ANTIMIKROBA DAN UJI KEPEKAANDAN UJI KEPEKAAN - …ocw.usu.ac.id/course/download/1110000102-basic-biology-of-cell-3/... · zMenghambathambat sintes sintesisis dinding sel bakteri zMerusak

ANTIMIKROBAANTIMIKROBAANTIMIKROBAANTIMIKROBADAN UJI KEPEKAANDAN UJI KEPEKAANDAN UJI KEPEKAANDAN UJI KEPEKAAN

dr. Evita Mayasari, MKes.dr. Evita Mayasari, MKes.

Medical Faculty, University of Sumatera UtaraMedical Faculty, University of Sumatera Utara

OBAT ANTIMIKROBAOBAT ANTIMIKROBAOBAT ANTIMIKROBAOBAT ANTIMIKROBA

ObatObat yangyang digunakandigunakan untukuntuk menghambatmenghambatObat Obat yang yang digunakandigunakan untukuntuk menghambatmenghambatpertumbuhanpertumbuhan dandan atauatau membunuhmembunuh bakteribakteripenyebabpenyebab infeksiinfeksi yang yang dapatdapat diberikandiberikan per oral, per oral, parenteralparenteral atauatau lokallokal sebagaisebagai obatobat luarluarparenteralparenteral atauatau lokallokal sebagaisebagai obatobat luarluar..

AntibiotikaAntibiotika bahanbahan yang yang dihasilkandihasilkan oleholeh ““biotikbiotik” ” tt kkhl khl k hidhid // ik iik i titiatauatau mamakkhlukhluk hiduphidup//mikroorganismemikroorganisme sepertiseperti

BakteriBakteri, , ActinomycetesActinomycetes, , jamurjamur..

22dr. dr. EdhieEdhie DjohanDjohan UtamaUtama, , SpMKSpMK..

ANTIMIKROBAANTIMIKROBAANTIMIKROBAANTIMIKROBA

ANTIBIOTIKA ANTIBIOTIKA CHEMOTHERAPEUTIKACHEMOTHERAPEUTIKAANTI FUNGUSANTI FUNGUSANTI VIRUSANTI VIRUSANTI VIRUSANTI VIRUS

ANTISEPTIKA ANTISEPTIKA DESINFEKTANSIADESINFEKTANSIA


PENEMUAN AWAL ANTIMIKROBAPENEMUAN AWAL ANTIMIKROBAPENEMUAN AWAL ANTIMIKROBAPENEMUAN AWAL ANTIMIKROBASALVARSAN : SALVARSAN : ditemukanditemukan padapada awalawal tahuntahun 1900 1900 oleholeh Paul EhrlichPaul Ehrlich untukuntuk pengobatanpengobatan penyakitpenyakitoleholeh Paul Ehrlich Paul Ehrlich untukuntuk pengobatanpengobatan penyakitpenyakitSyphilis.(Noble Prize)Syphilis.(Noble Prize)PRONTOSIL (Sulfonamide)PRONTOSIL (Sulfonamide) OlehOleh Gerard Domagk Gerard Domagk 19271927 dandan penggunaannyapenggunaannya tahuntahun 1935 (Noble1935 (Noble1927 1927 dandan penggunaannyapenggunaannya tahuntahun 1935 (Noble 1935 (Noble Prize)Prize)SULFADIAZINE 693 = SulfanilamideSULFADIAZINE 693 = Sulfanilamide oleholeh British British TeamTeam pimpinanpimpinan A J EvansA J Evans tahuntahun 19381938Team Team pimpinanpimpinan A.J.EvansA.J.Evans tahuntahun 19381938PENICILLINPENICILLIN oleholeh Alexander FlAlexander Fleemmingmming tahuntahun 1929 1929 dandan penggunaannyapenggunaannya tahuntahun 1940 (Noble Prize)1940 (Noble Prize)NYSTATINNYSTATIN : : antifungantifungalal pertamapertama dijumpaidijumpai tahuntahun1949 1949 oleholeh Elisabeth Hazen & BrownElisabeth Hazen & BrownSTREPTOMYCINSTREPTOMYCIN oleholeh Selman Waksman Selman Waksman tahuntahun1940 (Noble Prize)1940 (Noble Prize)

44

MIKROORGANISME YANG MENGHASILKAN MIKROORGANISME YANG MENGHASILKAN AANTINTIMIKROBAMIKROBA

BakteriBakteriActinomycetesActinomycetes (2100) ((2100) (StreptomycesStreptomyces))(400) (Genus Bacillus)(400) (Genus Bacillus)

Fungi (800) Fungi (800) (Mold = (Mold = PenicilliumPenicillium & & CephalosporiumCephalosporium))

AlgaeAlgaeProtozoaProtozoaProtozoaProtozoa

55dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK.

JENIS DAN CARA KERJAJENIS DAN CARA KERJAANTIMIKROBAANTIMIKROBA

MenghambatMenghambat sintessintesisis dindingdinding selsel bakteribakteriMerusakMerusak permeabilitaspermeabilitas membranmembranppsisitoplasmatoplasmaMenghambatMenghambat sintessintesisis proteinprotein..MenghambatMenghambat sintessintesisis proteinprotein..MenghambatMenghambat sintessintesisis asamasam nunukkleatleat..


PENICICLLIN (Mold = PENICICLLIN (Mold = PenicilliumPenicillium))PNCPNC--G G dandan Penicillin VPenicillin VMethicillinMethicillin OxacillinOxacillin CloxacillinCloxacillin DicloxacillinDicloxacillinMethicillinMethicillin, , OxacillinOxacillin, , CloxacillinCloxacillin, , DicloxacillinDicloxacillinAmpicillinAmpicillin & & AmoxacillinAmoxacillin, , CarbenicillinCarbenicillin, , TicarcillinTicarcillin, , PiperacillinPiperacillin, , MezlocillinMezlocillin

CEPHALOSPORIN (CEPHALOSPORIN ( ldld C h l iC h l i ))CEPHALOSPORIN (CEPHALOSPORIN (mold = mold = CephalosporiumCephalosporium))Gen.IGen.I : : CefachlorCefachlor, , CephalothinCephalothin, , CephalexinCephalexinGen.IIGen.II : : CefuroximCefuroxim, , CefiximeCefixime, , CefoxitinCefoxitinGen.III : Gen.III : CefotaximeCefotaxime, , CeftriaxoneCeftriaxone, , CefoperazonCefoperazonGen.IVGen.IV : : CefepimeCefepime, , CefpiromCefpirom

CARBAPENEMCARBAPENEM :: ImipenemImipenem && MeropenemMeropenemCARBAPENEM CARBAPENEM : : ImipenemImipenem & & MeropenemMeropenemMONOBACTAM MONOBACTAM : : AztreonamAztreonamGLYCOPEPTIDEGLYCOPEPTIDE : : VancomycinVancomycin dandan TeichoplaninTeichoplaninCYCLOSERINECYCLOSERINE :: d li tid li ti tbtbCYCLOSERINECYCLOSERINE : : second line anti second line anti tbctbcBACITRACINBACITRACIN : : UntukUntuk infeksi kulit infeksi kulit superfisuperfissialial 77

PENICILLIN GROUPPENICILLIN GROUP

PenicillinsPenicillins:: penicillin G (penicillin G (PfizerpenPfizerpen; ; BicillinBicillin; ; WycillinWycillin), ), penicillin V (penicillin V (BetapenBetapen; Pen; Pen--VeeVee K), K), methicillinmethicillin ((StaphcillinStaphcillin), ), ampicillinampicillin ((OmnipenOmnipen;; PolycillinPolycillin)) oxacillinoxacillin ((BactocillBactocill ))ampicillinampicillin ((OmnipenOmnipen; ; PolycillinPolycillin), ), oxacillinoxacillin ((BactocillBactocill ), ), amoxicillin (amoxicillin (AmoxilAmoxil; ; BiomoxBiomox; ; PolymoxPolymox), ), ticarcillinticarcillin ((TicarTicar), ), carbenicillincarbenicillin ((GeocillinGeocillin), ), piperacillinpiperacillin ((PipracilPipracil), ), mezlocillinmezlocillin((MezlinMezlin), ), bacampicillinbacampicillin ((SpectrobidSpectrobid), ), dicloxacillindicloxacillin ((DynapenDynapen), ), (( ),), pp (( pp ),), (( y py p ),),nafcillinnafcillin ((NallpenNallpen; ; UnipenUnipen).).

PenicillinsPenicillins plus plus ββ--lactamaselactamase inhibitorsinhibitors or compounds or compounds pre enting antibiotic degradation on the kidne spre enting antibiotic degradation on the kidne s::preventing antibiotic degradation on the kidneyspreventing antibiotic degradation on the kidneys: :

amoxicillin + amoxicillin + clavulanateclavulanate ((AugmentinAugmentin), ), ticarcillinticarcillin + + clavulanateclavulanate ((TimentinTimentin), ),

i illii illi ++ lb tlb t ((UU ))ampicillinampicillin + + sulbactamsulbactam ((UnasynUnasyn), ), piperacillinpiperacillin + + tazobactamtazobactam ((ZosynZosyn), ), imipenemimipenem + + cilastatincilastatin ((PrimaxinPrimaxin) . ) .


BETALACTAM GROUPS

99

STRUKTUR DINDING GRAM (+) & GRAM (STRUKTUR DINDING GRAM (+) & GRAM (--))


AmphotericinAmphotericin BB-- AmphotericinAmphotericin BB-- NystatinNystatin-- ColistinColistin-- PolymixinPolymixinPolymixinPolymixin

TidakTidak digunakandigunakan untukuntuk obatobat sistemiksistemik karenakarena toksiktoksik


::

-- ChloramphenicolChloramphenicol (50S)(50S) -- AminoglycosideAminoglycoside (30S)(30S)-- Erythromycin (50S)Erythromycin (50S) -- TetracyclinTetracyclin (30S)(30S)Erythromycin (50S) Erythromycin (50S) TetracyclinTetracyclin (30S)(30S)-- LyncomycinLyncomycin (50S)(50S)

RibosomRibosom MamaliaMamalia 80S, 80S, sedangkansedangkan bakteribakteri 70S, 70S, reseptorreseptordd b it 30Sb it 30S tt 50S50Spadapada subunit 30S subunit 30S atauatau 50S.50S.

MacrolidesMacrolides : erythromycin, : erythromycin, roxithromycinroxithromycin, , clarithromycinclarithromycin, , azithromycinazithromycin;; digunakan untuk bakteri Gdigunakan untuk bakteri Gramram (+)(+) ddan an beberapa bakteri Gbeberapa bakteri Gramram ((--))..

LincomycinLincomycin dandan ClindamycinClindamycin umumnya digunakan untukbakteri Gram (+).(+).


AminoglycosideAminoglycoside : : Streptomycin, Streptomycin, kanamycinkanamycin, , tobramycintobramycin, and , and amikacinamikacin..Most of Most of AminoglycosideAminoglycoside are effective are effective against against GGramram (+)(+) and and GGramram ((--)) bacteria.bacteria.A i l idA i l id b i id lb i id l hhAminoglycosideAminoglycoside ::bactericidalbactericidal,, others: others: bacteriostatibacteriostaticc


Selective antimicrobial action to a specific Selective antimicrobial action to a specific tt k th 70S ib f b t itt k th 70S ib f b t iattack on the 70S ribosome of bacteriaattack on the 70S ribosome of bacteria

Several medically important antibiotics owe their Several medically important antibiotics owe their y py pselective antimicrobial action to a specific attack on the selective antimicrobial action to a specific attack on the 70S ribosome of bacteria70S ribosome of bacteria, with , with mammalian 80S mammalian 80S ribosomesribosomes left unaffectedleft unaffectedribosomesribosomes left unaffected. left unaffected.

Those that act on the 30S ribosome are:Those that act on the 30S ribosome are:AmikacinAmikacinAmikacinAmikacinGentamycinGentamycinKanamycinKanamycin

iiNeomycinNeomycinStreptomycinStreptomycinTobramycinTobramycinyy


Antibiotics that act on the 50S Antibiotics that act on the 50S i f h ib i l di f h ib i l dportion of the ribosome include:portion of the ribosome include:

ChloramphenicolChloramphenicolClindamycinClindamycinFuradantinFuradantinFuradantinFuradantinFusidicFusidic acidacidLincomycinLincomycinNitrofuranNitrofuranNitrofuranNitrofuranPuromycinPuromycinQuinopristinQuinopristin//DalfopristinDalfopristinSpectinomycinSpectinomycinTetracyclineTetracycline


Sulfonamide (Sulfonamide (berkompetisiberkompetisi dengandengan PABA)PABA)Sulfonamide (Sulfonamide (berkompetisiberkompetisi dengandengan PABA)PABA)TrimethoprimTrimethoprim ((menghambatmenghambat dihidrofolicdihidrofolic acid acid redureducctasetase))redureducctasetase))RifampicinRifampicin ((StreptomycesStreptomyces,, menghambatmenghambatenzenziim RNAm RNA polpoliimerasemerase,, mencegahmencegah sintessintesisisenzenziim RNA m RNA polpoliimerasemerase, , mencegah mencegah sintessintesisisRNA)RNA)PyrimidinePyrimidineyyQuinoloneQuinolone : (: (blokadeblokade DNA DNA gyrasegyrase))-- NalidixicNalidixic acidacid -- CyprofloxacinCyprofloxacinypyp-- NorfloxacinNorfloxacin -- OfloxacinOfloxacin


QuinoloneQuinoloneFluoroquinolonesFluoroquinolones (synthetic (synthetic chemicals) are broad spectrum andchemicals) are broad spectrum andchemicals) are broad spectrum and chemicals) are broad spectrum and examples include examples include norfloxacin, norfloxacin, ciprofloxacin enoxacinciprofloxacin enoxacinciprofloxacin, enoxacin, ciprofloxacin, enoxacin, levofloxacin, and trovafloxacinlevofloxacin, and trovafloxacin. .

The fluoroquinolones inhibiting one or The fluoroquinolones inhibiting one or more of a group of enzymes called more of a group of enzymes called g p yg p ytopoisomerase, enzymes needed for topoisomerase, enzymes needed for bacterial nucleic acid synthesis. bacterial nucleic acid synthesis. yy


InhibisiInhibisi Pathway Folic Acid Pathway Folic Acid oleholehyySulfonamide Sulfonamide dandan TrimethoprimTrimethoprim

SulfonaSulfonamide mide TrimethoprimTrimethoprimPteridinePteridine HH22

++ PurinePurine

P A B AP A B A FAHFAH22 FAHFAH4 + 4 + CC11

++ ((DihydroDihydro ((TetrahydroTetrahydro PyrimidinePyrimidine++ ((DihydroDihydro-- ((TetrahydroTetrahydro-- PyrimidinePyrimidine

GlutamicGlutamic acidacid folic acfolic acidid)) folic acfolic acidid))

Amino acidAmino acid


Antimicrobial SpectrumAntimicrobial SpectrumppBROAD SPECTRUMBROAD SPECTRUM : Drugs that are effective : Drugs that are effective against a variety of both gramagainst a variety of both gram--positive andpositive andagainst a variety of both gramagainst a variety of both gram--positive and positive and gramgram--negative bacteria negative bacteria (e.g., tetracycline, (e.g., tetracycline, streptomycin, streptomycin, cephalosporinscephalosporins, , ampicillinampicillin, , p y ,p y , p pp p ,, pp ,,sulfonamides).sulfonamides).

NARROW SPECTRUMNARROW SPECTRUM : Those effective : Those effective against just against just GGramram (+)(+) bacteria, just bacteria, just GGram ram ((--))b t i l f ib t i l f ibacteria, or only a few speciesbacteria, or only a few species (e.g., penicillin G, (e.g., penicillin G, erythromycin, erythromycin, clindamycinclindamycin, , gentamicingentamicin).).


Range of Activity Organisms Affected Example Antibiotics

G

Narrow Spectrum

Gram-positives (Actinomyces, Corynebacteria, Bacillus, Clostridium, Pyogenic cocci,

Macrolides (Erythromycin) Polypeptides (Polymyxin)Clostridium, Pyogenic cocci,

Spirochetes)

Moderate SpectrumGram-positives plus systemic, enteric and

Sulfonamides Aminoglycosides Moderate Spectrum y

urinary tract Gram-negatives

g y(Streptomycin, Gentamycin, Tobramycin)

Narrow/Moderate Gram-positives plus Gram- Beta-lactams Narrow/Moderate Spectrum

Gram positives plus Gramnegatives (Penicillin, Ampicillin,

Cephalosporins)

Broad SpectrumAll prokaryotes except Mycobacteria and Chloramphenicol Broad Spectrum Mycobacteria and Pseudomonas

pTetracycline

Isoniazid EthambutolAnti-mycobacterial Mycobacteria Isoniazid EthambutolStreptomycin Rifampin


Antibacterial activity (spectrum) of antimicrobial agents.Aerobicbacteria

Anaerobic bacteria

Spectrum Gram Gram Gram GramExamples(+) (-) (+) (-)

Broad + + + + cefoxitin, chloramphenicol, imipenam, tetracyclines

Intermediate + + + ± carbenicillin, ticarcillin, ceftiofur, penicillin/clavulanic acid, cephalosporins

+ ± + ± ampicillin, amoxicillinNarrow + aztreonam, polymyxin

+ ± + ± benzyl penicillin Gy p+ + aminoglycosides, spectinomycin,

sulfonamides, trimethoprim+ + enrofloxacinenrofloxacin+ + + lincosamides, macrolides,pleuromutilins,

vancomycin

+ + bacitracin+ + bacitracin+ + nitroimidazoles

± : variable activity

2121

Antimicrobial Effects on CellsAntimicrobial Effects on CellsDrugs that actually kill microorganisms are Drugs that actually kill microorganisms are termed termed bactericidalbactericidal..Drugs that only inhibit the growth of Drugs that only inhibit the growth of microorganisms are termed microorganisms are termed bacteriostaticbacteriostatic..gg

The decision to use a bactericidal or The decision to use a bactericidal or bacteriostaticbacteriostatic drug to treat infectiondrug to treat infection dependsdependsbacteriostaticbacteriostatic drug to treat infection drug to treat infection depends depends entirely upon the type of infection. entirely upon the type of infection. BBactericidactericid agentagents will kill cells that are activelys will kill cells that are activelyBBactericidactericid agentagents will kill cells that are actively s will kill cells that are actively growing. growing. BacteriostaticsBacteriostatics, will only inhibit the , will only inhibit the growth of cells; ultimate elimination of the growth of cells; ultimate elimination of the organisms is organisms is dependent upon host dependent upon host phagocyticphagocyticactivityactivity. . 2222dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK.

Bactericidal Bactericidal andand BacteriostatiBacteriostaticcSome antimicrobial agents are Some antimicrobial agents are cidalcidal in in action: they kill microorganisms (e gaction: they kill microorganisms (e gaction: they kill microorganisms (e.g., action: they kill microorganisms (e.g., penicillins, cephalosporins, penicillins, cephalosporins, streptomycin neomycinstreptomycin neomycin))streptomycin, neomycinstreptomycin, neomycin). ).

Others are Others are static static in action: they inhibit in action: they inhibit microbial growth long enough for the microbial growth long enough for the body's own defenses to remove the body's own defenses to remove the organisms (e.g., organisms (e.g., tetracyclines, tetracyclines, erythromycin, sulfonamideserythromycin, sulfonamides). ).


Choice of AntimicrobialChoice of AntimicrobialA narrow spectrum is preferableA narrow spectrum is preferable since it will cause less since it will cause less destruction to the body's normal flora.destruction to the body's normal flora.

Indiscriminate use of broad spectrum antibiotics can Indiscriminate use of broad spectrum antibiotics can lead to lead to superinfectionsuperinfection by opportunistic by opportunistic

i i hi i h C didC did ( t i f ti )( t i f ti )microorganisms, such as microorganisms, such as CandidaCandida (yeast infections) (yeast infections) and and Clostridium Clostridium difficiledifficile (antibiotic(antibiotic--associated associated ulcerative colitis), when the body's normal flora isulcerative colitis), when the body's normal flora isulcerative colitis), when the body s normal flora is ulcerative colitis), when the body s normal flora is destroyed. destroyed.

Other dangers from indiscriminate use of antimicrobialOther dangers from indiscriminate use of antimicrobialOther dangers from indiscriminate use of antimicrobial Other dangers from indiscriminate use of antimicrobial chemotherapeutic agents include chemotherapeutic agents include drug toxicity, allergic drug toxicity, allergic reactions to the drug, and selection for resistant reactions to the drug, and selection for resistant t i f i it i f i istrains of microorganismsstrains of microorganisms. .


Site of Activity Example AntibioticsInhibition of cell wall integrity LysozymeInhibition of cell wall integrity Lysozyme

Inhibition of cell wall synthesis :1. Biosynthetic enzymes F f i C l i1. Biosynthetic enzymes (cytoplasmic) Fosfomycin, Cycloserine

2. Membrane-bound phospholipid carrier Bacitracincarrier3. Polymerization of subunits Beta-lactams4. Combine with wall substrates VancomycinInhibition of membrane integrity :

Surfactants, Polyenes, Polypeptides

I hibiti f bInhibition of membrane synthesis : None

Inhibition of nucleic acid Alkylating Intercalating agentsInhibition of nucleic acid integrity :

Alkylating, Intercalating agents (mitomycin, chloroquin)

2525

Inhibition of nucleic acid synthesis :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 Rifampin3. Synthesis of RNA Rifampin

Protein integrity : Phenolics, Heavy metals

Protein synthesis :

1 30S Subunit Streptomycin, Kanamycin, 1. 30S Subunit Tetracycline

2. 50S Subunit Chloramphenicol, Macrolides (Clindamycin, Erythromycin)

3. Folate metabolism Sulfonamides, Trimethoprim2626dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK.

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 Single amino acid change in RNA 3. Rifampin polymerase ß-subunit

4. Sulfonamide/trimethoprim Altered synthetase binds pABA preferentially/altered reductase for TMP

5. Nalidixic acid Altered gyrase6. Streptomycin Altered S12 protein in 30S subunit

Decreased Entry :Decreased Entry :1. Tetracycline Normally biphasic, active transport reduced2. Fosfomycin (chromosomal) Glucose-6-phosphate transport reduced

Destruction/Inactivation :1. Chloramphenicol acetyltransferase Acetylates chloramphenicol2 Beta-lactamase Cleaves ß-lactam ring2. Beta lactamase Cleaves ß lactam ring

3. Aminoglycosides Acetylation or phosphorylation as drug passes membrane 2727

Side effects/Toxic effects Examples

Overgrowth of pathogens Intestinal (C. difficile), Vaginal (Candida)

D i f i t ti lDepression of intestinal symbiotes Several

Nephrotoxicity Polypeptides, AminoglycosidesNephrotoxicity Polypeptides, AminoglycosidesOtotoxicity - 8th cranial nerve AminoglycosidesOphthalmic toxicity Ethambutolp yAplastic anemia ChloramphenicolHypersensitivity PenicillinBone seeking Tetracycline


CephalosporinsCephalosporins1st 1st

ggeneraenerationtion2nd 2nd

ggeneraenerationtion3rd 3rd

ggeneraenerationtion4th 4th

ggeneraenerationtion

Cefadroxil Cefaclor Cefdinir CefepimeCefazolin Cefamandole Cefoperaxone CefpiromCefelixin Cefonicid Cefotaxime

Cephalothin Ceforanide CeftazidimeCephaprin Cefotetan CeftibutenCephradine Cefoxitin Ceftizoxime

Cefuroxime CeftriaxoneCefiximeCefdinir

Cefetamet2929

The Future of Chemotherapeutic AgentsThe Future of Chemotherapeutic AgentsMany bacterial diseases, previously treatable with Many bacterial diseases, previously treatable with antibiotics have becomeantibiotics have become resistantresistant to antibioticsto antibioticsantibiotics, have become antibiotics, have become resistantresistant to antibiotics.to antibiotics.

Chemicals produced by plants and animals are Chemicals produced by plants and animals are providing providing new antimicrobial agentsnew antimicrobial agents, including , including antimicrobial peptides.antimicrobial peptides.

New antimicrobials include DNA that is New antimicrobials include DNA that is complementary to specific genes in a pathogen;complementary to specific genes in a pathogen;complementary to specific genes in a pathogen; complementary to specific genes in a pathogen; the DNA will bind to the pathogen's DNA or the DNA will bind to the pathogen's DNA or mRNA and inhibit protein synthesismRNA and inhibit protein synthesismRNA and inhibit protein synthesis.mRNA and inhibit protein synthesis.


Message From the Director General Message From the Director General WHO (2000)WHO (2000)WHO (2000)WHO (2000)

Drug resistance is the most telling sign that weDrug resistance is the most telling sign that weDrug resistance is the most telling sign that we Drug resistance is the most telling sign that we have failed to take the treat of infectious diseases have failed to take the treat of infectious diseases serioseriouusly. It suggests that we have mishandled of sly. It suggests that we have mishandled of disease fighting drugs, by disease fighting drugs, by misusing, misusing, underusingunderusingand overusing them.and overusing them.

“A World without Antibiotics”. It could bring back “A World without Antibiotics”. It could bring back to a preto a pre--antibiotic age. We are antibiotic age. We are vulnerable without vulnerable without effective medicines.effective medicines.


Impact of Resistance :Staph aureus 99% sensitive to penicillin G

1940's p p

and all other Beta lactam antibiotics.

Staph aureus 75% resistant to penicillin1970's

Staph aureus 75% resistant to penicillin 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 remainingtherapeutic options remaining.

1995 - Intensive care units - Acinetobacter and Moraxella species resistant to all1996 Moraxella species resistant to all antibiotics tested. 3232

MICROBIAL RESISTANCE TO MICROBIAL RESISTANCE TO ANTIMICROBIAL CHEMOTHERAPEUTIC ANTIMICROBIAL CHEMOTHERAPEUTIC

AGENTSAGENTSAGENTSAGENTS

A common problem in antimicrobialA common problem in antimicrobialA common problem in antimicrobial A common problem in antimicrobial chemotherapy is chemotherapy is the development of the development of resistant strains of bacteriaresistant strains of bacteria MostMostresistant strains of bacteriaresistant strains of bacteria. Most . Most bacteria become resistant to bacteria become resistant to antimicrobial agents by one or more ofantimicrobial agents by one or more ofantimicrobial agents by one or more of antimicrobial agents by one or more of the following mechanisms: the following mechanisms:


MekanismeMekanisme terjadinyaterjadinya strainstrain resistresisteenn

1. 1. Producing enzymes which detoxify or Producing enzymes which detoxify or inactivate the antibioticinactivate the antibiotic, e.g.,, e.g., penicillinasepenicillinaseinactivate the antibioticinactivate the antibiotic, e.g., , e.g., penicillinasepenicillinaseand other betaand other beta--lactamaseslactamases. .

2. 2. Altering the target site in the bacterium to Altering the target site in the bacterium to d bl k bi di f h ibi id bl k bi di f h ibi ireduce or block binding of the antibioticreduce or block binding of the antibiotic, ,

e.g., producing a slightly altered ribosomal e.g., producing a slightly altered ribosomal subunit that still functions but to which the drugsubunit that still functions but to which the drugsubunit that still functions but to which the drug subunit that still functions but to which the drug can't bind. can't bind.

3. 3. Preventing transport of the antimicrobial Preventing transport of the antimicrobial agent into the bacteriumagent into the bacterium, , egeg., producing an ., producing an altered altered cytoplasmiccytoplasmic membrane or outer membrane or outer membranemembranemembrane. membrane.


4. 4. Developing an alternate metabolic Developing an alternate metabolic e e op g a a te ate etabo ce e op g a a te ate etabo cpathway to bypathway to by--pass the metabolic step pass the metabolic step being blocked by the antimicrobial agentbeing blocked by the antimicrobial agent, , e g overcoming drugs that resemble substratese g overcoming drugs that resemble substratese.g., overcoming drugs that resemble substrates e.g., overcoming drugs that resemble substrates and tieand tie--up bacterial enzymes. up bacterial enzymes.

5. 5. Increasing the production of a certain Increasing the production of a certain bacterial enzymebacterial enzyme, e.g., overcoming drugs that , e.g., overcoming drugs that resemble substrates and tieresemble substrates and tie--up bacterial up bacterial enzymes. enzymes.

dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK. 3535

UJI KEPEKAAN BAKTERI UJI KEPEKAAN BAKTERI OOTERHADAP ANTIMIKROBATERHADAP ANTIMIKROBA

CARA PENGENCERANCARA PENGENCERAN (Dilution(DilutionCARA PENGENCERANCARA PENGENCERAN (Dilution (Dilution Methods) :Methods) :

MemakaiMemakai mediamedia caircairMemakaiMemakai media media caircairMemakaiMemakai media media padatpadat

Cara Cara iniini kwantitatipkwantitatip dandan akuratakuratppCARA DIFUSICARA DIFUSI (Diffusion Methods) :(Diffusion Methods) :

MemakaiMemakai cakramcakram antimikrobaantimikrobaMemakaiMemakai cakramcakram antimikrobaantimikrobaTablet Tablet antimikrobaantimikroba

Cara Cara iniini kwalitatipkwalitatip dandan rutinrutinppdilakukandilakukan


CARA PENGENCERANCARA PENGENCERANCARA PENGENCERANCARA PENGENCERAN

KWANTITATIPKWANTITATIPKWANTITATIPKWANTITATIPKHM (Kadar KHM (Kadar HambatanHambatan Minimal = MIC)Minimal = MIC)KBM (Kadar BKBM (Kadar Bunuhunuh Minimal = MBC)Minimal = MBC)KBM (Kadar BKBM (Kadar Bunuhunuh Minimal = MBC)Minimal = MBC)

AKURATAKURAT

UNTUK PENELITIAN / PERMINTAAN KHUSUSUNTUK PENELITIAN / PERMINTAAN KHUSUS


CARA PENGENCERAN (lanjutan)CARA PENGENCERAN (lanjutan)MEDIA CAIRMEDIA CAIR

CaraCara MakroMakro :: seriseri 1212 tabungtabung reaksireaksiCara Cara MakroMakro : : seriseri 12 12 tabungtabung reaksireaksiCara Cara MikroMikro : plat: plat mmikrotiterikrotiter, , pipetpipet mikromikro

MEDIA PADATMEDIA PADATMueller Hinton Agarg

AM AM diencerkandiencerkan kelipatankelipatan duadua (1 (1 ugug, 0,5 , 0,5 ugug, , 0 250 25 ugug 0 1250 125 ugug dstdst))0.25 0.25 ugug. 0.125 . 0.125 ugug, , dstdst))LarutanLarutan bakteribakteri log phase log phase MacFarlandMacFarland 11


CARA DIFUSICARA DIFUSIMEDIA :MEDIA :

Mueller Hinton Agar Mueller Hinton Agar atauatau SensitestSensitestggAgarAgarJikaJika bakteribakteri fastidifastidiuus : Agars : Agar DarahDarahJikaJika bakteribakteri fastidifastidiuus : Agar s : Agar DarahDarah

BAKTERI :BAKTERI :BakteriBakteri Log phaseLog phase kelarutankelarutan MacFarlandMacFarland 0 50 5BakteriBakteri Log phase, Log phase, kelarutankelarutan MacFarlandMacFarland 0,50,5DisemaikanDisemaikan dengandengan kapaskapas lidilidi sterilsteril 3 streak3 streak

CAKRAM :CAKRAM :CAKRAM :CAKRAM :KertasKertas saringsaringTabletTabletTabletTablet


MEMBACA DAERAH INHIBISIMEMBACA DAERAH INHIBISIDaerah Daerah inhibisiinhibisi diukurdiukurmenggunakanmenggunakan kkaliperaliper ((jangkajangkagggg pp ((j gj gsorongsorong) ) atauatau penggarispenggarisLebarLebar daerahdaerah inhibisiinhibisidi ikdi ik dd d fd fdisesuaikandisesuaikan dengandengan daftardaftardaridari setiapsetiap AM AM dandan BakteriBakteriyang yang diujidiuji kepekaannyakepekaannyay gy g jj p yp y((setelahsetelah dieramkandieramkan 1818--24 24 jam).jam).Di t kDi t kDinyatakanDinyatakan::

SensitiSensitif f ((ssusceptibleusceptible),),HampirHampir resistenresisten,,pp ,,ResistenResisten


ANTIMIKROBAGENUS

Kandungan disk (cakram

AM)

Diameter Zona Hambat (mm)

Resisten Intermediat SensitifResisten Intermediat Sensitif

β-LACTAMS

Ampicillin Enterobacteriaceae 10 µg <13 14-16 >17

Staphylococci 10 µg <28 >29

Enterococci 10 µg <16 >17

Carbenicillin Pseudomonas 100 µg <13 14-16 >16

Gram (-) 100 µg <19 20-22 >23

Methicillin Staphylococci 5 µg <9 13-Oct >14

Mezlocillin Pseudomonas 75 µg <15 >16

Other Gram (-) 75 µg <17 18-20 >21

Nafcillin Staphylococci 1 µg <10 12-Nov >13

Oxacillin Staphylococci 1 µg <10 12-Nov >13Oxacillin Staphylococci

Penicillin Staphylococci 10 units <28 >29

Enterococci 10 units <14 >15

Piperacillin Pseudomonas 100 µg <17 >18Piperacillin Pseudomonas µg

Other Gram (-) 100 µg <17 18-20 >214141dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK.

FAKTOR PENYEBAB RESISTENSIFAKTOR PENYEBAB RESISTENSIFaktorFaktor non non genetikgenetik ::

AM akan resisten jika bukan pada masa aktifpembelahan bakteri. PadaPada umumnyaumumnya semuasemuaAM AM barubaru bisabisa bekerjabekerja baikbaik padapada masamasa aktiaktiffpembelahanpembelahan bakteribakteripembelahanpembelahan bakteribakteri..HilangnyaHilangnya strukturstruktur target target untukuntuk AM (AM (kehilangankehilangandindingdinding selsel)),, sehinggasehingga obatobat betalaktambetalaktam jadijadigg )),, gggg jjresistenresisten. .

FaktorFaktor genetikgenetik :: TerjadiTerjadi perperuubahanbahan genetikgenetikmenimbulkanmenimbulkan resistensiresistensi bakteribakteri..

Resistensi kromosomalR i t i k t k l ( l l i Pl id)Resistensi ekstrakromosomal (melalui Plasmid)

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CARA TERJADINYA RESISTENSICARA TERJADINYA RESISTENSIINTRINSICINTRINSIC ::

Hal Hal iniini biasabiasa untukuntuk semuasemua spespessiesies dimanadimana spespessiesies tertentutertentutid ktid k memp n imemp n i t gett get tt e eptoe epto nt knt k ntimik obntimik obtidaktidak mempunyaimempunyai target target atauatau reseptorreseptor untukuntuk antimikrobaantimikroba, , atauatau adaada barrier barrier alamiahalamiah a.la.l.:.:= = BakteriBakteri anaerobanaerob terhadapterhadap AminoglAminoglikikosidosidaaa ea e a ae oba ae ob e adape adap ogog os dos daa= Streptococcus = Streptococcus resistenresisten terhadapterhadap AminoglAminoglikikosidosidaa karenakarena

mempunyaimempunyai //adanyaadanya barierbarier alamiahalamiah..= = EnterobacteriaceaeEnterobacteriaceae resistenresisten terhadapterhadap PNCPNC--GG

ACQUIREDACQUIRED : FAKTOR EKSTRA KHROMOSOMAL: FAKTOR EKSTRA KHROMOSOMALModifikasiModifikasi genetikgenetik karenakarena mutasimutasi, , tranfertranfer gene gene melaluimelaluitransfer Plasmid (transformasi, transduksi, konyugasi) sebabPlasmid membawa R Factor atau transposonPlasmid membawa R Factor atau transposon


PLASMIDPLASMIDPlasmid Plasmid == closed loop of DNAclosed loop of DNA, , elemen elemen genetigenetik yg sangat k yg sangat kecilkecil ((beratberat kira2 1kira2 1--3% 3% kromosomkromosom bakteribakteri)), , didi luarluarkkromosomromosom,, membawamembawa gengen resistenresisten terhadapterhadap antimikrobaantimikroba..kkromosomromosom, , membawamembawa gen gen resistenresisten terhadapterhadap antimikrobaantimikroba..

MMampuampu bebereplikasireplikasi didi dalamdalam ssel el bakteribakteri secarasecara autonomautonom

BisaBisa berpindahberpindah antarantar spespessiesies (broad host range)(broad host range)BisaBisa berpindahberpindah antarantar spespessiesies (broad host range) (broad host range)

BeradaBerada bebasbebas dalamdalam sitoplasmasitoplasma bakteribakteri

SalahSalah satusatu PlasmidPlasmid adalahadalah R FactorR Factor beberapabeberapa R FactorR FactorSalahSalah satusatu Plasmid Plasmid adalahadalah R FactorR Factor, , beberapabeberapa R Factor R Factor membawamembawa transposontransposon (gen resisten yang bisa berpindahdari satu Plasmid ke Plasmid lainnya atau ke kromosom).

Kini dikenal lagi INTEGRON

ContohContoh lain : lain : toksintoksin bakteribakteri dandan faktorfaktor F (fertility)F (fertility). . ( y)( y)


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CARA PERPINDAHAN GENCARA PERPINDAHAN GENTRANSDUKSITRANSDUKSIPlasmid DNA via Plasmid DNA via BaBakkterioterioffagagaa ((biasabiasa bakteribakteri GamGam positippositip) ) ditransferditransfer keke populasipopulasi kumankuman lainlainditransferditransfer keke populasipopulasi kumankuman lain.lain.

TRANSFORMASITRANSFORMASI (fragment DNA (fragment DNA bebasbebas dapatdapat melewatimelewatidindingdinding ssel el dandan kemudiankemudian bersatubersatu dalamdalam genomgenom selsel)).. BiasaBiasadil k kdil k k didi l b t il b t i (( kk tiktik)) Pi d hPi d hdilakukandilakukan didi laboratoriumlaboratorium ((rekayasarekayasa genetikgenetik)).. PindahPindahsecarasecara spontanspontanKONYUGASIKONYUGASIMelaluiMelalui Fertility Factor Fertility Factor makamaka RTF (ResistRTF (Resistaanntt Transfer Transfer Factor) Factor) pindahpindah daridari satu satu selsel keke selsel lain lain seringseringmenyebabkanmenyebabkan multidrugmultidrug resistenresisten..menyebabkanmenyebabkan multidrug multidrug resistenresisten..

TRANSLOKASI / TRANSPOSISITRANSLOKASI / TRANSPOSISIPerpindahanPerpindahan bagianbagian kkromosomromosom dalamdalam selsel


CONJUGATIVE TRANSPOSONCONJUGATIVE TRANSPOSON

TelahTelah dikenaldikenal type type barubaru elemenelemen conjugative conjugative yaituyaitu Conjugative Conjugative TransposonTransposonTerdapatTerdapat didalamdidalam khromosomkhromosom bakteribakteri..Conjugative Conjugative TransposonTransposon terintegrasiterintegrasi didalamdidalam Plasmid Plasmid atauatauberadaberada didi dalamdalam khromosomkhromosom bakteribakteri sehinggasehingga lebihlebih susahsusah untukuntukggggdideteksidideteksi..AdaAda kemungkinankemungkinan bertanggungbertanggung jawabjawab dalamdalam kebanyakankebanyakantransfer Plasmid transfer Plasmid Transfer Transfer terjaditerjadi tidaktidak hanyahanya antarantar species species padapada group group BakteriBakteriGram(+) Gram(+) atauatau antarantar group group BakteriBakteri Gram (Gram (--) ) tetapitetapi jugajuga antaraantaraBakteriBakteri Gram (+) Gram (+) dandan BakteriBakteri Gram (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.


INTEGRONINTEGRONKINI DIKENAL ELEMENT INTERGRATING KINI DIKENAL ELEMENT INTERGRATING BARU = INTEGRONBARU = INTEGRONBARU = INTEGRONBARU = INTEGRON

INTEGRON BERTANGGUNG JAWAB UNINTEGRON BERTANGGUNG JAWAB UN--TUK TUK BERBAGAI PLSMID YANG MEMBABERBAGAI PLSMID YANG MEMBA--WA WA MULTIPLE DRUG RESISTANCE GENEMULTIPLE DRUG RESISTANCE GENE

INTEGRON SEPERTI TRANSPOSON INTEGRON SEPERTI TRANSPOSON ADALAH SEGMEN DNA LINEARADALAH SEGMEN DNA LINEARADALAH SEGMEN DNA LINEAR.ADALAH SEGMEN DNA LINEAR.


RESISTENSI PADA BETALAKTAM :RESISTENSI PADA BETALAKTAM :

EnzEnziim m ββ--laktamaselaktamase yang yang dihasilkandihasilkan bakteribakteri membukamembuka( l )( l ) i ii i ββ l ktl kt hihi tdktdk ktiktiff B kt iB kt i(cleaves) (cleaves) cincincincin ββ--laktamlaktam sehinggasehingga tdk tdk aktiaktiff. . BakteriBakteriGram(Gram(--) ) menghasilkanmenghasilkan ββ--lalakktamasetamase dalamdalam periplasmaperiplasmasedangkansedangkan bakteribakteri Gram(+) Gram(+) : : dalamdalam cairancairan ekstraselulekstraselulaar.r.TidakTidak adanyaadanya PBP (Penicillin Binding Protein) PBP (Penicillin Binding Protein) reseptorreseptorbakteribakteri menjadimenjadi resistenresisten. (Alteration of the target of the . (Alteration of the target of the antibiotic)antibiotic) DalamDalam halhal iniini penambahanpenambahan ββ--laktamaselaktamaseantibiotic) antibiotic) DalamDalam halhal iniini penambahanpenambahan ββ laktamaselaktamaseinhibitor inhibitor tidaktidak bergunaberguna..


RESISTENSI PADA RESISTENSI PADA BETALAKTAM :BETALAKTAM :

BetalaktamBetalaktam tidaktidak berhasilberhasil mengaktivasimengaktivasiggautolyticautolytic enzyme enzyme ((yang yang menghancurkanmenghancurkanpeptidoglpeptidoglikikan), an), sehinggasehingga bakteribakteri menjadimenjaditolerantolerantolerantoleran..ResistenResisten terhadapterhadap AM AM GlycopeptideGlycopeptide : : walauwalaubelumbelum jelasjelas benarbenar tetapitetapi 2 gene (2 gene (vanAvanA &&belumbelum jelasjelas benarbenar, , tetapitetapi 2 gene (2 gene (vanAvanA & & vanHvanH) yang ) yang terlibatterlibat menyemenye--babkanbabkan dihasilkandihasilkanprotein yang protein yang berbedaberbeda yang yang tidaktidak mengimengi--katkatV iV iVancomycinVancomycin..

dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK. 5050

ANTI ENZYME BETALACTAMASEANTI ENZYME BETALACTAMASEObatObat golgol. . betalaktambetalaktam menjadi resisten karena bakterimenghasilkan enzim betalaktamase yang yang menghancurkanmenghancurkan cincincincin betabeta laktamlaktam daridari obatobatmenghancurkanmenghancurkan cincincincin betabeta--laktamlaktam daridari obatobat..

EnzEnziim m betalaktamasebetalaktamase tersebuttersebut bisabisa dirusakdirusak dengandenganb hkb hk l hl h tt tt didi b hb h i ii imenambahkanmenambahkan salahsalah satusatu zatzat didi bawahbawah iniini ::

+ + ClavulanicClavulanic acid (acid (AugmentinAugmentin))+ + SulbactamSulbactam ((SulperazonSulperazon))+ + TazobactamTazobactam ((PiperacillinPiperacillin + + TazobactamTazobactam))ob cob c (( pe cpe c ob cob c ))

PenambahanPenambahan salahsalah satusatu zatzat diatasdiatas menyebabkanmenyebabkan obatobatgolongangolongan betalaktambetalaktam menjadimenjadi sensitisensitiff kembalikembali..g gg g jj


MRSAMRSA,, VISAVISA,, VRSAVRSA,, ESBLsESBLsMRSA : MethMRSA : Methiicillincillin--rresistantesistant S. S. aaureusureus

MRSA refers to a type of bacteria (MRSA refers to a type of bacteria (Staphylococcus Staphylococcus aureusaureus) that is resistant to many antibiotics. It is a ) that is resistant to many antibiotics. It is a common cause of hospitalcommon cause of hospital--acquired infections.acquired infections.pp qq

•• MupirocinMupirocin ointment has also shown promising ointment has also shown promising results in decreasing nasal carriage. Wide spread use results in decreasing nasal carriage. Wide spread use g g pg g pis only indicated in certain settings to avoid is only indicated in certain settings to avoid mupirocinmupirocinresistance. resistance.

VISA : VISA : VancomycinVancomycin IntermIntermeediatediate S. S. aaureusureusVRSA : VRSA : VancomycinVancomycin Resistant Resistant S. S. aaureusureus


ESBL = Extended spectrum beta ESBL = Extended spectrum beta lactamaselactamase. . ppThis term refers to This term refers to beta beta lactamaselactamase enzymesenzymesproduced mainly by produced mainly by KlebsiellaKlebsiella and and E. coliE. coli that that encode for resistance to broadencode for resistance to broad--spectrum spectrum ββ--lactamlactam antibiotics that normally have activity antibiotics that normally have activity against Gramagainst Gram ((--)) bacilli. bacilli.

Examples areExamples are cefotaximecefotaxime ceftriaxoneceftriaxoneExamples are Examples are cefotaximecefotaxime, , ceftriaxoneceftriaxone, , ceftazidimeceftazidime, , aztreonamaztreonam and and cefpodoximecefpodoxime. .

These enzymes are These enzymes are not active againstnot active against the the cephamycinscephamycins, and are inhibited by , and are inhibited by clavulanicclavulanic

ididacid.acid.5353dr. Edhie Djohan Utama, SpMK.dr. Edhie Djohan Utama, SpMK.

AMINOGLAMINOGLIKIKOSIDOSIDAABaBakkteriterissidalidal, , inainakktitiff pd pH pd pH rendahrendah dandan anaerobanaerobdandan MO intraMO intrasselularelulardandan MO intraMO intrasselularelularSSiinergistiknergistik dengandengan grupgrup BetaBeta--lalakktamtamAmpuhAmpuh untukuntuk bakteribakteri BatangBatang GramGram (( ))AmpuhAmpuh untukuntuk bakteribakteri BatangBatang Gram Gram ((--))ToToksksiikk padapada dosisdosis tinggitinggiMenghambatMenghambat sintessintesisis proteinprotein dengandengan berberikatanikatanMenghambatMenghambat sintessintesisis protein protein dengandengan berberikatanikatanpadapada 30S ribosomal unit 30S ribosomal unit sehinggasehingga tjd tjd misreadingmisreadingmRNAmRNAmRNAmRNAStreptomycin, Streptomycin, KanamycinKanamycin, , GentamycinGentamycin, , TobramycinTobramycin,, AmikacinAmikacin,, NetilmicinNetilmicinTobramycinTobramycin, , AmikacinAmikacin, , NetilmicinNetilmicin


RESISTENSI PADA AMINOGLRESISTENSI PADA AMINOGLIKIKOSIDOSIDAARESISTENSI PADA AMINOGLRESISTENSI PADA AMINOGLIKIKOSIDOSIDAA

ReseptorReseptor subunit 30 Ssubunit 30 S hilanghilangReseptorReseptor subunit 30 S subunit 30 S hilanghilangTerdapatTerdapat enzenziim yang m yang menghancurkanmenghancurkanobatobat ((acethylaseacethylase adenylaseadenylase dandanobatobat ((acethylaseacethylase, , adenylaseadenylase dandanfosforilasefosforilase))P bilitP bilit t h dt h d b tb t ttPermeabilitasPermeabilitas terhadapterhadap obatobat turunturun, , transport transport obatobat keke dalamdalam ssel el berkurangberkurang

hihi tid ktid k ii RibRibsehinggasehingga tidaktidak mencapaimencapai RibosomRibosom


IMPLIKASI KLINIS RESISTENSIIMPLIKASI KLINIS RESISTENSITimbulnya resistensi bakteri terhadap antimikroba Timbulnya resistensi bakteri terhadap antimikroba bahkan terjadinya multiple drugs resistenbahkan terjadinya multiple drugs resisten (MDR)(MDR)bahkan terjadinya multiple drugs resisten bahkan terjadinya multiple drugs resisten (MDR)(MDR)bisa mengundang banyak problem berat dalam bisa mengundang banyak problem berat dalam pengobatan penyakit infeksipengobatan penyakit infeksi

Timbulnya Timbulnya “Kuman Rumah Sakit”“Kuman Rumah Sakit” yang amat yang amat resisten sebab RS sering menggunakan dosisresisten sebab RS sering menggunakan dosisresisten sebab RS sering menggunakan dosis resisten sebab RS sering menggunakan dosis tinggi dan dalam intensitas tinggi.tinggi dan dalam intensitas tinggi.

Antibiotik baru perlu riset yg lama (10Antibiotik baru perlu riset yg lama (10 20 tahun)20 tahun)Antibiotik baru perlu riset yg lama (10Antibiotik baru perlu riset yg lama (10--20 tahun) 20 tahun) sehingga bisa terjadi sehingga bisa terjadi tiadanya antibiotikatiadanya antibiotika yang yang bisa digunakan untuk mengobati penyakit infeksi.bisa digunakan untuk mengobati penyakit infeksi.bisa digunakan untuk mengobati penyakit infeksi.bisa digunakan untuk mengobati penyakit infeksi.


Prevention and control of antibiotic resistanceof antibiotic resistance

Reduce selective pressures:1 Use antibiotics for bacterial disease1. Use antibiotics for bacterial disease 2. Use appropriate dosing and length of time3. Change medication if ineffective4 U i t di ti f ifi it4. Use appropriate medication for a specific site5. Stop use of antibiotics in the animal husbandry for growth

promotionp6. Regulate prescribing practices in veterinary medicine7. Establish antibiotic prescribing practices and distribution

especially in countries that allow over the counterespecially in countries that allow over the counter medications without precripton

8. Educate the public to the dangers of overuse/misuse of tibi tiantibiotics


Antifungal DrugsAntifungal Drugs1.Polyenes, such as nystatin and amphotericin B,

bi ith l b t l dcombine with plasma membrane sterols and are fungicidal.

2. Azoles interfere with sterol synthesis and are used to treat cutaneous and systemic mycosesto treat cutaneous and systemic mycoses.

3. Griseofulvin interferes with eukaryotic cell division and is used primarily to treat skin infections caused by fungi.


Antifungals that bind sterols :gMembrane 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 sterolsof certain kinds of sterols.

There exist antibiotics that, consequently, more effectively recognize fungal plasma membrane than mammalianrecognize fungal plasma membrane than mammalian plasma membrane.

Examples include:= amphotericin B = nystatin = ketoconazole = miconazole


AntiviralAntiviral DrugsDrugsgg

1. 1. AmantadineAmantadine blocks penetration or uncoating of blocks penetration or uncoating of p gp ginfluenza A virusinfluenza A virus..

22 Nucleoside and nucleotide analogsNucleoside and nucleotide analogs such assuch as acycloviracyclovir2. 2. Nucleoside and nucleotide analogsNucleoside and nucleotide analogs such as such as acycloviracyclovir, , AZTAZT, , ddIddI, and , and ddC inhibit DNA or RNA synthesisddC inhibit DNA or RNA synthesis..

33 Protease inhibitorsProtease inhibitors such assuch as indinavirindinavir andand saquinavirsaquinavir3. 3. Protease inhibitorsProtease inhibitors, such as , such as indinavirindinavir and and saquinavirsaquinavir, , blockblock activity of an HIV enzyme essential for activity of an HIV enzyme essential for assembly of assembly of a new viral coata new viral coat..

4. 4. AlphaAlpha--interferonsinterferons inhibit the spread of viruses to new inhibit the spread of viruses to new cellscellscells.cells.



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