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 • Penicillium chrysogenum 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 • A relative term

9. Bactericidal • Agents affecting Cell wall synthesis • Examples • Beta-lactam antibiotics • Vancomycin • Aminoglycosides • Fluoroquinolones • First two are time dependent killers • Last two groups exhibit concentration dependent killing & show Post Antibiotic Effect (PAE)

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. Gram-positive and gram-negative Gram-pos & gram-negcocci GRAM POSITIVE COCCI Chains / pairs Clusters Staphylococcus Streptococcus AND Enterococci

16. 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 gp. B: Neonatal septicemia and meningitis • Streptococcuspneumoniae (diplococci): sinusitis, otitis media, pneumonia, septicemia in aspleenicindividual • Enterococcus: UTI, biliary tract infection, subacute endocarditis, pyelonephritis

17. Empiric therapy for pharyngitis is • 1. Ampicillin (kind of penicillin) • 2. Terbinafine • 3. Ivermectin • 4. Chloroquine

18. 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

19. 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.

20. Empiric Therapy

21. Empiric Therapy

22. Helicobacter pylori infection

23. Which of the following is the empiric therapy for PUD (H. pylori)? • 1. A Proton pump inhibitor • 2. Metronidazole • 3. Amoxicillin • 4. All of the above

24. Empiric Therapy

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

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

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

28. 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.

29. Concentration dependence & PAE 10 Broth Wash MIC 8 3 x MIC 2 x MIC 6 Log10 CFU/mL 4 x MIC 4 PAE 2 0 0 2 4 6 8 Time (h)

30. 10 8 6 Log10 CFU/mL 4 2 0 Time-Dependent Killing Wash > 5 x MIC MIC 0 2 4 6 8 Time (h)

31. Duration-Based Drug Action

32. Pharmacodynamics • Pharmacodynamic profile: A quantitative relationship • 3 pharmacodynamic parameters quantify relation b/w in vitro susceptibility, time course of dg. concentration & response of microbes • Ratio of the area under curve for plasma conc. Vs time curve to MIC • T>MIC: plasma concentration during dosing interval exceeds min. inhibitory conc. • C max / MIC: Ratio of maximum or peak drug concentration (C max) to MIC

33. Antibiotic Concentration vs Time Cmax Cmax > MIC (Concentration-Dependent) Antibiotic Concentration MIC Conc. at t >MIC (Time-Dependent) Time (h)

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

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

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

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

39. 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

40. 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 of : RNA methylation, drug Erythromycin efflux

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

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

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

44. ADDITIVE SYNERGISM Control Control Drug B Drug B Drug A Drug A Drug A + B Drug A + B 0 12 0 12 Time (h) Time (h) Combination Therapy: Outcomes Log10 CFU/mL

45. ANTAGONISM Control Drug B Drug A + B Drug A 0 12 Time (h) Combination Therapy: Outcomes Log10 CFU/mL

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

47. Combination of Pen. G with aminoglycoside (gentamicin) is a • 1. Good combination • 2. Bad combination • 3. Neutral combination • 4. Antagonistic combination

48. BAD COMBINITIONS

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

50. CASE A 65-yr old man, had undergone an emergency abdominal operation in which part of his bowel was resected. He was intubated throughout the postoperative period. During the 3rd week of his hospitalization he became confused and anxious; his blood pressure recorded as 70/30 mm/Hg and HR as 110 /min. His temp. was 40 C and his respiratory rate was 24 / min. Suction of the endotracheal tube reveals copious yellow green secretions. Cold extremities and circumoral pallor were prominent on general examination. On examination of respiratory system, ronchi with decreased breath sounds were heard on auscultation. His heart and abdomen was normal. Erythema (redness and swelling) was noted around IV lines. Chest radiograph revealed bilateral lower lobe infiltrates. Urine analysis revealed WBC count 20. Other important findings in reports included BUN= 56 mg/dl (N=8-18), WBC= 15000/ mm3 with bands present, blood sugar was 210 mg/dl. Blood, urine and tracheal aspirate cultures were pending.