ANTIMIKROBA DAN UJI KEPEKAAN dr. Evita Mayasari, MKes. Medical Faculty, University of Sumatera Utara
OBAT ANTIMIKROBA Obat yang digunakan untuk menghambat pertumbuhan dan atau membunuh bakteri penyebab infeksi yang dapat diberikan per oral, parenteral atau lokal sebagai obat luar luar.. Antibiotika bahan yang dihasilkan oleh “biotik” biotik” atau t mak makhluk hl k hidup hid /mikroorganisme hidup/ ik i seperti ti Bakteri,, Actinomycetes, Bakteri Actinomycetes, jamur. jamur.
2 dr. Edhie Djohan Utama, Utama, SpMK SpMK..
ANTIMIKROBA ANTIBIOTIKA CHEMOTHERAPEUTIKA ANTI FUNGUS ANTI VIRUS ANTISEPTIKA DESINFEKTANSIA dr. Edhie Djohan Utama, Utama, SpMK SpMK..
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PENEMUAN AWAL ANTIMIKROBA SALVARSAN : ditemukan pada awal tahun 1900 oleh Paul Ehrlich untuk pengobatan penyakit Syphilis.(Noble Prize) PRONTOSIL (Sulfonamide) Oleh Gerard Domagk 1927 dan penggunaannya tahun 1935 (Noble Prize) SULFADIAZINE 693 = Sulfanilamide oleh British Team pimpinan A.J.Evans A J Evans tahun 1938 PENICILLIN oleh Alexander Fle Flemming tahun 1929 dan penggunaannya tahun 1940 (Noble Prize) NYSTATIN : antifung antifungal al pertama dijumpai tahun 1949 oleh Elisabeth Hazen & Brown STREPTOMYCIN oleh Selman Waksman tahun 1940 (Noble Prize) 4
MIKROORGANISME YANG MENGHASILKAN ANTI NTIMIKROBA MIKROBA Bakteri Actinomycetes (2100) (Streptomyces (Streptomyces)) (400) (Genus Bacillus)
Fungi (800) (Mold = Penicillium & Cephalosporium) Cephalosporium) Algae Protozoa
dr. Edhie Djohan Utama, SpMK.
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JENIS DAN CARA KERJA ANTIMIKROBA
Menghambat sintes sintesis is dinding sel bakteri Merusak p permeabilitas membran sitoplasma si toplasma Menghambat sintes sintesis is protein protein.. Menghambat sintesis sintesis asam nu nukkleat. leat.
dr. Edhie Djohan Utama, SpMK.
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PENICICLLIN (Mold = Penicillium Penicillium)) PNC--G dan Penicillin V PNC Methicillin,, Oxacillin Methicillin Oxacillin,, Cloxacillin Cloxacillin,, Dicloxacillin Ampicillin & Amoxacillin, Amoxacillin, Carbenicillin Carbenicillin,, Ticarcillin Ticarcillin,, Piperacillin,, Mezlocillin Piperacillin CEPHALOSPORIN ((mold mold ld = Cephalosporium C h l Cephalosporium) i ) Gen.I : Cefachlor, Cefachlor, Cephalothin, Cephalothin, Cephalexin Gen.II : Cefuroxim, Cefuroxim, Cefixime Cefixime,, Cefoxitin Gen.III : Cefotaxime, Cefotaxime, Ceftriaxone, Ceftriaxone, Cefoperazon Gen.IV : Cefepime, Cefepime, Cefpirom CARBAPENEM : Imipenem & Meropenem MONOBACTAM : Aztreonam GLYCOPEPTIDE : Vancomycin dan Teichoplanin CYCLOSERINE : secondd line li anti ti tbc tb BACITRACIN : Untuk infeksi kulit superfis superfisial
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PENICILLIN GROUP Penicillins:: penicillin G ((Pfizerpen Penicillins Pfizerpen;; Bicillin; Bicillin; Wycillin), Wycillin), penicillin V ((Betapen Betapen;; PenPen-Vee K), methicillin (Staphcillin), Staphcillin), ampicillin (Omnipen Omnipen;; Polycillin Polycillin)), Polycillin), ) oxacillin (Bactocill ), ) amoxicillin (Amoxil (Amoxil;; Biomox; Biomox; Polymox), Polymox), ticarcillin (Ticar), Ticar), carbenicillin (Geocillin), Geocillin), piperacillin (Pipracil), Pipracil), mezlocillin (Mezlin Mezlin), ), bacampicillin p (Spectrobid Spectrobid), p ), dicloxacillin (Dynapen Dynapen), y p ), nafcillin (Nallpen; Nallpen; Unipen). Unipen).
Penicillins plus β-lactamase inhibitors or compounds pre enting antibiotic degradation on the kidneys: preventing kidneys kidne s: s: amoxicillin + clavulanate (Augmentin Augmentin), ), ticarcillin + clavulanate (Timentin Timentin), ), ampicillin i illi + sulbactam lb t (Unasyn U Unasyn), ) ), piperacillin + tazobactam (Zosyn), Zosyn), imipenem + cilastatin (Primaxin) Primaxin) . dr. Edhie Djohan Utama, SpMK.
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BETALACTAM GROUPS
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STRUKTUR DINDING GRAM (+) & GRAM ((-)
dr. Edhie Djohan Utama, Utama, SpMK SpMK..
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-
Amphotericin B Nystatin Colistin Polymixin
Tidak digunakan untuk obat sistemik karena toksik dr. Edhie Djohan Utama, SpMK.
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:
- Chloramphenicol (50S) - Aminoglycoside (30S) - Erythromycin (50S) - Tetracyclin (30S) - Lyncomycin (50S) Ribosom Mamalia 80S, sedangkan bakteri 70S, reseptor pada d subunit b it 30S atau t 50S. 50S Macrolides : erythromycin, roxithromycin, roxithromycin, clarithromycin clarithromycin,, azithromycin;; digunakan untuk bakteri Gram azithromycin Gram (+) dan beberapa bakteri Gram Gram (-). Lincomycin dan Clindamycin umumnya digunakan untuk bakteri Gram (+). dr. Edhie Djohan Utama, SpMK.
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Aminoglycoside : Streptomycin, kanamycin,, tobramycin, kanamycin tobramycin, and amikacin amikacin.. Most of Aminoglycoside are effective against Gram (+) and Gram (-) bacteria. A i Aminoglycoside l id :bactericidal, b bactericidal i id l, others: h bacteriostatic bacteriostati c
dr. Edhie Djohan Utama, SpMK.
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Selective antimicrobial action to a specific attack tt k on th the 70S ribosome ib off b bacteria t i Several medicallyy important p antibiotics owe their selective antimicrobial action to a specific attack on the 70S ribosome of bacteria, bacteria, with mammalian 80S ribosomes left unaffected. unaffected
Those that act on the 30S ribosome are: Amikacin Gentamycin Kanamycin Neomycin i Streptomycin Tobramycin y
dr. Edhie Djohan Utama, SpMK.
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Antibiotics that act on the 50S portion i off the h ribosome ib include: i l d Chloramphenicol Clindamycin Furadantin Fusidic acid Lincomycin Nitrofuran Puromycin Quinopristin/ Quinopristin /Dalfopristin Spectinomycin Tetracycline dr. Edhie Djohan Utama, SpMK.
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Sulfonamide (berkompetisi (berkompetisi dengan PABA) Trimethoprim (menghambat dihidrofolic acid reducctase) redu Rifampicin (Streptomyces Streptomyces,, menghambat enziim RNA pol enz poliimerase merase,, mencegah sintes sintesis is RNA) Pyrimidine y Quinolone : ((blokade blokade DNA gyrase gyrase)) - Nalidixic acid - Cyprofloxacin yp - Norfloxacin - Ofloxacin dr. Edhie Djohan Utama, SpMK.
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Quinolone Fluoroquinolones (synthetic chemicals) are broad spectrum and examples include norfloxacin, ciprofloxacin enoxacin ciprofloxacin, enoxacin, levofloxacin, and trovafloxacin. trovafloxacin. The fluoroquinolones inhibiting one or group p of enzymes y called more of a g topoisomerase, enzymes needed for bacterial nucleic acid synthesis. y dr. Edhie Djohan Utama, SpMK.
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Inhibisi Pathwayy Folic Acid oleh Sulfonamide dan Trimethoprim Sulfonamide Sulfona mide
Trimethoprim
Pteridine H2 +
PABA +
Glutamic acid
Purine FAH2 (Dihydro Dihydro--
FAH4 + C1 (Tetrahydro Tetrahydro--
folic ac acid id))
Pyrimidine
folic ac acid id))
Amino acid
9 dr. Edhie Djohan Utama, SpMK.
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Antimicrobial Spectrum p BROAD SPECTRUM : Drugs that are effective against a variety of both gramgram-positive and gram--negative bacteria (e.g., tetracycline, gram streptomycin, p y , cephalosporins, cephalosporins p p , ampicillin, ampicillin p , sulfonamides).
NARROW SPECTRUM : Those effective against just Gram (+) bacteria, just Gram (-) b t i or only bacteria, l a few f species i (e.g., penicillin G, erythromycin, clindamycin, clindamycin, gentamicin gentamicin). ). dr. Edhie Djohan Utama, SpMK.
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Range of Activity
Organisms Affected
Narrow Spectrum
Gram-positives G (Actinomyces, Macrolides (Erythromycin) Corynebacteria, Bacillus, Polypeptides (Polymyxin) Clostridium, Pyogenic cocci, Spirochetes)
Moderate Spectrum
Gram-positives plus y enteric and systemic, urinary tract Gramnegatives
Sulfonamides Aminoglycosides gy (Streptomycin, Gentamycin, Tobramycin)
Narrow/Moderate Spectrum
Gram positives plus GramGram-positives Gram negatives
Beta-lactams (Penicillin, Ampicillin, Cephalosporins)
Broad Spectrum
All prokaryotes except Mycobacteria and Pseudomonas
Chloramphenicol p Tetracycline
Anti-mycobacterial
Mycobacteria
Isoniazid Ethambutol Streptomycin Rifampin
dr. Edhie Djohan Utama, SpMK.
Example Antibiotics
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Antibacterial activity (spectrum) of antimicrobial agents. Aerobic bacteria
Anaerobic bacteria
Gram
Gram
Gram
Gram
(+)
(-)
(+)
(-)
Broad
+
+
+
+
cefoxitin, chloramphenicol, imipenam, tetracyclines
Intermediate
+
+
+
±
carbenicillin, ticarcillin, ceftiofur, penicillin/clavulanic acid, cephalosporins
+
±
+
±
ampicillin, amoxicillin
Spectrum
Narrow
+
aztreonam, polymyxin
+
±
+
+
+
aminoglycosides, spectinomycin, sulfonamides, trimethoprim
+
+
enrofloxacin
+
+
+
+ +
± : variable activity
Examples
±
+
benzyl y p penicillin G
lincosamides, macrolides,pleuromutilins, vancomycin bacitracin
+
nitroimidazoles
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Antimicrobial Effects on Cells Drugs that actually kill microorganisms are termed bactericidal bactericidal.. Drugs that only inhibit the growth of microorganisms g are termed bacteriostatic bacteriostatic.. The decision to use a bactericidal or bacteriostatic drug to treat infection depends entirely upon the type of infection. Bactericid agent agents s will kill cells that are actively growing. Bacteriostatics, Bacteriostatics, will only inhibit the growth of cells; ultimate elimination of the organisms is dependent upon host phagocytic activity.. activity dr. Edhie Djohan Utama, SpMK.
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Bactericidal and Bacteriostatic Bacteriostatic Some antimicrobial agents are cidal in action: they kill microorganisms (e.g., (e g penicillins, cephalosporins, streptomycin neomycin). streptomycin, neomycin neomycin)). ) Others are static in action: they inhibit microbial growth long enough for the body's own defenses to remove the organisms (e.g., tetracyclines, erythromycin, sulfonamides). sulfonamides). dr. Edhie Djohan Utama, SpMK.
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Choice of Antimicrobial A narrow spectrum is preferable since it will cause less destruction to the body's normal flora. Indiscriminate use of broad spectrum antibiotics can lead to superinfection by opportunistic microorganisms, i i such h as Candida C did (yeast ( t iinfections) f ti ) and Clostridium difficile (antibiotic (antibiotic--associated ulcerative colitis), when the body body'ss normal flora is destroyed. Other dangers from indiscriminate use of antimicrobial chemotherapeutic agents include drug toxicity, allergic reactions to the drug, and selection for resistant strains t i off microorganisms. microorganisms i i . dr. Edhie Djohan Utama, SpMK.
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Site of Activity
Example Antibiotics
Inhibition of cell wall integrity Lysozyme Inhibition of cell wall synthesis : 1. Biosynthetic enzymes (cytoplasmic)
F f Fosfomycin, i Cycloserine C l i
2. Membrane-bound phospholipid carrier
Bacitracin
3. Polymerization of subunits
Beta-lactams
4. Combine with wall substrates
Vancomycin
Inhibition of membrane integrity :
Surfactants, Polyenes, Polypeptides
IInhibition hibiti off membrane b synthesis :
None
Inhibition of nucleic acid integrity :
Alkylating, Intercalating agents Alkylating (mitomycin, chloroquin) 25
Inhibition of nucleic acid synthesis : 1. Metabolism of DNA
5-Fluorocytosine, Acyclovir, NTP analogs
2. Replication of DNA
Nalidixic acid, Novobiocin, Nitroimadazoles
3 Synthesis of RNA 3.
Rifampin
Protein integrity :
Phenolics, Heavy metals
Protein synthesis : 1 30S Subunit 1.
Streptomycin, Kanamycin, Tetracycline
2. 50S Subunit
Chloramphenicol, Macrolides (Clindamycin, Erythromycin)
3. Folate metabolism
Sulfonamides, Trimethoprim dr. Edhie Djohan Utama, SpMK.
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Altered Receptors : 1. Beta-lactams
Altered Penicillin Binding Proteins
2. Macrolides
Methylation of 2 adenine residues in 23S RNA of the 50S subunit
3 Rifampin 3.
Single amino acid change in RNA polymerase ß-subunit
4. Sulfonamide/trimethoprim
Altered synthetase binds pABA preferentially/altered reductase for TMP
5. Nalidixic acid
Altered gyrase
6. Streptomycin
Altered S12 protein in 30S subunit
Decreased Entry : 1. Tetracycline
Normally biphasic, active transport reduced
2. Fosfomycin (chromosomal)
Glucose-6-phosphate transport reduced
Destruction/Inactivation : 1. Chloramphenicol acetyltransferase
Acetylates chloramphenicol
2 Beta-lactamase 2. Beta lactamase
Cleaves ß-lactam ß lactam ring
3. Aminoglycosides
Acetylation or phosphorylation as drug 27 passes membrane
Side effects/Toxic effects
Examples Intestinal (C. difficile), Vaginal (Candida)
Overgrowth of pathogens Depression D i off iintestinal t ti l symbiotes Nephrotoxicity Ototoxicity - 8th cranial nerve Ophthalmic p toxicity y Aplastic anemia Hypersensitivity Bone seeking
Several Polypeptides, Aminoglycosides Aminoglycosides Ethambutol Chloramphenicol Penicillin Tetracycline
dr. Edhie Djohan Utama, SpMK.
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Cephalosporins 1st genera eneration tion
2nd genera eneration tion
3rd genera eneration tion
4th genera eneration tion
Cefadroxil
Cefaclor
Cefdinir
Cefepime
Cefazolin
Cefamandole
Cefoperaxone
Cefpirom
Cefelixin
Cefonicid
Cefotaxime
Cephalothin
Ceforanide
Ceftazidime
Cephaprin
Cefotetan
Ceftibuten
Cephradine
Cefoxitin
Ceftizoxime
Cefuroxime
Ceftriaxone
Cefixime Cefdinir Cefetamet
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The Future of Chemotherapeutic Agents Many bacterial diseases, previously treatable with antibiotics have become resistant to antibiotics. antibiotics, antibiotics Chemicals produced by plants and animals are providing new antimicrobial agents, agents, including antimicrobial peptides. New antimicrobials include DNA that is complementary to specific genes in a pathogen; the DNA will bind to the pathogen's DNA or mRNA and inhibit protein synthesis synthesis. dr. Edhie Djohan Utama, SpMK.
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Message From the Director General WHO (2000) Drug resistance is the most telling sign that we have failed to take the treat of infectious diseases seriou serio usly. It suggests that we have mishandled of disease fighting drugs, by misusing, underusing and overusing them. “A World without Antibiotics”. It could bring back to a pre pre--antibiotic age. We are vulnerable without effective medicines.
dr. Edhie Djohan Utama, SpMK.
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Impact of Resistance : Staph p aureus 99% sensitive to p penicillin G 1940's and all other Beta lactam antibiotics. Staph aureus 75% resistant to penicillin 1970's and ampicillin but still 99% sensitive to flucloxacillin and cephalosporin. Staph aureus 98% resistant to penicillin and 20% resistant to flucloxacillin and all 1990's Beta lactams. Vancomycin and Teicoplanin only therapeutic options remaining. remaining Intensive care units - Acinetobacter and 1995 Moraxella species resistant to all 1996 antibiotics tested.
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MICROBIAL RESISTANCE TO ANTIMICROBIAL CHEMOTHERAPEUTIC AGENTS A common problem in antimicrobial chemotherapy is the development of resistant strains of bacteria bacteria.. Most bacteria become resistant to antimicrobial agents by one or more of the following mechanisms: dr. Edhie Djohan Utama, SpMK.
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Mekanisme terjadinya strain resiste resisten 1. Producing enzymes which detoxify or inactivate the antibiotic, antibiotic, e.g., penicillinase and other betabeta-lactamases lactamases.. 2. Altering the target site in the bacterium to reduce d or bl block k binding bi di off the h antibiotic, antibiotic ibi i , e.g., producing a slightly altered ribosomal subunit that still functions but to which the drug can't bind. 3. Preventing transport of the antimicrobial agent into the bacterium, bacterium, eg., eg., producing an altered cytoplasmic membrane or outer membrane. membrane dr. Edhie Djohan Utama, Utama, SpMK SpMK..
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4. Developing e e op g a an a alternate te ate metabolic etabo c pathway to byby-pass the metabolic step being blocked by the antimicrobial agent, agent, e g overcoming drugs that resemble substrates e.g., and tie tie--up bacterial enzymes. 5. Increasing the production of a certain bacterial enzyme, enzyme, e.g., overcoming drugs that resemble substrates and tietie-up bacterial enzymes. dr. Edhie Djohan Utama, SpMK.
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UJI KEPEKAAN BAKTERI TERHADAP ANTIMIKROBA O CARA PENGENCERAN (Dilution Methods) : Memakai media cair Memakai media padat
Cara ini kwantitatip p dan akurat
CARA DIFUSI (Diffusion Methods) : Memakai cakram antimikroba Tablet antimikroba
Cara ini kwalitatip p dan rutin dilakukan dr. Edhie Djohan Utama, SpMK.
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CARA PENGENCERAN KWANTITATIP KHM (Kadar Hambatan Minimal = MIC) KBM (Kadar Bunuh Bunuh Minimal = MBC) AKURAT UNTUK PENELITIAN / PERMINTAAN KHUSUS
dr. Edhie Djohan Utama, SpMK.
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CARA PENGENCERAN (lanjutan) MEDIA CAIR Cara Makro : seri 12 tabung reaksi Cara Mikro : plat mikrotiter ikrotiter,, pipet mikro MEDIA PADAT Mueller Hinton Agar g AM diencerkan kelipatan dua (1 ug, ug, 0,5 ug ug,, 0 25 ug 0.25 ug.. 0.125 0 125 ug ug,, dst dst)) Larutan bakteri log phase MacFarland 1 dr. Edhie Djohan Utama, SpMK.
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CARA DIFUSI MEDIA :
Mueller Hinton Agar g atau Sensitest Agar Jika bakteri fastidi fastidiu us : Agar Darah BAKTERI : Bakteri Log phase, phase kelarutan MacFarland 0,5 05 Disemaikan dengan kapas lidi steril 3 streak CAKRAM : Kertas saring Tablet dr. Edhie Djohan Utama, SpMK.
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MEMBACA DAERAH INHIBISI Daerah inhibisi diukur menggunakan gg kaliper p (jjangka g sorong)) atau penggaris sorong Lebar daerah inhibisi di disesuaikan ik dengan d daftar d f dari setiap AM dan Bakteri yang y g diujij kepekaannya p y (setelah dieramkan 18 18--24 jam). Di Dinyatakan: Dinyatakan t k : Sensitif (susceptible Sensitif usceptible), ), Hampir p resisten resisten,, Resisten dr. Edhie Djohan Utama, SpMK.
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ANTIMIKROBA
GENUS
Kandungan disk (cakram AM)
Diameter Zona Hambat (mm) Resisten
Intermediat
Sensitif
14-16
>17
β-LACTAMS
Ampicillin
Carbenicillin
Enterobacteriaceae
10 µg
<13
Staphylococci
10 µg
<28
>29
Enterococci
10 µg
<16
>17
Pseudomonas
100 µg
<13
14-16
>16
Gram (-)
100 µg
<19
20-22
>23
13-Oct
>14
Methicillin
Staphylococci
5 µg
<9
Mezlocillin
Pseudomonas
75 µg
<15
Other Gram (-)
75 µg
<17
18-20
>21
Nafcillin
Staphylococci
1 µg
<10
12-Nov
>13
Oxacillin
Staphylococci
1 µg
<10
12-Nov
>13
Penicillin
Staphylococci
10 units
<28
>29
Enterococci
10 units
<14
>15
Pseudomonas
100 µg
<17
>18
Other Gram (-)
100 µg
<17
Piperacillin
dr. Edhie Djohan Utama, SpMK.
>16
18-20
>21 41
FAKTOR PENYEBAB RESISTENSI Faktor non genetik : AM akan resisten jika bukan pada masa aktif pembelahan bakteri. Pada umumnya semua AM baru bisa bekerja baik pada masa aktif aktif pembelahan bakteri bakteri.. Hilangnya struktur target untuk AM ((kehilangan kehilangan dinding g sel sel)), sehingga gg obat betalaktam jjadi resisten.. resisten Faktor genetik : Terjadi per peru ubahan genetik menimbulkan resistensi bakteri bakteri.. Resistensi kromosomal R i t Resistensi i ekstrakromosomal k t k l (melalui ( l l i Plasmid) Pl id) 42
CARA TERJADINYA RESISTENSI INTRINSIC : Hal ini biasa untuk semua spe spessies dimana spes spesies tertentu tid k mempunyai tidak memp n i target t get atau t reseptor e epto untuk nt k antimikroba, antimikroba ntimik ob , atau ada barrier alamiah a.l.: a.l.: = Bakteri a e a anaerob ae ob terhadap e adap Aminoglik Aminogl og ikosid osida os da da = Streptococcus resisten terhadap Aminogl Aminoglik ikosid osida a karena mempunyai /adanya barier alamiah alamiah.. = Enterobacteriaceae resisten terhadap PNCPNC-G
ACQUIRED : FAKTOR EKSTRA KHROMOSOMAL Modifikasi genetik karena mutasi, mutasi, tranfer gene melalui transfer Plasmid (transformasi, transduksi, konyugasi) sebab Plasmid membawa R Factor atau transposon dr. Edhie Djohan Utama, SpMK.
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PLASMID Plasmid = closed loop of DNA, elemen geneti genetikk yg sangat kecil (berat kira2 1 1--3% kromosom bakteri) bakteri), di luar kromosom romosom,, membawa gen resisten terhadap antimikroba antimikroba.. Mampu bereplikasi bereplikasi di dalam sel bakteri secara autonom Bisa berpindah antar spe spessies (broad host range) Berada bebas dalam sitoplasma bakteri Salah satu Plasmid adalah R Factor, beberapa R Factor membawa transposon (gen resisten yang bisa berpindah dari satu Plasmid ke Plasmid lainnya atau ke kromosom). Kini dikenal lagi INTEGRON Contoh lain : toksin bakteri dan faktor F ((fertility) y). dr. Edhie Djohan Utama, Utama, SpMK SpMK..
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CARA PERPINDAHAN GEN TRANSDUKSI Plasmid DNA via Bak Bakteriof teriofaga aga (biasa bakteri Gam positip positip)) ditransfer ke populasi kuman lain. lain
TRANSFORMASI (fragment DNA bebas dapat melewati
dinding sel dan kemudian bersatu dalam genom sel) sel). Biasa dil k k di laboratorium dilakukan l b t i (rekayasa k genetik) genetik tik)). Pindah tik Pi d h secara spontan KONYUGASI Melalui Fertility Factor maka RTF (Resista (Resistant Transfer Factor) pindah dari satu sel ke sel lain sering menyebabkan multidrug resisten resisten..
TRANSLOKASI / TRANSPOSISI Perpindahan bagian kromosom dalam sel dr. Edhie Djohan Utama, SpMK.
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CONJUGATIVE TRANSPOSON Telah dikenal type baru elemen conjugative yaitu Conjugative Transposon Terdapat didalam khromosom bakteri. bakteri. Conjugative Transposon terintegrasi didalam Plasmid atau gg lebih susah untuk berada di dalam khromosom bakteri sehingga dideteksi.. dideteksi Ada kemungkinan bertanggung jawab dalam kebanyakan transfer Plasmid
Transfer terjadi tidak hanya antar species pada group Bakteri Gram(+) atau antar group Bakteri Gram ((-) tetapi juga antara Bakteri Gram (+) dan Bakteri Gram ((--)
Transposons or "jumping genes" are capable of integration into the chromosome of a bacteria or into plasmids. The can be a whole gene or part of a gene. dr. Edhie Djohan Utama, SpMK.
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INTEGRON KINI DIKENAL ELEMENT INTERGRATING BARU = INTEGRON INTEGRON BERTANGGUNG JAWAB UNUN-TUK BERBAGAI PLSMID YANG MEMBAMEMBA-WA MULTIPLE DRUG RESISTANCE GENE INTEGRON SEPERTI TRANSPOSON ADALAH SEGMEN DNA LINEAR. LINEAR
dr. Edhie Djohan Utama, SpMK.
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RESISTENSI PADA BETALAKTAM : Enzim β-laktamase yang dihasilkan bakteri membuka Enzi ( l (cleaves) ) cincin i i β-laktam l kt sehingga hi tdk aktif akti ktiff. Bakteri kti B kt i Gram(--) menghasilkan β-la Gram( lak ktamase dalam periplasma sedangkan bakteri Gram(+) : dalam cairan ekstraselula ekstraselular. Tidak adanya PBP (Penicillin Binding Protein) reseptor bakteri menjadi resisten. resisten. (Alteration of the target of the antibiotic) Dalam hal ini penambahan β-laktamase inhibitor tidak berguna. berguna.
dr. Edhie Djohan Utama, SpMK.
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RESISTENSI PADA BETALAKTAM : Betalaktam tidak berhasil mengaktivasi g autolytic enzyme (yang menghancurkan peptidoglik peptidogl ikan), an), sehingga bakteri menjadi toleran.. toleran Resisten terhadap AM Glycopeptide : walau belum jelas benar benar,, tetapi 2 gene (vanA (vanA & vanH)) yang terlibat menyevanH menye-babkan dihasilkan protein yang berbeda yang tidak mengimengi-kat V Vancomycin. Vancomycin i .
dr. Edhie Djohan Utama, SpMK.
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ANTI ENZYME BETALACTAMASE Obat gol. gol. betalaktam menjadi resisten karena bakteri menghasilkan enzim betalaktamase yang menghancurkan cincin beta beta--laktam dari obat obat.. Enzim betalaktamase tersebut bisa dirusak dengan Enzi menambahkan b hk salah l h satu t zatt di bawah b h ini i i:
+ Clavulanic acid (Augmentin (Augmentin)) + Sulbactam (Sulperazon) Sulperazon) + Tazobactam ob c (Piperacillin pe c + Tazobactam) Tazobactam ob c ) Penambahan salah satu zat diatas menyebabkan obat golongan g g betalaktam menjadi j sensitif sensitif kembali kembali.. dr. Edhie Djohan Utama, SpMK.
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MRSA,, VISA, MRSA VISA, VRSA, VRSA, ESBLs MRSA : Meth Methiicillincillin-resistant S. aureus MRSA refers to a type of bacteria (Staphylococcus aureus) that is resistant to many antibiotics. It is a common cause of hospital hospitalp -acquired q infections. • Mupirocin ointment has also shown promising results in decreasing g nasal carriage. g Wide spread p use is only indicated in certain settings to avoid mupirocin resistance.
VISA : Vancomycin Interme Intermediate S. aureus VRSA : Vancomycin Resistant S. aureus dr. Edhie Djohan Utama, SpMK.
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ESBL = Extended spectrum p beta lactamase lactamase.. This term refers to beta lactamase enzymes produced mainly by Klebsiella and E. coli that encode for resistance to broadbroad-spectrum β-lactam antibiotics that normally have activity against Gram (-) bacilli. Examples are cefotaxime cefotaxime,, ceftriaxone ceftriaxone,, ceftazidime,, aztreonam and cefpodoxime. ceftazidime cefpodoxime. These enzymes are not active against the cephamycins,, and are inhibited by clavulanic cephamycins acid. id dr. Edhie Djohan Utama, SpMK.
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AMINOGLIK AMINOGL IKOSID OSIDA A Bakteri Bak terissidal, idal, inak inakti tiff pd pH rendah dan anaerob dan MO intras intraselular Sinergistik dengan grup BetaBeta-la lakktam Ampuh untuk bakteri Batang Gram (-) Toks To ksiik pada dosis tinggi Menghambat sintes sintesis is protein dengan ber berikatan ikatan pada 30S ribosomal unit sehingga tjd misreading mRNA Streptomycin, Kanamycin, Kanamycin, Gentamycin, Gentamycin, Tobramycin,, Amikacin Tobramycin Amikacin,, Netilmicin dr. Edhie Djohan Utama, SpMK.
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RESISTENSI PADA AMINOGLIK AMINOGLIKOSID OSIDA A Reseptor subunit 30 S hilang Terdapat enz enziim yang menghancurkan obat (acethylase acethylase,, adenylase dan fosforilase)) fosforilase P Permeabilitas bilit terhadap t h d obat b t turun t turun, , transport obat ke dalam sel berkurang sehingga hi tidak tid k mencapaii Ribosom Rib
dr. Edhie Djohan Utama, SpMK.
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IMPLIKASI KLINIS RESISTENSI Timbulnya resistensi bakteri terhadap antimikroba bahkan terjadinya multiple drugs resisten (MDR) bisa mengundang banyak problem berat dalam pengobatan penyakit infeksi Timbulnya “Kuman Rumah Sakit” yang amat resisten sebab RS sering menggunakan dosis tinggi dan dalam intensitas tinggi. Antibiotik baru perlu riset yg lama (10(10-20 tahun) sehingga bisa terjadi tiadanya antibiotika yang bisa digunakan untuk mengobati penyakit infeksi. dr. Edhie Djohan Utama, SpMK.
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Prevention and control of antibiotic resistance Reduce selective pressures: 1. Use antibiotics for bacterial disease 1 2. Use appropriate dosing and length of time 3. Change medication if ineffective 4 U 4. Use appropriate i t medication di ti ffor a specific ifi site it 5. Stop use of antibiotics in the animal husbandry for growth p promotion 6. Regulate prescribing practices in veterinary medicine 7. Establish antibiotic prescribing practices and distribution especially in countries that allow over the counter medications without precripton 8. Educate the public to the dangers of overuse/misuse of antibiotics tibi ti dr. Edhie Djohan Utama, SpMK.
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Antifungal Drugs 1.Polyenes, such as nystatin and amphotericin B, combine bi with ith plasma l membrane b sterols t l andd are fungicidal. 2. Azoles interfere with sterol synthesis and are used to treat cutaneous and systemic mycoses. mycoses 3. Griseofulvin interferes with eukaryotic cell division and is used primarily to treat skin infections caused by fungi. dr. Edhie Djohan Utama, SpMK.
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Antifungals g that bind sterols : Membrane structural differences : The composition of the fungal plasma membrane differs from the composition of the mammalian plasma membrane particular in terms of the presence or absence of certain kinds of sterols. sterols There exist antibiotics that, consequently, more effectively recognize fungal plasma membrane than mammalian plasma membrane. Examples include: = amphotericin B = nystatin = ketoconazole = miconazole dr. Edhie Djohan Utama, SpMK.
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Antiviral Drugs g 1. Amantadine blocks p penetration or uncoating g of influenza A virus. virus. 2 Nucleoside and nucleotide analogs such as acyclovir 2. acyclovir,, AZT,, ddI AZT ddI,, and ddC inhibit DNA or RNA synthesis. synthesis. 3 Protease inhibitors, 3. inhibitors, such as indinavir and saquinavir saquinavir,, block activity of an HIV enzyme essential for assembly of a new viral coat. coat. 4. Alpha Alpha--interferons inhibit the spread of viruses to new cells. cells dr. Edhie Djohan Utama, SpMK.
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dr. Edhie Djohan Utama, SpMK.
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