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Antimicrobials

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antimicrobials, classification of antimicrobials, drug resistance, mode of action.

antimicrobials, classification of antimicrobials, drug resistance, mode of action.

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  • 1. ANTIMICROBIALS MAJID MOHIUDDIN
  • 2.
    • Drugs designed to inhibit/kill the infecting organism and to have no/minimal effect on the recipient. T – Chemotherapy
    • Treatment of systemic infections with specific drugs .
    • Both synthetic and microbiologically .
    • Antimicrobial agent (AMA) to designate synthetic as well as natural.
  • 3. CLASSIFICATION OF ANTIMICROBIALS
    • Chemical structure
    • Mechanism of action
    • Type of organisms against which primarily active.
    • Spectrum of activity
    • Type of action
    • Antibiotics are obtained from.
  • 4. Chemical structure
    • Sulfonamides and related drugs: Sulfadiazine and other, Sulfones – Dapsone(DDS), Paraaminaosalicyclic (PAS)
    • Diaminopyrimidines: Trimethoprim, Pyrimethamine.
    • Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin etc.
    • β -lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems.
    • Tetracyclines: Oxytetracycline, Doxycycline etc.
    • Nitrobenzene derivative: Chloramphenicol
    • Aminoglycosides: Streptomycin, Gentamicin, Neomycin etc.
    • Macrolide antibiotics: Erythromycin, Roxithromycin, Azithromycin etc.
    • Polypepetide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin.
    • Nitrofuran derivatives: Nitrofurantoin, Furazolidone.
    • Nitroimidazoles: Metronidazole, Tinidazole.
    • Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide.
    • Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin.
    • Imidazole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole.
    • Others: Rifampin, Lincomycin, Clindamycin, Spectinomycin, Vancomycin, Sod. Fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin.
  • 5. MECHANISM OF ACTION
    • Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin.
    • Cause leakage from cell membranes:
      • Polypeptides : Polymyxins, Colistin, Bacitracin
      • Polyenes – Amphotericin B, Nystatin, Hamycin.
    • Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin.
    • Cause misreading of m-RNA code and affect permeability: Aminoglycosides – Streptomycin, Gentamicin etc.
    • Inhibit DNA gyrase: Fluoroquinolones – Ciprofloxacin.
    • Interfere with DNA function: Rifampin, Metronidazole.
    • Interfere with DNA synthesis: Idoxuridine, Acyclovir, Zidovudine.
    • Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol.
  • 6. TYPE OF ORGANISMS AGAINST WHICH PRIMARILY ACTIVE
    • Antibacterial: Penicillins, Aminoglycosides, Eruthromycin etc.
    • Antifungal: Griseofulvin, AmphotericinB, Ketoconazole etc.
    • Antiviral: Idoxuridine, Acyclovir, Amantadine, Zidovudine etc.
    • Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide etc.
    • Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine etc.
  • 7. SPECTRUM OF ACTIVITY
    • NARROW SPECTRUM: Penicillin G, Streptomycin Erthromycin
    • BROAD SPECTRUM: Tetracyclines, Chloramphenicol.
  • 8. TYPE OF ACTION
    • PRIMARILY BACTERIOSTATIC:
    • Sulfonamides, Tetracyclines, Chloramphenicol, Erythromycin, Ethambutol
    • PRIMARILY BACTERICIDAL: Penicillins, Aminoglycosides, Polypeptides, Rifampin, Cotrimoxazole, Cephalosporins, Vancomycin, Nalidixic acid, Ciprofloxacin, Isoniazid.
  • 9. ANTIBIOTICS ARE OBTAINED FROM
    • FUNGI: Penicillin, Cepholosporin,Griseofulvin.
    • BACTERIA: Polymyxin B, Colistin, Bacitracin, Tyrothricin, Aztreonam.
    • ACTINOMYCETES: Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolides, Polyenes.
  • 10. PROBLEMS THAT ARISE WITH THE USE OF AMAs.
    • TOXICITY:
    • HYPERSENSITIVITY REACTIONS:
    • DRUG RESISTANCE
        • Mutation
        • Gene Transfer
        • Cross resistance
        • Prevention of drug resistance.
    • SUPERINFECTION (SUPRAINFECTION)
  • 11.
    • TOXICITY:
    • A) LOCAL IRRITANCY: Erythromycin, Tetracyclines, certain cephalosporins and chloramphenicol.
    • B) SYSTEMIC TOXICITY: Dose related and predictable organ toxicities
    • - High therapeutic index – Penicillins, some cephalosporins and erythromycin.
    • - Lower Therapeutic index – individualized and toxicity watched
    • Aminoglycosides: 8 th cranial nerve and kidney toxicity.
    • Tetracyclines : Liver and kidney damage, antianabolic effect.
    • Chloramphenicol: Bone marrow depression.
    • - Very low Therapeutic index - Use is highly restricted
    • Polymyxin B : neurological and renal toxicty.
    • Vancomycin : hearing loss, kidney damage.
    • Amphotericin B : kidney, bone marrow and neurological toxicity.
  • 12.
    • 2. HYPERSENSITIVITY REACTIONS:
    • Practically All AMAs.
    • Unpredictable and unrelated to dose.
    • Reactions from rashes to anaphylactic shock.
    • Penicillins, cephalosporins, sulfonamides.
  • 13.
    • 3. DRUG RESISTANCE:
    • Natural resistance: always resistance.
    • Pencillin G – Gram –ve bacilli.
    • Tetracyclines – M.tuberculosis
    • Acquired resistance: develop resistance
    • rapid acquisition – staphylococci, coliforms, tubercle bacilli.
    • Strep.pyogenes & spirochetes – penicillin when >40 years.
    • Gonococci – quick to sulfonamides but low to penicillin.
    • Resistance may be developed by mutation or gene transfer
  • 14.
    • MUTATION:
    • 1. Single Step: high degree of resistance, emerges rapidly – e.g. Enterococci to streptomycin
    • E.Coli and Staphylococci to Rigampin
    • 2. Multistep: Resistance to erythromycin, tetracyclines and chloramphenicol
    • Low grade penicillin resistant gonococci have decreased virulence. Staphylococci to rifampin.
  • 15.
    • Gene transfer (infectious resistance) from one organism to another can occur by:
      • Conjugation: R – factor (Resistance transfer factor (RTF)). Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of E.coli, Penicillin resistance of Haemophilus and gonococci.
      • Transduction: Penicillin, erythromycin and Chloramphenicol – phage mediated.
      • Tranformation: Pneumococcal resistance to penicillin G due to altered penicillin binding protein.
  • 16.
    • Resistant Organisms can be:
    • Drug tolerant: loss of affinity of the target biomolecule of the microorganism for a particular AMA. E.g., resistant Staph.aureus and E.coli developa RNA polymerase that does not bind rifampin.
    • Drug destroying: β - lactamase by Staphylococci, Haemophilus, Gonococci etc., which inactivate penicillin G. Chloramphenicol acetyl transferase is acquired by resistant E.coli, H.influenzae and S.typhi.
    • Aminoglycoside resistant coliforms – produce enzymes which adenulate/acetylate/phosphorylate specific aminoglycoside antibitotics.
    • c) Drug impermeable: Many hydrophilic antibiotics access though porins, or need specific transport mechanisms. Glycosides and tetracyclines in the resistant gram negative bacterial strains.
  • 17.
    • Cross resistance: Acquisition of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance.
    • Sulfonamide – to all others.
    • Tetracycline – insensitivity to all others.
    • Aminoglycoside – not extend to another
      • Gentamicin - amikacin also
      • Cross resistance e.g., between tetracyclines and chloramphenicol, between erythromycin and lincomycin.
      • Newmycin resistance by enterobacteriaceae – insensitive to streptomycin.
  • 18.
    • 4. Superinfection ( Suprainfection)
    • Appearance of a new infection as a result of antimicrobial therapy.
    • The normal flora contributes to host defence by elaborating substances called bacteriocins which inhibit pathogenic organisms.
    • Superinfections are more common when host defence is compromised, as in:
    • Corticosteriod therapy
    • Leukemias and other malignancies (WBC count)
    • Acquired immunodeficiency syndrome (AIDS)
    • Agranulocysis
    • Diabetes, disseminated Lupus Erythematosus.
  • 19. MAJID MOHIUDDIN Thank you