Principles of Antimicrobial Therapy

1. Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD

2. Learning Objectives • Definition • Classification • Bacteriostatic & bactericidal • Mechanism of action of each Major class • Empiric drug therapy with help of gram stain and with knowledge of common pathogens • Out come of therapy, factors related to therapy • Development and mechanism of resistance • Various combinations; advantages & disadvantages of combo therapy

3. Antibiotic • A chemical substance produced by various species of organisms that is capable of killing or inhibiting the growth of other microbes or cells • Penicilliumchrysogenum vs • Staphylococcus aureus

4. Classification • Chemical classification • Mechanism of action • Bactericidal and bacteriostatic • Broad & narrow spectrum

5. Classification of antibiotics

6. Mechanism of Action • Target: Cell wall synthesis; all β-lactam drugs • Target: Protein synthesis; macrolides, chloramphenicol, tetracycline, aminoglycosides • Target: RNA polymerase; rifampin

7. Mechanism of Action • Affecting cellular components: DNA gyrase inhibitors: Quinolones • DHF reductase inhibitor: Trimethoprim PABA: Sulfonamides • Inhibit reverse transcriptase enzyme: Zidovudine • Cell wall permeability: Amphotericin B; Polymyxin B • Inhibitors of biosynthetic pathways:Bacitracin

8. Bacteriostatic • Protein Synthesis Inhibitors (except aminoglycosides) • Tetracyclines • Macrolides • Clindamycin • Chloramphenicol • Linezolid • Sulphonamides

9. Bactericidal • Agents affecting Cell wall synthesis • Examples of bactericidal drugs • Beta-lactam antibiotics • Vancomycin • Aminoglycosides • Fluoroquinolones

10. Bactericidal antibiotics • Bactericidal drugs are preferred in: • Impaired host defense • Infections with poor blood flow (endocarditis, endovascular infections) • Low WBC (<500) • Cancer patients • CSF penetration (meningitis)

11. Effect of bactericidal and bacteriostatic on bacterial growth Log

12. Narrow & Broad Spectrum • Broad Spectrum: Drugs which affect both gram-pos and gram-neg bacteria;tetracycline, imipenem, 3rd generation cephalosporins • Narrow Spectrum: Drugs whichhave activityagainst only gram-positive bacteria i.e. antistaphylococcalpenicillins and 1st generation cephalosporins

13. Selecting a Therapeutic Regimen • Confirm presence of infection: (a). History (b) signs and symptoms • Fever • Pain, tenderness and inflammation • Symptoms related to organ • WBC count and ESR (c) Identify predisposing factors • Before selecting Empiric therapy get material for c/s or for microscopy • Consider the spectrum of activity; narrow vs broad spectrum • Special conditions like sepsis or meningitis

14. Empiric therapy • To start empiric therapy • Know the microbiology of pathogens • Know the common pathogens responsible for common infections

15. Disease by staph. and strep. groups • Staphylococcus: pneumonia, abscesses, infective endocarditis, surgical wound infections, food poisoning • Streptococci :pharyngitis, scarlet fever, rheumatic fever, impetigo, acute glomerulonephritis • Streptococcus : Neonatal septicemia and meningitis • Streptococcus pneumoniae (diplococci): sinusitis, otitis media, pneumonia, septicemia in aspleenic individual • Enterococcus: UTI, biliary tract infection, subacute endocarditis, pyelonephritis

16. -Empiric therapy for pharyngitis is • Ampicillin (kind of penicillin) • Terbinafine • Ivermectin • Chloroquine

17. Disease by gram negative cocci Diplococci • Neisseria meningitidis: Meningitis & meningococcemia 2. Neisseria gonorrhea: Urethritis, endocervicitis, arthritisand ophthalmianeonatum 3. Moraxella cattarhalis Otitis media, bronchopneumonia in COPD, bronchitis

18. Bacilli or Rods Bacilli Gram-pos Gram-neg Bacillus anthracisP. aeruginosa Bacillus cereus H. influenzae Clostridium species B. purtusis C. diphtheria Brucella Campylobacter *Enterobacteriaceae *Family consists of E. coli, Salmonella spp., Shigella spp., Klebsiella, V. cholera, Proteus spp.

19. Identification of the pathogen Collection of infected material before beginning antimicrobial therapy 1. Stains—Gram or acid-fast (which is already done) 2. Serology 3. Culture and sensitivity 4. Thin layer smears Minimal inhibitory concentration (MIC) is the lowest concentration of antimicrobial that prevents visible growth of microbes

20. Other factors for selection of therapy HOST FACTORS • Allergy • Age • Pregnancy • Metabolic abnormalities • Organ dysfunction • Concomitant use of drugs • Comorbid disease states

21. Selecting a Drug: Drug Factors a. Resistance to drug ( ceftazidime) b. Pharmacokinetic & Pharmacodynamic factors • Concentration-dependent killing & post antibiotic effect. e.g. Aminoglycosides, Fluoroquinolones • Time-dependent killinge.g. β-lactum, vancomycin, macrolides, linezolid

22. Post-Antibiotic Effect / Loading Dose • The Post-Antibiotic Effect (PAE) shows the capacity of an antimicrobial drug to inhibit the growth of bacteria after removal of the drug from the culture. • The PAE provides additional time for the immune system to remove bacteria that might have survived antibiotic treatment before they can eventually regrow after removal of the drug.

23. Selecting a drug • Tissue penetration CSF, abscesses, diabetic foot infection • Protein binding • Toxicity:chloramphenicol, vancomycin, aminoglycosides, clindamycin • Cost

24. Monitoring Therapeutic Response • Clinical assessment • Laboratory tests • Assessment of therapeutic failure • Due to drug selection • Due to host factors • Due to resistance

25. Mechanisms Of Resistance Resistance Intrinsic Acquired Mutation Transferred Conjugation Transformation Transduction

26. Mechanisms for acquired resistance • A mutation in a relevant gene occur as a random selection under the pressure exerted by antibiotic; trait can be passed vertically to daughter cells • Transfer of an extrachromosomal DNA carrier (plasmid), is the most common of acquired resistance; Transfer can occur via • Transduction • Transformation • Conjugation

27. Transduction; occurs when bacteria-specific viruses (bacteriophages) transfer DNA between two closely related bacteria • Transformation; is a process where parts of DNA are taken up by the bacteria from the external environment. This DNA is normally present in the external environment due to the death and lysis of another bacterium.  • Conjugation; occurs when there is direct cell-cell contact between two bacteria and transfer of small pieces of DNA called plasmids takes place

28. Cellular Resistance • ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly. Jan 07

29. Resistance in some antibiotics • Β- lactams: Hydrolysis , mutant PBP • Tetracycline: Active eflux from the cell • Aminoglycosides: Inactivation by enzymes • Sulfonamides: Overproduction of target • Fluoroquinolones: Mutant DNA gyrase • Bleomycin: Binding by immunity prot. • Chloramphenicol: Reduced uptake into cell • Vancomycin: Reprograming of D-ala-D-ala • Quinupristin/ dalfopristin: Ribosomal methylation • Macrolides Erythromycin: RNA methylation, drug efflux

31. Preventing/Decreasing Resistance • Consult experts! • Control use of antibiotics • Rotate drugs • Use narrow spectrum drugs • Combination chemotherapy • Pharmacodynamics principles

32. Superinfections • New infection • Most common organisms Enterobacteriaceae Pseudomonas Candida • Due to removal of inhibitory mechanisms •  Spectrum   alteration in normal flora   risk of superinfection

33. Combination Therapy: Uses • Empirical therapy • Polymicrobial infections • Synergism desired • Prevent development of resistance • Good combo is 2 bactericidal e.g. cell wall inhibitor & aminoglycosides.

34. Synergism • Synergism is usually defined as a four-fold or greater DECREASE in the MIC(Minimum inhibitory concentration) or MBC(Minimum bactericidal concentration) of the individual antibiotics when they are present together. • E.g. Aminoglycoside with a cell wall synthesis inhibitor (penicillin, cephalosporin, vancomycin). • Probably due to increase entry of the AG into the bacterium where it interacts with the ribosome inhibiting protein synthesis.

35. Synergism may result if one drug inhibits the inactivation of the other. E.g. clavlanate has little antibacterial activity but in irreversibly inhibits ß-lactamase and is used in combination with penicillins. • Two drugs may act at different steps in a critical metabolic pathway. E.g. trimthoprim and sulfamethoxazole. Sulfonamides inhibit the synthesis of folic acid and trimethoprim inhibits the reduction of folate to tetrahydrofolate.

36. ANTAGONISM • More likely to occur when a bactericidal drug (e.g., penicillin, aminoglycoside) is combined with a primarily bacteriostatic drug (e.g. tetracycline). • The explanation is that the bactericidal drugs require the cells to be growing or actively synthesizing protein and that the bacteriostatic drugs prevent growth or protein synthesis and thereby counter the effect of the bactericidal drug. • The effect of the combination is not likely to be less than the effect of the bacteriostatic agent alone.

37. GOOD COMBINITION • Two bactericidal e.g. cell wall inhibitor & aminoglycosides • Two bacteriostatic e.g. Quinupristin and dalfopristin

38. Combination Tx: Disadvantages • Antagonism of antibacterial effect • Increased risk of toxicity

39. THE END