Bet Alak Tam
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1
ANTIBIOTIK PENGHAMBAT DINDING SEL
Hany Yusmaini, dr., MKesDept Farmakologi FK UPN VJ
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ANTIBIOTIK PENGHAMBAT DINDING SEL
1. ANTIBIOTIK BETALAKTAM- PENISILIN (……,……,……,…….,…….)- SEFALOSPORIN (……..,……..,……..,)- KARBAPENEM- MONOBAKTAM
BETALAKTAMASE INHIBITOR Asam Klavulanat, Sulbaktam
2. ANTIBIOTIK PENGHAMBAT DDG SEL LAINNYA Vankomisin, Basitrasin
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BETALAKTAM
Antibiotik yg banyak digunakan Struktur & Mekanisme Kerja sama Struktur : Mengandung cincin betalaktam
penting u/ aktivitas antibakterial
Menghambat sintesis peptidoglikan dinding sel Tidak berefek pd bakteri yg tidak tumbuh Bakterisidal
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1. PENISILIN
Banyak dipakai ; efektif, relatif tdk toksik, eso utama berupa rx hipersensitifitas
Kimia- Inti penisilin
tdd cincin thiazolidine dan cincin betalaktam(ptg u/ aktivitas antibakterial)
- Perubahan kimia bagian ini misalnya oleh betalaktamase mybbkan hilangnya aktivitas antibakterial
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O
R C NH CHCH
S
C
CH 3
CH 3
C NB
CHA
COOH2
1O
O
R CH NH 2 CHCH
S
C
CH 3
CH 3
C N CH COOHO
+
Am idase
O
R C NH CHCH
S
C
CH 3
CH 3
C N CH COOHO
HOH
Penisilinase
Penisilin
1 Tem pat kerja penisilin2 Tem pat kerja am idaseA Cincin T iazolidinB Cincin b-Laktam
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Mekanisme kerja menghambat pembentukan dinding sel mikroba
Penisilin berikatan dgn reseptor (PBP)
menghambat rx transpeptidasi yg membentuk peptidoglikan ddg sel
Proses autolitik Lisis sel
selKematian sel
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Gambaran e coli yang lysis krn antibiotik betalaktam
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Farmakologi & Klasifikasi Penisilin
berbeda berdasarkan :
- Spektrum Antimikroba (sempit, luas)
- Ketahanan terhadap asam lambung
- Ketahanan thd penisilinase/ betalaktamase
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KLASIFIKASI PENISILIN
PENISILIN ALAM (NATURAL)
(Penisilin G, Penisilin V) PENISILIN-RESISTEN PENISILINASE (ANTI STAFILOKKOKKUS)
(Metisilin, Nafsilin, Oksasilin, Kloksasilin, Dikloksasilin) AMINOPENISILIN
(Ampisilin, amoksisilin) PENISILIN ANTI PSEUDOMONAS
(Karbenisilin, Piperasilin, Tikarsilin, Mezlosilin, Azlosilin)
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PENISILIN ALAM
Penisilin G (Benzil penicillin)- Spektrum : sempit kokkus gr(+),(-), basil gr(+), bbrp basil gr(-) spirochaeta- Dirusak asam lambung p.e- Diinaktivasi oleh betalaktamase
Penisilin V- Spektrum = penisilin G- Lebih tahan thd asam lambung p.o- Diinaktivasi oleh betalaktamase
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PENISILIN RESISTEN PENISILINASE(PRP/ ANTI STAFILOKOKKUS)
Metisilin, Nafsilin, Oksasilin, Kloksasilin, Dikloksasilin Spektrum : sempit
untuk antimikroba penghasil betalaktamaset.u stafilokokkus aureus
Stabil terhadap asam lambung Resisten/ tahan terhadap betalaktamase
MRSA (Metisilin Resisten Stafilokokkus Aureus) ????
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AMINOPENISILIN (EXTENDED SPECTRUM PENICILLIN)
Ampisilin, amoksisilin Spektrum : Luas
Kokkus gr(+), (-), Bacil gr(+), Bacil gr(-), enterobacteriaceae, Listeria monocytogenes
Stabil terhadap asam lambung Diinaktivasi betalaktamase, kecuali kombinasi dg
betalaktamase inhibitor (asam klavulanat, sulbaktam)
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PENISILIN ANTI PSEUDOMONAS
Karbenisilin, Tikarsilin, Piperasilin, Mezlosilin, Azlosilin
Spektrum : sempit
Pseudomonas aeroginosa, batang gr(-) Dirusak asam lambung (i.v), (i.m) Diinaktivasi betalaktamase
kecuali kombinasi tikarsilin dengan asam klavulanat
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FARMAKOKINETIK
ABSORPSI
1. Poor p.e Good p.o Penisilin G Penisilin V
Nafsilin Oksasilin cs Metisilin Ampisilin Tikarsilin Amoksisilin Mezlosilin cs Bakampisilin Karbenisilin Karbenisilin indanyl
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2. Effect of food
Abs ↓↓ : Penisilin G , Nafsilin, Metisilin Abs ↓ : Oksasilin, Ampisilin, Karbenisilin
None : Amoksisilin Bakampisilin
3. Effect of gastric acidity Penisilin G (i.m) Penisilin antipseudomonas (i.m, i.v)
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DISTRIBUSI Baik di slrh tubuh, melewati barier plasenta, tdk teratogenik, penetrasi pd tulang & lqs rendah, kecuali bila ada
peradangan
EKSKRESIt.u ginjal kecuali nafsilin : feses
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Ekskresi penisilin dihambat oleh probenecid
Kadar penisilin plasma me↑
Kombinasi Betalaktam dengan Aminoglikosid : Efek sinergis
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Comparison Of Ampicillin - Amoxicillin
Ampicillin Amoxicillin
% absorbed 40 95Effect of food decreased absorbs noneADR diarrhea/rash less diarrheaActivity against• Salmonella fair good good• Shigella good poorAdministration 4dd1 3dd1
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Efek samping
1. Reaksi hipersensitifitas ; paling sering
Ringan - Berat(urtikaria) (angioedema, reaksi anafilaktik)
asam penisiloik + protein hapten (reaksi immune)
Reaksi silang (+)
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2. Diare : ggn mikroorganisma dlm sal cerna
3. Efek iritasi langsung (dosis tinggi i.m atau i.v)
4. Nefritis : metisilin dosis tinggi
5. Disfungsi platelet (karbenisilin, tikarsilin, penisilin G)
6. Depresi sumsum tulang : granulositopenia
(metisilin, oksasilin, kloksasilin, dikloksasilin
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Resistensi
Resistensi akibat penisilinase (betalaktamase)Stafilokokkus aureus, H influenzae, bbrp gram (-) mghslkan betalaktamase yg dpt memecah cincin betalaktam asam penisiloat (tdk punya aktifitas anti bakteri
Resistensi krn mikroba tidak mengandung reseptor spesifik atau krn permeabelitas membran sel luar berkrg
Resistensi krn enzim autolitik dlm sel tidak teraktivasi
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Resistensi yg tidak berhubungan dgn penisilinase misalnya resistensi thd metisilin pada MRSA
Mikroba tanpa dinding sel (mycoplasma) atau yang metabolismenya tdk aktif
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2. SEFALOSPORIN
struktur & fungsi mirip dgn penisilin
Mekanisme kerja dan mekanisme resistensi mirip dgn penisilin, tetapi sefalosporin lebih tahan thd betalaktamase
Berdasarkan spektrum antimikrobanya dibagi menjadi 3 generasigenerasi 1 : bakteri gram (+) , kec penghasil
betalaktamase, gram negatif (-) generasi 2 : gram (-) , gram (+) generasi 3 : batang gram (-) , gram (+) generasi 4 : idem
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Farmakokinetik
- Absorpsi
umumnya p.o buruk, hrs diberikan i.v kec : sefadroksil, sefaleksin, sefadrin, sefaklor, sefuroksim, sefiksim (p.o)
- Distribusi
baik ke slrh tubuhpenetrasi lqs hanya oleh sefalosporin generasi 3 (sefotaksim)
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Eliminasi
t.u ginjal : perlu penyesuaian
dosis pada renal failure, kecuali : sefamandol, sefoperazon, seftriakson ekskresi lewat empedu
doc pd insuffisiensi renal
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INDIKASI
1. Alternatif dari penisilin
2. Infeksi serius oleh Kleibsiella, Enterobacter, Proteus, Haemophilus, Providencia, Serratia
3. Infeksi nosokomial (4th G) * Cefazolin : Profilaktik * Cefoxitin : Bakteriodes fragilis
Sepsis intraabdominal – pelvis * Ceftriaxone : GO, Salmonella thypi dll.
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EFEK SAMPING
Reaksi hipersensitifitas (cross rx to penicillin 5-15%) Diare Nefrotoksik : sefaloridin, sefalotin Superinfeksi
Disulfiram-like effect : sefamadol, sefoperazon, moksalaktam taking with alcohol
Perdarahan : anti-vit K effect : sefamandol, sefoperazon, moksalaktam
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3. KARBAPENEM
Imipenem (+ silastatin), meropenem
Mempunyai struktur betalaktam ttp tdk termsk gol penisilin dan sefalosporin, cincin thiazolidine mgdg atom sulfur
Spektrum antibakteri : luas : gr (+), gr (-), anaerob, pseudomonas & resisten thd betalaktamase
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Farmakologi absorpsi per oral (-), pemberian hrs i.v Cepat dihidrolisis enzim dihidropeptidase pd brush
border tubulus proksimal ginjal mjd metabolit toksik
hrs kombinasi dengan silastatin Distribusi : baik pd CNS, afinitas sangat baik pd jaringan
otak
Efek Samping alergi Ggn GIT (nausea, vomiting, diare) Eosinofilia, neutropenia, seizure (jarang)
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4. MONOBAKTAM
Struktur kimia : cincin betalaktam tidak bersatu dengan cincin lainnya
Available preparat : aztreonam® Spektrum : sempit, t.u utk enterobacteriaceae resisten terhadap betalaktamase Pemberian i.v atau i.m Potensi antigenik rendah, reaksi silang (-)
alternatif utk os alergi penisilin/ sefalosporin
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INHIBITOR BETALAKTAMASE
Aktivitas antibakterial (<-0) Penghambat betalaktamase
Kombinasi dgn betalaktam
Memperluas spektrum antibakterial antibiotik betalaktam
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ASAM KLAVULANAT Aktivitas antibakterial lemah, ttp dapat menghambat
betalaktamase dari bakteri gr (+) dan gr (-) Kombinasi dengan gol penisilin : mencegah inaktifasi,
memperkuat daya anti mikroba, memperluas spektrum Kombinasi dgn amoksisilin ; augmentin (p.o) Kombinasi dgn tikarsilin ; timentin (p.e)
SULBAKTAM Sruktur kimia mirip asam klavulanat
Kombinasi dgn ampisilin ; Unasyn (i.v, im)
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102
105
104
106
103
Jum
lah b
akte
ri h
idup
W aktu
Am oksisilin danasam klavulanat
Hanyaam oksisilin
Hanya asamklavulanat
Kontrol(tanpa obat)
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ANTIBIOTIK PENGHAMBAT DINDING SEL LAINNYA
VANKOMISIN
Glikopeptida trisiklik yang ptg krn aktivitasnya pada MRSA (Metisilin Resisten Stafilokokkus Aureus)
Mekanisme Kerja : menghambat sintesis fosfolipid ddg sel mikroba dan polimerisasi peptidoglikan
Indikasi : infeksi oleh MRSA, infeksi yg resisten thd antibiotik lain, kolitis krn clostridium deficile, endokarditis enterokokkus
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Resistensi : permeabelitas membran ↓pengikatan reseptor ↓
Tidak diabsorpsi peroral (penggunaan peroral hanya utk enterocolitis)
Pemberian i.v Ekskresi : ginjal ESO : demam, menggigil, flebitis, red man syndrome krn
pelepasan histamin, syok (infus cepat)
BASITRASIN Polipeptida yg menghambat sintesis ddg sel Penggunaannya dibatasi untuk topikal krn nefrotoksik