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Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use

Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use. Edward L. Goodman, MD Hospital Epidemiologist Core Faculty July 11, 2013. Outline . Basic Clinical Bacteriology Antibiotics Categories Pharmacology Mechanisms of Resistance

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Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use

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  1. Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD Hospital Epidemiologist Core Faculty July 11, 2013

  2. Outline • Basic Clinical Bacteriology • Antibiotics • Categories • Pharmacology • Mechanisms of Resistance • Antibiotic Stewardship • “Pearls”

  3. Scheme for the Four Major Classes of Bacterial Pathogens in Hospitalized Patients • Gram Positive Cocci • Gram Negative Rods • Fastidious Gram Negative Organisms • Anaerobes

  4. 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

  5. Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin resistant • At PHD ~53% of SA are hetero (methicillin) resistant = MRSA (less than national average) • Glycopeptide (vancomycin) intermediate (GISA) • MIC 8-16 • Eight nationwide • First VRSA reported July 5, 2002 MMWR • Seven isolates reported (5/7 from Michigan) • MICs 32 - >128 • No evidence of spread w/in families or hospital

  6. 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 • S. lugdunensis is rarely a contaminant • Causes destructive endocarditis

  7. 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

  8. Other Beta hemolytic • S. agalactiae (Group B) • Peripartum/Neonatal • Diabetic foot • Bacteremia/endocarditis/metastatic foci • Group C/G Streptococcus • large colony variants: similar clinical illness as GAS plus bacteremia, endocarditis, septic arthritis • Small colony variants = Strept milleri

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

  10. Enterococci • Formerly considered Group D Streptococci now a separate genus • Bacteremia without IE does not need cidal/syngergistic therapy • Endocarditis does need cidal/syngergistic • Bacteriuria in elderly, obstructed • Part of mixed abdominal/pelvic infections • Role in mixed flora intra-abdominal infection trivial- therapy for 2° peritonitis need not cover it • Intrinsically resistant to cephalosporins • No bactericidal single agent • For endocarditis need pen/amp/vanc plus AG • Daptomycin is cidal in vitro • Little experience in endocarditis • Resistance develops (NEJM Aug 25, 2011)

  11. Fermentors Oxidase negative Facultative anaerobes Enteric flora Numerous genera Escherischia Enterobacter Serratia, etc UTI, IAI, LRTI, 2°B Non-fermentors Pure aerobes Pseudomonas (oxidase +) and Acinetobacter (oxidase -) Nosocomial LRTI, bacteremia, UTI Opportunistic Inherently resistant New mechanisms of MDR emerging Gram Negative Rods

  12. Fastidious Gram Negatives • Neisseria, Hemophilus, Moraxella, HACEK • Growth requirements • CO² and enrichment • Culture for Neisseria must be plated at bedside • Chocolate agar with CO2 • Ligase chain reaction (like PCR) has reduced number of GU cultures for N. gonorrhea • Can’t do MIC without culture (at reference lab only) • FQ resistance 13% in 2011 • FQ not recommended for empiric Rx since 2007

  13. Anaerobes • Gram negative rods • Bacteroides (gut/gu flora) • Fusobacteria (oral and gut) • Prevotella (mostly oral) • Gram positive rods • Clostridia (gut) • Proprionobacteria (skin) • Gram positive cocci • Peptostreptococci and peptococci (oral, gut, gu)

  14. Anaerobic Gram Negative Rods • Fastidious • Produce beta lactamase • Endogenous flora • When to consider • Part of mixed infections • Confer foul odor • Heterogeneous morphology • Gram stain shows GNR but routine cults negative

  15. (My) Antibiotic Classification • Narrow Spectrum • Active against only one of the four classes of bacteria • Broad Spectrum • Active against more than one of the classes

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

  17. Narrow Spectrum

  18. BROAD SPECTRUMPenicillins/Carbapenems

  19. Cephalosporins

  20. 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

  21. Pharmocodynamics: Dosing for Efficacy Peak Blood Level MIC Trough Time

  22. Parameters of antibacterial efficacy • Time above MIC (non concentration killing) - beta lactams, macrolides, clindamycin, glycopeptides • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin • Peak/MIC (concentration dependent killing) - aminoglycosides, fluoroquinolones, daptomycin,

  23. Time over MIC • For beta lactams, should exceed MIC > 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 temperature labile drugs such as imipenem, ampicillin) • For Vancomycin, evolving consensus that troughs should be >15 for most serious MRSA infections, especially pneumonia and bacteremia • If MRSA MIC >= 2 and patient responding slowly or poorly, should change vancomycin to daptomycin, linezolid or tigecycline • Few THD MRSA have MIC >1

  24. 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 achieved for Streptococcus pneumoniae • Daptomycin • Dose on actual body weight

  25. FQ 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 FQ AUIC should >= 125 • For MRSA, vancomycin AUIC needs to be >=400. Not easily achieved when MIC >=2.

  26. A Brief Overview of Antimicrobial Resistance

  27. ESKAPE Organisms (mechanism) Enterococcus faecium VRE (Van A) Staphylococcus aureus MRSA (MEC A) Klebsiella pneumoniae (ESBL – KPC) Acinetobacter baumanii (KPC – NDM1) Pseudomonas aeruginosa(AmpC, KPC, NDM-1) Enterobacter species (AmpC)

  28. Mechanisms of Antimicrobial Resistance in BacteriaFC Tenover Amer J Med 2006;119: S3-10

  29. DNA gyrase DNA-directed RNA polymerase Quinolones Cell wall synthesis Rifampin ß-lactams & Glycopeptides (Vancomycin) DNA THFA mRNA Trimethoprim Protein synthesis inhibition Ribosomes Folic acid synthesis DHFA 50 50 50 Macrolides & Lincomycins 30 30 30 Sulfonamides PABA Protein synthesis inhibition Protein synthesis mistranslation Tetracyclines Aminoglycosides Cohen. Science 1992; 257:1064

  30. Mechanisms of Antibiotic ResistancePM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J 1998;317: 657-660

  31. Interplay of β lactam antibiotics and bacteriaPM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J 1998;317: 657-660

  32. Bad Beta Lactamases (for dummies like me) • ESBL • Klebsiella and E coli • Require carbapenems although for UTI Pip/tazo might work • Not clear how transmissible but use Contact Isolation • AMP C • SPICE organisms • Inducible/derepressed chromosomal beta lactamases • Requires carbapenems when AMP C expressed • Do not require Contact Isolation unless associated plasmid transmits MDR

  33. Really Bad Beta Lactamases • Carbapenem Resistant Enterobacteraciae (CRE) • Resistant to everything but colistin and sometimes tigecycline • New Delhi Metalloproteinases (NDM) • Pseudomonas and enterobacteraciae • Resistant to all but colistin • These patients require Contact Isolation and Cohorting

  34. 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

  35. 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

  36. When to Cover for MRSA Severe purulent SSTI Necrotizing pneumonia/empyema Central line associated (Known MRSA carriers?) Go To Drug = Vancomycin

  37. Is Vancomycin Needed for every patient with SSTI? CID 2011:1-38

  38. When to Cover for Pseudomonas • Severe COBPD/bronchiectasis • Frequent ABX • Steroid dependent • Known airway colonization • Neutropenic septic leukemic • (Burn patients)

  39. Is Pseudomonas Coverage Needed for Every Diabetic Foot Infection?CID 2012; 54 (12):132-173

  40. 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 – 2000’s: Take this new antibiotic, it is a bigger miracle! • ?2014: Eat this root!

  41. Thanks to • Shahbaz Hasan, MD for allowing me to use slides from his 6/6/07 Clinical Grand Rounds on Streptococci • Eliane S Haron, MD for allowing me to use the “Eat this root” slide • Terri Smith, PharmD for collecting data from the Antibiotic Stewardship Program

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