lecture chapter 19
TRANSCRIPT
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Microbiology: A Clinical Approach Garland Science
CHAPTER 19
ANTIBIOTICS
CDC / Gilda L. Jone
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WHY IS THIS IMPORTANT?Antibiotics have drastically reduced the number o deaths
due to inection!They have chan"ed the ace o health care!
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O#$R#I$W
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HISTORI%A& P$RSP$%TI#$SThe discovery o the irst antibiotic 'as an accident!Ale(ander )lemin" accidentally contaminated a *late 'ith a
un"us!He observed a clearly deined re"ion o no bacterial "ro'th
'here the un"i had contaminated the *late!The area around the un"us 'as eventually reerred to as a
+one o inhibition!
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,HISTORI%A& P$RSP$%TI#$SIt is estimated that over -. million *rescri*tions are
'ritten in America each year!
/012.. tons o antibiotics are *roduced annually!0232. 4 is ed to livestoc5 to increase the rate o 'ei"ht
"ain!
)rom /6.. to /6-.1 mortality rom inectious diseases
dro**ed rom 767 *er /..1... *ersons to 89 *er /..1...*ersons!
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,HISTORI%A& P$RSP$%TI#$SNo ma:or discoveries o natural antibiotic substances have
occurred or several years!$orts have no' shited to modiyin" e(istin" antibiotics!Searchin" in ne' *laces or *otential antibiotics has also
"ained in *rominence!Many antibiotics are *roduced by microor"anisms as *art
o their survival mechanism!They 5ee* other or"anisms a'ay!They *rotect the su**ly o nutrients and o(y"en!
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ANTI;IOTI%S AR$ PART O);A%T$RIA& S$&) PROT$%TIONMicroor"anisms that *roduce these substances have
molecular mechanisms to control *roduction and *revent
sel3destruction!Naturally *roduced antibiotics are *roducts o secondary
metabolic *ath'ays!These *ath'ays are not turned on all the time!
%ontinuous *roduction could adversely aect the or"anism!Some bacteria restrict antibiotic *roduction to the stationary
*hase!Others 5ee* the intracellular concentrations at lo' levels!
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,ANTI;IOTI% SP$%TRAThe irst molecules that inhibited bacterial "ro'th 'ere
natural *roducts!Over time1 these natural molecules have been modiied!Several ty*es o semi3synthetic antibiotics have been
derived rom these molecules!
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,ANTI;IOTI% SP$%TRAThe ori"inal natural molecules used by humans as
antibiotics have a very narro' s*ectrum!Penicillin activity is restricted to
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,ANTI;IOTI% SP$%TRA
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P$NI%I&&INSThere are semi3synthetic orms o *enicillin!They are created throu"h modiications that can be made in
a laboratory!
%hemists can create and modiy side chains!This *roduces ne' orms o *enicillin!
Natural *enicillin has a very narro' s*ectrum!%hemically modiyin" *enicillin broadens the s*ectrum!
Semi3synthetic *enicillins can be urther modiied toincrease the eiciency o inhibitin" bacterial "ro'th!
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%$PHA&OSPORINSThe same 5ind o mani*ulation can be seen 'ith
ce*halos*orin amily!Modiication o the natural molecule has resulted in several
"enerations o semi3synthetics!Modiications result rom chan"in" the side chains
leavin" core intact!Modiications also chan"e reactivity *atterns and
s*ectrum!
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R$SISTAN%$ TO ANTI;IOTI%S;acteria are constantly indin" 'ays to counteract
antibiotics!
One o the most im*ortant bacterial deense mechanismsis the *roduction o en+yme =3lactamase!
Or"anisms that *roduce =3lactamase are resistant to
*enicillin!
One 'ay to overcome *enicillin resistance is to combine*enicillin dru" 'ith molecule that *rotects the *enicillin!This diminishes or im*edes =3lactamase activity!An e(am*le o this is *otassium clavulanate!
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ANTI;IOTI% TAR
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,ANTI;IOTI% TAR
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!!ANTI;IOTI% TARThe bacterial cell 'allThe bacterial *lasma membraneSynthesis o bacterial *roteins;acterial nucleic acids;acterial metabolism
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,ANTI;IOTI% TAR
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,ANTI;IOTI% TAR
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ANTI#IRA& R@
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,ANTI#IRA& R@
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,ANTI#IRA& R@
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ANTI)@N
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!!ANTI)@N
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R@GuinineMetronida+ole!
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R@
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N$W TARPe*tide )ra"mentsSeveral antibiotic com*ounds are com*osed o*e*tide
ra"ments and disru*t the bacterial *lasma membrane!;acitracin1 "ramicidin S1 and *olymy(in ;
Ma"inins *roduced by ro"s
eensins *roduced by humans
So ar1 over 2.. 5no'n *e*tides *roduced bymulticellular or"anisms have antibiotic actions!
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N$W TAR
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!!N$W TAR
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TH$ %OST O) R$S$AR%H AN$#$&OPM$NTThe costs o dru" develo*ment are not trivial even thou"h
thousands o com*ounds can be ra*idly identiied!
Thousands o *romisin" com*ounds may yield only onecandidate!Ri"orous and e(*ensive testin" is reuired beore a ne'
dru" can be brou"ht to mar5et!
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!!TH$ %OST O) R$S$AR%H
AN $#$&OPM$NT%andidate com*ounds have to *ass tests or>
To(icity
Aller"ic eectsMuta"enicity
%arcino"enicity
The estimated cost o a ne' dru" is bet'een J/.. million
to J2.. million!evelo*ment can ta5e as lon" as 23/. years!
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T$STIN< O) ANTI;IOTI%Sevelo*ment o ne' antibiotics ollo's a very strin"ent
hi"hly re"ulated *ath'ay!Selective to(icity reuired to 5ee* the *ublic sae
The need or *roduct saety t'o3ed"ed s'ord!It reuires a "reat deal o time and money!
Several testin" systems can be used to evaluate ne'
com*ounds!
Eirby3;aueris the most 'idely used!The $3test is more advanced!
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!!T$STIN< O) ANTI;IOTI%S>Eirby3;auer TestAn a"ar *late is covered 'ith 5no'n*atho"en!)ilter3*a*er dis5s im*re"nated 'ith 5no'n concentrations
o the com*ound!
They are *laced on a"ar!
Fones o inhibition can be identiied!
The method is also used to com*are the relative
eectiveness o dierent com*ounds!&ar"e +one o inhibition does not necessarily mean a more
*o'erul com*ound!
Fones are evaluated usin" standardi+ed tables!
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Microbiology: A Clinical Approach Garland Science
!!T$STIN< O) ANTI;IOTI%S>
Eirby3;auer Test
K %% L
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!!T$STIN< O) ANTI;IOTI%S>Eirby3;auer TestThe resistance o s*eciic or"anisms can be classiied as>SensitiveIntermediateResistant
The Eirby3;auer test is inadeuate or most clinical
*ur*oses!
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!!T$STIN< O) ANTI;IOTI%S>
$3testThe $ test is a more advanced diusion test!Permits determination o the minimal inhibitory
concentration BMI%C! The lo'est antibiotic concentration that *revents "ro'th
@ses *lastic3coated stri*s containin" "radients o antibiotic
concentrations!Ater incubation MI% can be read rom the scale
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Microbiology: A Clinical Approach Garland Science
!!T$STIN< O) ANTI;IOTI%S>$3test
K %% L r! Richard )ac5lam
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T$STIN< O) ANTI;IOTI%S>
;roth ilution TestEirby3;auer and $3test sho' 'hich com*ounds inhibit
*atho"en "ro'th!
They cannot determine bet'een microbicidal andmicrobistatic!
Thebroth dilution test used or this *ur*ose!Permits determination o the minimal bactericidal
concentration BM;%C!
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!!T$STIN< O) ANTI;IOTI%S>
;roth ilution TestA s*eciic or"anism is incubated in decreasin" amounts o
antibiotic!Wells that sho' no "ro'th are recultured in nutrient broth
medium!
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,T$STIN< O) ANTI;IOTI%S>;roth ilution Testilution tests are hi"hly automated!Additional testin" uses colorimetric methods
@sed to determine serum concentrationsIm*ortant because dru"s are to(ic at hi"h concentrations
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ReferencesMicrobiology, A clinical Approach -Danielle
Moszyk-Strelkauskas-Garland Science 2010
http://en.wikipedia.org/wiki/Scientifc_method