dr. lilian - beta lactam antibiotik.pptx

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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