Beta lactam & other cell wall- & membrane-active antibiotics
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8/9/2019 dr. lilian - beta lactam antibiotik.pptx
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The Beta-Lactam (BLA)
Antibiotics
Dr. Hj. Rika Yuliwulandari, M.Hlt.Sc., PhD
Department of Pharmacology, Faculty of Medicine, YRS! "ni#er$ity%
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Structure
Penicillin
&ephalo$porin
Mono'actam
&ar'apenem(
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How do BLA work
H)*+++Function Pre#ent
the $ynthe$i$ ofthe 'acteria cellwall
Peptidoglycan
layer
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Classifcation
/atural Penicillin
minopenicillin
0etalactam 'eta lactama$e inhi'itorcom'ination
Penicillina$e re$i$tant penicillin
ntip$eudomonal
penicillin
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History
Fir$t noticed 'y 1rne$t Duchene, %234Redi$co#ered 'y le5ander Fleming
6founder of the name7, %3(3Further inten$i#e re$earch and
production Dr. Howard Florey, %3-3
ndrew 8. Moyer with ma$$ productionpatent, %32
/atural Penicillin Source ++++++
Penicillin 9, Penicillin :;, 0en
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General eatures
9eneral mechani$m$ of re$i$tancy !nacti#ation of anti'iotic 'y 'eta>lactama$e 6mo$t common7
▪ Staphylococcu$ aureu$, Haemophillu$ $pecie$, 1. coli
▪ P$eudomona$ aerugino$a, 1ntero'acter $pecie$
Modi?cation of target P0P !mpaired penetration of drug to target P0P$
@he pre$ence of an eAu5 pumpPharmacokinetic$ 6P;7 Po
▪ #ary among Penicilin depend on acid $ta'ility and protein 'inding▪ Methicillin acid Bla'ile >>>> not for Po
▪ Diclo5acillin, mpicillin, mo5icillin acid>$ta'le, well a'$or'ed,impaired 'y food 6e5cept mo5icillin7
Pe▪ '$orption i$ complete and rapid
▪ Prefera'le 'y i# than im, due to local pain4
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General eatures (!)
*idely di$tri'uted in 'ody Cuid$ 6within cellE intracellular Cuid$E7 and ti$$ue$
Poor penetration into eye, pro$tate, central ner#ou$
$y$tem 6&/S7 15cretion
▪ Mo$tly in urine, al$o $putum, milk
▪ /afcillin 'iliary tr
▪ )5acillin, Diclo5acillin, &lo5acillin kidney and 'iliary
&linical u$e$ Mo$t widely eGecti#e and e5ten$i#ely u$ed anti'iotic
#oid meal time when taking drug$ 6e5ceptmo5icillin7
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"atural #enicillin
Penicillin : Pota$$ium $alt pheno5ymethyl penicillin
)ral well a'$or'ed @ ma5 4I mnt
!ndication▪ Mild gr J infection in throat, re$p tr, $oft ti$$ue
▪ Doc for 9r Streptococcal pharyngiti$▪ "$eful in oral ca#ity inf. due to anaero'ic 'acteria
Penicillin 9 /ot well a'$or'ed po
2
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Penicillin 9 Major limitation
▪ !n$ta'le in acidic pH
▪Su$cepti'le to 'eta>lactama$e 6Penicillina$e7▪ !nacti#e again$t gram > 'acilli
Pe im, i#
Do& 9ram J, >, $pirochaeta 6e5 @. pallidum, /.meningitidi$, 9roup $treptococcu$ and ctinomyco$i$7
Kong acting form$▪ Procaine Pen9 6%( hr$7
▪ 0en
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Pharmacokinetic 6P;7▪ Sen$iti#e to ga$tric acid 6pH(7
▪ @%L( I.= hr
▪ Di$tri'ution wide, e5cept &SF 6&ere'ro SpinalFluid7
▪ 15cre$$ion renal▪ !nhi'ited 'y Pro'enecid, Fenil'uta
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#enicillinase-$esistant#enicillins
!ncrea$e re$i$tance of $taphylococci to natural penicillin$cti#e againt$ Streptococcou$ and Staphylococcu$
producing penicillina$e/ot acti#e Methicillin>re$i$tant S. aureu$
9ram negati#e0e$t oral a'$orption 6% or ( hr$ 'efore meal$7 &lo5acillin
Diclo5acillinPoor a'$orption /afcillin
)5acillin !ndication Skin and $oft ti$$ue infection
%%
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Amino%enicillinsAm%icillin&Amo'icillin
Fir$t penicillin acti#e again$t gram negati#e rod$ 61. coli and H.inCuen
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d#er$e Reaction !n general non to5ic
&ro$$>$en$iti
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Beta lactam beta lactamaseinhibitor combination
)ral com'ination only amo5icillin>cla#ulanate&o#erage 0eta lactama$e producing $train 6S. aureu$, H. inCuen
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Anti%seudomonal%enicillin
Po &ar'enicllin'$orption e5cellent
Meta'oli$m too rapid, $erum le#ellowKimited clinical u$age
%=
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ral #enicillincom%arison
Class ru*Antimicrobial
s%ectrum"atural %enicillin Penicillin : Streptococcu$ $pecie$ and
oral ca#ity anaero'e$#enicillinase-resistant
%enicillin
&lo5acillin 6@egopen7 Methicillin>$en$iti#e
Staphylococcu$ aureu$ and
Streptococcu$ $pecie$
Diclo5acillin 6Dynapen7/afcillin 6"nipen7
)5acillin 6Pro$taphlin7Amino%enicillin mo5icillin Same co#erage a$ penicillin :,
plu$ Ki$teria monocytogene$,
1nterococcu$ $pecie$, Proteu$
mira'ili$ and $ome $train$ of
1$cherichia coli
mpicillin0acampicillin 6Spectro'id7
Beta-lactam+beta-
lactamase inhibitor
combination
mo5icillin>cla#ulanate
6ugmentin7
Same co#erage a$
aminopenicillin$, plu$
'etalactama$eBproducing
$train$ of methicillin>$en$iti#e
S. aureu$, Haemophilu$
inCuen
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#roblems o #enicillins
Mi$u$ed and o#eru$ed anti'ioticPenicillin>re$i$tant organi$m>>>3IN of
$taphylococcal $train$ are 'eta>lactama$e producer$0road $pectrum penicillin al$o
eradicate normal Cora >>>>$uperinfection with opportuni$tic anddrug re$i$tant $pecie$ 6proteu$,p$eudomona$, entero'acter,
$erratia, $taphylococci, yea$t, etc7 %
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Ce%halos%orin
%2
0a$ed on $pectrum of antimicro'ialacti#ity
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Ce%halos%orin, st *enerationSimilar to Penicillin$ gr J, gr >
0roader co#erage Methicillin $en$iti#e S. aure$. 1. coli, P.mira'ili$, ;le'$iella $pp
Poor P. aerugino$a, indoleJ proteu$, enterococcu$ $pp,Serratia marce$cen$, H. inCuen producing 'etalactama$e
P; )ral &ephale5in, cephradine, cefadro5il
▪ '$orption in 9! tr good 6not inCuenced 'y food7
▪ 15cretion "rine 6high concentration>>> OOO !n $e#ere renal failure7
▪ !mpaired renal function reduce do$e
▪ Pro'enecid 6tu'ular 'locking agent7 increa$e $erum le#el of drug$
Pe▪ @he only %$t gen. gi#en Pe cefa
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st *eneration (!)
&linical u$e Skin and $oft ti$$ue infection due $treptococcu$ $pp and methicillin
$en$iti#e S. aureu$▪ Prefera'le to penicillina$e>re$i$tance penicilline due to lower 9! $e, 'etter ta$te
"@!▪ (nd line drug after uinolone and @MPLSMQ for "@! 'y gr B organi$m$
▪ /ot acti#e to P$eudomona$, 1nterococcu$ $pp
▪ Relati#e $afe for pregnant woman
Pharyngiti$ with delayed type penicillin allergy
9enerally not eGecti#e againt$ H. inCuen>>> not eGecti#e for meningiti$
(I
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!nd *eneration
Heterogenou$ group of drug$ DiGerent in acti#ity, pharmacokinetic$, to5icity
Spectrum 0etter $pectrum than %$t generation
▪ gaint$ 'eta>lactama$e producing re$piratory pathogen$ H. inCuean
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!nd *eneration (!)
P; Po &efaclor, cefuro5ime a5etil, cefprolactam$e>producing H. inCuean
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.rd *eneration
Spectrum 15tended gr B co#erage 6e5cept cefopera
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/th *eneration
0etter acti#ity than -rd gen. More re$i$tant to hydroly$i$ 'y chromo$omal
'eta>lactama$e 6e5. Produced 'y entero'acter7
cti#e P. aerugino$a, entero'acteriaceae,S. aureu$, S. pneumonia, haemophillu$,nei$$eria
15cre$$ion kidney$&linical role almo$t $imilar to -rd gen. 'ut
more acti#e again$t mo$t penicillin>re$i$tant $train$ of $treptococci
(
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Ad0erse 12ects
llergy :ariety of hyper$iti#ity
▪ naphyla5i$, fe#er, $kin ra$he$, nephriti$, granulocytopenia, hemolytic anemia
▪ &ro$$ allergenicity 'etween cephalo$porin>penicillin i$ around =>%IN
▪ 0e careful with hi$tory of anaphyla5i$ to penicillin
@o5icity Kocal irritation with po$$i'le $e#ere pain after i.m. injection
@hrom'ophle'iti$ after i.#. injection
Renal to5icity 6inter$titial nephriti$, tu'ular necro$i$7 >>>> withdrawal ofcephalo$porin
&efamandole, mo5alactam, cefmeta>>>>>>>> po$$i'le $uperinfection duringtreatment
(=
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How to choose3
*hat i$ the likely organi$m+*hat i$ the major mode of re$i$tance*here i$ the infection
*hat i$ the local 6e5. Ho$pital7 en#ironment+*hat doe$ the micro'iology la' $ay+How much doe$ it co$t+&omor'id condition in the patientRi$k of $ide eGect+#aila'ility of drug !n$urance $upport
(4
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Com%arison
Class ru* Antimicrobial s%ectrum4irst-*eneration ce%halos%orin &efadro5il 6Duricef7 !mpro#ed co#erage of methicillin>$en$iti#e S. aureu$, 1. coli, P.
mira'ili$ and ;le'$iella $pecie$
&ephale5in 6;eCe57
&ephradine 6:elo$ef7
Second-*eneration
ce%halos%orin
&efaclor 6&eclor, &eclor &D7 &ompared with ?r$t>generation
agent$, 'etter co#erage of 'eta>
lactama$eBproducing organi$m$
&efpro
generation cephalo$porin$
Third-*eneration ce%halos%orin &efdinir 6)mnicef7 :aria'le lo$$ of Staphylococcu$ and
Pneumococcu$ co#erageU
compared with $econd>generationcephalo$porin$, $omewhat
e5panded co#erage of gram>
negati#e organi$m$U enhanced
co#erage of Proteu$ #ulgari$ and
Pro#idencia $pecie$
&e?5ime 6Supra57
&efpodo5ime 6:antin7&efti'uten 6&eda57
4ourth *eneration ce%halos%orin &efepime
&efpirone
More re$i$tance to 1ntero'acter $pp,
P$eudomona$
More acti#e again$t penicillin>re$i$tant
$treptococci (
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Clinical indication or oralbeta lactam antibiotic
5nection #reerred dru*(s) Alternati0e dru*(s)titis media mo5icillin mo5icillin>cla#ulanate 6ugmentin7,
trimethoprim>$ulfametho5ageneration cephalo$porin$,
$ome third>generation cephalo$porin$,
macrolide anti'iotic$
Stre%tococcal %haryn*itis Penicillin : !n patient$ with penicillin allergy macrolide
anti'iotic$, ?r$t>generation cephalo$porin$
Sinusitis mo5icillin, trimethoprim>$ulfametho5acla#ulanate, $econd>generation
cephalo$porin$, third>generation
cephalo$porin$
Animal and human bites mo5icillin>cla#ulanate Depend$ on type of 'ite 6e.g., cefuro5ime
a5etil &eftinE or do5ycycline :i'ramycinE for
cat 'ite$7
Bacterial endocarditis %ro%hyla'is mo5icillin !n patient$ with penicillin allergy clindamycin
6&leocin7, cephale5in 6;eCe57, acla#ulanate, $econd>generation
cephalo$porin$, third>generationcephalo$porin$
Bronchitis (contro0ersial) Do5ycycline, trimethoprim>$ulfametho5acla#ulanate
Macrolide anti'iotic$, uinolone anti'iotic$,
$econd>generation cephalo$porin$, $ome third>
generation cephalo$porin$
Skin and sot tissue inections (cellulitis) Fir$t>generation cephalo$porin$, clo5acillin
6@egopen7, diclo5acillin 6Dynapen7
Macrolide anti'iotic$, amo5icillin>cla#ulanate,
cefpodo5ime 6:antin7, cefdinir 6)mnicef7
6rinary tract inection Wuinolone anti'iotic$, trimethoprim>
$ulfametho5acla#ulanate, cefuro5ime
a5etil or other cephalo$porin$, do5ycycline,nitrofurantoin 6Furadantin7
(2
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ther beta-lactam dru*s
Mono'actam$ allergic patient$ d#. R5
▪ Skin ra$he$
▪ 1le#ation of $erum aminotran$fera$e$
0eta>lactama$e inhi'itor$ &al#ulanic acid, Sul'actam, @alactama$e$ 6$taphylococci, H. inCuen
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&ar'apenem$ For infection$ 'y organi$m$ re$i$tant to other drug$
!mipenem
▪ *ide $pectrum gr B rod$, gr J, anaero'e$▪ !nacti#ated 'y dehydropeptida$e$ in renal tu'ule$
▪ dmini$tered together with cila$tatin 6inhi'itor of renaldehydropeptida$e7
▪ d#er$e eGect▪ /au$ea, #omiting, diarrhea, $kin ra$he$, reaction at infu$ion $ite$, $ei
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ther inhibitors o cell wallsynthesis:ancomycin Produced 'y Streptococcu$ orientali$
cti#e only again$t gr J 'acteria 6e$p. $taphylococci7
Mechani$m▪ !nhi'it tran$gyco$yla$e, pre#ent elongation of peptidoglycan and weakend the cell wall >>>
ly$i$ of cell
cti#e again$t gr J P;
▪ Poorly a'$or'ed from 9! tr.
▪ P) only for enterocoliti$ 'y &lo$tridium diTcile, Pe 6i#.7 for $e#ere infection
▪ *idely di$tri'uted in the 'ody, &SS
▪ 15creted mainly 'y glomerular ?ltration
!ndication▪ Pe $ep$i$, endocarditi$ cau$ed 'y methicillin>re$i$tant $taphylococci
▪ :ancomycinJ9entamycin enterococcal endocarditi$ with penicillin allergy
▪ :ancomycinJcefota5imLceftria5onLrifampin meningiti$ 'y penicillin re$i$tant $train ofpneumococcu$
d#er$e reaction▪ Minor reaction phle'iti$, chill$, fe#er
▪ dmini$tration with aminoglyco$ide ototo5icity and nephroto5icity
▪ Red man or red neck $yndrome -%
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@eicoplanin :ery $imilar to #ancomycin in mechani$m of action and $pectrum
&an 'e gi#en im. )r i#.Fo$fomycin cti#e gr J and gr B
#aila'le oral and pe.
15cretion #ia kidney
For treatment of uncomplicated lower urinary tract infection in women0acitracin cti#e gr J
/o cro$$>re$i$tance 'etween 'acitracin>other antimicro'ial drug$ /ephroto5ic
)nly for topical u$e
0acitracinJplymi5inLneomycin $urface le$$ion$ of $kin, wound$,mucou$ mem'rane$
-(
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&yclo$erine Produced 'y Streptomyce$ orchidaceu$
!nhi'it grJ and gr> For tu'erculo$i$ 'y M. tu'erculo$i$
re$i$tant to ?r$t line drug$
d#er$e reaction▪ Do$e>related central ner#ou$ $y$tem to5icity
6headache$, tremor$, acute p$ycho$i$,con#ul$ion$7
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$eerences
Farmakologi dan @erapi 6F;"!, (II70a$ic and &linical Pharmacology 6@he
Mc9raw>Hill, (II%7 8ame$ &*, 9urk>@urner. &ro$$>reacti#ity of 'eta>lactam anti'iotic$.0"M& Proceeding$ (II%U %%I4>%I
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