resistensi antibiotika

55
 Lecture 19 Evolution of antimicrobial resistance

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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