Principles of Antimicrobial Use

1. Principles of Antimicrobial Use Siriluck Anunnatsiri, MD, MCTM, MPH Infectious Diseases & Tropical Medicine Department of Medicine Khon Kaen University

2. Identification of the Infective Organisms • History taking • Physical examination • Laboratory

3. Duration of fever Associated symptoms: Systematic review History of treatment Underlying diseases and Medication Occupation Living place Traveling Pets Vaccination and drug prophylaxis Illness in family Diseases outbreak Food consumption History Taking

4. Physical Examination

5. Physical Examination

6. Laboratory Investigation in the Diagnosis of Infectious Agents Mandell, Douglas, and Bennett’s Principle and Practice of Infectious Diseases

7. Gram Stain

8. Gram Stain

9. AFB Stain

10. Modified AFB Stain

11. Wright Stain

12. India Ink Preparation

13. Fresh Smear / KOH Preparation

14. Microbial Factors:Antimicrobial susceptibility • Appropriate specimen collection and transport • Disk diffusion susceptibility testing • Minimal inhibitory concentration (MIC)

15. Resistant Bacteria Chromosomal mutations XX Resistance Gene Transfer New Resistant Bacteria Microbial Factors:Antimicrobial Resistance Susceptible Bacteria http://www.cdc.gov

16. Mechanism of R-gene Transfer Levy, SB. The challenge of antibiotic resistance. Sci Am 1998:46-53.

17. x x Resistant StrainsRare Antimicrobial Exposure Resistant Strains Dominant x x x x x x x x x x Selection for Antimicrobial-resistant Strains http://www.cdc.gov

18. Mechanisms of Antimicrobial Resistance Levy, SB. The challenge of antibiotic resistance. Sci Am 1998:46-53.

19. Host Factors • Underlying diseases • Drug allergy • Pregnancy/Breast feeding • Age • Genetic or Metabolic abnormalities • Sites of infection • Immune status • Hepatic and renal function

20. Spectrum Mechanisms of action Pharmacokinetic Pharmacodynamic Drug interaction Side effect Drug monitoring Antimicrobial Factors

21. Mechanisms of Action Bactericidal agents Bacteriostatic agents Bactericidal agents

22. Pharmacokinetics of Antimicrobial Agents • Absorption • Consider extent and rate of absorption via route of administration • Consider drug interaction and food effect • Distribution to the site of infection • Volume of distribution (Vd) • Water soluble drug, small Vd  high serum conc. • Lipophilic drug, large Vd extensively distributed in body fluid and tissue • Vascular supply

23. Pharmacokinetics of Antimicrobial Agents • Distribution to the site of infection (cont.) • Protein binding • Local factor at site of infection: pH, dense population of organism, foreign body • Metabolism • Mainly in liver • Active vs. Inactive metabolites • Route of metabolism esp. CYP P450 system • Elimination • Route of elimination: mainly by kidney, liver • Rate of elimination: T1/2

24. Pharmacodynamics of Antimicrobial Agents • Pharmacodynamic characteristics • Time-dependent bactericidal action • Concentration-dependent bactericidal actions • Bacteriostatic action • Postantibiotic effect • Inoculum effect • In vitro action of antibiotic combination

25. PD Parameters affecting Antibiotic Potency AUC/MIC >125 for GNB >25-50 for GPC Cmax/MIC >10 > 40-50% of dosing interval Postantibiotic effect

26. Inoculum Effect • The effect of inoculum size on antimicrobial activity • Dense population can be less susceptible to -lactams • Failure to express receptor (PBP) • High concentration of -lactamases • Trend to presence of resistant subpopulation

27. In Vitro Testing of Antibiotic Combination

28. Indications for Antimicrobial Combinations Therapy • Prevention of the emergence of resistant organisms • Polymicrobial infections • Empirical therapy As narrow as possible, as broad as necessary • Synergistic/Additive activity

29. Disadvantages of Inappropriate Use of Antimicrobial Combinations • Antagonism • Superinfection • Cost • Adverse effects

30. Reasons for Treatment Failure • Delay in diagnosis or therapy • Wrong or incomplete diagnosis • No infection • Nonbacterial infection • Polymicrobial infection • Errors in susceptibility testing • Decreased activity at site of infection • Chemical factor (pH and others) • Antibiotic antagonism

31. Reasons for Treatment Failure • Inadequate concentration of antibiotic at the site of infection • Improper dose • Decreased absorption from food or drug interaction • Increased elimination of agent • High protein binding • Poor delivery (eg. shock, vascular diseases)

32. Reasons for Treatment Failure • Other host factors • Collection requiring drainage • Necrotic tissue • Foreign body • Impaired immune defenses • Development of drug resistance • Superinfection

33. Summary: Step in Approaching Patients When Considering Antibiotic Therapy • Make a tentative diagnosis based on the history and physical examination including bed-side lab. • Determine if antibiotic therapy is necessary for the given infection • Choose the individual agent for the infection based on the following: • In vitro activity of the antibiotic against the most likely pathogens in the disease

34. Summary: Step in Approaching Patients When Considering Antibiotic Therapy • Evidence-based results demonstrate efficacy, safety, and cost-effectiveness of the antibiotic in the disease and in patient populations similar to that of the presenting patient • Side effect profile of the drug: • Allergic reaction • Direct adverse effects of drug • Drug-drug and drug-food interaction • Use least expensive and narrowest-spectrum drug possible(Optimal drug, dose, and duration)

35. Use Antimicrobials Wisely Treat infection, NOT contamination or colonization A major cause of antimicrobial overuse is “treatment” of contaminated cultures or colonization. Use local data Know your local antibiogram Know your patient population Not all infections need antimicrobial therapy http://www.cdc.gov

36. Use Antimicrobials WiselyStop antimicrobial treatment • When infection is cured • When cultures are negative and infection is unlikely • When infection is not diagnosed http://www.cdc.gov