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ANTIMICROBIAL THERAPYCHAPTER 13

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Chemotherapeutic Agents

Antibiotics: bacteriocidal vs bacteriostatic

Synthetic Drugs vs natural product

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History

Ancient remedies

Ehrlich

Domagk

Fleming

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Properties of Antimicrobial Agents

Selective Toxicity

Spectrum of Activity– Narrow

– Broad

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Spectrum of Activity

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Drug Mechanisms of Action

Inhibition of Cell Wall Synthesis

Disruption of Cell Membrane Function

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Drug Mechanisms of Action

Inhibition of Protein Synthesis

Inhibition of Nucleic Acid Synthesis

Antimetabolites

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Summary of Targets

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Side Effects

Toxicity

Allergy

Disruption of Microflora

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Classes of antibiotics Aminoglycosides Tetracyclines Sulfonamides Quinolones Polypeptides B-lactams Macrolides Glycopeptides Cephalosporins

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aminoglycosides

kanamycin, neomycin, amikacin

Binds 30 S ribosome

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tetracyclines

Tetracycline, Doxycycline

Binds 30 S ribosome

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sulfanamides

Sulfacetamide

Trimethoprim

Sulfamethizole

Folate synthesis inhibition. They are competitive inhibitors of the enzyme

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B-lactams

AmoxicillinCarbenicillinPenicillinAmpicillin

disrupt the synthesis of the peptidoglycan layer of bacterial cell walls.

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quinolones

inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme

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polypeptides

bacitracin

Polymyxin B

Inhibits isoprenyl pyrophosphate

Interacts with the bacterial cytoplasmic membrane, changing its permeability.

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macrolides

Azithromycin

Clarithromycin

Spectinomycin

Erythromycin

Binds to 50s ribosome

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Glycopeptides

Vancomycin- last resort drug

inhibiting peptidoglycan synthesis

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cephalosporins

CefaclorCefalexinCeftobiproleCefotaxime

Same mode of action as other beta-lactam antibiotics: disrupt the synthesis of the peptidoglycan layer of bacterial cell walls.

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Resistance to Drugs

Chromosomal - Klebsiella B lactamases

Plasmid borne - ribosomal protein mutations

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Mechanisms of Drug Resistance

Mutations in Target molecules

Alterations in membrane permeability

Enzyme development

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Fig. 27-27

PhosphorylationAdenylation

Streptomycin

Chloramphenicol

-Lactamase

Penicillin

Acetylation

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Table 27-7

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Mechanisms of Drug Resistance

Enzyme Activity Changes

Alterations in Anabolic Pathways

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Generations of Drugs

First/Second/Third Line Drugs

Cross Resistance

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Limiting Drug Resistance

Effective Drug Concentrations

Simultaneous Drug Administration• Synergism - clavulanic acid• Antagonism -

Restricting Drug Prescriptions

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Determining Microbial Sensitivities

Disk Diffusion Method

Dilution Method

Serum Killing Power

Automated Methods

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Ideal Antimicrobial Attributes

Solubility

Selective toxicity

Stable toxicity level

Allergenicity

Tissue stability

Resistance Acquisition

Shelf Life

Cost

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Antibacterials — Cell Wall Target Penicillins

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Antibacterials — Cell Wall Target

Cephalosporins

Carbapenems

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Antibacterials — Cell Membrane Target

Polymyxins

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Antibacterials — Protein Synthesis Inhibition

Aminoglycosides

Tetracyclines

Chloramphenicol

Macrolides

Insert Fig. 13.13

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Antibacterials — Nucleic Acid Synthesis Inhibition

Rifampin

Quinolones

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Antibacterials — Antimetabolites

Sulfonamides

Isoniazid

Ethambutol

Nitrofurans

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Antifungals

Imidazoles

Polyenes

Griseofulvin

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Antifungals

Flucytosine

Tolnaftate

Terbinafine

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Antivirals

Nucleotide analogs

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Antivirals

Amantidine/Rimantidine

Interferons/Immunoenhancers

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Antiprotozoan Drugs

Quinine/derivatives

Metronidazole

Pyrimethamine

Suramin

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Antihelminthic Drugs

Niclosamide

Mebendazole

Ivermectin

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Special Drug Resistance Problems