resistensi antibiotika
TRANSCRIPT
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Lecture 19
Evolution of antimicrobial
resistance
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Today:Today:
1. History of antimicrobials
2. Evolution of antimicrobial resistance:
“natural” selection in action
3. Were not necessarily !oin! to "ell in a
"andbas#et $it" res%ect to resistance
&. T"en a!ain' maybe $e are(
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Brief history of antimicrobialsBrief history of antimicrobials
• )ntimicrobials are “ma!ic bullets” sensu
E"rlic"
• *irst modern antimicrobial $as Salvarsan'
an arsenic+based ma!ic bullet discovered
by t"e ,erman infectious disease s%ecialist
-aul E"rlic". sed to treat sy%"ilis
• /uinine became $idely used as an
antimalarial after it $as isolated in 102
from t"e bar# of t"e cinc"ona tree
• ulfonamides $ere introduced in t"e
193s. T"ey are synt"etic antimicrobials
t"at bloc# folic acid %roduction in bacteria
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Brief history of antimicrobialsBrief history of antimicrobials
• T"e first antibiotic in t"e ori!inal sense
of t"e $ord4 $as penicillin
• T"e term “antibiotic” ori!inally $as used
to denote formulations derived from livin!
or!anisms but is no$ used for %artially or
$"olly synt"etic antimicrobials too
• T"e *renc" %"ysician Ernest 5uc"esne
first noted t"at certain moulds #ill
bacteria' but "is $or# $as for!otten
• )le6ander *lemin! rediscovered t"at
Penicillium #ills bacteria in 1920
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Brief history of antimicrobialsBrief history of antimicrobials
•
*lemin! $as convinced t"at t"eobservation could never lead to
t"era%eutic a!ents
• *lorey and 7"ain resurrected t"e $or#'
isolated %enicillin' and by WW88 $ere
treatin! millions $it" antibiotics
• T"e a!e of antibiotics c"an!ed t"e
landsca%e of modern medicine and
antibiotics are one of t"e #ey medical
interventions t"at "ave im%acted "uman"ealt"
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Evolution of resistanceEvolution of resistance
•
*or "umans' antibiotics are lifesavin! dru!s forbacteria' t"ey are %o$erful a!ents of selection
• W"en a%%lied to a %o%ulation of bacteria' an antibiotic
uic#ly sorts out t"e resistant individuals from t"e
susce%tible ones
• )n evolutionary %ers%ective su!!ests t"ese dru!s
s"ould be used ;udiciously ot"er$ise' t"ese miracle
dru!s may undermine t"eir o$n success
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Evolution of resistanceEvolution of resistance
•
T"ere are do<ens of antibiotics and do<ens ofmolecular mec"anisms $"ereby bacteria can become
resistant
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Evolution of resistanceEvolution of resistance
• Mycobacterium tuberculosis
%rovides an e6am%le
• 8sonia<id %oisons bacteria by
interferin! $it" com%onents of
t"e cell $all.
• =efore it can do so' "o$ever' it
must be converted into an active
form by t"e !ene KatG
• >utations in KatG t"at reduce or
eliminate its activity render
bacteria tolerent to isonia<ids
effects
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Evolution of resistanceEvolution of resistance
• ?t"er mec"anisms involve !ains of function
• >any e6trac"romosomal elements of bacteria' li#e
%lasmids and trans%osons' carry !enes conferrin!
resistance to one or more antibiotics
• T"e %lasmids Tn3' for e6am%le' found in E. coli '
contains a !ene called bla
• T"is !ene encodes an en<yme' @+lactamase' t"at
brea#s do$n t"e en<yme am%icillin
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Evidence that antibiotics select forEvidence that antibiotics select for
resistant bacteriaresistant bacteria
•
Evidence comes from a variety of studies acrossmany scales
• ?n t"e smallest scale' William =is"ai and
collea!ues monitored an )85 %atient $it"
tuberculosis
• %on dia!nosis' t"ey cultured bacteria and found
t"em sensitive to a variety of antibiotics includin!
rifam%in
• Treated $it" rifam%in
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Evidence that antibiotics select forEvidence that antibiotics select for
resistant bacteriaresistant bacteria
•
Tuberculosis became undetectable
• -atient rela%sed and died' $it" resur!ence of
tuberculosis
• =acteria $ere resistant to tuberculosis' $it"
seuencin! indicatin! a sin!le %oint mutation $as to
blame' and t"at t"e mutation "ad arisen in t"at
%atient
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Evidence that antibiotics select forEvidence that antibiotics select for
resistant bacteriaresistant bacteria
•
?n a lar!er scale' researc"ers can com%are t"eincidence of susce%tible versus resistant bacterial
strains in ne$ly dia!nosed' untreated %atients
versus t"ose $"o "ave rela%sed after treatment
• 8f antibiotics select for dru! resistance' e6%ect a
"i!"er fraction of rela%sed %atients $it" resistant
bacteria
• ?ne study on resistance to isonia<id in tuberculosis%atients s"o$ed 0.2A of ne$ cases to carry
resistant bacteria versus 21.BA of rela%sed cases
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Evidence that antibiotics select forEvidence that antibiotics select for
resistant bacteriaresistant bacteria
•
?n t"e lar!est scale' researc"ers can evaluate t"erelations"i% over time bet$een t"e fraction of
%atients $it" resistant bacteria and t"e society$ide
level of antibiotic use:
Frequency of penicillin
resistance among
Pneumococcus bacteria
in Icelandic children as a
function of time.
Austin et al. (1999)
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• 5ata on %enicillin resistance in Pseudomonas $as
%lotted for #ids in 8celand.
• 8n t"e late 190s and early 199s resistance rosedramatically
• -ublic "ealt" aut"orities cam%ai!ned a!ainst
%enicillin overuse startin! in 1992' consum%tion
dro%%ed
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Evaluating the costs of resistance toEvaluating the costs of resistance to
bacteriabacteria
• W"y do you t"in# %enicillin resistance dro%%edC
• W"y $ould t"ere be costsC
• W"at is t"e %rediction if t"ere are costsC
• W"at if all susce%tible variants are $i%ed out
various scales4C
• W"en mi!"t costs fail to %ersistC
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Schrag, Perrot, and
Levin (1997), Proc.
Roy. Soc.
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•Stephanie Schrag and colleagues (1997) investigated whether
costs in E. coli of resistance to streptomycin can disappear over
time
•Screened for SM resistant mutants
•SM interferes with protein synthesis by binding to rpsL gene
product
•Point mutations in rpsL can render them resistant
•In one experiment, resistant strains were restored to wild-type
by splicing in a normal rpsL gene
•If resistance comes with a cost, what should happen when the
resistant strains compete with sensitive strains in culture?
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•What happens if you give resistant strains a long time to evolve,
then do the same competition experiment?
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The rise and fall of resistanceThe rise and fall of resistance
• )%%earance and !ro$t" of antimicrobial resistance
reuires several ste%s
• T"e rate of s%read of resistance de%ends on t"e
rate at $"ic" t"ese ste%s are accom%lis"ed
• *irst' resistance must be !enetically and
%"ysiolo!ically %ossible e.!. T=' vancomycin
resistant Enterococcus, !rou% ) stre%tococcus4
• ) second ste% reuired for many clinically im%ortant
resistance mec"anisms is transfer of !enes from
anot"er bacterial s%ecies can be rare or common4
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The rise and fall of resistanceThe rise and fall of resistance
• T"ird' for t"e %revalence of resistance to s%read in
t"e "ost %o%ulation i.e. ne$ "osts !et resistant
strains4 resistant %at"o!en must coloni<e ne$ "osts
• T"e rate at $"ic" t"is occurs %lays a #ey role in
determinin! t"e timescale on $"ic" resistance
s%reads
• *or bacteria t"at coloni<e "os%itali<ed %atients' t"is
can occur on a scale of days' or less' via
transmission by "ealt"care $or#ers orenvironmental contamination' resultin! in e6%losive
outbrea#s of resistant bacteria cf HD' s%read and
!eneration time4
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The rise and fall of resistanceThe rise and fall of resistance
• *inally' resistance often substantially im%airs t"e
!ro$t" rate or transmissibility of some %at"o!ens'
t"ereby limitin! t"e ability of resistant infections to
s%read evolutionary cost4
• 5ifferent rates of com%ensatory evolution $ill t"us
"el% determine t"e rise and fall of resistance
• 5ifferent %at"o!enantimicrobial combinations $ill
ac"ieve and reverse t"ese ste%s at different rates'
so t"ere is not one sin!le %attern of resistanceevolution t"at can be a%%lied universally
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Antiviral resistance Antiviral resistance
• T"ere are several antiviral dru!s available' and as
$it" bacteria' t"e selective %ressure e6erted by t"e
antimicrobial can lead to resistance
• Well loo# in detail at t"e evolution of resistance to
)FT in H8D
• *irst lets loo# at influen<a and HD
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Antiviral resistance Antiviral resistance
• ) model of t"e use of amantadine and rimantadine
durin! and influen<a e%idemic %redicted tat
substantial levels of resistance $ould arise $it"in
$ee#s of $ides%read antiviral use
• !"#
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Antiviral resistance Antiviral resistance
• Hi!" %robability of initial emer!ence of resistance
3A in a treated "ost4
• Gesistant forms are "i!"ly transmissible
• "ort !eneration time days4
• Hi!" efficacy stron! selection for resistance
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Antiviral resistance Antiviral resistance
• imilar studies of resistance to nucleoside analo!s
in HD+1 and +2 %redict t"at it $ould ta#e decades
or lon!er for resistance to !et to even a fe$ %ercent
• !"#
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Antiviral resistance Antiviral resistance
• Lo$ %robability of initial emer!ence of resistance +
.2A in a treated "ost4
• Gesistant forms "ave reduced transmissibility
• Lon! !eneration time years4
• Lo$ efficacy $ea# selection for resistance
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Antiviral resistance Antiviral resistance
• W"y does )FT $or# in t"e s"ort run' a!ainst H8D'
but fail in t"e lon! runC
• )FT a<idot"ymidine
• Iote t"e thymidine: its a nucleoside analo!ue t"at
tric#s t"e viruss reverse transcri%tase
• GT uses nucleotides from "ost cell to build a 5I)
strand com%lementary to t"e viral !enomic GI)
• )FT mimics a normal nucleotide $ell enou!" to fool
GT' but lac# t"e attac"ment site for t"e ne6t
nucleotide in t"e c"ain
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Antiviral resistance$ !%& and A'T Antiviral resistance$ !%& and A'T
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Antiviral resistance Antiviral resistance
• Ho$ mi!"t )FT lose its effectivenessC
• +lessen viral GTs affinity for )FT
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Antiviral resistance$ !%& and A'T Antiviral resistance$ !%& and A'T
A ti i l i t !%& d A'T
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Antiviral resistance$ !%& and A'T Antiviral resistance$ !%& and A'T
A ti i l i t !%& d A'T
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Antiviral resistance$ !%& and A'T Antiviral resistance$ !%& and A'T
A ti i l i t !%& d A'TA ti i l i t !%& d A'T
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Antiviral resistance$ !%& and A'T Antiviral resistance$ !%& and A'T
A ti i l i tA ti i l i t
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Antiviral resistance Antiviral resistance
• ?n $"at time scale does resistance ariseC
• W"at "a%%ens $"en )FT treatment sto%sC
• W"at could you do to reduce t"e c"ances of
resistance to )FT arisin!C
h t d i l t fi hth t d i l t fi ht
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#Infections caused by resistant bacteria can strike anyone—the young and the old, the
healthy and the chronically ill. Antibiotic resistance also is a serious problem for patientswhose immune systems are compromised, such as people with HIV/AID and patients incritical care units.
! About " million people ac#uire bacterial infections in $.. hospitals each year,and %&,&&& die as a result. About '& percent of those infections are resistant to at leastone drug, according to the (enters for Disease (ontrol and )re*ention.
! +he total cost of antimicrobial resistance to $.. society is nearly - billionannually, according to the Institute of edicine I01. +reating resistant pathogens oftenre#uires more e2pensi*e drugs and e2tended hospital stays.
! I0 and federal agencies ha*e identified antibiotic resistance and the dearth
of antibiotic 34D as increasing threats to public health.
! Staphylococcus aureusstaph1 is a common cause of hospital infections thatcan spread to the heart, bones, lungs, and bloodstream with fatal results. In "&&", -'.5percent an estimated 5&",&&& cases1 of the staph bacteria found in $.. hospitals weremethicillin6resistant 3A1, according to (D(.
h t d i l t fi hth t d i l t fi ht
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
! Although 3A used to be limited primarily to hospital patients, it isbecoming increasingly common in the broader community. A study of children withcommunity6ac#uired staph infections at the $ni*ersity of +e2as found nearly '& percentinfected with 3A. In a "&&" outbreak, "7- 3A infections were reported amongmilitary recruits at a training facility in the southeastern $nited tates. In addition,5",&&& cases of community6ac#uired 3A were found in three correctional facilities in8eorgia, (alifornia, and +e2as between "&&5 and "&&7.
! ince "&&&, (D( has reported outbreaks of 3A among athletes, includingcollege football players in )ennsyl*ania, wrestlers in Indiana, and a fencing club in(olorado. In eptember of "&&7, this issue was brought to national attention when 3Abroke out in 9lorida among the iami Dolphins, sending two players to the hospital fortreatment.
h t d i l t fi hth t d i l t fi ht
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#! Vancomycin6resistant enterococci V3:1 can cause wound infections,
infections in blood, the urinary tract and heart, and life6threatening infections forhospital patients. In "&&", "'.- percent an estimated ";,&&& cases1 of testedenterococci samples from I($s were resistant to *ancomycin, according to (D(.
! +he percentage of Pseudomonas aeruginosa bacteria resistant to eitherciproflo2acin or oflo2acin, two common antibiotics of the fluoro#uinolone class 9<3)1,has increased dramatically. 3ecent (D( data show that in "&&", nearly 77 percent of
tested samples from I($s were resistant to fluoro#uinolones. P. aeruginosa causesinfections of the urinary tract, lungs, and wounds and other infections commonly foundin intensi*e care units.
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h t d i l t fi hthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
• Economic c"an!es
• Ge!ulatory c"an!es
•
cientific c"an!es
?ct 21 2& issue of )ature
hat can e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Economic changes
• 5emand for bloc#busters for
c"ronic disease
•
=road s%ectrum antibiotics $ider mar#et
• -ressure to s%are use as
resistance increases bad
investment
• -rofits restrained in medical
arena' %"arma sends about "alf
of out%ut to food industry
hat can (e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Economic changes
• 8ts not ;ust t"at antibiotics are
"ard to develo%' its t"at muc"
less effort is !oin! into
develo%ment
• Ieed a not+for+%rofit dru!
com%any
• “%roblems $ill be easier to
mana!e t"an as#inf 21st century
societies to acce%t 19t" century
deat" rates from infection.”
hat can (e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Regulatory changes
• 7urrent re!ulations discriminate
a!ainst develo%ment of ne$
antibiotics
• >a#es no allo$ance for s%ecific
case of antibiotic resistance
• 7ombination t"era%y s"ould be
su%%orted
• Ie$ dru!s s"ould be banned
from $ides%read administration to
"ealt"y animals
hat can (e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Stalled science
• G J 5 mainly %roduces variants of
older antibiotics
•
Kno$led!e is !ro$in! !enomics4but yield declinin!
• Io lon!er any need to confine
ourselves to dru!s t"at in"ibit
synt"esis of %rotein' nucleic
acids' cell $alls' and folate
• >ust find ne$ tar!ets
-roteasomes' core metabolism'
%at"o!en defenses
hat can (e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Stalled science
• %n vivo rat"er t"an in vitro
%ers%ective $"en tar!ettin!
essential en<ymes
• Tar!et !ene combinations t"at are
essential to!et"er t$o !enes for
li%id metabolism in tuberculosis4
• -at"o!en+s%ecific dru!s rat"er
t"an broad+s%ectrum reuires
better dia!nostics4
• E6%loit microbial diversity better
hat can (e do in general to fighthat can (e do in general to fight
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hat can (e do, in general, to fighthat can (e do, in general, to fight
antimicrobial resistance#antimicrobial resistance#
Stalled science
• %n vivo rat"er t"an in vitro
%ers%ective $"en tar!ettin!
essential en<ymes
• Tar!et !ene combinations t"at are
essential to!et"er t$o !enes for
li%id metabolism in tuberculosis4
• -at"o!en+s%ecific dru!s rat"er
t"an broad+s%ectrum reuires
better dia!nostics4
• E6%loit microbial diversity better