Antimicrobial drugsAntimicrobial drugs

Prof. Dr. Asem Shehabi Prof. Dr. Asem Shehabi

Faculty of Medicine Faculty of Medicine

University of JordanUniversity of Jordan

IntroductionIntroduction

Origin and ScopeOrigin and Scope of of Antibiotics & Antimicrobial Antibiotics & Antimicrobial AgentsAgents.. .. Host-Drug-MicroorganismHost-Drug-Microorganism

The discovery of Antimicrobial drugs have The discovery of Antimicrobial drugs have successfully controlled the majority of bacterial, successfully controlled the majority of bacterial, parasitical, fungal infections during the last 70-year.parasitical, fungal infections during the last 70-year.

SulfonamideSulfonamide 1934, 1934, Penicillin GPenicillin G 1941 (Penicillium 1941 (Penicillium notatum).. Followed Aminoglycosides (notatum).. Followed Aminoglycosides (StreptomycinStreptomycin, , KanamycinKanamycin,,1946, Soil Bacteria..Actinomyces) 1946, Soil Bacteria..Actinomyces)

At present 100 antimicrobial At present 100 antimicrobial drugsdrugs of different classes of different classes are available for use in humans.are available for use in humans.

Clinically effective antimicrobial agents should exhibit Clinically effective antimicrobial agents should exhibit selective toxicityselective toxicity toward the bacterium not the toward the bacterium not the hosthost.. .. Few Few Side EffectsSide Effects.. Good .. Good pharmacokineticspharmacokinetics

General Antimicrobial EffectsGeneral Antimicrobial Effects

Drugs kill only actively growing microorganisms Drugs kill only actively growing microorganisms bactericidal..bactericidal.. PenicillinsPenicillins,, AminoglycosidesAminoglycosides

Drugs that only inhibit the growth of microorganisms Drugs that only inhibit the growth of microorganisms bacteriostaticbacteriostatic.... Sulfonamides, ChloramphenicolSulfonamides, Chloramphenicol, , TetracyclinesTetracyclines

The decision to use a bactericidal / bacteriostatic The decision to use a bactericidal / bacteriostatic drug to treat infection depends entirely upon the drug to treat infection depends entirely upon the type- site of infection & host.. Child, Adults..type- site of infection & host.. Child, Adults..

Ultimate elimination of the organisms is dependent Ultimate elimination of the organisms is dependent upon host upon host phagocytic activity and specific antibodiesphagocytic activity and specific antibodies..

Action of Antimicrobial Drugs on BacteriaAction of Antimicrobial Drugs on Bacteria

Antimicrobials are also classified by their Antimicrobials are also classified by their range of range of activity/activity/spectrum:spectrum: NarrowNarrow (Antimycobacterials), (Antimycobacterials), Narrow- moderate,Narrow- moderate, broad spectrumbroad spectrum (Gram-ve/ (Gram-ve/ Gram+ve, Facultative Anaerobic, Anaerobes)Gram+ve, Facultative Anaerobic, Anaerobes)

AntimicrobialsAntimicrobials affect various affect various bacterial cellular bacterial cellular targetstargets .. cell wall, plasma membrane, nucleic acids, .. cell wall, plasma membrane, nucleic acids, proteins synthesis.proteins synthesis.

1- 1- Inhibition Cell Wall Synthesis:Inhibition Cell Wall Synthesis: Beta-Lactam drugsBeta-Lactam drugs Bactericidal.. Penicillin Binding Proteins (PBPs).. Bactericidal.. Penicillin Binding Proteins (PBPs)..

catalyze the final transpeptidation reaction of bacterial catalyze the final transpeptidation reaction of bacterial cell wall (Cross-Linking of peptidoglycan) biosynthesis.cell wall (Cross-Linking of peptidoglycan) biosynthesis.

Activation cell wall autolysins enzymes. Activation cell wall autolysins enzymes.

Beta-Lactam StructuresBeta-Lactam StructuresBenzylpenicillin (5-Thazolidine Ring)Benzylpenicillin (5-Thazolidine Ring)

Cepalosporins (6-Dihydrothiazine Ring)Cepalosporins (6-Dihydrothiazine Ring)

Beta-Lactams-PenicillinsBeta-Lactams-Penicillins

Beta-Lactam Drugs:Beta-Lactam Drugs: Narrow-Narrow- moderatemoderate spectrum spectrum Penicillin Penicillin G, VG, V .. Affect Mainly G+e, Anaerobic .. Affect Mainly G+e, Anaerobic Bacteria.. Less G-ve Aerobic. Bacteria.. Less G-ve Aerobic.

Ampicillin, AmoxacillinAmpicillin, Amoxacillin.. Wide spectrum, Developed .. Wide spectrum, Developed 1960s...G+ve/G-negative.. All B-lactams ..Susceptible 1960s...G+ve/G-negative.. All B-lactams ..Susceptible to Penicillinases /ß-Lactamases actions.to Penicillinases /ß-Lactamases actions.

Penicillinase-R drugs:Penicillinase-R drugs: Methicillin /Methicillin /Oxacillin/ CloxacillinOxacillin/ Cloxacillin 1960s, Used 1960s, Used

Only against G+ve.. Staph.-R To Only against G+ve.. Staph.-R To Penicillins Penicillins /Ampicillin../Ampicillin.. Methicillin-R Staphylococcus Methicillin-R Staphylococcus aureus (MRSA).. Worldwide spread.. Serious aureus (MRSA).. Worldwide spread.. Serious Infections.Infections.

Inhibition Cell Wall-1 Inhibition Cell Wall-1 Amoxacillin+Clavulinic AcidAmoxacillin+Clavulinic Acid ( B-lactamase inhibitor) / ( B-lactamase inhibitor) /

Broad Spectrum.. Broad Spectrum.. Penicillinase-RPenicillinase-R Carbencillin, Piperacillin, Ticarcillin.. 1970s, Used Carbencillin, Piperacillin, Ticarcillin.. 1970s, Used

Mainly against G-ve Pseudomonas spp. Mainly against G-ve Pseudomonas spp. Penicillinase-Penicillinase-S S .. IV,IM.. IV,IM

Monobactam / Monobactam / AztreonamAztreonam ( G-ve, Pseudomonas ( G-ve, Pseudomonas aeruginosa).. IV,IM, Nosocomial infection. aeruginosa).. IV,IM, Nosocomial infection.

Carbapenem / Carbapenem / Imipenem Imipenem & & meropenem (Mid 1990s) meropenem (Mid 1990s) Ertrapenem (2000Ertrapenem (2000 ).. Broad Spectrum.., IV,IM, ).. Broad Spectrum.., IV,IM, Penicillinase-R, Mainly against G-ve Enteric Bacteria.. Penicillinase-R, Mainly against G-ve Enteric Bacteria.. Serious - Nosocomial Infection.. Serious - Nosocomial Infection.. Pseudomonas Pseudomonas aeruginosa, Acinetobacter spp., E.coli-Klebsiella-aeruginosa, Acinetobacter spp., E.coli-Klebsiella-Enterobacter sppEnterobacter spp..

Inhibition Cell Wall-2Inhibition Cell Wall-2

CephalosporinsCephalosporins:: 1-4 Generations..1965-1990s..Oral, 1-4 Generations..1965-1990s..Oral,

IV, IM.IV, IM. 11thth (1960) (1960) CephalexinCephalexin, , CephradineCephradine,, Broad spectrumBroad spectrum.... 22thth (1970s) (1970s) CefoxitinCefoxitin, , CefuroximeCefuroxime,, Broad spectrumBroad spectrum.... 33thth (1980s) (1980s) CeftriaxoneCeftriaxone, , CefotaximeCefotaxime.... maninly G-ve maninly G-ve 44th th (late 1990s) (late 1990s) CefepimeCefepime.... MainlyMainly G-veG-ve UTI, RTI, Intestinal, Blood, CSF infectionsUTI, RTI, Intestinal, Blood, CSF infections.. .. Not Not

Anaerobes or Entercoccus spp.Anaerobes or Entercoccus spp. Polypeptides:Polypeptides: Bacitracin..Bacitracin.. Affects membrane-bound Affects membrane-bound

phospholipid carrier.. Bactericidal, Toxic, phospholipid carrier.. Bactericidal, Toxic, Topical use.. Topical use.. G+veG+ve

Inhibition Cell Wall-3Inhibition Cell Wall-3

Resistance DevelopmentResistance Development ::ß-lactamases/ ß-lactamases/ Extended ß-Extended ß-lactamaseslactamases.. Produced mostly by G-ve Enteric .. Produced mostly by G-ve Enteric bacteria.. Altered Penicillin Binding Proteins.. inactive bacteria.. Altered Penicillin Binding Proteins.. inactive ß-lactam ring..ß-lactam ring..

Side Effects:Side Effects: Sensitization, Penicillin Allergy, Fever, Sensitization, Penicillin Allergy, Fever, Serum Sickness, Nephritis, Anaphylactic Shock Serum Sickness, Nephritis, Anaphylactic Shock

Glycopeptides: Glycopeptides: Vancomycin, TeicoplaninVancomycin, Teicoplanin Glycopeptides also interfere with the synthesis of the Glycopeptides also interfere with the synthesis of the

bacterial cell wall .. by a different mechanism than the bacterial cell wall .. by a different mechanism than the beta-lactams.. beta-lactams.. Prevent formation the cross-linkingPrevent formation the cross-linking . .

Treatment Methicillin-R Treatment Methicillin-R Staphylococcus sppStaphylococcus spp., Multi-R ., Multi-R Enterococci (E. fecalis)..Enterococci (E. fecalis).. High doses/ long period High doses/ long period Toxic.. Vacomycin-Resistance ..still Rare.. worldwideToxic.. Vacomycin-Resistance ..still Rare.. worldwide

22 - -Inhibition of membrane integrityInhibition of membrane integrity

Colistin/Polymixen EColistin/Polymixen E:: Polyenes- complex Polyenes- complex polypeptides ..Bactericidal, Both G-ve, G +ve , Topical Drugs.. polypeptides ..Bactericidal, Both G-ve, G +ve , Topical Drugs.. Wounds, systemic.. against Wounds, systemic.. against MR- PathogensMR- Pathogens,.. Nephrotoxic,.. Nephrotoxic

Antifungal DrugsAntifungal Drugs: All : All affect the cell membrane by inhibit affect the cell membrane by inhibit forming complex with its ergosterol.. forming complex with its ergosterol.. required in fungal cell required in fungal cell wall synthesis.. wall synthesis.. Yeast cells Candida, filmentous fungiYeast cells Candida, filmentous fungi

polyene drugspolyene drugs:: Large circular molecule consisting of a Large circular molecule consisting of a hydrophobic and hydrophilic regionhydrophobic and hydrophilic region .. .. NystatinNystatin, oral , Safe , oral , Safe AmphotercinAmphotercin BB ..systemic.. Toxic..systemic.. Toxic

B) B) Imidazole Group:Imidazole Group: Ketoconazole (oral), Clotrimazole.. All Ketoconazole (oral), Clotrimazole.. All forms forms

C) C) Triazole Group:Triazole Group: New .. More effective.. less toxicNew .. More effective.. less toxic Fluconazol,Fluconazol, ItraconazoleItraconazole ..Oral, topical,Systemic use ..Oral, topical,Systemic use

Colistin-FluconazoleColistin-Fluconazole

3-Inhibition Protein Synthesis3-Inhibition Protein Synthesis

Bacterial Ribosomes composed 30s+50s=70sBacterial Ribosomes composed 30s+50s=70s AminoglycosidesAminoglycosides:: Inhibit protein synthesis by binding to the Inhibit protein synthesis by binding to the

30S ribosomal subunits.. prevent formation 30S ribosomal subunits.. prevent formation complex with complex with messenger RNAmessenger RNA.. .. Increase cell membrane leakageIncrease cell membrane leakage..

Bactericidal, Broad-spectrum of activity, Mainly against G-ve.. Bactericidal, Broad-spectrum of activity, Mainly against G-ve.. Not Anaerobes.. Serious Infection, .. Hospital ..IV, IM, Not Anaerobes.. Serious Infection, .. Hospital ..IV, IM, StreptomycinStreptomycin, Neomycin, , Neomycin, AmikacinAmikacin, , GentamicinGentamicin, Tobramicin, , Tobramicin, Netilmicin, Netilmicin,

Side Effects:Side Effects: Otototoxicity.. Nephrotoxicity.. Ototoxicity - 8th Otototoxicity.. Nephrotoxicity.. Ototoxicity - 8th cranial nerve- hearing loss.. blood-level monitoring .cranial nerve- hearing loss.. blood-level monitoring .

Resistance:Resistance: Production Acetylate, Phosphorylate,denylate Production Acetylate, Phosphorylate,denylate Enzymes ..during the drug passes cell membraneEnzymes ..during the drug passes cell membrane

AminoglycosideAminoglycoside-Tetracycline-Tetracycline

33--Inhibition Protein SynthesisInhibition Protein Synthesis Tetracyclines, Mid1950sTetracyclines, Mid1950s: Bacteriostatic.. : Bacteriostatic.. Accumulate Accumulate

in cytoplasmic membrane.. inhibit essential enzymesin cytoplasmic membrane.. inhibit essential enzymes .. .. prevent attachment of the prevent attachment of the amino-acyl tRNA to 30Samino-acyl tRNA to 30S ribosome complex.. ribosome complex.. Broad Spectrum.. Side effect.. over Broad Spectrum.. Side effect.. over growth of yeast ( Candida spp.) .. develop of resistance by growth of yeast ( Candida spp.) .. develop of resistance by reduced active transport.reduced active transport.

DoxcyclineDoxcycline, , MinocyclineMinocycline.. Cholera, Respiratory & .. Cholera, Respiratory & Genital Infection.. Genital Infection.. MycoplasmaMycoplasma, , ChlamydiaChlamydia, , Legionella Legionella infections.. infections..

Chloramphenicol Mid1950s Chloramphenicol Mid1950s : Bacteriostatic ..: Bacteriostatic ..Acts by Acts by binding to the binding to the 50S ribosomal subunit50S ribosomal subunit and blocking the and blocking the formation of the formation of the peptide bondpeptide bond .. .. Broad Spectrum.. Broad Spectrum.. Intracellular bacteria.. Meningitis, Septicemia Tyhoid fever.. Intracellular bacteria.. Meningitis, Septicemia Tyhoid fever.. Intracellular Bacteria.. Toxic.. Liver, Aplastic AnemiaIntracellular Bacteria.. Toxic.. Liver, Aplastic Anemia

Chloramphenicol-Ciprofloxacin -Chloramphenicol-Ciprofloxacin -StructuresStructures

Macrolides-1Macrolides-1 These have a large, lactone ring structure. These may These have a large, lactone ring structure. These may

be 14- or 16-membered rings.. be 14- or 16-membered rings.. binds to the binds to the 50S 50S ribosomal subunitribosomal subunit .. inhibits either peptidyl .. inhibits either peptidyl transferase activity & translocation of the transferase activity & translocation of the growing peptide to ribosome. growing peptide to ribosome.

Most widely used Macrolides .. Most widely used Macrolides .. ErythromycinErythromycin, , ClarithromycinClarithromycin, , AzithromycinAzithromycin ( Long acting-12 ( Long acting-12 hours) hours) Oral.. Less IV Oral.. Less IV

Relatively non-toxic drugs, mostly active against Relatively non-toxic drugs, mostly active against Gram-positive/ Intracellular bacteria.. Respiratory –Gram-positive/ Intracellular bacteria.. Respiratory –Genital Infections.. Pneumoniae, diphtheria.., Genital Infections.. Pneumoniae, diphtheria.., B-H-B-H-StreptococciStreptococci, , Staphylococcus,Staphylococcus, MycoplasmaMycoplasma, , ChlamydiaChlamydia, , LegionellaLegionella pneumophilapneumophila InfectionsInfections. .

2/2/

LincosamidesLincosamides//Clindamycin, Lincomycin Clindamycin, Lincomycin : : StaphylococcusStaphylococcus.. Streptococci.. Bones, Oral cavity.. .. Streptococci.. Bones, Oral cavity.. Anaerobic Infections.. Common Cause Anaerobic Infections.. Common Cause Pseudomembranous ColitisPseudomembranous Colitis.. Blood Diarrhea. .. Blood Diarrhea. Increase Growth Increase Growth Clostridium difficileClostridium difficile Intestine. Intestine.

Nalidixic acidNalidixic acid, , NitrofurantoinNitrofurantoin.. Replication of DNA.. .. Replication of DNA.. Only Urinary tract Infection.. G-ve.. Resistance altered Only Urinary tract Infection.. G-ve.. Resistance altered DNA gyrase.DNA gyrase.

fusidic acidfusidic acid : A steroid antibiotic used to treat Gram- : A steroid antibiotic used to treat Gram-positive infections.. positive infections.. prevent translocation of l tRNA to prevent translocation of l tRNA to Ribosome. Ribosome.

MetronidazolMetronidazol: Anti-protozoa.. Anaerobic Bacteria.. : Anti-protozoa.. Anaerobic Bacteria..

nhibitionnhibition Nucleic Acid SynthesisNucleic Acid Synthesis-4-4

QuinolonesQuinolones / /FloroquinolonesFloroquinolones:: (1980s-1990s).. (1980s-1990s).. inhibit inhibit DNA Gyrase.. inhibiting DNA replicationDNA Gyrase.. inhibiting DNA replication & & transcription. transcription. Bactericidal, Bactericidal, NorfloxacinNorfloxacin, , CiprofloxacinCiprofloxacin, , LevofloxacinLevofloxacin.. Broad spectrum.. More .. Broad spectrum.. More G-ve than G+e Infections.. G-ve than G+e Infections.. intracellular pathogens, intracellular pathogens, Urinary Tract, Pneumonia, Septicemia.. Resistance by Urinary Tract, Pneumonia, Septicemia.. Resistance by altered DNA gyrase.. May Develop during treatment. altered DNA gyrase.. May Develop during treatment.

Rifamycin /RifampinRifamycin /Rifampin: binds to the RNA polymerase: binds to the RNA polymerase.... Prevent its transcription from DNA .. Bactericidal, Prevent its transcription from DNA .. Bactericidal, Mycobacteria.. Intracellular bacteria.. Chlamydia, Mycobacteria.. Intracellular bacteria.. Chlamydia, Brucella, Resistance due to change in RNA Brucella, Resistance due to change in RNA polymerase ß-subunit .polymerase ß-subunit .

55--Inhibition Synthesis of Essential MetabolitesInhibition Synthesis of Essential Metabolites

Sulfa drugs / SulfonamidesSulfa drugs / Sulfonamides : Structure analogue to : Structure analogue to PABA.. compete with it .. PABA.. compete with it .. Block folic acid synthesisBlock folic acid synthesis.. Essential .. Essential for nucleic acid synthesis ..Mammals don’t need PABA or its for nucleic acid synthesis ..Mammals don’t need PABA or its analogs .. can tolerate sulfa drugs. Bacteriostatic.. Now Rare analogs .. can tolerate sulfa drugs. Bacteriostatic.. Now Rare

used alone.. Rapid develop Resistance.. used alone.. Rapid develop Resistance.. alteredaltered binds PABAbinds PABA Sulfamethoxazole-trimethoprim (Co-trimoxazole).. Combination Sulfamethoxazole-trimethoprim (Co-trimoxazole).. Combination

Synergism.. Broad Spectrum, UTI, RTISynergism.. Broad Spectrum, UTI, RTI Antituberculosis DrugsAntituberculosis Drugs:: Inhibition Mycolic acid in Inhibition Mycolic acid in

Mycobacterial Cell Wall.. Mycobacterial Cell Wall.. Mycobacterium tuberculosisMycobacterium tuberculosis.. Others.. Others Isoniazid (INH), Ethambutol, Para-Aminosalicylic Acid, Isoniazid (INH), Ethambutol, Para-Aminosalicylic Acid, Rifampin, Streptomycin..6-24 months treatment.. Rapid Rifampin, Streptomycin..6-24 months treatment.. Rapid

Resistance Development.Resistance Development.

Structure Structure AnaloguesAnalogues

Antimicrobial ResistanceAntimicrobial Resistance

ResistanceResistance is becoming a serious problem Worldwide.. more is becoming a serious problem Worldwide.. more strains of communsel /pathogenic microorganisms ( Bacteria, strains of communsel /pathogenic microorganisms ( Bacteria, Yeast, Viruses)Yeast, Viruses) are become untreatable with commonly used are become untreatable with commonly used antimicrobials.. antimicrobials.. Acinetobacter sppAcinetobacter spp., ., Pseudomonas sppPseudomonas spp., ., MR-MR-staphylococcistaphylococci, , Mycobacteria sppMycobacteria spp. .

This problem is due to This problem is due to over use/ misuseover use/ misuse of antimicrobials in of antimicrobials in

medicine & agriculture and misuse by medicine & agriculture and misuse by general populationgeneral population..

Antibacterial resistanceAntibacterial resistance is often is often plasmid-borneplasmid-borne,, readily readily transferred by Conjugation.. Human-animal intestinal tract.. transferred by Conjugation.. Human-animal intestinal tract.. environment (water, food).. environment (water, food)..

Selective Pressure.. Extensive Use ..Slow to Rapid Develop Selective Pressure.. Extensive Use ..Slow to Rapid Develop

Acquired Resistance.. Natural Mutation.Acquired Resistance.. Natural Mutation.

Antibiotic Susceptibility TestsAntibiotic Susceptibility Tests

Laboratory Antibiotic Susceptibility Tests:Laboratory Antibiotic Susceptibility Tests: Culture, Isolation, Identification of Bacteria from Culture, Isolation, Identification of Bacteria from

clinical specimen as E. coli, S. aureus, clinical specimen as E. coli, S. aureus, Culture of only one pure bacteria species on Mueller-Culture of only one pure bacteria species on Mueller-

Hinton Broth & Agar.. Disk Diffusion test .. Measure Hinton Broth & Agar.. Disk Diffusion test .. Measure inhibition zone after 24 hrs incubation 37inhibition zone after 24 hrs incubation 37ooC C

Minimal Inhibitory Concentration (MIC/ug/ml)Minimal Inhibitory Concentration (MIC/ug/ml) .. .. E-testE-test consists of a strip containing an exponential consists of a strip containing an exponential

gradient of one antibiotic(1-2-4-8-16-32-64-128-256) gradient of one antibiotic(1-2-4-8-16-32-64-128-256) ug/mlug/ml

Lab ReportLab Report: Susceptible isolates (S) .. Intermediate : Susceptible isolates (S) .. Intermediate susceptible (IS).. Resistant (R)susceptible (IS).. Resistant (R)

Multi-resistant.. Resistance to Multi-resistant.. Resistance to >>2 antibiotic classes.2 antibiotic classes.

Disc-Diffusion Test-E-test (Mueller-Disc-Diffusion Test-E-test (Mueller-Hinton Broth/Agar, Single Pure cultureHinton Broth/Agar, Single Pure culture

E-Test (MIC/mg/L)E-Test (MIC/mg/L)