 7 . Bu t the p ers is tent im p ortance ofdis eas es em inently treatab le b y antib iotics
indicates the continu ing s cop e for b etter-targeted acces s to antib iotics ,es p ecially in
redu cing child m ortality.
3 .W elfare Im p lications
A p rop er u nders tanding ofthe likely cos ts ofAM Ru nderlines the need to find a
s olu tion to it. Tw o recent es tim ates b y RAN D and KPM G offer b leak s cenarios in
term s offu tu re m ortality and GDP,p rop os ing es tim ates ofthe glob alim p act ofAM R
in term s ofGDPforegone in 2 0 5 0 .1 8 H ere Ifocu s ins tead on w hat his tory can tellu s
ab ou t the w elfare im p lications ofincreas ing AM R.
Becau s e GDPdoes not take accou nt ofhow w e valu e ou r health,econom is ts
have p rop os ed s everalalternative m eas u res . The b es t know n ofthem ,the H u m an
8
Develop m ent Index (H DI),inclu des health (p rox ied b y life ex p ectancy)as one ofthree
elem ents contrib u ting to ‘
hu m an develop m ent’;the others are incom e and edu cation.
Since 2 0 1 0 the m eas u re,w hich ow es its origin to a req u es t to Am artya Sen to p rodu ce
a m eas u re ofhu m an w ellb eing that ‘
cap tu res in one nu m b er an ex trem ely com p lex
s tory’1 9 ,has b een es tim ated as the geom etric m ean ofm eas u res ofincom e,edu cation,
and health relative to a m ax im u m . Its theoreticalu nderp innings have often b een
criticized2 0 b u t it has endu red,and has b een invoked,s om etim es in m odified form ,b y
econom ic his torians 2 1 as an im p rovem ent on GDPp er cap ita.2 2
[T ab le 3 ab ou t here]
T ab le 3 com p ares es tim ates ofBritis h H DIand realGDPp er cap ita in 1 8 7 0 ,1 9 1 3 ,
1 9 5 0 ,and 2 0 1 3 . W hile GDPp er cap ita grew m ore than s ix -fold b etw een 1 8 7 0 and 2 0 1 3 ,
H DIm oved p rop ortionally m u ch clos er to its ‘
m ax im u m ’valu e of1 . W hat is m os t
notew orthy is that the contrib u tion ofhealth,as p rox ied b y life ex p ectancy,to the ris e
in H DIdw arfed that ofliteracy and incom e b etw een 1 8 7 0 and 1 9 5 0 ,w hile GDPp er
cap ita contrib u ted m os t thereafter. In other w ords ,m os t ofthe gains p receded the
antib iotics revolu tion. Another p oint w orth noting is that Britain’s H DIvalu e in 1 8 7 0
w ou ld p lace it w ellb ehind,s ay,Ghana or Zam b ia today.2 3
A s econd w idely u s ed m eas u re ofthe w elfare gains to increas ed life ex p ectancy
is the valu e ofa s tatis ticallife (VSL),or w hat an individu alis p rep ared to p ay to s ave a
life. T his valu e is m eas u red indirectly,throu gh s u rveys or throu gh ob s erving how
p eop le ins u re them s elves agains t b eing killed. The ap p roach w as develop ed initially
w ith high-incom e contex ts in m ind;the ap p lication ofes tim ates ofVSLin highincom e cou ntries to m u ch p oorer cou ntries ,p erhap s in an earlier era,entails an
9
as s u m p tion ab ou t w hich incom e elas ticity to u s e,i.e. w hat is the p rop ortionate change
in VSLres u lting from a change in incom e.2 4 A m eta-m eta-analys is b as ed m ainly on
s tu dies in advanced econom ies b y Dou cou liagos et al.(2 0 1 4 )finds that the elas ticity,η,
is ‘
clearly and rob u s tly inelas tic’. There is a p res u m p tion that η falls as cou ntries get
richer,how ever,and the higher η,the m ore p oor econom ies dis cou nt VSL. Es tim ates
ofw elfare gains are q u ite s ens itive to the elas ticity u s ed.2 5
Below Irep ort ‘
firs t cu t’es tim ates ofthe w elfare gains from eradicating p lagu e
in London,s m allp ox in England,and m alaria in India and China u s ing the VSL
ap p roach,and m ore carefu les tim ates ofthe w elfare los s es ens u ing from b acteria
b ecom ing res is tant to anti-tu b ercu los is dru gs .2 6
3 .1 .Plagu e in London and Sm allp ox in England
London’s (and England’s )las t p lagu e ep idem ic w as in 1 6 6 5 ;in the s p ace ofa
few m onths it w as res p ons ib le for the deaths ofab ou t one hu ndred thou s and p eop le,
or one-fifth ofthe city’s p op u lation. Betw een 1 5 6 0 and 1 6 6 5 p lagu e w as res p ons ib le for
ab ou t 1 5 p er cent ofallLondon deaths (Slack 1 9 8 5 ;Cu m m ins ,Kelly,and Ó Gráda
2 0 1 4 ).
W hat w ere the w elfare gains for London ofthe dis ap p earance ofp lagu e? The
VSLm ethodology offers one w ay ofans w ering this q u es tion. The p op u lation of
London in 1 6 6 6 w as ab ou t 0 .5 m illion. Before the p lagu e’s dis ap p earance a cru de
death rate of3 0 -3 2 p er thou s and im p lies that ep idem ics w ere res p ons ib le for an
average of2 ,5 0 0 deaths annu ally over the p reviou s centu ry. Let u s s u p p os e ou tp u t p er
head in London w as 5 0 p er cent higher than the Englis h average,s o ab ou t $1 ,3 0 0
2 7
,
vers u s $3 0 ,4 9 0 for the U .S. in 2 0 1 0 . As s u m ing a U .S. VSLof$9 m illion yields a VSLof
10
ab ou t $3 8 0 ,0 0 0 for London c. 1 6 6 5 w hen η=1 . The gain as a p ercentage ofLondon’s
GDPw as [(2 ,5 0 0 )*3 8 0 ,0 0 0 ]*1 0 0 /(1 ,3 0 0 *5 0 0 ,0 0 0 )],or over 1 4 0 p er cent ofLondon’s
GDP. N atu rally this hu ge p ercentage leaves ou t ofaccou nt other econom ic and
dem ograp hic im p acts ofthe p lagu e’s dis ap p earance. As s u m ing an elas ticity ofη=1 .2
w ou ld yield 7 6 p er cent,η=1 .4 a s tillw hop p ing 4 1 p er cent.
Already endem ic in Eu rop e b y the s ix teenth centu ry,s m allp ox w as a deadly
s cou rge in the s eventeenth and eighteenth centu ries . As s u m ing,cons ervatively,that it
w as res p ons ib le for 5 p er cent ofdeaths in England b efore inocu lation b ecam e
w ides p read w ou ld m ean that it killed ab ou t 7 ,5 0 0 p eop le annu ally. A firs t-cu t es tim ate
ofVSLc. 1 7 0 0
2 8
for η=1 yields an es tim ated w elfare gain of3 9 p er cent ofGDP;
as s u m ing η=1 .4 retu rns s tills ignificant 1 2 p er cent.
3 .2 .M alaria in India and China:A Cas e Stu dy
Sam u elPep ys contracted it;O liver Crom w elldied ofit;and DanielDefoe
des crib ed the fate of‘
you ng las s es from the hilly cou ntry’w ho on m oving into the
m ars hes ofKent and Eas t Anglia to m arry ‘
p res ently changed their com p lex ion,got an
agu e or tw o,and s eldom held it ab ove halfa year,or a year at m os t’b efore
s u ccu m b ing. It is not that long ago s ince m alaria— ‘
agu e’or ‘
m ars h fever’— w as
endem ic in thos e p arts ofEngland,s o m u ch s o that their infant m ortality rates rivalled
thos e ofLondon.2 9 Thos e w ith no im m u nity,like Defoe’s ‘
las s es ’,w ere p articu larly at
ris k. A com b ination ofdrainage and an increas e in the lives tock p op u lation,increas ed
im m u nity,and im p roving nu trition redu ced the m os q u ito p op u lation in the fens and
the p revalence ofagu e,b u t it took q u inine to rid England offatalcas es .3 0
Du ring the 1 9 5 0 s India’s N ationalM alaria Eradication Program m e redu ced the
11
nu m b er ofdeaths from m alaria b y nearly half. Betw een indep endence (1 9 4 7 )and 1 9 6 5
the nu m b er ofdeaths fellfrom 0 .8 m illion to virtu ally zero. In other w ords ,m alaria
killed far m ore p eop le in India in 1 9 4 7 than it kills w orldw ide today. H ow did the
b enefits from virtu ally elim inating deaths from m alaria com p are to the eradication of
s m allp ox in England? Skip p ing the arithm etic,the w elfare gain from elim inating 0 .8
m illion deaths from m alaria as a p ercentage ofGDPfor η=1 w as 4 7 p er cent ofGDP.
M alaria killed even m ore p eop le in China than in India in the early 1 9 5 0 s . Bu t
b eginning in the early 1 9 5 0 s the Chines e au thorities em p loyed a s eries ofp reventive
m eas u res — filling w ater holes ,draining m ars hes ,s p rays and b ed nets ,b arefoot
doctors — w ith the res u lt that b y 1 9 9 0 the dis eas e w as virtu ally elim inated. The s am e
calcu lation ap p lied to China w ith η=1 yields a w elfare gain of5 6 p er cent of1 9 5 0 GDP.
T he rou gh-and-ready character ofthes e es tim ates ofthe w elfare gains from
eradicating m alaria is clear. In p articu lar,the choice ofη=1 is controvers ial:choos ing
η=1 .2 ins tead ofη=1 w ou ld redu ce the es tim ated w elfare gains from eradicating m alaria
from India in the 1 9 5 0 s from 4 7 p er cent to a s tills ignificant 2 6 p er cent ofGDP.
Rou gh as they are,thes e es tim ates s tillp oint to the s ignificance ofthe w elfare gains
as s ociated w ith fou r w ell-know n his toricalex am p les (Tab le 4 ).
[Tab le 4 ab ou t here]
3 .2 .A Clos er Look at Tu b ercu los is
As noted earlier,tu b ercu los is w as once the m ajor killer dis eas e in England.
Althou gh m ortality from TB b egan to decline long b efore the arrivalofan effective
antib iotic rem edy,it took a com b ination ofantib iotics and BCG to elim inate it (Figu re
3 ). T B rem ains a m ajor killer in low -incom e cou ntries today,and as m u ltidru g
12
res is tant tu b ercu los is (M DR-TB)b ecom es m ore com m onp lace s om e ofthe w elfare
gains as s ociated w ith its eradication in high-incom e p op u lations s u ch as the U K w ill
b e los t u nles s an alternative rem edy is fou nd.
[Figu re 3 ab ou t here]
H ow m u ch? Kerry H icks on (2 0 1 4 )has p rodu ced u p p er and low er b ou nds ofthe
los s for the U K. The form er p u ts a valu e on the gains from the redu ctions in TB
b etw een 1 9 5 0 and 2 0 0 0 . N ote that this ex clu des the b ig gains m ade in the era b efore
antib iotics . Still,the nu m b er is b ig:$3 5 b illion. Bu t it is very u nlikely to b e incu rred,
s ince not allthe gains from eradicating the dis eas e w ou ld b e los t. For one thing,
hou s ing and nu trition— im p rovem ents in w hich redu ced the incidence ofTB b efore
1 9 5 0 — have greatly im p roved s ince then. Then BCG,w hich w as introdu ced in 1 9 5 3 ,
offers a s trong s econd line ofdefence agains t TB. BCG is totally effective w ith children
and cu rrent es tim ates ofits efficacy agains t res p iratory tu b ercu los is (the m ain adu lt
form )range from 5 0 to 7 8 p er cent.3 1 Taking thes e factors into accou nt redu ces the
u p p er b ou nd es tim ate to a m ore realis tic $9 b illion.
T his rep res ents a p ertinent his toricalex am p le for the w ider is s u e ofAM R. As in
the cas e ofM RSA (M ethicillin-res is tant Stap hyloccocu s au reu s ),for m any infections
p u b lic health interventions ,or les s efficaciou s or s afe s econd line antim icrob ials ,m ay
m itigate the im p act ofAM R. The realw orry is ab ou t the s m allnu m b er ofcas es w here
this m ay not b e s o.
H icks on’s low er b ou nd es tim ate involves com p aring the cu rrent s itu ation w ith
the m os t likely M DR-T B s cenarios ,w hich allow for a higher m orb idity b u rden only,
13
given that M DR-TB tends to b e res olved in longer treatm ent tim es and not m ortality.
T he es tim ated los s is calcu lated b y ap p lying a VSLfu nction to the nu m b er oflife years
b u rdened w ith M DR-T B in 2 0 1 3 ;this yields an es tim ate of$1 .9 b illion.
N ote that this refers only to the early (cu rrent)p has e ofAM R. H ow ever,the
tim e-p ath ofany p articu lar res is tant m icroorganis m tends to have a s igm oid s hap e. It
is virtu ally flat b efore res is tance b egins to ap p ear,b u t then takes offw ith the rap id
increas e in the p rop ortion ofres is tant organis m s ,b efore levelling offas the p rop ortion
ofres is tant s trains has reached eq u ilib riu m . W ors e cas e s cenarios involve m oving
clos er to the u p p er b ou nd es tim ate of$9 b illion as the p rop ortion ofdru g-res is tant
cas es increas es . The s igm oidalevolu tion ofantim icrob ialres is tance als o highlights the
need for p olicy b efore the lag p has e is com p lete.
4 .Su p p ly:the Pip eline
Econom ics is ab ou t s u p p ly and dem and,b u t cu rrent s trategies to com b at
AM Rfocu s m u ch m ore on s u p p ly— the p ip eline— than on dem and. H ere Iw illfocu s
on b oth in tu rn,b eginning w ith s u p p ly.
Becau s e the his tory ofantib iotics is als o a his tory ofantib iotic res is tance,
m aintaining a s u p p ly ofrep lacem ent dru gs is es s ential. M ethicillin,develop ed b y
Beecham in 1 9 5 9 ,follow ed p enicillin in the 1 9 6 0 s as a treatm ent agains t
Stap hylococcu s au reu s ,b u t the firs t cas e ofM RSA w as diagnos ed w ithin a few years (in
1 9 6 8 ),and new er dru gs rep laced m ethicillin. Sim ilarly,as s trep tom ycin res is tance in
the treatm ent oftu b ercu los is b ecam e a p rob lem from the late 1 9 4 0 s on,m ore effective
antib iotics rep laced s trep tom ycin in the initialtreatm ent ofthat dis eas e.
Artem is inin,the p rodu ct ofa m as s ive res earch effort on the p art ofthe Chines e
14
in the late 1 9 6 0 s and 1 9 7 0 s ,follow ed the increas ingly m alaria-res is tant dru g
chloroq u ine. In 2 0 1 4 Sanofiannou nced the delivery ofits firs t b atches ofs em is ynthetic artem is inin to African cou ntries w here m alaria is endem ic. Bu t m eanw hile
in recent years artem is inin has b een m eeting s om e res is tance in Sou theas t As ia. The
s am e holds for tetracyclines ,gentam icin,flu oroq u inolones ,and,very recently,
dap tom ycin. So res is tance is natu raland inevitab le:it b ecom es an is s u e only ifthe
antim icrob ialartillery is not b eing cons is tently u p dated. The m ore you u s e an
antim icrob ialagent the s horter its s helflife. M icrob es adap t and evolve q u ickly and
are q u ite p rom is cu ou s w ith genetic m aterialthat acq u ires res is tance.
T he p rob lem — s o w e are rep eatedly w arned— is that the artillery has not b een
u p dated. W arnings like ‘
Today’s dearth in the antib acterialres earch and develop m ent
p ip eline w illtake decades to revers e… ’or ‘
The antib iotic p ip eline p rob lem m ay change
the p ractice ofm edicine as w e know it’are com m onp lace.3 2 W hy the s u p p ly ofnew
antib iotics s eem ed am p le to cop e w ith res is tant b acterials trains in the 1 9 5 0 s and
1 9 6 0 s ,and then p ractically dried u p b etw een then and centu ry’s end,is a b it ofa
m ys tery. Again and again,the ans w ers given are [a]the s heer difficu lty ofdevelop ing
new b road-s p ectru m antib iotics and [b ]the les s er com m ercialap p ealofdru gs w ith
s p ecific targets (and therefore low er retu rns on inves tm ent). Zyvox (linezolid)created
q u ite a fanfare w hen ap p roved b y the U .S. FDA in 2 0 0 0 ,and it continu es to b e an
effective treatm ent for Gram -p os itive b acteria res is tant to s everalother antib iotics .
Bu t there is a p ervas ive im p res s ion today that the s u p p ly ofnew antim icrob ials has
virtu ally dried u p in the new m illenniu m .
T his techno-p es s im is m ,w hich is not new
3 3
,is b as ed on a s ens e that allthe
‘
eas y’dis coveries have already b een m ade,and that m ajor p harm aceu tical
15
corp orations have los t interes t b ecau s e the rew ards for generating new dru gs are low .
T he m ajor p harm aceu ticalcom p anies b lam e ‘
a range ofs cientific,regu latory,and
financialfactors ’3 4 . Certainly,there is a tens ion b etw een the W H O ’s p ercep tion ofthe
threat p os ed b y AM R,on the one hand,and the lack ofactivity on the p art ofBig
Pharm a,on the other.
Econom ics is s om ew hat agnos tic ab ou t the fu tu re oftechnologicalchange in
general. Som e econom is ts ,like T yler Cow en and Rob ert Gordon,hold that allthe low
hanging fru it has b een p lu cked;others ,like econom ic his torian JoelM okyr,invoke the
p as t to p aint a m u ch m ore cheerfu lp ictu re offu tu re p ros p ects . For M okyr
ins titu tionalb lockages ,not the lack ofnew know ledge,are the greates t b arriers to
continu ed technologicalp rogres s in the s tru ggles agains t b ad b acteria and other areas
ofconcern,s u ch as glob alw arm ing.3 5 In s u p p ort,rem em b er that w hen the firs t
antib iotics em erged,little w as know n ab ou t cellu lar and m olecu lar genetics ,
b acteriology,or virology. Science has advanced b y leap s and b ou nds s ince,w hich
s hou ld m ake it eas ier to develop far m ore effective w eap ons agains t m icrob es .3 6 And
there are early s igns ofthis . Linking the u s e ofb acteriop hages (or p hages )as
therap eu tic agents to w hat is b eing learnt ab ou t CRISPR(clu s tered regu larly
inters p aced s hort p alindrom ic rep eats )b iology is a p rom is ing cas e in p oint;u s ing
CRISPRto create m os q u itoes w ith a p aras ite-b locking gene in order to p revent m alaria
is another.3 7 M okyr als o rem inds u s that the ICT revolu tion s hou ld p rove a b oon to
fu tu re R& D,not leas t in m edicine.3 8
T he p u b lic good character offinding s olu tions to AM Rim p lies that m arket
forces alone w illnot generate an adeq u ate s u p p ly ofthe ap p rop riate technologies .
Pu b lic inves tm ent in the ‘
b lu e s ky’res earch neces s ary to p rodu ce new rem edies has
16
long acknow ledged this . Su ch inves tm ent s hou ld target the u nivers ities that s tand to
gain little from their dis coveries ,and the s m aller b iotech com p anies w ho take the
b igges t ris ks b u t lack the fu nds to s u s tain the later p has es ofR& D.3 9 T hu s com p arative
advantage m ay ex p lain the em erging p attern oflarger p harm aceu ticalcom p anies
foregoing b as ic res earch b u t b u ying u p s u cces s fu ls m aller fry and b acking likely
w inners ,i.e. focu s ing on the ‘
D’in R& D.4
0
A clos er look at the s u p p ly ofnew antib iotics s u gges ts that althou gh the lack
ofnew effective s u b s titu tes is w orris om e,technology is not at a s tands till. As of
Decem b er 2 0 1 4 ,the U .S. Food and Dru gs Adm inis tration’s regis ter lis ted thirty-s even
new antib iotic dru gs u nder develop m ent.4 1 Som e,to b e s u re,are b ou nd to failand
s om e are only in the early s tages ofdevelop m ent. Bu t ifeven halfa dozen ofthes e
dru gs s u cceed,they w ou ld go s om e w ay tow ards alleviating fears ofs om e form s of
AM Rfor a w hile. A b riefreview ofw here things s tand in early 2 0 1 5 is ap p rop riate
(T ab le 5 ).
Tab le 5 ab ou t here
4 .1 .M RSA
N ot allantim icrob ial-res is tant b u gs are eq u ally s eriou s ,nor is their p ecking
order u nchanging over tim e. In Britain,for ex am p le,the threats p os ed b y M RSA and
C. diff. have decreas ed m arkedly in recent years :The nu m b er ofC.diff.related deaths
in England and W ales fellfrom 8 ,3 2 4 to 1 ,6 4 6 b etw een 2 0 0 7 and 2 0 1 2 ,and over the
s am e p eriod the nu m b er ofdeath notices m entioning M RSA or Stap h.au reu s
p lu m m eted from 3 ,6 4 5 to 8 4 9 . M eanw hile the U SCenter for Dis eas e Control
cons iders the threat p os ed b y M RSA today to b e ‘
s eriou s ’rather than ‘
u rgent’,a
17
category it res erves for CRGN Bs ,C. diff.,and N eis s erea gonorrhoeae.4
2
The credit for
redu cing the threat from M RSA goes to factors des crib ed b elow .
At the s am e tim e,dru gs s u ch as vancom ycin,dap tom ycin,and linezolid are s till
p retty effective agains t Stap h.au reu s ,and it is als o s im p ly incorrect to s ay that the
p ip eline for new dru gs targeting Stap h.au reu s is dry. Iam not referring here to the
u np leas ant ninth-centu ry concoction(‘
garlic and onions or leeks as w ellas w ine and
the b ile from a cow ’s s tom ach… b oiled in a b ras s ves s el,then s trained and left for nine
days ’)recently recreated b y s cientis ts at the U nivers ity ofN ottingham .4 3 In 2 0 1 4 the
FDA ap p roved three new dru gs targeting S.au reu s u nder the 2 0 1 2 Generating
Antib iotic Incentives N ow (GAIN )Act. The firs t tw o w ere develop ed b y relatively
s m allb iotech com p anies (Cu b is t Pharm aceu ticals and Du rata),w hich w ere acq u ired
b y b igger fis h— M SD and Actavis ,res p ectively— in the w ake ofFDA ap p roval. The
third,O rb activ,has a longer his tory. O riginally develop ed b y EliLilly,it failed to gain
FDA ap p rovalin 2 0 0 8 . In 2 0 0 9 it w as acq u ired b y The M edicines Com p any,w hich
carried ou t fu rther trials and w hos e ap p lication to the FDA w as s u cces s fu l. In Janu ary
2 0 1 5 the Eu rop ean M edicines Agency (EM A)als o granted m arket au thorization for
O rb activ and Sivex tro.
T he race b etw een thes e new dru gs is now on. For w hat s u ch nu m b ers are
w orth,m arket analys ts p redict s ales of$2 0 4 m illion for Dalvance,of$3 0 9 m illion for
O rb activ,and of$2 1 6 m illion for Sivex tro b y 2 0 2 0 .4
4
A fou rth new antib iotic Zerb ax a
als o w on FDA ap p rovalin 2 0 1 4 ,althou gh it does not claim efficacy agains t S.au reu s .
Fou r new ap p rovals targeting AM Rin a year com p ares favou rab ly w ith five in the
p reviou s decade.
18
T here has b een m u ch m ore hyp e ab ou t Teix ob actin,a new antib iotic w hich has
p roven effective in m ice agains t b oth Stap h.au reu s and M ycob acteriu m tu b ercu los is .
T he ou tcom e ofa p u b lic-p rivate p artners hip b etw een academ ic res earchers and a
p rivately ow ned b iotech com p any b as ed in Cam b ridge,M as s .,and des crib ed as ‘
the
firs t new clas s ofantib iotics to b e dis covered in 3 0 years ’,Teix ob actin claim s to b e
res is tant to res is tance. Bu t it has s om e w ay to go,clinicaltrials on hu m ans b eing a few
years aw ay.4
5
4 .2 .M alaria
T he es tim ated nu m b er ofdeaths from m alaria w orldw ide drop p ed from
8 7 5 ,0 0 0 in 2 0 0 2 to 5 8 4 ,0 0 0 in 2 0 1 3 . In 2 0 0 2 m alaria s tillaccou nted for 1 .8 p er cent of
alldeaths w orldw ide;a decade later the p ercentage had fallen to 1 p er cent.4
6
Antim icrob ialagents claim s om e ofthe credit for this ,b u t now there are s igns in p arts
ofSou theas t As ia ofp aras ite res is tance to the m ain antim icrob ialtreatm ent,
artem is inin,w hen u s ed as a s tand-alone dru g agains t one typ e ofp aras ite
(Plas m odiu m falcip aru m ). So far,W H O data revealno s ignificant increas e in rep orted
deaths in any ofthe five cou ntries at ris k,b u t their data s hou ld b e regarded as p art of
w hat is in effect an early w arning s ys tem .4
7
H ere too there are s om e hop efu ls igns on the s u p p ly front. In Ju ly 2 0 1 4
N ovartis des crib ed as ‘
encou raging’the res u lts ofp has e IItrials on their anti-m alarial
dru g KAE 6 0 9 ,w hich rap idly cleared p atients in Thailand ofthe p las m odialp aras ites
P.falcip aru m and P.vivax . N ovartis are cu rrently p lanning Phas e IIb trials ,w hich
focu s on the efficacy ofp articu lar dos age levels ,for KAE6 0 9 and hop e to have it on the
m arket b y 2 0 1 8 . In addition in Ap ril2 0 1 4 GKN annou nced Phas e IIIp lans for its anti-
19
m alarialdru g,tafenoq u ine,w hich,althou gh des ignated a ‘
b reakthrou gh therap y’b y
the FDA,has s o far received no ap p rovalfrom any dru g agency. M eanw hile,PATH
and Glax oSm ithKline,w ith help from the Billand M elinda Gates Fou ndation,have
develop ed a rather p rom is ing vaccine for m alaria (RTS,S),w hich s hou ld b e ready for
u s e b efore the end of2 0 1 5 . W hile an im p erfect s u b s titu te for antim icrob ials ,s u ch a
vaccine can help b y redu cing the dem and for antib iotics .4
8
4 .3 .M DR-TB
T he s u p p ly-s ide ou tlook for M DR-TB is als o m ildly encou raging.4
9
The FDA (in
Decem b er 2 0 1 2 )and the Eu rop ean Com m is s ion (M arch 2 0 1 4 )have granted conditional
ap p rovalto Sirtu ro (b edaq u iline)as a treatm ent for M DR-TB in adu lt p atients . This is
the firs t T B dru g to gain FDA ap p rovals ince the 1 9 6 0 s . Ap p rovalis conditional
b ecau s e the dru g is highly tox ic,and s o u s e is res tricted to w hen there is no effective
alternative. Res earch now focu s es on redu cing b edaq u iline’s tox icity.5 0
4 .4 .CRGN B
Ifthe ou tlook on m alaria and M RSA is m ildly ‘
encou raging’,the threat p os ed b y
the ‘
nightm are’carb ap enem -res is tant gram -negative b acteria (CRGN B)m entioned
earlier,agains t w hich few therap eu tic op tions ex is t,is indeed w orris om e. Fos fom ycin,
tigecycline,p olym yx in B,and colis tin are the las t-line-of-defens e therap ies agains t
CRGN Bs ,b u t s om e b acteria are res is tant to fos fom ycin;p olym ix in B has lim ited
therap eu tic s cop e;s om e carb ap enem -res is tant b acteria are als o intrins ically res is tant
to colis tin;and there have b een rep orts recently oftigecycline-related and p olym x in Brelated deaths .5 1 W here s u ch infections are a threat,clearly early detection and rap id
20
s creening are cru cial.5 2 Dow n the road,carb ap enem -res is tant b acteria m ay req u ire
m ore dras tic p u b lic health interventions .
T he highly res trictive— and controvers ial5 3 — natu re ofthe FDA’s ap p rovalfor
the dru g Avycaz (ceftazidim e-avib actam )in Feb ru ary 2 0 1 5 is an indication ofthe
gravity ofthe CRGN B p rob lem . A recent u s efu lap p rais alb y one indu s try ins ider
conclu des that w hile ‘
noveldru gs for b ad b u gs are em erging’all‘
have s om e holes in
their s p ectru m s agains t M DRgram -negative p athogens ’.5 4 The dangers p os ed b y
CRGN Bs s u gges t the need for a p ip eline s trategy that focu s es not on res is tance in
general,b u t on w here it p res ents the greates t threat (as w ith Eb ola).
5 .Dem and Als o M atters
Policy has a role to p lay in redu cing the dem and for antib iotics ,b u t w hat m ay
s eem s traightforw ard in p rincip le is not s o eas y in p ractice.5 5 Take,for ex am p le,the
very large b etw een-cou ntry and w ithin-cou ntry variation in the cons u m p tion of
antim icrob ials . In 2 0 1 3 antib iotics cons u m p tion p er cap ita w as three tim es as high in
Belgiu m as in the N etherlands nex t door.5 6 Redu cing average cons u m p tion els ew here
in Eu rop e to the Du tch levelw ou ld cu t the cons u m p tion ofantib iotics on the
continent b y alm os t half. Redu cing u s e in Ireland as a w hole today to the rates fou nd
in the cou nties ofRos com m on and M eath w ou ld cu t aggregate cons u m p tion b y tw ofifths ,w hile redu cing U .S. cons u m p tion to levels fou nd in the s ix low es t cons u m ing
s tates w ou ld cu t the aggregate b y over a q u arter (Figu re 4 ).5 7
[Figu re 4 ab ou t here]
21
A m ore intelligent ap p roach tow ards antib iotics u s age cou ld thu s increas e the
s helflife ofindividu altreatm ents and thereb y redu ce the incidence ofAM R. H ow ever,
u s age is als o a fu nction ofhos p italhygiene,w hich is m ore eas ily im p roved in s om e
environm ents than in others . For ex am p le,b etw een 2 0 1 0 and 2 0 1 4 the M RSA rate p er
thou s and u s ed b ed days in tw o ofDu b lin’s p rivate hos p itals ,Vincent’s and the M ater,
w as zero,w hile in the ep onym ou s adjoining p u b lic hos p itals the rate averaged 0 .8 5
over the s am e p eriod. The variation in res is tance rates acros s Eu rop e s u p p orts the
p res u m p tion ofa correlation b etw een u s age and AM R5 8 ,b u t how m u ch ofthis
variation in cons u m p tion is du e to s ocioeconom ic contex t,and how m u ch to hu m an
agency? Again,there are choices to b e m ade b etw een infection controlp olicies . The
trade-offs involved here req u ire m ore s tatis ticalp recis ion and contex tu alization— and
p u b licity..5 9
Forcefu lm eas u res to cu rb the u s e ofantim icrob ials in agricu ltu re w ou ld help
too:ideally,one w ou ld like to s ee their u s e res tricted to the treatm ent ofinfections .
Bu t s u ch m eas u res face op p os ition from p harm aceu ticalcom p anies and from
p rodu cers . Recently,ChiefM edicalO fficer Dam e Sally Davies s ingled ou t the U S
w here fou r tim es as m any antim icrob ials are u s ed on anim als as on hu m ans and w here
the au thorities are content ‘
to w ork w ith indu s try’and to have veterinarians (hardly
dis interes ted p arties )s u p ervis e dru g u s e,b u t this ignores the difficu lty that the
cons u m p tion ofantib iotics b y lives tock in s om e Eu rop ean cou ntries rivals that in the
U .S.,and als o the role ofChina,w here antim icrob ialcons u m p tion in lives tock
p rodu ction (2 3 p er cent ofthe glob altotal)cu rrently far ex ceeds that in the U S(1 3 p er
cent). M oreover,China’s s hare is s et to reach 3 0 p er cent ofa m u ch higher aggregate
b y 2 0 3 0 .6
0
This highlights b oth the need for and the difficu lty ofreaching a glob al
22
s olu tion to a p rob lem w here ves ted interes ts loom large. An alternative or
com p lem entary s olu tion— to genetically engineer lives tock agains t infections — s eem s
w ithin reach. W hat is very controvers ialtoday m ay s eem the only w ay ou t s om e years
from now .6
1
H ealth edu cation als o has a role to p lay in redu cing dem and. A good ex am p le
is the French p u b lic health cam p aign b as ed on the s logan ‘
Les antib iotiq u es c'es t p as
au tom atiq u e’,w hich,it is claim ed,led to a redu ction ofover a q u arter in the nu m b er
ofantib iotic p res crip tions p er head over a five-year p eriod.6
2
Recent random ized
controltrials ofthe effect ofrem inders directed at ou tp atients in Stockholm and in
Los Angeles b oth fou nd that they had a s u b s tantialnegative effect on u s age. H ow ever,
neither the drop in antib iotics cons u m p tion in France nor the im p rovem ent in hand
hygiene in Belgiu m — focu s ofanother cam p aign in the 2 0 0 0 s — p roved las ting. In s u m ,
there is s om ething to b e s aid for inform ation cam p aigns ,b u t ifthey are to b e effective
they cannot b e once-offm eas u res .6
3
O ne m ore related thou ght:a recent U Ss tu dy 6 4 reveals that the likelihood ofa
clinician p res crib ing an antib iotic for an acu te res p iratory infection (ARI)increas es
s ignificantly over the cou rs e ofclinic s es s ions ,im p lying that the tem p tation to
p res crib e inap p rop riately increas es w ith decis ion fatigu e (s ee Figu re 5 ). This s u gges ts
the need for m andatory b reaks and s horter s es s ions and for w ays ofnu dging clinicians
(as op p os ed to p atients ).
[Figu re 5 ab ou t here]
23
Finally,other develop m ents m ay als o help to redu ce dem and for antib iotics .
Firs t,in ins titu tionals ettings there is the p ros p ect oftechnologies that w illredu ce the
s p read ofm u ltidru g res is tant organis m s :ex am p les inclu de m ore effectiv e hand
hy giene;antib iotic coatings that hinder the s p read ofb acteria or killthem ;and the
p rev ention ofdu odenos cop e infections . Second,ifp ers onalized m edicine ‘
takes off’it
s hou ld b e p os s ib le to s p ecify w hich antib iotics are ap p rop riate to any giv en p ers on,and
thereb y redu ce u s age.65 Third,a new s tu dy in PLoS Biology rais es the intrigu ing
p os s ib ility that alternating com b ination therap ies m ay offer s om e res p ite agains t
b acteria.66 Fou rth,the s am e goes for w hat the New Yorker du b b ed the ex crem ent
ex p erim ent67 ,i.e.treating C. diff. infections w ith faecaltrans p lants or ‘crap s u les ’. Is it
too m u ch to hop e that this relativ ely s im p le and ap p arently s afe therap y can reliev e
w hat the U.S.Center for Dis eas e Controlcategoriz es ‘an u rgent threat’?6 8
[Tab le 6 ab ou t here]
6 .Conclu ding Rem arks
T his lectu re has s ou ght to p u t ou r p res ent concerns ab ou t AM Rin econom ic
his toricalp ers p ective. It b egan b y s tres s ing the m ajor w elfare gains from redu ced
m ortality du e to infectiou s dis eas es ,w hile at the s am e tim e giving du e credit to p u b lic
health reform s that p receded the w ides p read u s e ofantib iotics . W arnings ab ou t
antim icrob ialres is tance are not new :Alex ander Flem ing cau tioned in his N ob el
Lectu re in 1 9 4 5 that m is u s e w ou ld res u lt in m icrob es b ecom ing res is tant.6
9
W arnings
reached a new levelin the 1 9 9 0 s and a cres cendo du ring the las t few years . The
dreadfu lp ros p ect ofan ‘
antim icrob ialap ocalyp s e’w hen,in the w ords ofDam e Sally
24
Davies ,‘
rou tine op erations like hip rep lacem ents or organ trans p lants cou ld b e deadly
b ecau s e ofthe ris k ofinfection’has finally s u nk in. Bu t s he w as referring to M RSA,
w hereas the p eop le m os t at ris k today from AM Rare not thos e req u iring s u rgery b u t
p atients ,es p ecially elderly p atients ,at the m ercy ofcarb ap enem -res is tant b acteria.
T he w ar agains t m icrob es is a w ar agains t Darw inian evolu tion:the p oint is not
to w in it b u t to s tay ahead. Is the s itu ation regarding AM Rm ore s eriou s now than it
w as five or ten years ago? Des p ite the alarm b ells ,Iw ou ld argu e p erhap s not,for
s everalreas ons . Firs t,aw arenes s ofthe p rob lem is m u ch greater. That ex p lains the
tim ing ofins titu tionalres p ons es s u ch as the GAIN Act7 0 ,greatly increas ed U .S. federal
fu nding7 1 ,the H arris on Prize,the U K Five Year Antim icrob ialRes is tance Strategy
(w ith du e focu s on cons ervation and s tew ards hip ),and the joint res earch initiative
annou nced b y the U K Science M inis ter in Ju ly 2 0 1 4 in the w ake ofthe Prim e M inis ter’s
w arnings . A really s eriou s ou tb reak ofs om e infectiou s dis eas e w ou ld p rom p t a b igger
res p ons e from governm ents . O ne has only to cons ider the ex am p le ofEb ola w here
‘
trials ,w hich w ou ld norm ally take years and decades ,are b eing fas t-tracked on a
tim es cale ofw eeks and m onths ’.7 2 Tw o years ago the p ros p ect ofan Eb ola vaccine
b eing develop ed s eem ed rem ote. Yet in late O ctob er 2 0 1 4 the W H O annou nced p lans
to b egin tes ting tw o ex p erim entalEb ola vaccines in areas at ris k from Eb ola b y Janu ary
2 0 1 5 and ap p lying a b lood s eru m treatm ent availab le for u s e in Lib eria ‘
w ithin tw o
w eeks ’7 3 . By M arch 2 0 1 5 fou r p rom is ing vaccines had b een develop ed. Increas ing
p u b lic aw arenes s ofthe AM Rp rob lem is als o b eginning to cons train corp orate
b ehavior.7 4
Second,the b ig redu ctions in M RSA res is tance and in the nu m b er ofdeaths
attrib u tab le to Stap h.au reu s and C.diff. in the U K over the p as t decade are evidence
25
ofw hat can b e done to arres t res is tance in hos p itals ettings at nationallevel(Figu re
4 ). Increas ed b ios ecu rity and higher hygiene s tandards in health care s ettings and
ins titu tions can redu ce the p os s ib ility ofinfection fu rther,and thereb y the u s e antim icrob ialagents . Qu icker and m ore effective diagnos es ofantib iotic needs are als o
vital,as recognized b y the EU Com m is s ion’s recent annou ncem ent ofthe H orizon
Prize.7 5 Bu t cons ervation and s u s tainab ility als o req u ire glob alaction on as p ects s u ch
as u s e in lives tock p rodu ction,s u rveillance,infection control,and s ales p rom otion.
T hird,the new dru gs p ip eline is finally b eginning to s how m ore s igns ofactivity
than at any p oint s ince the 1 9 6 0 s . Three new anti-M RSA dru gs have recently ap p eared
on the m arket;the realw orries now are thos e carb ap enem -res is tant gram -negative
b acilli(CRGN B)(s ee too Tab le 6 ). This s u gges ts the need for a narrow er p olicy focu s
on w here the threat is greates t,rather than on new dru gs generally. Pas t ex p erience
u rges cau tion ab ou t w hat new antib iotics w illem erge from cu rrent efforts ,how
effective they w illb e,and how long it w illb e b efore they too encou nter res is tance. In
the end,the challenge p os ed b y AM Ris very realand there is no room for
com p lacency:m eeting that challenge req u ires not ju s t keep ing a clos e w atch on the
p ip eline b u t p aying m u ch m ore attention to dem and and cons ervation. The s itu ation
is challenging b u t b y no m eans hop eles s .
26
T ab le 1 . Dis trib u tion ofcau s es ofdeath,1 8 5 0 – 2 0 1 2 (% )
England and
W ales 1 8 5 0
Cau s es
Infectious
diseases
Infectiou s (not
res p iratory)
Res p iratory
infections
M aternal
conditions
N eonatal
conditions
N oncom m u nicab le
Inju ries
T otaldeaths
Life ex p ectancy
England and
W ales 1 9 0 0
England and
W ales 1 9 3 9
H igh-incom e
cou ntries 2 0 1 2
Low -incom e
cou ntries 2 0 1 2
44.7
35.8
14.5
6.0
38.6
2 6 .2
1 8 .2
3 .7
2 .6
2 8 .2
1 8 .5
1 7 .6
1 0 .8
3 .4
1 0 .4
0 .9
0 .8
0 .4
0 .0 2
1 .7
6 .0
3 .7
3 .7
0 .3 4
9 .3
4 4 .8
5 6 .1
7 6 .5
8 7 .3
4 0 .3
3 .6
3 .6
4 .9
6 .4
1 0 .1
3 6 8 ,9 9 5
5 8 7 ,8 3 0
4 9 8 ,9 6 8
1 ,16 7 1 ,3 6 1
5 ,6 9 6 ,9 6 9
4 3
4 6
6 4
7 9
6 2
Sou rces :Davenp ort,2 0 0 7 ;O N S,2 0 0 3 ;W H O Glob alH ealth O b s ervatory;H u m an M ortality Datab as e.
N otes :the infectiou s dis eas es category ex clu des infectiou s cau s es ofm aternaland neonatalm ortality;
the non-com m u nicab le dis eas es category inclu des deaths du e to nu tritionaldeficiencies . H igh (Gros s
N ationalIncom e p er cap ita ≥ $1 2 ,4 7 6 ) and low -incom e (≤ $1 ,0 2 5 ) grou p s are as defined b y the W orld
Bank in 2 0 1 2 .
T ab le 3 . H DIand GDPp er cap ita in Britain,1 8 7 0 -2 0 1 3
Year
18 7 0
19 13
19 5 0
2 0 13
[1 ]H DI
0 .4
0 .6
0 .7
0 .9
7 6
2 8
6 2
2 3
[2 ]GDPp er
head
3 ,19 0
4 ,9 2 1
6 ,9 3 9
2 3 ,5 0 0
Period
1 8 7 0 -1 9 1 3
1 9 1 3 -1 9 5 0
1 9 5 0 -2 0 1 3
Relative Contrib u tion
(p ercentage oftotal)
Y
H
L
1 4 .2
5 4 .1
3 1 .7
1 4 .6
6 3 .3
2 2 .1
4 4 .0
3 9 .5
1 6 .5
Sou rce:Crafts 2 0 0 2 :3 9 6 -7 ;M addis on w eb s ite [http ://w w w .ggdc.net/m addis on/oriindex .htm ]
N ote: GDP p er head is m eas u red u s ing 1 9 9 0 international Geary-Kham is dollars ; edu cation
com p onent es tim ated u s ing years s chooling as a p rop ortion of1 5 years (as s u m ed to b e 3 years in
1 8 7 0 ).
Tab le 4 . Es tim ated W elfare Gains as Percentage ofGDPU s ing VSL
Dis eas e
η=1
η=1 .2
η=1 .4
Plagu e in London
14 0
7 6
4 1
Sm allp ox in England
3 9
2 2
12
M alaria in India
4 7
2 6
15
M alaria in China
5 6
2 4
10
27
T ab le 2 . M ajor dis eas es and their p revention and treatm ent
Dis eas e
Prevention
Date
Dis eas es redu ced or elim inated b efore 1 7 5 0
Bu b onic p lagu e
Qu arantine,
From
is olation
c1 5 in
Eu rop e
Dis eas es redu ced or elim inated 1 7 5 0 -1 8 7 0
typ hu s
Qu arantine,
C1 8 redu ctions
is olation,
hygiene,DDT to
1 9 4 3 (not
killlice
cu rrently in
Vaccine
p rodu ction)
Sm allp ox
Qu arantine,
C1 7 [?],C1 8
is olation
C1 8
Inocu lation
17 9 8
Vaccination
Cholera
W ater
Las t ep idem ic in
p u rification,
Britain 1 8 6 6
notification and
(1 8 9 0 s in
is olation of
continental
cas es
T reatm ent
Date
Antib iotics
1 9 4 6 (s trep tom ycin)
Antib iotics
19 4 8
(chloram p henicol)
N one
O ralrehydration
19 6 8
Eu rop e). Still
endem ic in
s ou th As ia
T yp hoid
W ater
p u rification,
is olation ofcas es
Vaccine
Redu ced in
im p ortance over
cou rs e ofC1 9 in
England
18 9 7
Antib iotics ,oral
rehydration
19 4 8
(chloram p henicol);
1 9 6 8 (O RT )
M alaria
Redu ction in
m os q u ito hos t
p op u lations
(drainage,
DDT)and
p revention of
b ites (b ednets ,
ins ecticide)
Elim inated in
England b y early
C2 0 th. Very
large glob al
redu ctions
throu gh DDT
u se1 9 4 0 s+
q u inine,
chloroq u ine,
artem is inin and
com b ination
therap ies
q u inine u s ed in
Bolivia and Peru
at leas t s ince C1 5
Dis eas es redu ced or elim inated 1 8 7 0 -1 9 4 0
Yellow Fever
Redu ction in
Early C2 0 ,u s ed
m os q u ito hos t
p op u lations
(drainage,
DDT)and
p revention of
b ites (b ednets ,
ins ecticides )
Vaccination
T u b ercu los is
BCG vaccination
M eas les
Vaccination
s u cces s fu lly
du ring Panam a
canal
cons tru ction
N one
1 9 3 6 ,u s ed b y U S
arm y W W II
1 9 2 1 (rou tine u s e Antib iotics
in England 1 9 5 3 )
19 6 3
N one
28
1 9 4 6 (s trep tom ycin)
Antib iotics
1 9 4 2 (p enicillin)
Vaccine
Ap p arent
decline in
viru lence 1 8 7 0 +
19 4 7
Antib iotics
1 9 4 6 (s trep tom ycin)
Vaccination
(w ith 'antitox in')
1 8 9 0 ,b u t u s ed
w idely only
from 1 9 4 0 s
Antitox in and
antib iotics
(latter largely to
p revent
trans m is s ion)
Scarlet fever
W hoop ing
cou gh
Dip htheria
Dis eas es redu ced or elim inated after 1 9 4 0
Poliom yelitis
Pneu m onia
Vaccination
Vaccination
1 9 5 4 ,1 9 5 7
19 7 5
Chickenp ox
M RSA
Vaccine
H ygiene
19 7 5
Redu ctions in
hos p italacq u ired
infections from
1 8 8 0 s du e to
as ep tic and
antis ep tic
s u rgical
techniq u es and
im p rovem ents
in w ou nd
treatm ent
29
N one
Su lp honam ide,
p enicillin
N one
Antib iotics
1 9 3 7 ,1 9 4 4
Su lfa dru gs (1 9 3 0 s )
p enicillin (1 9 4 2 ).
Rap id evolu tion of
res is tance
T ab le 5 . T he Pip eline in early 2 0 1 5
Dru g
Year
Statu s
Target
O ther
Zyvox (linezolid)
2 0 0 0
Availab le
Gram -p os itive
b acteria,
M RSA
Pharm acia/U p john
Sivex tro (tedizolid)
2 0 14
Availab le
M RSA
Triu s /Cu b is t
Dalvance (dalb avancin)
2 0 14
Availab le
M RSA
Pfizer/Du rata
O rb activ (oritavancin)
2 0 14
Ready
M RSA
EliLilly/The
M edicines Com p any
Zerb ax a (ceftolozane/
tazob actam )
2 0 14
Availab le
E.coli,cU TI
Cu b is t
teix ob actin
2 0 15
Early s tages
M RSA,
M ycob acteriu m
tu b ercu los is
Academ ic/Big Pharm a
collab oration
KAE 6 0 9
2 0 14
Phas e IIb
M alaria
STI/N ovartis
tafenoq u ine
2 0 14
Phas e III
M alaria
GKN
ceftazidim e-avib actam
(Avycaz)
2 0 15
Res trictive
FDA
ap p roval
Com p licated
CIAIs and U TIs
As traZeneca/Fores t
Lab oratories /Actavis
T ab le 6 . O ther Develop m ents
Concep t
Target
O b s ervations
Phages
Selectively kill
b acteria containing
AM Rgenes
O ngoing,inform ed b y CRISPR
b iology
Res earch on genetic
com p os ition ofE.coli
b acteria
E.colivaccine
O ngoing,b u t E.coliare attracted to
anim als and the environm ent as w ell
as to hu m ans .
Genetically engineering
carriers agains t p aras ite
genes
M alaria,res is tance
generally
Feas ib le,b u t p olitically contentiou s
N DV-3 vaccine
Fu ngaland b acterial
infections
Phas e I‘
s trong antib ody and T-cell
im m u ne res p ons es in healthy adu lts ’
[Dec. 2 0 1 2 ]
N anos p onge vaccine
M RSA
Develop ed at U CSD 2 0 1 3
RTS,S
Anti-m alaria vaccine
Path/GSN /Gates ,likely lau nch 2 0 1 5
‘
Crap s u les ’
Clos tridiu m difficile
H eralded as im p ortant b reakthrou gh
in late 2 0 1 4
(N ovaDigm
Therap eu tics )
30
Figu re 1 . Glob alconvergence in life ex p ectancy at b irth,1 9 5 0 – 2 0 0 0
Sou rce:W orld Bank
Figu re 2 . Incom e p er cap ita and life ex p ectancy at b irth,India and Sw eden
31
deaths/1000 population
4
3
female
male
1918 influenza
pandemic
2
streptomycin
treatment
1
0
1860 1880 1900 1920 1940 1960 1980 2000
year
Figu re 3 . T u b ercu los is m ortality in England and W ales ,age-s tandardis ed to the U .K.
p op u lation in 2 0 0 0 .
Sou rces :Davenp ort,2 0 0 7 ;O ffice ofN ationalStatis tics ,2 0 0 6 .
Figu re 3 . Antib iotic Pres crib ing and the Tim e ofDay
Sou rces :Linder et al. 2 0 1 4
32
MRSA (% S .a ure us resistant)
A
DK
GR
IRL
NL
UK
BE
IT
GER
50
40
30
20
10
0
2000
2005
year
2010
B
DK
GR
IRL
NL
UK
BE
IT
GER
ESP
antibiotic resistance
(% E.coliresistant)
50
40
30
20
10
0
2000
MRSA (% S .a ure us resistant)
C
2005
year
2010
60
50
40
30
20
10
0
0
10
20
30
antibiotic consumption
(daily DDD per 1,000 population)
40
Fig. 4 . Antib iotic res is tance in Stap hyloccocu s au reu s (A) and E.coli(B) in Denm ark
(DK),Greece (GR),Ireland (IRL),N etherlands (N R),U .K.,Belgiu m (BE),Italy (IT)and
Germ any (GER) 2 0 0 0 –2 0 1 2 , and antib iotic res is tance according to antib iotic
cons u m p tion b y cou ntry in 2 0 1 2 (C).
Sou rce:ECD
33
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Tim e ofDay and
the Decis ion to Pres crib e Antib iotics ’,JAM A Intern M ed.1 7 4 (1 2 ):2 0 2 9 -2 0 3 1 .
Ling,Los ee L.,Tanja Schneider,Aaron J. Peop les ,Am y L. Sp oering,et al. 2 0 1 5 .
‘
A new antib iotic kills p athogens w ithou t detectab le res is tance’N atu re 5 1 7 ,4 5 5 –
4 5 9 ,2 2 Janu ary.
35
M azzu cato,M ariana. 2 0 1 3 . The Entrep reneu rialState:Deb u nking Pu b lic vs
Private Sector M yths ,London:Anthem Pres s .
M azzu cato,M ariana and GiovanniDos i,eds . 2 0 0 6 . Know ledge Accu m u lation
and Indu s try Evolu tion:the Cas e ofPharm a-Biotech. Cam b ridge:Cam b ridge
U nivers ity Pres s .
M eeker,Daniella,Tara K. Knight,M ark W . Friedb erg,Jeffrey A. Linder,N oah
J. Golds tein,Craig R. Fox ,Alan Rothfeld,Gu illerm o Diaz,and Jas on N . Doctor.
2 0 1 4 .‘
N u dging gu ideline-concordant antib iotic p res crib ing:a random ized
clinicaltrial’JAM A InternalM edicine 1 7 4 (3 ):4 2 5 -4 3 1 .
M okyr,Joel. 2 0 1 3 . ‘
The N ex t Age ofInvention:technology’s fu tu re is b righter
than p es s im is ts allow ’,Vox EU ,8 Sep tem b er.
[http ://w w w .vox eu .org/article/technological-p rogres s -thing-p as t].
M okyr,Joel. 2 0 1 4 . ‘
Secu lar s tagnation:not in you r life’,in C. Teu lings and R.
Baldw in,eds . Secu lar Stagnation:Facts ,Cau s es ,and Cu res . London:CEPR
Pres s ,p p .8 3 -8 9 .
N ordm ann,P.,L. Dortet,L. Poirel. 2 0 1 2 . ‘
Carb ap enem res is tance in
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O ECD. 2 0 1 2 . M ortality Ris k Valu ation in Environm ent, H ealth and Trans p ort
Policies .Paris :O ECD.
O N S(O ffice ofN ationalStatis tics ). 2 0 0 3 . ‘
Tw entieth Centu ry M ortality:1 0 0
Years ofM ortality Data in England and W ales b y Age,Sex ,Year and U nderlying
Cau s e’,CD-RO M .
Pau l,M ical,Yehu da Carm eli,Em anu ele Du rante-M angoni,Johan W . M ou ton,
et al. 2 0 1 4 . ‘
Com b ination therap y for carb ap enem -res is tant Gram -negative
b acteria’,Jou rnalofAntim icrob ialChem otherap y,M ay 2 8
[http ://jac.ox fordjou rnals .org/content/early/2 0 1 4 /0 5 /2 7 /jac.dku 1 6 8 .fu ll.p df+ht
m l].
Pennington,Thom as H . 2 0 1 4 . ‘
E.coliO 1 5 7 ou tb reaks in the U nited Kingdom :
p as t,p res ent,and fu tu re’,Infect Dru g Res is t. 7 :2 1 1 –2 2 2 ,p u b lis hed online 1 9
Au gu s t.
Plachou ras , D., D. Kavatha, A. Antoniadou , E. Giannits ioti, G. Pou lakou , K.
Kanellakop ou lou ,and H . Giam arellou . 2 0 1 0 . ‘
Dis p ens ing of antib iotics w ith
p res crip tion in Greece, 2 0 0 8 : another link in the antib iotic res is tance chain’,
Eu ros u rveillance 1 5 [7 ],1 8 Feb ru ary.
Poirel,Lau rent and P. N ordm ann. 2 0 0 6 . ‘
Carb ap enem res is tance in
36
Acinetob acter b au m annii:m echanis m s and ep idem iology’,Clinical
M icrob iology and Infection.1 2 (9 ):8 2 6 -3 6 .
Pu cci,M ichaelJ.,M alcolm G. P. Page,and Karen Bu s h. 2 0 1 4 . ‘
Cau tiou s
op tim is m for the antib acterialp ip eline’,M icrob e M agazine,Ap ril.
Qu res hi,Zu b air A.,Lau ren E. H ittle,Jes s ica A. O ’H ara,et al. 2 0 1 5 . ‘
Colis tinRes is tant Acinetob acter b au m annii:Beyond Carb ap enem Res is tance’,Clinical
Infectiou s Dis eas es ,p u b lis hed online 2 8 Janu ary.
RAN D Corp oration. 2 0 1 4 . Es tim ating the Econom ic Cos t ofAntim icrob ial
Res is tance.Santa M onica:RAN D Corp oration.
Richards on,Lau ren. 2 0 1 5 . ‘Alternating Antib iotics Render Res is tant Bacteria
Beatab le’. PLoSBiology 1 3 [4 ]:e1 0 0 2 1 0 5 . doi:10 .1 3 7 1 /jou rnal.p b io.1 0 0 2 1 0 5
RT S,SClinicalTrials Partners hip . 2 0 1 5 . ‘
Efficacy and s afety ofRTS,S/AS0 1
m alaria vaccine w ith or w ithou t a b oos ter dos e in infants and children in Africa:
finalres u lts ofa p has e 3 ,individu ally random is ed,controlled trial’,Lancet,
p u b lis hed online 2 3 Ap ril
[http ://w w w .thelancet.com /jou rnals /lancet/article/PIIS0 1 4 0 -6 7 3 6 (1 5 )6 0 7 2 1 8 /ab s tract].
Ryan,S. Arnold,KerriA. Thom ,Saarika Sharm a,M ichaelPhillip s ,J. Kris tie
Johns ton,and DanielJ. M organ. 2 0 1 1 . ‘
Em ergence ofKleb s iella p neu m oniae
Carb ap enem as e (KPC)-Produ cing Bacteria’,Sou thern M edicalJou rnal,1 0 4 [1 ]:
4 0 -4 5 .
Sab u ncu E.,J. David,C. Bernède-Bau du in,S. Pép in,M . Leroy,et al. 2 0 0 9 .
‘
Significant redu ction ofantib iotic u s e in the com m u nity after a nationw ide
cam p aign in France,2 0 0 2 –2 0 0 7 ’,PLoSM ed 6 (6 ):e1 0 0 0 0 8 4 .
Sads ad,Ros em ary,Vitaly Sintchenko,G.D. M cDonnell,and G.L. Gilb ert. 2 0 1 3 .
‘
Effectivenes s ofH os p ital-W ide M ethicillin-Res is tant Stap hylococcu s au reu s
(M RSA)Infection ControlPolicies Differs b y W ard Sp ecialty’. PLoSO N E 8 (1 2 ).
Slack,Pau l. 1 9 8 5 . The im p act ofp lagu e in Tu dor and Stu art England. London:
RKP.
Sm ith,Richard and Joanna Coas t. 2 0 1 2 . The econom ic b u rden ofantim icrob ial
res is tance:W hy it is m ore s eriou s than cu rrent s tu dies s u gges t.2 0 1 2 . Technical
Rep ort. London SchoolofH ygiene & Trop icalM edicine,London.
Sm ith,Richard and Joanna Coas t. 2 0 1 3 . ‘
The tru e cos t ofantib acterial
res is tance’,Britis h M edicalJou rnal3 4 6 :f1 4 9 3 ,1 1 M arch.
So,Anthony D.,N eha Gu p ta and Otto Cars .20 1 0 . ‘Tackling antib iotic res is tance:
concerted action is needed to p rov ide new technologies and cons erv e ex is ting
dru gs ’British Medical Journal 3 4 0 [N o.7 7 56]:1 0 91 -92,22 M ay 20 1 0 .
37
Sp ellb erg,Brad,John H . Pow ers ,Eric P. Bras s ,Loren G. M iller and John
E.Edw ards ,Jr. 2 0 0 4 . ‘
Trends in antim icrob ialdru g develop m ent:im p lications
for the fu tu re’,ClinicalInfectiou s Dis eas es ,3 8 [9 ]:1 2 7 9 -1 2 8 6 .
Sp ellb erg,Brad,Rob ert Gu idos ,David Gilb ert,John Bradley,H elen W . Bou cher,
W . M ichaelScheld,John G. Bartlett and John Edw ards ,Jr. 2 0 0 8 . ‘
The ep idem ic
ofantib iotic-res is tant infections :a callto action for the m edicalcom m u nity
from the Infectiou s Dis eas es Society ofAm erica’,ClinicalInfectiou s Dis eas es ,
4 6 [2 ]:1 5 5 -1 6 4 .
Sp ellb erg,Brad and Bonnie Taylor-Blake. 2 0 1 3 . ‘
O n the ex oneration ofDr.
W illiam H . Stew art:deb u nking an u rb an legend’,Infectiou s Dis eas es ofPoverty,
2 [3 ][http ://w w w .ncb i.nlm .nih.gov/p m c/articles /PM C3 7 0 7 0 9 2 /].
T ängdén,Thom as . 2 0 1 4 . ‘
Com b ination antib iotic therap y for m u ltidru gres is tant Gram -negative b acteria’,U p s ala Jou rnalofM edicalSciences 1 1 9 (2 ):
1 4 9 –1 5 3 ,p u b lis hed online 1 9 M ay.
T ravis ,John. 1 9 9 4 . ‘
Reviving the Antib iotic M iracle?’Science,2 6 4 [N o. 5 1 5 7 ]
3 6 0 -6 2 ,Ap ril1 5 .
T u n,Kyaw M .,M allika Im w ong,et al. 2 0 1 5 . ‘
Sp read ofartem is inin-res is tant
Plas m odiu m falcip aru m in M yanm ar :a cros s -s ectionals u rvey ofthe K1 3
m arker’,Lancet Infectiou s Dis eas es 1 5 :4 1 5 -2 1
[http ://w w w .thelancet.com /jou rnals /laninf/article/PIIS14 7 3 -3 0 9 9 (1 5 )7 0 0 3 2 0 /ab s tract].
Vaidya,A. B. et al. 2 0 1 4 . ‘
Pyrazoleam ide com p ou nds are p otent antim alarials
+
that target N a hom eos tas is in intraerythrocytic Plas m odiu m falcip aru m ’.
N atu re Com m u nications .5 :5 5 2 1 .
Van Boeckel,Thom as P.,Charles Brow er,M ariu s Gilb ert,et al.2 0 1 5 . ‘
Glob al
trends in antim icrob ialu s e in food anim als ’,Proceedings ofthe N ational
Academ y ofSciences ,1 8 Feb ru ary
[w w w .p nas .org/cgi/doi/1 0 .1 0 7 3 /p nas .1 5 0 3 1 4 1 1 1 2 ].
Vijg,Jan. 2 0 1 1 . The Am erican TechnologicalChallenge:Stagnation and Decline
in the 2 1 s t Centu ry. N ew York:Algora Pu b lis hing.
W icks tröm Ö s tervall,Linnea. 2 0 1 4 . ‘
Es s ays on antib iotics u s e:N u dges ,
p references & w elfare b enefits ’,u np u b lis hed PhD dis s ertation,Stockholm
U nivers ity.
W iedenheft,Blake. 2 0 1 3 . ‘
In defens e ofp hageVirals u p p res s ors ofCRISPRm ediated adap tive im m u nity in b acteria’,RN A Biology 1 0 [5 ].
W H O . 2 0 1 3 . The U s e ofBedaq u iline in the Treatm ent ofM u ltidru g-res is tant
Tu b ercu los is ,Interim Policy Gu idance [availab le at:
38
http ://ap p s .w ho.int/iris /b its tream /1 0 6 6 5 /8 4 8 7 9 /1 /9 7 8 9 2 4 1 5 0 5 4 8 2 _eng.p df].
W oods ,Rob ert. 2 0 0 0 . The Dem ograp hy ofVictorian England and W ales .
Cam b ridge:Cam b ridge U nivers ity Pres s .
Yeam an,M ichaelR. Scott G. Filler,Siyang Chaili,Kevin Barr,et al. 2 0 1 4 .
‘
M echanis m s ofN DV-3 vaccine efficacy in M RSA s kin vers u s invas ive infection’.
Proceedings ofthe N ationalAcadem y ofSciences ;2 0 1 4 1 5 6 1 0 DO I:
1 0 .1 0 7 3 /p nas .1 4 1 5 6 1 0 1 1 1
You ngs ter,I.,G. H . Ru s s ell,C. Pindar,T. Zvi-Baran,J. Sau k,and E. L.
H ohm ann. 2 0 1 4 . ‘
O ral,cap s u lized,frozen fecalm icrob iota trans p lantation for
relap s ing Clos tridiu m difficile infection’. JAM A 3 1 2 [1 7 ]:1 7 7 2 -8 .
Zavas cki,Alex andre P.,Ju rgen B. Bu litta,Cornelia B. Landers dorfer. 2 0 1 3 .
‘
Com b ination Therap y for Carb ap enem res is tant Gram -negative Bacteria’,
Ex p ert Review ofAntiInfective Therap y 1 1 (1 2 ):1 3 3 3 -1 3 5 3 .
39
EN DN O TES:
1
T ex t w ith footnotes ofa p u b lic lectu re delivered at the U nivers ity ofW arw ick,
2 8 Ap ril2 0 1 5 . The com m ents ofSean Boyle,Kevin Denny,Alu n Evans ,M ark
H arris on,David M adden,JoelM okyr,Rafiq u e M ottiar,Lau rent Poirel,Patrick
W all,and Brendan W als h on earlier drafts is gratefu lly acknow ledged. Thanks
als o to RachelZetts (Pew Res earch)for data. Parts ofthe lectu re draw heavily
on joint w ork at CAGE w ith Rom ola Davenp ort and Kerry H icks on,b u t they are
not res p ons ib le for the op inions ex p res s ed here.
2
W oods 2 0 0 0 :3 5 0 -1 .
3
Com p are Cu tler,Deaton,and Lleras -M u ney 2 0 0 6 .
4
U N DP. H u m an Develop m ent Rep ort 2 0 1 4 . ‘
The H u m an Develop m ent Index
and its Com p onents ’[http ://hdr.u ndp .org/en/content/tab le-1 -hu m andevelop m ent-index -and-its -com p onents ].
5
Glob alH ealth Rep os itory [availab le at:
[http ://ap p s .w ho.int/gho/data/node.m ain.1 2 ?lang=eng]
6
From s tatem ent b y W H O director-generalM argaret Chan on W orld H ealth
Day 2 0 1 1
[http ://w w w .w ho.int/m ediacentre/new s /s tatem ents /2 0 1 1 /w hd_2 0 1 1 0 4 0 7 /en/].
Com p are Jam es Gallagher,‘
Analys is :Antib iotic ap ocalyp s e’,
BBCN ew s ,1 1 M arch 2 0 1 3 [http ://w w w .b b c.com /new s /health-2 1 7 0 2 6 4 7 ];Arju n
Srinivas an,“W e’ve reached ‘
The end ofantib iotics ,p eriod’”,PBSFrontline,2 2
O ctob er 2 0 1 3 [http ://w w w .p b s .org/w gb h/p ages /frontline/health-s ciencetechnology/hu nting-the-nightm are-b acteria/dr-arju n-s rinivas an-w eve-reachedthe-end-of-antib iotics -p eriod/]. Srinivas an is as s ociate director ofthe U .S.
Center for Dis eas e Control.
Poireland N ordm ann 2 0 0 6 ;N ordm ann et al. 2 0 1 2 ;Ryan et al.2 0 1 1 ;Johns on
and W oodford 2 0 1 3 .
7
8
Sarah Bos eley,“‘
N ew w ave ofs u p erb u gs p os es dire threat’,s ays chiefm edical
officer”,Gu ardian,1 1 M arch 2 0 1 3 ;Peter Dom iniczak,“Su p erb u gs cou ld 'cas t the
w orld b ack into the dark ages ',David Cam eron s ays ”,Daily Telegrap h,1 Ju ly
2 0 14 .
9
Slack 1 9 8 5 .
10
See The BCG W orld Atlas :a Datab as e ofGlob alBCG Vaccination Policies and
Practices [http ://w w w .b cgatlas .org/index .p hp ].
11
M angtaniet al.,2 0 1 4 .
40
On the b as is ofdata on am p u tations in the era b efore antib iotics ,Sm ith and
Coas t (2 0 1 3 )reckon that w ithou t antib iotics the infection rate cou ld hit 4 0 -5 0
p er cent and that 3 0 p er cent ofthos e infected w ou ld not s u rvive.
12
13
T he coefficient ofvariation oflife ex p ectancy at b irth acros s the glob e has
fallen b y alm os t halfs ince the 1 9 5 0 s .
14
Dys on and Das Gu p ta (2 0 0 1 )have attrib u ted thes e im p rovem ents ,w hich date
from the 1 9 2 0 s ,to colonialp olicies that im p roved food dis trib u tion,m onitored
p lagu e ou tb reaks and increas ed s m allp ox vaccination coverage.
15
Livi-Bacci,2 0 0 1 ;Riley 2 0 0 1 ;Caldw ell,1 9 8 6 .
16
For data on life ex p ectancy s ee
http ://w w w .gap m inder.org/data/docu m entation/gd0 0 4 /.
17
For data on p rices s ee http ://w w w .avert.org/antiretroviral-dru g-p rices .htm ;
W H O ,Trans action Prices for AntiretroviralM edicines from 2 0 1 0 to 2 0 1 3 :Glob al
Price Rep orting M echanis m
[http ://ap p s .w ho.int/iris /b its tream /1 0 6 6 5 /1 0 4 4 5 1 /1 /9 7 8 9 2 4 1 5 0 6 7 5 5 _eng.p df?u a=
1 ].
18
RAN D 2 0 1 4 ;KPM G 2 0 1 4 ;com p are Sm ith and Coas t 2 0 1 2 ,2 0 1 3 .
19
Cited in e.g. Jon Gertner,‘
The ris e and fallofthe GDP,’N ew York Tim es ,3 0
M ay 2 0 1 0 .
2 0
E.g. Kelley 1 9 9 1 ;Srinivas an 1 9 9 4 ;Ravallion 1 9 9 7 ,2 0 1 2 . For a review of
critiq u es ofH DIs ee Kovacevic 2 0 1 0 .
2 1
E.g. Cos ta and Steckel1 9 9 7 ;Crafts 2 0 0 2 ;Prados de la Es cos u ra 2 0 1 3 .
2 2
T he health com p onent has alw ays b een p rox ied b y the gap b etw een actu al
and m ax im u m achievab le life ex p ectancy at b irth. The incom e index u s es the
gap b etw een the log valu es ofactu alincom e and a m ax im u m cu rrently cap p ed
at $7 5 ,0 0 0 . The edu cation index originally com b ined inform ation b oth on
literacy and s choolattendance,b u t in recent years u s es data on actu al
attendance rates relative to anticip ated fu tu re attendance rates .
2 3
It m ight b e added that one criticis m m ade ofH DIis the relatively low valu e it
im p licitly p laces on gains to life ex p ectancy.
2 4
An es tim ate ofthe valu e ofa s tatis ticallife in Cou ntry C in year t m ay b e
ob tained b y calcu lating (O ECD 2 0 1 2 ):
VSLC,t = [VSLU S,2 0 1 0 ][YC,t/YU S,2 0 1 0 ]η
w here Y is GDP,VSLU S,2 0 1 0 and YU S,2 0 1 0 refer to p res ent-day U Svalu es and η is
the incom e elas ticity ofdem and for s taying alive. PPP-adju s ted U S$ es tim ates
41
ofYC,t m ay b e ob tained from the Penn W orld tab les or (for the p re-1 9 5 0 p eriod)
Angu s M addis on’s his toricalnationalaccou nts es tim ates .
2 5
H am m itt and Rob ins on 2 0 1 1 :2 1 ;Leon and M igu el2 0 1 3 ;b u t s ee too W ang and
H e 2 0 1 0 . M iller (2 0 0 0 )recom m ends η=1 as the ‘
b es t es tim ate’and a recent
O ECD rep ort (2 0 1 2 )recom m ends η=0 .8 ,w hile H am m itt and Rob ins on (2 0 1 1 )
advis e analys ts not to rely on a s ingle valu e b u t to rep ort ou tcom es u s ing a
range ofes tim ates ofη.
2 6
T hes e res u lts are fu lly ex p lained in Davenp ort et al. 2 0 1 4 .
2 7
GDPp er head in GB (inclu ding Ireland)in 1 6 5 0 w as $9 2 5 (1 9 9 0 international
GK dollars ):M addis on Project datab as e.
2 8
U s ing the form u la in fn2 4 .
W illiam Farr noted the low er m ortality from cholera in thos e w ho lived on
higher grou nd. H e w as w ellaw are that w ater does not flow u p hillb u t dis m is s ed
the role ofw ater in favou r ofthos e w ho live higher u p b eing fitter!Iam gratefu l
to Alu n Evans for this p oint.
29
3 0
Dob s on 1 9 9 7 :3 5 8 -5 9 .
31
For a detailed accou nt s ee Dav enp ort et al.(20 1 4 :fn1 5).
3 2
T hes e q u otes are taken from So et al.2 0 1 0 ;Infectiou s Dis eas es Society of
Am erica 2 0 1 3 . See als o EzekielEm anu el,‘
H ow to develop new antib iotics ’,N ew
York Tim es ,2 4 Feb ru ary 2 0 1 5 .
3 3
See e.g. Travis 1 9 9 4 ;H ancock 1 9 9 7 ;Sp ellb erg et al. 2 0 0 4 ;Sp ellb erg et al.
2 0 0 8 .
3 4
InternationalFederation ofPharm aceu ticalM anu factu rers and As s ociations ,
‘
IFPM A Pos ition on Antim icrob ialRes is tance’,7 Ap ril2 0 1 1
[http ://w w w .ifp m a.org/fileadm in/content/Innovation/AntiM icrob ical% 2 0 Res is tance/IFPM A_Pos ition_on_Antim icrob ial_Res is tance_N ew
Logo2 0 1 3 .p df]. See too As s ociation ofthe Britis h Pharm aceu ticalIndu s try
[ABPI],AM R:An U rgent N eed for Econom ic Incentives in a N ew Econom ic
M odel:Princip les to Cons ider;and O ffice ofH ealth Econom ics [O H E],‘
N ew
Bu s ines s M odels for Antib iotics . W hat Can W e Learn from O ther Indu s tries ?’,7
Ap ril2 0 1 5 [http s ://w w w .ohe.org/new s /new -b u s ines s -m odels -antib iotics -w hatcan-w e-learn-other-indu s tries ]. O H E is an affiliate ofABPI.
35
E.g. M okyr 2 0 1 3 ,2 0 1 4 . Com p are Vijg 2 0 1 1 .
3 6
Iow e this p oint to JoelM okyr.
3 7
‘
Battling s u p erb u gs :tw o new technologies cou ld enab le novels trategies for
com b ating dru g-res is tant b acteria’,M IT N ew s ,2 1 Sep tem b er 2 0 1 4
42
[http ://new s office.m it.edu /2 0 1 4 /fighting-dru g-res is tant-b acteria-0 9 2 1 ];M ichael
Eyre,‘
N ovelantib iotic clas s created’,BBC N ew s H ealth,2 4 Sep tem b er 2 0 1 4
[http ://w w w .b b c.com /new s /health-2 9 3 0 6 8 0 7 ];Balcazar 2 0 1 4 ;W iedenheft 2 0 1 3 ;
The Econom is t,‘
Strange m edicine:a w ay to treat b acterialinfections w ith
artificialviru s es ’,2 8 Feb ru ary 2 0 1 5 ;Jenny Rood,‘
CRISPRchain reaction:a
p ow erfu lnew CRISPR/Cas 9 toolcan b e u s ed to p rodu ce hom ozygou s
m u tations w ithin a generation,b u t s cientis ts callfor cau tion’,The Scientis t,
M arch 1 9 ,2 0 1 5 .
3 8
M okyr 2 0 1 4 .
3 9
M azzu cato and Dos i2 0 0 6 ;M azzu cato 2 0 1 3 . Com p are Brogan and M os s ialos
2 0 1 3 ;N IH Directors Blog,‘
N ew s trategies in b attle agains t antib iotic res is tance’,
1 8 Sep tem b er 2 0 1 4 [http ://directors b log.nih.gov/2 0 1 4 /0 9 /1 8 /new -s trategies -inb attle-agains t-antib iotic-res is tance/].
4 0
The Econom is t,‘
Invent it,s w ap it or b u y it:w hy cons tant dealm aking am ong
dru gm akers is inevitab le’,1 5 N ovem b er 2 0 1 4 ;The Econom is t,‘
Dru g res earch:all
together now ,charities help Big Pharm a’,2 1 Ap ril2 0 1 2 . Ex am p les inclu de
Am gen’s p u rchas e ofO nyx (w hich had develop ed a p rom is ing cancer dru g)in
Au gu s t 2 0 1 3 ;Actavis ’s acq u is ition ofDu rata,O ctob er 2 0 1 4 ;M erck’s acq u is ition
ofCu b is t,Decem b er 2 0 1 4 ;Sanofi-Aventis ’s licens ing ofthe s em i-s ynthetic
artem is inin develop ed b y Am yris Technologies in 2 0 0 8 . According a s ou rce
cited b y the W allStreet Jou rnal(‘
Dru gm akers tip toe b ack into antib iotics R& D’,
2 3 Janu ary 2 0 1 4 )‘
s m alland m ediu m -s ize com p anies are now res p ons ib le for
7 3 % ofantib iotics in develop m ent’.
4 1
Pew Charitab le Tru s ts ,‘
Antib iotics Cu rrently in ClinicalDevelop m ent
Decem b er 3 1 ,2 0 1 4 ’[http ://w w w .p ew tru s ts .org/en/m u ltim edia/datavis u alizations /2 0 1 4 /antib iotics -cu rrently-in-clinical-develop m ent];Center
W atch,‘
FDA ap p roved dru gs ’[http ://w w w .centerw atch.com /dru ginform ation/fda-ap p roved-dru gs /year/2 0 1 5 ].
CDC:http ://w w w .cdc.gov /dru gres is tance/b igges t_threats .htm l,1 6 Sep tem b er
20 1 3 .
42
4 3
BBCN ew s ,‘
1 ,0 0 0 -year-old onion and garlic eye rem edy kills M RSA’,3 0 M arch
2 0 1 5 [http ://w w w .b b c.com /new s /u k-england-nottingham s hire-3 2 1 1 7 8 1 5 ];
Jonathan O w en,‘
A new (old)cu re for M RSA? Revolting recip e from the Dark
Ages m ay b e key to defeat infection’,The Indep endent,3 1 M arch 2 0 1 5 .
4 4
E.P. Vantage,‘
U p com ing events :Dalvance data and U Sdecis ions for
Lynp arza and Zerb ax a’,1 2 Decem b er 2 0 1 4
[http ://w w w .ep vantage.com /U nivers al/View .as p x ?typ e=Story& id=5 4 7 1 4 4 & is EP
Vantage=yes ]. The dru gs are ex p ens ive [s ee:
http ://w w w .p odiatrytoday.com /b logged/key-cons iderations -cos ts -and-u s edalb avancin-and-oritavancin].
43
4 5
Ling et al. 2 0 1 5 ;Ju dy Stone,‘
Teix ob actin And iChip Prom is e H op e Agains t
Antib iotic Res is tance’,Forb es ,8 Janu ary 2 0 1 5
[http ://w w w .forb es .com /s ites /ju dys tone/2 0 1 5 /0 1 /0 8 /teix ob actin-and-ichip p rom is e-hop e-agains t-antib iotic-res is tance/];Ed Yong,‘
A N ew Antib iotic That
Res is ts Res is tance’,N ationalGeograp hic,7 Janu ary 2 0 1 5
[http ://p henom ena.nationalgeograp hic.com /2 0 1 5 /0 1 /0 7 /antib iotic-res is tanceteix ob actin/].
4 6
Derived from data in W H O Glob alH ealth O b s ervatory Data Rep os itory.
4 7
Com p are Tu n et al. 2 0 1 5 . The nu m b er ofrep orted cas es is given only from
2 0 0 0 on,s ince the data for the 1 9 9 0 s s eem very s u s p ect. Given the s igm oid
s hap e ofthe res is tance tim e-p ath,it w ou ld b e foolhardy to b as e p olicy on s u ch
data.
4 8
Path M alaria Vaccine Initiative [http ://w w w .M alariaVaccine.org/];RTS,S
ClinicalTrials Partners hip 2 0 1 5 .
4 9
W H O 2 0 1 3 ;W H O 2 0 1 5 (‘
Freq u ently as ked q u es tions on b edaq u iline’:
http ://w w w .w ho.int/tb /challenges /m dr/b edaq u ilinefaq s /en/).
5 0
‘
Bedaq u iline for m u ltidru g-res is tant tu b ercu los is ’. Dru g and Therap eu tics
Bu lletin 2 0 1 4 ,5 2 [1 1 ]:1 2 9 -1 3 2
[http ://dtb .b m j.com /content/5 2 /1 1 /1 2 9 .fu ll.p df+htm l];‘
Verap am ilincreas es
anti-tu b ercu los is activity ofb edaq u iline’,Pharm aceu ticalJou rnal,1 7 Janu ary
2 0 1 5 ,2 9 4 [7 8 4 5 ].
5 1
Cru s io et al. 2 0 1 4 ;Du b rovs kaya et al.2 0 1 3 ;Qu res hiet al. 2 0 1 5 . Cru s io et al.
(2 0 1 4 )find that m ortality linked to carb ap enem -res is tant Gram -negative
b acteria (CRGN B)affects the elderly is related to age,s everity ofm edical
condition,and ex tent ofp reviou s antib iotic ex p os u re. Pau let al. (2 0 1 4 )
q u es tion the effectivenes s ofcarb ap enem -colis tin com b ination therap ies .
Colis tin is ineffective agains t Proteu s and Serratia s p p .,and increas ingly s o
agains t Acinob acter b au m annii.
Com p are Tängdén 2 0 1 4 ;Diet al. 2 0 1 5 .
52
Dortet et al. 2 0 1 4 .
5 3
‘
N ationalCenter for H ealth Res earch,‘
Letter to FDA Com m is s ioner H am b u rg
on N ew Antib iotic Produ ct (CAZ-AVI)’,1 9 Decem b er 2 0 1 4
[http ://center4 res earch.org/p u b lic-p olicy/letters -to-governm entofficials /letter-to-fda-com m is s ioner-ham b u rg-on-new -antib iotic-p rodu ct-cazavi/];FDA,‘
FDA ap p roves new antib acterialdru g Avycaz’,2 5 Feb ru ary 2 0 1 5
[http ://w w w .fda.gov/N ew s Events /N ew s room /Pres s Annou ncem ents /u cm 4 3 5 6 2
9 .htm ].
44
5 4
Pres entation b y Joyce Su tcliffe ofTetrap has e Pharm aceu ticals
[http ://w w w .tu fts .edu /m ed/ap u a/p ractitioners /res ou rces _2 3 _2 8 1 7 9 8 0 0 1 3 .p df].
5 5
‘
M ore m u s t b e done to cu t u nneces s ary antib iotic p res crip tions ,s ay ex p erts ’,
The Gu ardian,5 Au gu s t 2 0 1 4 . Com p are Blom m aert et al. 2 0 1 3 ;Plachou ras et al.
2 0 0 8 .
5 6
ECDC:Qu ality indicators for antib iotic cons u m p tion in the com m u nity
(p rim ary care s ector)in Eu rop e 2 0 1 2
(http ://ecdc.eu rop a.eu /en/healthtop ics /antim icrob ial_res is tance/es ac-netdatab as e/Pages /q u ality-indicators -p rim ary-care.as p x ).
5 7
Data in Sab u ncu et al. (2 0 0 9 :4 )im p ly that redu cing cons u m p tion in the res t
ofFrance to levels fou nd in the low es t q u artile ofregions w ou ld cu t the
aggregate intake b y 1 5 -2 0 p er cent.
5 8
Figu re 3 a rep orts trends in M RSA in a cros s -s ection ofEu rop ean cou ntries
s ince 2 0 0 0 . N ote the very low rates ofM RSA in the N etherlands and very high
rates in Greece and Italy,and the s ignificant drop in res is tance rates in Ireland
and the U K,in p articu lar. Figu re 3 b des crib es the trends in E.colires is tance to
flu oroq u inolones in the s am e s et ofcou ntries ;again Greece and Italy p erform
rather p oorly relative to others . Figu re 3 c p lots the relations hip b etw een
cons u m p tion and M RSA in 2 0 1 2 (com p are Blom m aert et al. 2 0 1 3 ,Tab le 3 ).
5 9
Com p are Sads ad et al. ‘
Effectivenes s ofhos p ital-w ide M ethicillin-Res is tant
Stap hylococcu s au reu s (M RSA)infection controlp olicies ’.
6 0
Dam e Sally Davies ,cited in Anne Gu lland,‘
Antim icrob ialres is tance w ill
s u rge u nles s u s e ofantib iotics in anim alfeed is redu ced’,BM J,3 4 7 ,7 O ctob er
2 0 1 3 ;FDA,‘
FDA's Strategy on Antim icrob ialRes is tance’,2 8 M arch 2 0 1 4
[http ://w w w .fda.gov/Anim alVeterinary/Gu idanceCom p lianceEnforcem ent/Gu i
danceforIndu s try/u cm 2 1 6 9 3 9 .htm ];Van Boeckelet al. 2 0 1 5 . In 2 0 1 1 in the U S
3 .2 9 m illion kilogram s ofdru gs w ere s old for hu m an cons u m p tion,w hereas
1 3 .7 7 m illion kilogram s ofantib iotics w ere ap p roved for u s e in food-p rodu cing
anim als . Betw een 2 0 0 9 and 2 0 1 2 the totalfor anim alu s e ros e from 1 2 .8 m illion
kilogram s to 1 4 .7 m illion kilogram s . The figu re for hu m an cons u m p tion
ex clu des w hat w as adm inis tered directly [U nited States Food and Dru g
Adm inis tration,
http ://w w w .fda.gov/Dru gs /Dru gSafety/Inform ationb yDru gClas s /u cm 2 6 1 1 6 0 .htm ;
http ://w w w .fda.gov/ForIndu s try/U s erFees /Anim alDru gU s erFeeActADU FA/u cm
0 4 2 8 9 6 .htm ].
6 1
BBCN ew s Science and Environm ent,‘
Scientis ts p rodu ce dis eas e-res is tant
cow s ’,3 M arch 2 0 1 5 [http ://w w w .b b c.com /new s /s cience-environm ent3 1 7 0 9 1 0 7 ].
62
Sab u ncu et al. 2 0 0 9 .
45
Sab u ncu et al. 2 0 0 9 ;M eeker et al.2 0 1 4 ;W icks tröm Ö s tervall2 0 1 4 ;Goos ens et
al. 2 0 0 8 .
63
64
Linder et al.,‘
Tim e ofDay and the Decis ion to Pres crib e Antib iotics ’.
6 5
Com p are Sm itha M u ndas ad,‘
Rap id b lood tes t to cu t antib ioticu s e’,BBCN ew s
health,1 9 M arch 2 0 1 5 [http ://w w w .b b c.com /new s /health-3 1 9 4 1 5 3 8 ].
66
Richards on,‘Alternating antib iotics ’.
6 7
N ew Yorker,‘
The ex crem ent ex p erim ent:treating dis eas e w ith fecal
trans p lants ’,1 Decem b er 2 0 1 4 ;BBC N ew s M agazine,‘
The b rave new w orld of
DIY faecaltrans p lant’,2 6 M ay 2 0 1 4 [http ://w w w .b b c.com /new s /m agazine2 7 5 0 3 6 6 0 ].
6 8
Res is tant b acteria agains t w hich,s o far,no rep lacem ent dru g has b een
annou nced or p rom is ed inclu de Enterotox igenic E.coli(ETEC). In this cas e
res is tance rates have ris en from near zero at the tu rn ofthe centu ry to 1 0 -1 5 p er
cent acros s Eu rop e today (and m u ch higher in Italy). Althou gh ETEC infections
are rarely life threatening,the lack ofrep lacem ent antib iotics m akes it
im p erative to focu s on any s econd-b es t s olu tions availab le. It has b een
s u gges ted that recent findings on the genetic com p os ition ofE.colib acteria
cou ld op en the w ay for vaccines cap ab le ofp reventing infection glob ally. See
‘
Large-s cale s tu dy rais es hop es for develop m ent ofE.colivaccine’,1 0 N ovem b er
2 0 1 4 [http ://w w w .s anger.ac.u k/ab ou t/p res s /2 0 1 4 /1 4 1 1 1 0 .htm l]. Bu t given that E.
coliis a com m ens alorganis m w ides p read in hu m ans ,anim als ,and the
environm ent,it is not clear how a vaccine cou ld com b at s u ch a p athogen.
6 9
Alex ander Flem ing,‘
Penicillin’
[http ://w w w .nob elp rize.org/nob el_p rizes /m edicine/lau reates /1 9 4 5 /flem inglectu re.p df].
7 0
By ex tending the p atent life ofantib iotics that treat s eriou s or lifethreatening infections ,the U .S. GAIN Act s eeks to energize Big Pharm a
(althou gh this entails w elfare cos ts too).
7 1
PBSFrontline,‘
O b am a Bu dget W ou ld Dou b le FederalSp ending to Fight
Su p erb u gs ’,2 7 Janu ary 2 0 1 5 [http ://w w w .p b s .org/w gb h/p ages /frontline/healths cience-technology/hu nting-the-nightm are-b acteria/ob am a-b u dget-w ou lddou b le-federal-s p ending-to-fight-s u p erb u gs /].
7 2
BBCN ew s H ealth,‘
Eb ola:the race for dru gs and vaccines ’,2 4 Feb ru ary 2 0 1 5
[http ://w w w .b b c.com /new s /health-2 8 6 6 3 2 1 7 ].
7 3
‘
W H O aim s for Eb ola s eru m in w eeks and vaccine tes ts in Africa b y Janu ary’,
Gu ardian,2 2 O ctob er 2 0 1 4 .
7 4
As w ith Perdu e Chicken and M cDonalds in the U S,for ex am p le.
46
7 5
EU Com m is s ion Res earch and Innovation,‘
Eu rop ean Com m is s ion lau nches
€ 1 m p rize for a diagnos tic tes t to com b at antib iotic res is tance’,2 5 Feb ru ary 2 0 1 5
[http ://ec.eu rop a.eu /res earch/index .cfm ?p g=new s alert& year=2 0 1 5 & na=na2 6 0 2 1 5 ].
47