Antimicrobial Agents Mohammad Reza Fazeli, PharmD, PhD Professor of Microbiology Department of Drug...

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Transcript of Antimicrobial Agents Mohammad Reza Fazeli, PharmD, PhD Professor of Microbiology Department of Drug...

  • Antimicrobial AgentsMohammad Reza Fazeli, PharmD, PhDProfessor of MicrobiologyDepartment of Drug and Food ControlFaculty of PharmacyTehran University of Medical Sciences

  • Overview of Antibiotics as Therapeutic AgentsSelective Inhibition/Toxicity Due to the differences in structure and metabolic pathwaysHarm microorganisms, not the hostFour major sites:Cell wallRibosomesDNACell membrane

  • Spectrum of ActivityBroad Spectrum Antibiotics:Effective against many types Example: Tetracycline

    Narrow Spectrum Antibiotics:Effective against very few types Example: Penicillin

  • Bactericidal v. BacteriostaticBactericidal:

    Kill bacteria

    Used when the host defense mechanisms are impaired

    Bacteriostatic:

    Inhibit bacteria

    Used when the host defense mechanisms are intact

  • MECHANISMS OF ACTION OF MAJOR GROUPS OF ANTIBIOTICS

  • STRUCTURE OF -LACTAM ANTIBIOTICS

  • PENICILLIN HOME

  • Penicillin HomeLooks like a house with a new room added to the sideThink of the R-group as of an antennaChanging antennae and or finishing the basement will create better homes (penicillins)

  • [Penicillin] Home Improvement Project Adding a new antenna creates broad spectrum penicillins Example: Ampicillin

    Adding additional antennae and finishing the basement creates cephalosporinsExample: 1st, 2nd, 3rd, & 4th generation cephalosporins

  • SPECTRUM OF ACTIVITY OF CEPHALOSPORINS

  • MECHANISM OF ACTION OF -LACTAM ANTIBIOTICS

  • -Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation

    The -lactam moiety of penicillin binds to the enzyme (transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium

    Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide

  • Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin

    -lactam antibiotics are ineffective against protoplasts and spheroplasts:

  • MECHANISMS OF ACTION OF ANTIRIBOSOMAL ANTIBIOTICS

  • Inhibition of Protein SynthesisAnti-ribosomal antibiotics impair ribosomes by binding to either 50S or 30S ribosomal subunits Ribosomes are essential for translation of mRNA into proteinsNo translation No protein synthesisNo protein synthesis No growth

  • MECHANISM OF ACTION OF SULFONAMIDES AND TRIMETHOPRIM

  • Folic acid (also known as folate , vitamin M, vitamin B9, vitamin Bc or folacin are forms of the water-soluble vitamin B9.

    Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.

  • Vitamin B9 (folic acid and folate) is essential for numerous body functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions. It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.

  • Mechanisms of Resistance

    Genetic Mechanisms

    Non-Genetic Mechanisms

  • Genetic MechanismsChromosome-mediatedDue to spontaneous mutation: in the target molecule in the drug uptake systemPlasmid-mediatedCommon in Gram-negative rodsTransferred via conjugationMultidrug resistanceTransposon-mediated

  • Non-Genetic MechanismInaccessibility to drugs (e.g., abscess, TB lesion)

    Stationary phase (insusceptible to inhibitors of cell wall synthesis)

    Protoplasts and spheroplasts (insusceptible to inhibitors of cell wall synthesis)

  • The End Result of Genetically Conferred Resistance

    Production of drug-inactivating enzymes

    Modification of target structures

    Alteration of membrane permeability

  • Resistance to Beta-LactamsGram +

    -lactamase (Penicillinase)

    Alteration of the transpeptidase enzyme

    Gram -

    -Lactamase (Penicillinase)

    Alteration of porins

  • How can we test for susceptibility/resistance?

  • Antibiotic Susceptibility TestingDilution Method

    Disc Diffusion Method

    E-test

    High-Tech Methods

  • Dilution MethodPrepare two fold [antibiotic] dilutions Add 1/2 a million bacterial cells per tube Incubate overnight Check for turbidityEstablish the MIC: The lowest concentration of the drug that prevented the bacterial growth (no turbidity)

  • Disc Diffusion MethodSeed agar plates with bacteria in questionPlace antibiotic-discs over the seeded plateIncubate overnight Measure the inhibition zonesRelate the results to the zones given in the interpretive chartThere is an inverse relationship between the MICs and zone diameters

  • Therapeutic Index =Max. Safely Achievable Level MIC