ANTIMICROBIAL CHEMOTHERAPY

ANTIMIKROBIAL

DR.HUSNI SAMADIN

http://ssmmid.orgANTIMICROBIAL CHEMOTHERAPY CHEMOTHERAPEUTIC AGENTSCmpounds used in treatment of diseases ANTIMICROBIAL AGENTSCompounds used in treatment of microbial diseasesCategories of antimicrobial agentsAntibiotics : biologically produced by microbesSynthetic Semi-synthetic : other chemical groups are added to a nucleus of antibioticWWW.SSMMID.ORG2Antibiotic/Antimicrobial Antibiotic: Chemical producedby a microorganism that kills orinhibits the growth of anothermicroorganism Antimicrobial agent: Chemicalthat kills or inhibits the growth ofmicroorganismsAntimicrobial Agents Disinfectant: antimicrobial agentused only on inanimate objects

Chemotherapeutic agent:antimicrobial agent that can beused internallyDisinfection

Pasteurization: destruction of alldisease-producing microorganismsor reduction in spoilagemicroorganisms

Sterilization: killing or removal of allliving organisms and their viruseshttp://ssmmid.orgCharacteristics of Antibacterial Agents1.Selective ToxicityInhibit growth of bacteria without damage to hostDue to differences between bacterial and human cells at four major sites:Cell wallCell membraneRibosomes Nucleic acidsFew antiviral agents due to lack of selective toxicityWWW.SSMMID.ORG6http://ssmmid.orgCharacteristics of Antibacterial Agents2. Spectrum of ActivityBroad Spectrum: Active against both gram-positive and gram-negative bacteria e.g. tetracycline, quinolones.Narrow spectrum: Active against one or very few types of bacteria Vancomycin for Staph. & Enterococci.Metronidazole- antiamoebic and antiprotozoal.

WWW.SSMMID.ORG7http://ssmmid.orgCharacteristics of Antibacterial Agents3. Cidal vs Static

Bactericidal Agents that kill bacteria Are useful in life-threatening infectionsAlso useful in patients with low WBC count Bacteristatic Agents that inhibit but do not kill bacteriaBacteria may grow again when drug is withdrawnHost defences are needed to kill bacteria In large doses may become bactericidalWWW.SSMMID.ORG8http://ssmmid.orgANTIMICROBIALS : MECHANISMS OF ACTIONTranscriptionmRNATransalationProteins Enzymatic activityReplication5. Inhibition of nucleic acid synthesisRifampicinQuinolones4.Inhibition of enzymatic activity Trimethoprim, Sulphamethoxazole6. Uncertain site of action Metronidazole, INH2.Injury to plasma membrane Polymyxin B, Nystatin, Amphotericin B, Azoles1.Inhibition of cell wall synthesis Penicillins, Cephalosporins Vancomycin, Bacitracin3. Inhibition of protein SynthesisErythomycin, tetracyclinWWW.SSMMID.ORG9http://ssmmid.orgGroups of Antimicrobial Agents (Mechanisms of Action)Inhibitors of cell wall synthesisInhibitors of cell membrane functionsInhibitors of protein synthesisInhibitors of enzymatic activityInhibitors of nucleic acids synthesisWWW.SSMMID.ORG10http://ssmmid.orgNAGNAMA-pentapeptideNAG+Dephosphorylation of lipidsNAMATransfer to peptidoglycanCross-linking of peptidoglycanFosfomycinBacitracinVancomycinBeta-lactamsLipid carrier(membrane)AminoAcidsNAG = N-acetylglucosamineNAMA = N-acetylmuramic acidSite of action of inhibitors of cell wall synthesisCell wall synthesisWWW.SSMMID.ORG11http://ssmmid.orgInhibitors of cell wall synthesisA: BETA LACTAMS Have a beta-lactam ring in their moleculePenicillinsCephalosporinsCarbapenemsMonobactams

B: GLYCOPEPTIDESVancomycin & TeicoplaninC: CYCLOSERINE & BACITRACINall are bactericidalWWW.SSMMID.ORG12http://ssmmid.orgInhibitors of cell wall synthesis A: BETA LACTAMS PenicillinsAct by inhibiting cross-linking of peptidoglycan by binding with penicillin binding proteins (PBPs) on the cytoplasmic mamebrane leads to :cell lysisovoid cellfilament cellAccoridng to type of PBPs

WWW.SSMMID.ORG13http://ssmmid.orgAction of penicillins on gram-positive bacterial cell wallPBPPBPCapsulePeptidoglycanlayerPhospholipidTransport proteinTcytoplasmic membranePenicillinCell lysisOvoid cellFilamentResults of action of penicillinsWWW.SSMMID.ORG14http://ssmmid.orgInhibitors of cell wall synthesis A: BETA LACTAMSPenicillins e.g.Penicillin GAmpicillin, AmoxycillinCarbenicillin, Piperacillin for pseudomonasMethicillin for penicillinase-producing S. aureusWWW.SSMMID.ORG15http://ssmmid.orgInhibitors of cell wall synthesisA: BETA LACTAMSCephalosporinsInhibit cross-linking of peptidoglycanMajority are produced by molds of genus cephalosporiumAdvantage over PenicillinsBroad range of activityLess susceptibility to b-lactamasesFewer hypersensitivity reactionsWWW.SSMMID.ORG16http://ssmmid.orgInhibitors of cell wall synthesis A: BETA LACTAMSCephalosporinsGenerationNamesUseActivityFirstCephradineI.M/I.V & G+ve bacteriaCephalexin oralSecondCefactorI.M/ I.V &G+ve + G-veoralThirdCefotaximeI.M/I.VMostly G-ve, G+veCeftazidimeMarked resistance to beta-lactamasesFourthCefpiromeI.M., I.V.WWW.SSMMID.ORG17http://ssmmid.orgInhibitors of cell wall synthesis A: BETA LACTAMSCarbapenems (imipenem, meropenem)Broadest activity of the b-lactams G+ve, G-ve and anaerobesMarked resistance to b-lactamasesMonobactamsSelective activity against G-ve bacilli including PseudomonasResistant to most b-lactamasesWWW.SSMMID.ORG18http://ssmmid.orgInhibitors of cell wall synthesis

Vancomycin, Cycloserine, bacitracinBlock the formation of precursors of peptidoglycanVancomycin - bactericidal against G+ve. Drug of choice against MRSACycloserine - second-line anti-TB drugBacitracin - for superficial skin infections

WWW.SSMMID.ORG19http://ssmmid.orgInhibitors of Cell Membrane FunctionsA. Antibacterials A few drugs in this group Due to structural similarity of bacterial and human cell membranes Polymyxins disrupt phospholips leakage of cell contents.

WWW.SSMMID.ORG20B. Anti-fungals1. Polyenes Act by binding with ergosterol in cell membrane large pores leakage of cell contentsNystatin, amphotericin-B, candicidin, trichomycin2.Imidazoles Act by inhibiting ergosterol synthesisClotrimazole (Canesten) -Topical agentsKetoconazoleFluconazole

Inhibitors of Cell Membrane FunctionsSystemic agentsWWW.SSMMID.ORG2170S prokaryoticribosome50S30SmRNAtRNAGrowing polypeptideDirection of ribosome travelDNATranscriptionStreptomycinErythromycinTetracyclineChloramphenicolInhibitors of protein synthesis : sites of action WWW.SSMMID.ORG22Inhibitors of Protein SynthesisSelective toxicity is due to differences in ribosomesIn human cells 80S = 60S & 40 S subunitsBacterial cells 70S = 50S & 30S subunitsA. Drugs that act on 30S subunit1.Aminoglycosides Streptomycin Gentamicin/AmikacinChange shape of 30S portion & blocks initiation of translationAre bactericidalAre toxic for kidneys and earsPoorly absorbed from GIT given by injectionsWWW.SSMMID.ORG23Inhibitors of Protein Synthesis A. Drugs that act on 30S subunit2.Tetracyclines - Doxycycline Minocycline Block attachment of tRNA to mRNA-ribosome complexAre bacteriostatic against G+ve & G-ve bacteria mycoplasma, chlamydiae and rickettsiaeCause staining of teeth in young children

WWW.SSMMID.ORG24 Drugs that act on 50S subunit1. Chloramphenicol Inhibit formation of peptide bond Bacteriostatic / Bactericidal Causes bone marrow suppression aplastic anaemia2. Macrolides Erythromycin,Clarythromycin, Azithromycin Prevent movement of ribosome along mRNABacteriostaticOne of the least toxic drugsInhibitors of Protein SynthesisWWW.SSMMID.ORG25Inhibitors of Nucleic acid synthesisA. Inhibitors of mRNA synthesisRifampicinInhibits mRNA synthesis by affecting DNA-dependent polymerase of bacterial cell without affecting human cells First-line anti-TB drug.

WWW.SSMMID.ORG26Inhibitors of Nucleic acid synthesisB. Inhibitors of DNA synthesis1. Quinolones (naldixic acid)Inhibit DNA gyrase which maintains the supercoiling of closed circular DNAAre broad spectrum bactericidal 2.Fluroquinolones Ciprofloxacin,Ofloxacin, SparfloxacinAre broader spectrum than quinolonesDamage growing bones so not given to pregnant women and young children.WWW.SSMMID.ORG27Para-aminobenzoic acid (PABA)Dihydrofolic acidTetrahydrofolic acidPurines and otherprecursorsDNASulfamethxazoleTrimethoprimInhibitors of Nucleic acid synthesis B. Inhibitors of DNA synthesis (anti-metabolites)3.Sulfonamides and trimethoprimCompete with PABA to stop synthesis of folic acid which is needed for purine synthesis. These are used in combinationWWW.SSMMID.ORG28Uncertain mechanisms of actionIsoniazid (INH), Ethambutol, PyrazinamideAre first line anti-TB drugsMetronidazole (Flagyl)Probably inhibit DNA synthesisBactericidal against G-ve anaerobes and Protozoa (Giardia and Trichomonas)WWW.SSMMID.ORG29ChemoprophylaxisIs the use of antimicrobial agents to prevent infections as:A. In normal persons exposed to pathogensRifampicin 600 mg twice daily during outbreaks of meningitis.Isoniazid (INH) to prevent TB in those recently infected.Tetracycline to prevent plaque

WWW.SSMMID.ORG30ChemoprophylaxisB. In persons with high susceptibility to infections Opportunistic infections in immunosuppressed persons like AIDSRecurrent urinary tract infections (UTI )Congenital and rheumatic heart diseasesC. Prior to SurgeryTooth extraction to prevent endocarditisColorectal surgery to prevent peritonitis and wound infectionsWWW.SSMMID.ORG31Antimicrobial Resistance

Relative or complete lack of effectof antimicrobial against a previouslysusceptible microbe

Increase in MIC

Asal usul ResistensiA. Non genetic. Mencegah aksesMenghilangkan agen antimkroba dari sel menggunakan efflux pumpInanktivasi agen anti mikroba melalui modifikasi dan degradasi.Modifikasi dari target antimikrobaB. Genetic.Transfer gen.MutasiMekanisme resistensi terhadap antimikrobaMencegah aksesMenghilangkan agen antimkroba dari sel menggunakan efflux pumpInanktivasi agen anti mikroba melalui modifikasi dan degradasi.Modifikasi dari target antimikroba

Mekanisme Resistensi Terhadap antimikrobaMEKANISME RESISTENSI KHUSUS SARANA UNTUK MENCAPAI RESISTENCONTOH Enzimatik Penghancuran cincin beta-laktamase oleh enzim. Dengan cincin beta-laktam hancur, antibiotik tidak akan lagi memiliki kemampuan untuk mengikat PBP (Penisilin-mengikat protein), dan mengganggu sintesis dinding sel. Resistensi staphylococi terhadap penisilin; Resistensi Enterobacteriaceae terhadap penicllins, sefalosporin, dan aztreonam Perubahan sasaran Perubahan pengikat protein penisilin Perubahan Mutasi untuk PBPs asli atau akuisisi PBPs akan menyebabkan ketidakmampuan antibiotik untuk mengikat PBP dan menghambat sintesis dinding sel Resistensi terhadap methicillin staphylococci dan oksasilin Penurunan serapan Menurun nya pembentukan saluran Porin Karena ini adalah di mana beta-laktam menyeberangi membran luar untuk mencapai PBP dari bakteri Gram-negatif, perubahan dalam angka atau karakter dari saluran ini dapat mengurangi penyerapan Betalactam .. Enterobacter aerogenes , Klebsiella pneumoniae dan Pseudomonas aeruginosa terhadap imipenem Perubahan sasaran Perubahan dalam struktur molekul komponen dinding sel prekursor menurun mengikat vankomisin sehingga sintesis dinding sel mampu untuk melanjutkan. Resistensi terhadap vankomisin enterococci Enzimatik modifikasi Enzim mengubah Memodifikasi berbagai situs pada molekul aminoglikosida sehingga kemampuan dari obat ini untuk mengikat ribosom dan sintesis protein berhenti sangat berkurang atau hilang sama sekali. Resistensi beberapa bakteri negatif Gram-positif dan Gram untuk aminoglikosida Penurunan serapan Perubahan angka atau karakter saluran Porin (melalui aminoglikosida yang melintasi membran luar untuk mencapai ribosom dari bakteri gram negatif) sehingga penyerapan aminoglikosida berkurang. Perlawanan dari berbagai bakteri Gram-negatif untuk aminoglikosida Perubahan sasaran Modifikasi protein ribosomal atau rRNA 16. Ini mengurangi kemampuan aminoglikosida untuk berhasil mengikat dan menghambat sintesis protein Resistensi Mycobacterium spp terhadap streptomisin Penurunan serapan Perubahan pada membran luar mengurangi penyerapan obat dan / atau aktivasi pompa yang menghilangkan kuinolon sebelum konsentrasi intraseluler cukup untuk metabolisme DNA menghambat. Perlawanan Gram negatif dan staphylococci (penghabisan mekanisme saja) untuk berbagai kuinolon Perubahan sasaran Perubahan subunit girase DNA menurunkan kemampuan kuinolon untuk mengikat enzim ini dan mengganggu proses DNA Gram negatif dan Gram positif ketahanan terhadap kuinolon berbagai Resistensi diperoleh melalui mutasi dan transfer gen horizontal Mutasi adalah perubahan spontan dalam urutan DNA dalam gen yang dapat menyebabkan perubahan dalam sifat yang kode untuk. Setiap perubahan dalam pasangan basa tunggal dapat menyebabkan perubahan yang sesuai pada satu atau lebih asam amino untuk yang dikode, yang kemudian dapat mengubah enzim atau struktur sel yang berakibat pada perubahan afinitas atau aktivitas antimikroba yang efektif dari yang ditargetkan.

Dalam genom prokariotik, mutasi sering terjadi karena perubahan dasar yang disebabkan oleh agen eksogen, kesalahan DNA polimerase, penghapusan, insersi dan duplikasiTransfer gen horizontal, atau proses swapping materi genetik antara tetangga "kontemporer" bakteri, merupakan sarana dimana resistensi dapat diperoleh. Banyak dari gen resistensi antibiotik dilakukan pada plasmid, transposon atau integrons yang dapat bertindak sebagai vektor yang mentransfer gen untuk anggota lain dari spesies bakteri yang sama, serta bakteri di lain genus atau spesies. Transfer gen horizontal dapat terjadi melalui tiga mekanisme utama: transformasi, transduksi atau konjugasi. Transformasi melibatkan pengambilan fragmen pendek DNA t oleh bakteri alami . Transduksi melibatkan transfer DNA dari satu bakteri ke lain melalui bakteriofag.. Konjugasi melibatkan transfer DNA melalui pilus seksual dan membutuhkan sel-sel kontak. Fragmen DNA yang mengandung gen resistensi dari donor resisten, kemudian dapat membuat bakteri sebelumnya rentan mengekspresikan perlawanan sebagai kode oleh gen resistensi baru diperoleh.

What Factors Promote Antimicrobial Resistance?

Exposure to sub-optimal levels of antimicrobial

Exposure to microbes carrying resistance genesInappropriate Antimicrobiale use Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due to lack of hygieneWWW.SSMMID.ORG46Inappropriate Antimicrobial Use Lack of quality control in manufacture or outdateantimicrobial Inadequate surveillance or defective susceptibility assay Poverty or war Use of antibiotics in foodsProposals to CombatAntimicrobial Resistance Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Direct observed dosing (TB)Proposals to CombatAntimicrobial Resistance

Use more narrow spectrumantibiotics Use antimicrobial cocktails Effect of combinations of drug.

Synergism occurs when the effect oftwo drugs together is greater than theeffect of either alone. Antagonism occurs when the effect oftwo drugs together is less than theeffect of either alone.Effects of Combinations of