Introduction to Antibacterial Therapy

1. Introduction to Antibacterial Therapy Clinically Relevant Microbiology and Pharmacology Edward L. Goodman, MD July 19, 2004

2. Rationale • Antibiotic use (appropriate or not) leads to microbial resistance • Resistance results in increased morbidity, mortality, and cost of healthcare • Appropriate antimicrobial stewardship will prevent or slow the emergence of resistance among organisms (Clinical Infectious Diseases 1997; 25:584-99.) • Antibiotics are used as “drugs of fear” • (Kunin CM Annals 1973;79:555)

4. Antibiotic Misuse • Surveys reveal that: • 25 - 33% of hospitalized patients receive antibiotics (Arch Intern Med 1997;157:1689-1694) • 22 - 65% of antibiotic use in hospitalized patients is inappropriate (Infection Control 1985;6:226-230)

5. Consequences of Misuse of Antibiotics • Contagious RESISTANCE • No equivalent downside to overuse of endoscopy, calcium channel blockers, etc. • Morbidity - drug toxicity • Mortality • Cost

6. Outline • Basic Clinical Bacteriology • Categories of Antibiotics • Pharmacology of Antibiotics

7. Goodman’s Scheme for the Major Classes of Bacterial Pathogens • Gram Positive Cocci • Gram Negative Rods • Fastidious GNR • Anaerobes

8. Gram stain: clusters Catalase pos = Staph Coag pos = S aureus Coag neg = variety of species Chains and pairs Catalase neg = streptococci Classify by hemolysis Type by specific CHO Gram Positive Cocci

9. Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin resistant • At PHD ~50% of SA are hetero (methicillin) resistant = MRSA • Glycopeptide (vancomycin) intermediate (GISA) • MIC 8-16 • Eight nationwide (one at PHD) • First VRSA reported July 5, 2002 MMWR • Third isolate reported May 2004 • MICs 32 - >128 • No evidence of spread in families or hospital

10. Methicillin Methicillin-resistant S. aureus (MRSA) [1970s] Vancomycin [1997] [1990s] [ 2002 ] Vancomycin Vancomycin-resistant Vancomycin- resistant S. aureus intermediate- enterococci (VRE) resistant S. aureus (VISA) Evolution of Drug Resistance in S. aureus Penicillin Penicillin-resistant S. aureus [1950s] S. aureus

11. MSSA vs. MRSA Surgical Site Infections(1994 - 2000)

12. Coagulase Negative Staph • Many species – S. epidermidis most common • Mostly methicillin resistant (65%) • Often contaminants or colonizers – use specific criteria to distinguish • Major cause of overuse of vancomycin

13. Nosocomial Bloodstream Isolates All gram-negative (21%) Other (11%) SCOPE Project Viridans streptococci (1%) Coagulase-negative staphylococci (32%) Candida (8%) Staphylococci aureus (16%) Enterococci (11%) Clin Infect Dis 1999;29:239-244

14. Streptococci • Beta hemolysis: Group A,B,C etc. • Invasive – mimic staph in virulence • S. pyogenes (Group A) • Pharyngitis, • Soft tissue • Non suppurative sequellae: ARF, AGN

15. Beta strept - continued • S. agalactiae (Group B) • Peripartum/Neonatal • Diabetic foot • Bacteremia/endocarditis/metastatic foci • Group D (non enterococcal) = S. bovis • Associated with carcinoma of colon

16. Viridans Streptococci • Many species • Streptococcus intermedius group • Liver abscess • Endocarditis • GI or pharyngeal flora • Most other are mouth flora – cause IE

17. Enterococci • Formerly considered Group D Streptococci now a separate genus • Bacteremia/Endocarditis • Bacteriuria • Part of mixed abdominal/pelvic infections • Intrinsically resistant to cephalosporins • No bactericidal single agent • Role in intra-abdominal infection debated

18. Fermentors Oxidase negative Facultative anaerobes Enteric flora Numerous genera Escherischia Enterobacter Serratia, etc Non-fermentors Oxidase positive Pure aerobes Pseudomonas and Acinetobacter Nosocomial Opportunistic Inherently resistant Gram Negative Rods

19. Fastidious Gram Negative Rods • Neisseria, Hemophilus, Moraxella, HACEK • Require CO2 for growth • Neisseria must be plated at bedside • Chocolate agar with CO2 • Ligase chain reaction (like PCR) has reduced number of cultures for N. gonorrhea • Can’t do MIC without culture • Increasing resistance to FQ

20. Anaerobes • Gram negative rods • Bacteroides • Fusobacteria • Gram positive rods • Clostridia • Proprionobacteria • Gram positive cocci • Peptostreptococci and peptococci

21. Anaerobic Gram Negative Rods • Produce beta lactamase • Endogenous flora • Part of mixed infections • Confer foul odor • Heterogeneous morphology • Fastidious

22. Antibiotic Classificationaccording to Goodman • Narrow Spectrum • Active against only one of the four classes • Broad Spectrum • Active against more than one of the classes • Boutique • Active against a select number within a class

23. Narrow Spectrum • Active mostly against only one of the classes of bacteria • gram positive: glycopeptides, linezolid, daptomycin • aerobic gram negative: aminoglycosides, aztreonam • anaerobes: metronidazole

24. Narrow Spectrum

25. Broad Spectrum • Active against more than one class • GPC and anaerobes: clindamycin • GPC and GNR: cephalosporins, penicillins, T/S, newer FQ • GPC, GNR and anaerobes: ureidopenicillins ± BLI, carbapenems • GPC and fastidious: macrolides

26. Penicillins

27. Cephalosporins

28. Pharmacodynamics • MIC=lowest concentration to inhibit growth • MBC=the lowest concentration to kill • Peak=highest serum level after a dose • AUC=area under the concentration time curve • PAE=persistent suppression of growth following exposure to antimicrobial

29. Parameters of antibacterial efficacy • Time above MIC - beta lactams, macrolides, clindamycin, glycopeptides • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin • Peak/MIC - aminoglycosides, fluoroquinolones

30. Time over MIC • Should exceed MIC for at least 50% of dose interval • Higher doses may allow adequate time over MIC • For most beta lactams, optimal time over MIC can be achieved by continuous infusion (except unstable drugs such as imipenem, ampicillin)

31. Higher Serum/tissue levels are associated with faster killing • Aminoglycosides • Peak/MIC ratio of >10-12 optimal • Achieved by “Once Daily Dosing” • PAE helps • Fluoroquinolones • 10-12 ratio achieved for enteric GNR • PAE helps • not achieved forPseudomonas • Not always for Streptococcus pneumoniae

32. AUC/MIC = AUIC • For Streptococcus pneumoniae, FQ should have AUIC >= 30 • For gram negative rods where Peak/MIC ratio of 10-12 not possible, then AUIC should >= 125.

33. Antibiotic Use and Resistance • -Strong epidemiological evidence that antibiotic use in humans and animals associated with increasing resistance • -Subtherapeutic dosing encourages resistant mutants to emerge; conversely, rapid bactericidal activity discourages • -Hospital antibiotic control programs have been demonstrated to reduce resistance

34. Total Antibiotic Doses / Day

35. Changes in Bug/Drug Susceptibility Patterns

36. Other Activities of CAMP • Decrease inappropriate fluoroquinolone use • Staff education • Restricted reporting • Decrease inappropriate sputum and urine cultures • Staff education • Laboratory disclaimer • Decrease inappropriate vancomycin levels • Education about unnecessary peak levels

37. Further Activities of CAMP • Monitor surgical site infections and intervene as necessary • Improved timing and administration of pre-op antibiotics • clipping not shaving • nasal decolonization • changing pathogens (MRSA, gram- rods) • Automated protocol-driven antibiotic prescribing • Computerized physician order entry

38. Antibiotic Armageddon “There is only a thin red line of ID practitioners who have dedicated themselves to rational therapy and control of hospital infections” Kunin CID 1997;25:240

39. Historic overview on treatment of infections • 2000 BC: Eat this root • 1000 AD: Say this prayer • 1800’s: Take this potion • 1940’s: Take penicillin, it is a miracle drug • 1980’s: Take this new antibiotic, it is better • ?2004 AD: Eat this root