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Lecture Chapter 19

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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


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