4 introduction to antimicrobials

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Pharmacology
Third Year

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4 introduction to antimicrobials

  1. 1. Introduction to Antimicrobials
  2. 2. Definitions CHEMOTHERAPY : • Treatment of infection/cancer with drugs that selectively kill the micro-organisms or cancer cells • Anti-microbials: Drugs/substances to kill micro-organisms (viruses, bacteria, fungi & protozoa, etc) • Antibiotics – Antimicrobials obtained from microorganisms, such as fungus, etc. – Bactericidal – kill the bacteria – (Beta lactam antibiotics, Cotrimoxazole, Aminoglycosides, etc.) – Bacteriostatic – prevent the multiplication of bacteria – (Macrolides, Tetracyclines, Sulfonamides, Trimethoprim, etc.) CHEMOPROPHYLAXIS: • Prevention of infection by chemicals/drugs
  3. 3. Mechanism of Action of Antibacterial drugs • Inhibition of bacterial cell wall synthesis: – Penicillins, Cephalosporins, Vancomycin, etc • Inhibition of cell membrane: – Polymixins, Amphotericin B & Nystatin • Inhibition of protein synthesis : – Tetracyclines, Aminoglycosides, Macrolides, • Inhibition of DNA synthesis : – Flouroquinolones, Rifampicin, Metronidazole • Anti-metabolites: – Sulphonamides (inhibit folic acid synthesis), – Trimethoprim (inhibits conversion of folic acid to folinic acid)
  4. 4. Mechanism of action (overview) 50S & 30S Inhibitors of cell wall synthesis Inhibitors of DNA & cell division Inhibitors of cell membrane synthesis Inhibitors of protein synthesis PABA Pteridine Folic acidFolinic acid Purines Pyrimidines DNA Ribosome mRNA
  5. 5. Resistance to Antibiotics Unresponsiveness of microorganisms to an antimicrobial agent Mechanisms of Resistance: • Inactivation of the drug by bacterial enzymes – beta-lactamases inactivate some Penicillins & Cephalosporins • ↓↓bacterial permeability to drug: Tetracyclines • ↑↑elimination of the drug from the cell: Fluoroquinolones • Change in ribosomal binding site: Erythromycin • Genetic methods - Mutation, Plasmid mediated, Cross resistance: Resistance to one drug usually leads to resistance against other drugs in the same group
  6. 6. Prophylactic Antibiotics Certain clinical situations require the use of antibiotics for the prevention of infections. • 1. Prevention of streptococcal infections in patients with a history of rheumatic heart disease. – Patients may require years of treatment • 2. Bacterial endocarditis following dental extractions • 3. Tuberculosis in close contacts of an infective TB patient • 4. Surgical procedures (bowel surgery, joint replacement & some gynecological operations) to prevent infections • 5. Neonatal HIV infection (Vertical transmission) Zidovudine to HIV infected pregnant mother • 6. Prevention of epidemics: Meningitis, Influenza, Cholera, Typhoid
  7. 7. Antimicrobial drug combinations • Broad-spectrum empiric therapy in seriously ill pts • To treat mixed (polymicrobials) infections – Intra-abdominal abscesses due to a combination of anaerobic & aerobic gram-negative organism, and enterococci) • To enhance (synergism) anti-microbial activity • To decrease the emergence of resistance
  8. 8. Antimicrobial drug combinations • Synergism: When the inhibitory or killing effects of two or more antimicrobials used together are greater than expected from their effects when used individually. • Penicillin or Ampicillin in combination with Gentamicin or Streptomycin is superior to monotherapy with penicillin – Enterococcal endocarditis – Febrile neutropenic patients – Infections caused by Pseudomonas aeruginosa Trimethoprim-sulfamethoxazole –treatment of bacterial infections and Pneumocystis jiroveci (carinii) infection Beta lactamase inhibitors – prevent the hydrolysis of Beta lactams by inhibiting beta lactamases produced by the bacteria
  9. 9. Antimicrobial drug combinations • Mechanisms of synergism a. Inhibition of enzymatic inactivation Beta-lactam antibiotics (penicillins & ceophalosporins) combined with beta-lactamase inhibitors (clavulanic acid) b. Increased uptake: Penicillins increase uptake of aminoglycosides c. Blockade of sequential steps in metabolic pathway Sulphonamides folic acid synth. & Trimethoprim conversion of folic acid to folinic acid Mechanisms of antagonism a. Inhibition of -cidal activity by -static agents Tetracyclines decrease action of penicillins & cephalosporins b. Enzyme induction: Imipenem & ampicillin formation of beta- lactamase by some bacteria, will action of effective antibiotics
  10. 10. SULFONAMIDES • Bacteriostatic • Folate antagonists Mechanism of Action : Inhibition of bacterial folic acid synthesis • Sulfonamides inhibit the enzyme Dihdropteroate synthetase which is responsible for the incorporation of PABA into the precursor of folic acid. – PABA - essential metabolite of bacterial cells required for the synthesis of folic acid.
  11. 11. Uses: • Sulfacetamide: Bacterial conjunctivitis • Sulmethoxazole: Urinary tract infection • Sulfadiazine + Pyrimethamine: Acute toxoplamosis • Sulfadoxin + Pyrimethamine (FANSIDAR) – Chloroquine resistant Malaria. Sulmethoxazole + Trimethoprim (COTRIMOXAZOLE) SULFONAMIDES
  12. 12. SULFONAMIDES Adv effects: • Crystalluria • Allergy, Skin rash, Stevens-Johnson Syndrome- skin & mm eruptions • Kernicterus ( Displace bilirubin from serum albumin, the free bilirubin can cross the immature blood brain barrier in new born babies ). • Hemolytic anaemia in G6PD deficiency • Megaloblastic anemia Contraindications: • Pregnancy at term, • New born & infants < 2 months of age. • Hypersensitivity
  13. 13. COTRIMOXAZOLE • Trimethoprim/Sulmethoxazole ratio (1:5) • Synergistic action Mech of action : Sequential blockade in the synthesis of Folic acid. Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic acid precursors, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate. – Tetrahydrofolate is required for purine, pyrimidine, & amino acid synthesis. Adv effects: Skin rash, Megaloblastic anaemia, Hemolytic anemia in patients with G6PD deficiency Uses: Lower UTI, Chronic bronchitis, Pneumocystis carinii pneumonia, Shigellosis, Salmonellosis,

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