ANTIMICROBIAL%20AGENTS

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ANTIMICROBIAL AGENTS
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• ANTIBIOTICS
• ANTIMICROBIAL AGENTS
• CHEMOTHERAPEUTIC AGENTS

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ANTIBIOTICS

• Natural substances produced by various species of
  microorganisms
• bacteria
• fungi
• actinomycetes
• suppress growth / kill other microorganisms

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ANTIMICROBIAL AGENTS

• Synthetic analogues
• ANTIMICROBIAL AGENTS
• includes synthetic as well as naturally obtained
  drugs that attenuate microorganisms

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CHEMOTHERAPEUTIC AGENTS

• Drugs in this class differ from all others in
  that they are
• Designed to inhibit/kill the infecting organism
  and have no/minimal effect on the recipient.

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• Classification
• Of AMAs

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• Microorganisms of medical impotance fall into
  four categories
• Bacteria
• Viruses
• Fungi
• Parasites

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• Anti-bacterial
• Anti-viral
• Anti-fungal
• Anti-parasitic agents

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Mechanism of Action

• Agents that inhibit synthesis of bacterial cell
  walls
• Penicillins cephalosporins
• Cycloserine,
• Vancomycin
• Bacitracin
• Azole antifungal agents (clotrimazole,
  fluconazole, itraconazole)

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• Agents that act directly on the cell membranes of
  the microorganisms
• Polymixin
• Polyene antifungal agents
• (Nystatin, Amphotericin B)
• Alter cell memb. Permeability,
• leakage of intracellular comp.

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• Agents that affect the function of 30S or 50S
  ribosomal subunits to cause a reversible
  inhibition of protein synthesis
• Bacteriostatic drugs
• Chloramphenicol, Tetracyclines,
  Erythromycin, Clindamycin, Pristinamycins

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• Agents that bind to 30S ribosomal subunit
  alter protein synthesis, which eventually leads
  to cell death
• Aminoglycosides

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• Agents that affect bacterial nucleic acid
  metabolism.
• Rifamycins which inhibit RNA polymerase
• Quinolones which inhibit topoisomerases

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• Anti-metabolites
• including trimethoprim sulphonamides
• Antiviral agents
• Nucleic acid analogues,
• Non-nucleoside reverse transcriptase
  inhibitors,
• Inhibitors of viral enzymes

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TYPE OF ACTION

• Bacteriostatic Agents
• Bactericidal Agents

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• Bacteriostatic Agents
• Sulphonamides
• Tetracyclines
• Chloramphenicol
• Erythromycin
• Ethambutol

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• Bactericidal Agents
• Penicillins/Cephalosporins/Carbapenems
• Aminoglycosides
• Rifampin
• Isoniazid
• Pyrazinamide

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• Cephalosporins
• Vancomycin
• Nalidixic acid
• Ciprofloxacin
• Metronidazole
• Cotrimoxazole

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• Some primarily static drugs may become cidal at
  higher concentrations (as attained in the urinary
  tract) vice-versa.

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SPECTRUM Of ACTIVITY

• Narrow spectrum
• Broad spectrum

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SPECTRUM Of ACTIVITY

• Narrow spectrum Penicillin G Streptomycin
  
• Broad spectrum
• Tetracyclines
• Chloramphenicol

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Successful Antimicrobial Therapy

• Concentration site of infection
• Concentration should inhibit microorganisms
• simultaneously it should be below the level
  toxic to human beings.
• Host Defences
• Immunity intact - Bacteriostatic Agents
• Impaired immunity - Bactericidal Agents

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Source of antibiotics

• Fungi
• Bacteria
• Actinomycetes.

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Source of antibiotics

• Fungi
• Penicillin, Griseofulvin, Cephalosporin
• Bacteria
• Polymyxin B, Colistin, Bacitracin, Aztreonam.
• Actinomycetes.
• Aminoglycosides, Macrolides, Tetracyclines,
  Polyenes, Chloramphenicol

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• Resistance

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Bacterial resistance to ANTIMICROBIAL AGENTS

• 3 general categories
• Drug does not reach its target
• Drug is not active
• Target is altered

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Drug does not reach its target

• Porins
• Absence/mutation
• Reduce drug entry
• Reduced effective drug concentration at the
  target site.
• Efflux pumps
• Transport drugs out of the cell
• Resistance to tetracyclines ß-lactam antib

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Inactivation of Drug

• Second general mechanism of drug resistance
• ß-lactam antibiotics - ß-lactamase
• Aminoglycosides - Aminoglycoside modifying
  enzymes
• Variant failure of bacterial cell to convert an
  inactive drug to its active metabolite.
  Resistance to INH in mycobacterium TB

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Alteration of the Target

• Mutation of natural target
• Target modification
• The new target does not bind the drug for native
  target
• Resulting in resistance to antibiotic.

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• Components mediating resistance to ß lactam
  antibiotics in psuedomonas aeruginosa

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• ß lactam antibiotics hydrophilic
• Must cross outer membrane barrier of the cell via
  outer membrane protein (Omp) channel or porins
• Mutation/missing/deleted
• Drug entry slow or prevented.

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• ß - lactamase concentrated between the inner
  outer membrane in the periplasmic space
• constitutes an enzymatic barrier
• Drug destroyed
• Effective concentration not achieved

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• Target PBP penicillin binding protein
• Low affinity for drug
• Altered

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• Efflux transporter
• Mex A, Mex B Opr F
• Pumps the antibiotic across the outer membrane
• Reduced intracellular concentration of active
  drug
• RESISTANCE

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Mutations

• May occur in
• Target protein
• Drug transport protein
• Protein important for drug activation
• Random events
• Survival advantage upon re-exposure to the drug

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• Resistance is acquired by horizontal transfer of
  resistance determinants from a donor cell, often
  of another bacterial species by
• Transduction
• Transformation
• Conjugation

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• Insatiable need for new antibiotics

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• Emergence of antibiotic resistance in bacterial
  pathogens both nosocomially in the community
  setting is a very serious development that
  threatens the end of antibiotic era.

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• Responsible approach to the use of antibiotics
• That are now available new agents that might be
  developed in future
• Is essential
• If the end of antibiotic era is to be averted.

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• CROSS RESISTANCE

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CROSS RESISTANCE

• Acquisition of resistance to one AMA conferring
  resistance to another antimicrobial agent to
  which the organism has not been exposed,is called
  cross resistance
• Seen b/w chemically or mechanistically related
  drugs.

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• Resistance to one sulphonamide means resistance
  to all others
• Resistance to one tetracyclines means
  insenstivity to all others
• Complete cross resistance

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• Resistance to one aminoglycoside may not extend
  to others, Gentamycin resistant strains may
  respond to amikacin.
• partial cross resistance

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• Sometimes unrelated drugs show partial cross
  resistance,
• e.g. Tetracyclines
• Chloramphenicol

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• Prevention DRUG RESISTANCE

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Prevention DRUG RESISTANCE

• Use of AMAs should not be
• indiscriminate
• inadequate
• unduly prolonged
• Use rapidly acting narrow spectrum (Selective)
  AMA whenever possible.

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Prevention DRUG RESISTANCE

• Combination AMA
• whenever prolonged therapy is undertaken.
  Tuberculosis, SABE
• Infection by organism notorious for developing
  resistance Staph, E. Coli, M. Tuberculosis must
  be treated intensively.