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Introduction to Antibacterial Therapy

Introduction to Antibacterial Therapy. Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD July 2, 2007. Rationale. Antibiotic use (appropriate or not) leads to microbial resistance Resistance results in increased morbidity, mortality, and cost of healthcare

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Introduction to Antibacterial Therapy

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  1. Introduction to Antibacterial Therapy Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD July 2, 2007

  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)

  3. 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)

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

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

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

  7. 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

  8. Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin resistant • At PHD ~60% of SA are hetero (methicillin) resistant = MRSA (lower than national average) • 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

  9. 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

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

  11. Coagulase Negative Staph • Many species – S. epidermidis most common • Mostly methicillin resistant (65-85%) • Often contaminants or colonizers – use specific criteria to distinguish • Major cause of overuse of vancomycin

  12. 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

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

  14. Pyogenic groups Most, but not all of the beta-hemolytic strep S. pyogenes: Group A S. agalactiae: Group B S. dysgalactiae: Group C and G

  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. Viridans group Anginosus sp. Bovis sp.: Group D Mutans sp. Salivarius sp. Mitis sp.

  18. Streptococcus anginosus Group Formerly ‘Streptococcus milleri’ or ‘Streptococcus intermedius’. S. intermedius; S. constellatus; S. anginosus Oral cavity, nasopharynx, GI and genitourinary tract.

  19. S. anginosus Group Propensity for invasive pyogenic infections ie. abscesses. Grow well in acidic environment polysaccharide capsule resists phagocytosis produce hydrolytic enzymes: hyaluronidase, deoxyribonucleotidase, chondroitin sulfatase, sialidase

  20. S. anginosus Group Oral and maxillofacial infections Brain, epidural and subdural abscesses intraabdominal abscesses empyema and lung abscesses bacteremias usually secondary to an underlying focus of infection. Look for the Abscess!

  21. S. anginosus Group Most remain penicillin sensitive, but there are increasing reports of resistance to penicillin and cephalosporins. Consider adding gentamicin to PenG until sensitivities come back. Vancomycin and clindamycin are reasonable alternatives. Don’t forget surgical drainage!

  22. Streptococcus bovis Group D, alpha or gamma hemolytic can be misidentified as enterococci or other viridans strep. Biotype I and II. GI tract, hepatobiliary system, urinary tract.

  23. S. bovis Bacteremias. 25-50% of bacteremias associated with endocarditis, usually with preexisting valve disease or prosthetic valves. Rarely osteomyelitis, meningitis Bacteremia caused by Biotype I is associated with GI malignancy and endocarditis (71% and 94%). Remain very susceptible to penicillin

  24. Other viridans strep: mitis, mutans and salivarius groups Normal flora of the oral cavity. Also found in upper respiratory, gastrointestinal and female genital tracts. Low virulence organisms

  25. 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 ( See 5/1/06 Lecture to Residents)

  26. 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

  27. 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

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

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

  30. 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

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

  32. Narrow Spectrum

  33. 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, tigecycline • GPC and fastidious: macrolides

  34. Penicillins

  35. Cephalosporins

  36. 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

  37. 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

  38. Time over MIC • For beta lactams, 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) • For Vancomycin, evolving consensus that troughs should be >10 for most MRSA, >15 for pneumonia

  39. 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

  40. 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.

  41. 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

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