Antimicrobial drugsAntimicrobial drugs

Prof. Dr. Asem ShehabiProf. Dr. Asem Shehabi

Faculty of MedicineFaculty of Medicine

University of JordanUniversity of Jordan

IntroductionIntroduction 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 1941....Penicillium Penicillium notatumnotatum.. Aminoglycosides (.. Aminoglycosides (StreptomycinStreptomycin, , Kanamycin)Kanamycin)19461946.. ..

Source: Source: Soil Bacteria Actinomyctes group.Soil Bacteria Actinomyctes group. At present about 100 antimicrobial At present about 100 antimicrobial drugsdrugs of different of different

classes are available for use in humans.classes 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 Drugs kill only actively growing actively growing microorganisms are microorganisms are termed termed BactericidalBactericidal.... PenicillinsPenicillins, , Aminoglycosides Aminoglycosides

Drugs that only inhibit the growth of microorganisms Drugs that only inhibit the growth of microorganisms are termed are termed BacteriostaticBacteriostatic.... Sulfonamides, Sulfonamides, ChloramphenicolChloramphenicol, , Tetracyclines Tetracyclines

The decision to use a The decision to use a bactericidalbactericidal / / bacteriostatic bacteriostatic drug to treat infection depends entirely upon the type drug to treat infection depends entirely upon the type & body site of infection, patients age, kidney–Liver & body site of infection, patients age, kidney–Liver functions.. acute or chronic infection.functions.. acute or chronic infection.

Ultimate elimination of the organisms is dependent Ultimate elimination of the organisms is dependent upon host defense..upon host defense..phagocytic activity and specific phagocytic activity and specific antibodiesantibodies

Action of Antimicrobial Drugs on BacteriaAction of Antimicrobial Drugs on Bacteria Antimicrobials are classifiedAntimicrobials are classified: Range of activity : Range of activity

/spectrum/spectrum.. .. NarrowNarrow (Antimycobacterial drugs), (Antimycobacterial drugs), Narrow-Narrow-moderatemoderate (Gram-ve/Gram+ve) Amoxicillin..(Gram-ve/Gram+ve) Amoxicillin.. Broad Broad spectrumspectrum Tetracylines , ChloramphenicolTetracylines , Chloramphenicol

AntimicrobialsAntimicrobials affect specific or various affect specific or various bacterial bacterial cellular targetscellular targets.. cell wall, plasma membrane, nucleic .. cell wall, plasma membrane, nucleic acids, proteins synthesis.acids, proteins synthesis.

1- 1- Inhibition Cell Wall Synthesis:Inhibition Cell Wall Synthesis: Group of 6-Amino Group of 6-Amino penicillanic acid includepenicillanic acid include all Beta-Lactam drugs ..Bactericidal.. all Beta-Lactam drugs ..Bactericidal.. They differs only by the presence of an They differs only by the presence of an amino /carboxyl amino /carboxyl groupgroup.. helps the drug penetrate the outer membrane of gram-.. helps the drug penetrate the outer membrane of gram-negative bacteria. negative bacteria.

Inhibition Cell Wall-1Inhibition Cell Wall-1

All Beta-Lactam DrugsAll Beta-Lactam Drugs attached to Penicillin Binding attached to Penicillin Binding Proteins (PBPs).. inhibit transpeptidases.. peptide Proteins (PBPs).. inhibit transpeptidases.. peptide cross-linking of growing peptidoglycan.. Stop cell wall cross-linking of growing peptidoglycan.. Stop cell wall synthesis .. Activation cell autolysins.synthesis .. Activation cell autolysins.

1) Narrow- moderate1) Narrow- moderate.. .. Penicillin G, VPenicillin G, V .. affects .. affects mainly G+e & G-ve cocci aerobic & anaerobic mainly G+e & G-ve cocci aerobic & anaerobic bacteria.. Less G-ve bacilli Facultative aerobic.. bacteria.. Less G-ve bacilli Facultative aerobic.. Streptococci, Staphylococci, Bacateriodes , Streptococci, Staphylococci, Bacateriodes ,

2) Broad spectrum2) Broad spectrum.... Ampicillin, Ampicillin, AmoxacillinAmoxacillin.. .. Developed 1960s..Most G+ve/G-negative.. B-lactam Developed 1960s..Most G+ve/G-negative.. B-lactam drugs are susceptible to Penicillinases /ß-Lactamases.drugs are susceptible to Penicillinases /ß-Lactamases.

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

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

Inhibition Cell Wall-2Inhibition Cell Wall-2 3) Penicillinase-R drugs3) Penicillinase-R drugs:: Oxacillin, flucloxacillinOxacillin, flucloxacillin ,Methicillin .. 1970s.. used only ,Methicillin .. 1970s.. used only

against G+ve.. Staph-R To against G+ve.. Staph-R To Penicillins-Ampicillin..Penicillins-Ampicillin.. Methicillin-R Staphylococcus aureus Methicillin-R Staphylococcus aureus (MRSA)..(MRSA).. Jordan Jordan up 50%up 50% ..Worldwide spread.. Serious Infections. ..Worldwide spread.. Serious Infections.

Amoxacillin+Clavulinic AcidAmoxacillin+Clavulinic Acid (B-lactamase inhibitor) (B-lactamase inhibitor) compound)/ Broad Spectrum.. compound)/ Broad Spectrum.. Penicillinase-RPenicillinase-R

Carbencillin, Piperacillin,TicarcillinCarbencillin, Piperacillin,Ticarcillin.. 1970s.. .. 1970s.. Carboxyl Penicillin group.. used mainly against G-ve Carboxyl Penicillin group.. used mainly against G-ve Pseudomonas spp. Pseudomonas spp. Penicillinase-Susceptible bacteriaPenicillinase-Susceptible bacteria

Monobactam/ AztreonamMonobactam/ Aztreonam (1990s) used mostly (1990s) used mostly against serious Facultative G-ve infection.against serious Facultative G-ve infection.

Carbapenem / imipenem Carbapenem / imipenem & & meropenemmeropenem.... (1990s) (1990s) Broad Spectrum.., Penicillinase-R, used mainly Broad Spectrum.., Penicillinase-R, used mainly against G-ve Enteric bacilli.. Serious Nosocomial against G-ve Enteric bacilli.. Serious Nosocomial Infection.. Infection.. Pseudomonas aeruginosa, Acinetobacter Pseudomonas aeruginosa, Acinetobacter

Penicillin-Binding protein-Penicillin-Binding protein-Bacterial Cell WallBacterial Cell Wall

Inhibition Cell Wall-3Inhibition Cell Wall-3 4) Cephalosporins: 4) Cephalosporins: 4 Generations..1965-1990s..Oral, 4 Generations..1965-1990s..Oral,

IV, IM. IV, IM. 11thth (1960) (1960) CephalexinCephalexin, , CephradineCephradine,, Broad spectrumBroad spectrum.... 22thth (70s) (70s) CefoxitinCefoxitin, , CefuroximeCefuroxime,, Broad spectrumBroad spectrum.... 33thth (80s) (80s) CeftriaxoneCeftriaxone, , CefotaximeCefotaxime.... mainly G-ve Enteric mainly G-ve Enteric

bacteriabacteria.... 44th th (1990s) (1990s) CefepimeCefepime.... mainlymainly G-ve Enteric bacteriaG-ve Enteric bacteria UTI, RTI, Intestinal, Blood sepsis, CSF infectionsUTI, RTI, Intestinal, Blood sepsis, CSF infections.. ..

Not used against anaerobes.. Increased resistance Not used against anaerobes.. Increased resistance Enterococcus group ( E.fecalis) in human intestinalEnterococcus group ( E.fecalis) in human intestinal

Inhibition Cell Wall-4Inhibition Cell Wall-4 Resistance Development Resistance Development ::

All G-ve enteric bacteria develop rapidly resistance to All G-ve enteric bacteria develop rapidly resistance to B-lactam drugs by B-lactam drugs by mutation & Plasmid transfer. mutation & Plasmid transfer.

ß-lactamases genesß-lactamases genes..or ..or Extended ß-lactamases Extended ß-lactamases spectrumspectrum..( > 60 types).. Altered Penicillin Binding ..( > 60 types).. Altered Penicillin Binding Proteins.. inactive ß-lactam ring..spread mostly during Proteins.. inactive ß-lactam ring..spread mostly during treatment hospitalized patients.treatment hospitalized patients.

Recently Klebsiella pneumoniae carbanemase-R Recently Klebsiella pneumoniae carbanemase-R (KPC)..(KPC)..Resistant to all available antibiotics Resistant to all available antibiotics

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

Inhibition Cell Wall-5Inhibition Cell Wall-5

D) GlycopeptidesD) Glycopeptides: : Vancomycin ,TeicoplaninVancomycin ,Teicoplanin

large polycyclic peptides..interfere with the large polycyclic peptides..interfere with the synthesis of the bacterial cell wall..different synthesis of the bacterial cell wall..different mechanism than the beta-lactams.. mechanism than the beta-lactams.. Prevent Prevent formation the cross-linkingformation the cross-linking. .

Treatment Treatment Methicillin-R Staphylococcus spp., Methicillin-R Staphylococcus spp., Multi-R Enterococci Multi-R Enterococci (E. fecalis).. High doses/ (E. fecalis).. High doses/ long period Toxic for host..Vacomycin-R..still long period Toxic for host..Vacomycin-R..still very rare worldwidevery rare worldwide

22 - -Inhibition of membrane integrityInhibition of membrane integrity

Colistin /Polymixen EColistin /Polymixen E: : Polyenes .. Large Polyenes .. Large circular molecule consisting of a hydrophobic circular molecule consisting of a hydrophobic and hydrophilic region..and hydrophilic region.. Complex Complex polypeptides ..Bactericidal, Both G-ve, G +ve , polypeptides ..Bactericidal, Both G-ve, G +ve , Topical Drugs.. Wounds, systemic infection Topical Drugs.. Wounds, systemic infection (blood sepsisi, meningitis, pneumonia) against (blood sepsisi, meningitis, pneumonia) against MDR- Gram-negative PathogensMDR- Gram-negative Pathogens .. .. Acinetobacter & Pseudomonas.. Causing Acinetobacter & Pseudomonas.. Causing Nephrotoxic Nephrotoxic

Polypeptides: Polypeptides: Large molecule isolated from Large molecule isolated from Bacillus spp.Bacillus spp. Bacitracin..Bacitracin.. Affects cell Affects cell membrane-bound phospholipid carrier.. membrane-bound phospholipid carrier.. Bactericidal, Toxic Bactericidal, Toxic Topical use.. Topical use.. G+ve bacteriaG+ve bacteria

3-Inhibition Protein Synthesis3-Inhibition Protein Synthesis • Bacterial Ribosomes composed 30s+50s=70s Aminoglycosides: Inhibit protein synthesis by

binding to the 30S ribosomal subunits.. prevent formation complex polypeptides with messenger RNA.. Increase cell membrane leakage.

• Bactericidal, Broad-spectrum of activity, Mainly used against G-ve.. Not Anaerobes.. Used in Serious Infection, .. Hospital ..IV, IM, Streptomycin, Neomycin, Amikacin, Gentamicin, Tobramicin, Netilmicin,

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

• Resistance: Production Accetylate, Phosphorylate, adenylate Enzymes..during the drug passes cell membrane..chromosomal & plasmid resistance

AminoglycosideAminoglycoside-Tetracycline-Tetracycline

33--Inhibition Protein SynthesisInhibition Protein Synthesis TetracyclinesTetracyclines,, Mid1950s Mid1950s : : BacteriostaticBacteriostatic, , Broad Broad

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

DoxcyclineDoxcycline, , MinocyclineMinocycline.. Cholera, Respiratory & .. Cholera, Respiratory & Genital Infection.. Genital Infection.. MycoplasmaMycoplasma, , ChlamydiaChlamydia, , Legionella Legionella infections.. New introduced 2005 infections.. New introduced 2005 TigecyclineTigecycline..

Chloramphenicol, Mid1950s Chloramphenicol, Mid1950s : : Bacteriostatic Bacteriostatic ....Acts by Acts by binding to the binding to the 50S ribosomal subunit50S ribosomal subunit and blocking and blocking the formation of the 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

MacrolidesMacrolides Large lactoneLarge lactone ring structure ranged between 14-16 ring structure ranged between 14-16

membered ringsmembered rings.. .. binds to the binds to the 50S ribosomal subunit50S ribosomal subunit .. inhibits either peptid transferase activity or .. inhibits either peptid transferase activity or translocation of the growing peptide to mRNA. translocation of the growing peptide to mRNA.

Most widely used Most widely used MacrolidesMacrolides .. .. Erythromycin, Erythromycin, Clarithromycin, Clarithromycin, Azithromycin Azithromycin ( Long acting-12 hours) ( Long acting-12 hours) Oral Oral

Relatively non-toxic drugs, mostly active against Gram-positive/ Relatively non-toxic drugs, mostly active against Gram-positive/ Intracellular bacteria.. Respiratory Infections.. Pneumoniae, Intracellular bacteria.. Respiratory Infections.. Pneumoniae, diphtheria.., diphtheria.., B-H-StreptococciB-H-Streptococci- - StaphylococcalStaphylococcal MycoplasmaMycoplasma, , ChlamydiaChlamydia, , LegionellaLegionella pneumophilapneumophila InfectionsInfections. .

B) B) LincosamidesLincosamides//Clindamycin, Lincomycin Clindamycin, Lincomycin : : StaphylococcusStaphylococcus.. .. Streptococci.. Bones, Oral cavity.. Anaerobic Infections.. Streptococci.. Bones, Oral cavity.. Anaerobic Infections..

* Common Cause * Common Cause Pseudomembranous ColitisPseudomembranous Colitis.. Bloody .. Bloody diarrhea.. Increase Growth diarrhea.. Increase Growth Clostridium difficileClostridium difficile in Intestine.. in Intestine..

IInhibitionnhibition Nucleic Acid SynthesisNucleic Acid Synthesis-4-4 Nalidixic acid ( Basic QuinolonesNalidixic acid ( Basic Quinolones)) Inhibit DNA Inhibit DNA

ReplicationReplication.. Bactericidial. .. Bactericidial. NitrofurantoinNitrofurantoin..Damage ..Damage DNA.. Both synthetic drugs..Active against G-ve enteric DNA.. Both synthetic drugs..Active against G-ve enteric bacteria..bacteria..E.coli..E.coli.. used in Urinary tract Infection. used in Urinary tract Infection.

FloroquinolonesFloroquinolones:: (1980s).. inhibit (1980s).. inhibit DNA GyraseDNA Gyrase.. DNA .. DNA replicationreplication & transcription. & transcription. BactericidalBactericidal, , Norfloxacin, Norfloxacin, Ciprofloxacin, Levofloxacin , Ofloxacin..Ciprofloxacin, Levofloxacin , Ofloxacin..Broad Broad spectrum.. More G-ve than G+e Infections.. spectrum.. More G-ve than G+e Infections.. intracellular pathogens, Urinary Tract, Pneumonia, intracellular pathogens, Urinary Tract, Pneumonia, Septicemia.. Resistance by altered DNA gyrase.. May Septicemia.. Resistance by altered DNA gyrase.. May Develop during treatment. Develop during treatment.

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

to Ribosome. to Ribosome.

Anti-tuberculosisAnti-tuberculosis Rifamycin /RifampinRifamycin /Rifampin: : binds to the binds to the RNA RNA

polymerase..polymerase.. Prevent its transcription from Prevent its transcription from DNA .. DNA .. BactericidalBactericidal,, MycobacteriaMycobacteria.. .. Intracellular bacteria.. Intracellular bacteria.. ChlamydiaChlamydia, , BrucellaBrucella, , Resistance due to change in RNA Resistance due to change in RNA

AntituberculosisAntituberculosis Drugs: Drugs: Inhibition Inhibition Mycolic Mycolic acid acid ..Part of Mycobacterial Cell Wall.. ..Part of Mycobacterial Cell Wall.. Mycobacterium tuberculosisMycobacterium tuberculosis.. ..

IsoniazidIsoniazid (INH), (INH), EthambutolEthambutol, , CycloserineCycloserine, , Rifampin,Rifampin, StreptomycinStreptomycin.. 6-24 months .. 6-24 months treatment.. Rapid Resistance if used treatment.. Rapid Resistance if used alone..Combination.. Treatment 6-28 months.alone..Combination.. Treatment 6-28 months.

55--Inhibition Synthesis of Essential Inhibition Synthesis of Essential MetabolitesMetabolites

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 for nucleic acid synthesis ..Mammals don’t Essential for nucleic acid synthesis ..Mammals don’t need PABA or its analogs .. can tolerate sulfa drugs. need PABA or its analogs .. can tolerate sulfa drugs. BacteriostaticBacteriostatic.. Now Rare used alone.. Rapid .. Now Rare used alone.. Rapid develop Resistance by develop Resistance by altered binds PABAaltered binds PABA

Sulfamethoxazole-trimethoprimSulfamethoxazole-trimethoprim / (Cotrimoxazole).. / (Cotrimoxazole).. Combination Synergism.. Broad Spectrum, UTI, RTI.Combination Synergism.. Broad Spectrum, UTI, RTI.

MetronidazolMetronidazol:: Anti-protozoa & Most Anaerobic Anti-protozoa & Most Anaerobic Bacteria. polymerase ß-subunit.Bacteria. polymerase ß-subunit.

Inhibition Folic acid synthesisiInhibition Folic acid synthesisi

Antibiotic Susceptibility TestsAntibiotic Susceptibility Tests

Laboratory Antibiotic Susceptibility TestsLaboratory 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 ConcentrationMinimal Inhibitory Concentration (MIC/ug/ml) (MIC/ug/ml) .. .. E-testE-test consists of a strip containing an exponential gradient of consists of a strip containing an exponential gradient of

one antibiotic(1-2-4-8-16-32-64-128-256) ug/mlone antibiotic(1-2-4-8-16-32-64-128-256) ug/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.

Antibiotic Disc -TestAntibiotic Disc -Test

Control Antimicrobial ResistanceControl Antimicrobial Resistance

ResistanceResistance is becoming a serious problem Worldwide.. more is becoming a serious problem Worldwide.. more commensal /pathogenic microorganisms ( Bacteria, Yeast, commensal /pathogenic microorganisms ( Bacteria, Yeast, Viruses)Viruses) are become untreatable with commonly used are become untreatable with commonly used antimicrobials.. antimicrobials.. Acinetobacter sppAcinetobacter spp., ., Pseudomonas sppPseudomonas spp., ., MR-MR-staphylococcistaphylococci (MRSA), Va-R Enterococcus, MR- (MRSA), Va-R Enterococcus, MR-Mycobacteria Mycobacteria sppspp… … High Mortality & High Treatment Cost High Mortality & High Treatment Cost . .

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 including β-lactamases, efflux pumps, including β-lactamases, efflux pumps,

porin mutations, modifying enzymes and binding site mutations. porin mutations, modifying enzymes and binding site mutations. horizontal transfer of combined resistance by plasmids.. horizontal transfer of combined resistance by plasmids.. Develop multidrug resistance..Develop multidrug resistance..  Mostly Not ReversibleMostly Not Reversible..

Antibiotics selective Pressure..Human, Animals, Environment. Antibiotics selective Pressure..Human, Animals, Environment.