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Introduction to Clinically Relevant Microbiology and Antibiotic Use

Learn about basic bacteriology, antibiotics, resistance mechanisms, and stewardship schemes for hospitalized patients. Discussing Gram-positive, Gram-negative, anaerobes, and fastidious organisms. Understand the importance of identifying pathogens in real-time.

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Introduction to Clinically Relevant Microbiology and Antibiotic Use

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  1. Introduction to Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD, FACP, FIDSA, FSHEA Hospital Epidemiologist Core Faculty Clinical Professor, UTSWMS Adjunct Professor, TTUHSC July 12 , 2018

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

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

  4. Gram Positive Cocci • 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

  5. Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin/ampicillin resistant • At PHD in 2017: 52% (inpatient), 48% (ED) of S aureus are MRSA • Empiric Rx of SA bacteremia and other serious infections must cover MRSA until proven otherwise • For OSSA, beta lactams (cefazolin or nafcillin) are always superior to vancomycin. • Molecular speciation now available in real time from some blood cultures! Look in “Results History.”

  6. CoagNeg Staph (CoNS) • Many species – S. epidermidis most common • Others include S. hominis, warnerii, etc. • Usually Methicillin Resistant • Via MecA gene, same as MRSA • Cefoxitin susceptible = oxacillin susceptible • Often contaminant in BC – especially when “one of two” • S. lugdunensis is NOT a contaminant!

  7. Streptococci • Beta hemolysis: Group A,B,C etc. • Invasive – mimic staph in virulence • S. pyogenes (Group A) • Pharyngitis, • Soft tissue - add anti-toxin protein inhibitor (clinda) only if: • Necrotizing fascitis • TSS • Non suppurative sequellae: ARF, AGN

  8. Other (virulent) Beta Hemolytic Streptococci • 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. Partially hemolytic (viridans = green) Streptococci Species Anginosus Bovis: Group D Mutans Salivarius Mitis Major causes of infectious endocarditis Often part of mixed flora in empyema, liver abscess

  10. Enterococci • 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 minor- • As part of community acquired peritonitis need not cover it • Intrinsically resistant to cephalosporins • No consistently bactericidal single agent • For endocarditis need pen/amp or vanc plus AG or amp plus ceftriaxone • Daptomycin is cidal in vitro • Active vs VRE • Little experience in endocarditis • Resistance develops (NEJM Aug 25, 2011)

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

  12. Fastidious Gram Negatives • Neisseria, Hemophilus, Moraxella, HACEK • Growth requirements • CO² and enrichment • Culture for Neisseria gonorrheae must be plated at bedside • Chocolate agar with CO2 • Prompt transport to lab • Nucleic Acid Amplification Tests does not detect resistance and only approved for GU specimen • Need culture for MIC (only done at CDC) • FQ resistance in MSM 32 % in 2015 • FQ not recommended for empiric Rx since 2007 • Ceftriaxone dose now increased to 250 mg

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

  14. Anaerobic Gram Negative Rods • Fastidious • Produce beta lactamase • Require either BLI/BL, metronidazole, carbapenem, (clindamycin, cefoxitin/cefotetan – less predictable) • Surgeons love to double cover – pip/tazo and metronidazole! Lots of sticky notes sent!! • Endogenous flora • When to consider • Part of infections adjacent to mucosal surfaces • Foul odor • Heterogeneous morphology • Gram stain shows GNR but routine cults negative

  15. A Word on Bacteremia

  16. What Does This Mean? • Within a few hours of detecting a positive BC: • OSSA: vancomycin should be changed to cefazolin for most, but nafcillin for IE/meningitis • CoNS: vancomycin can be stopped when only one of two BC positive • PsAerug: Ceftriaxone or levofloxacin must be escalated to an anti-pseudomonal • Not all ESBL targets are tested (11% of E coli, 6% of Klebs are ESBL +)

  17. Antibiotic Classification Goodman’s Nomenclature • Narrow Spectrum • Active against only one of the four groups of bacteria • Broad Spectrum • Active against more than one of the groups

  18. Defining Spectrum

  19. Narrow Spectrum ( )= not on formulary • Only for gram positive: vancomycin, linezolid/ (tedizolid,) daptomycin, (telavancin, dalbavancin/ oritovancin) • Only for gram negative aerobes: aminoglycosides, aztreonam • Only for gram negative anaerobes: metronidazole

  20. Narrow Spectrum

  21. BROAD SPECTRUMPenicillins/Carbapenems

  22. Parenteral Cephalosporins

  23. Advanced Cephalosporins (non formulary = Only ID Can Order) • Ceftaroline • Like ceftriaxone but with MRSA activity • FDA approved for • SSTI • CAP (not MRSA!) • Ceftazidime-avibactam • Protects ceftaz against certain beta lactamases (some ESBL, amp C, KPC) • FDA approved for • C-UTI • C-IAI but requires metronidazole • Ceftolozane-tazobactam • Active against most ESBL and some MDR Pseudomonas, some Amp C • FDA approved for • C-UTI • C-IAI with metronidazole

  24. Miscellaneous ABX • Macrolides • Azithromycin, Clarithromycin, Erythromycin • Mycoplasma, Chlamydophilia, Bordetella, Legionella, Atypical mycobacteria • TMP-SMX • 67% against E coli in UTI • Pneumocystis jiroveci = TOC! • 94% against in-patient MRSA, 98% outpt MRSA • Clindamycin • Most streptococci, gram positive anaerobes • 68% for MRSA • Doxy/minocycline • Chlamydophilia, Rickettsia, Bartonella • 90-94% for MRSA

  25. Boutique Antibiotics: ID Docs Only Quinupristin/Dalfopristin – for VRE faecium, (not faecalis,) MRSA Tigecycline – MRSA, non bacteremic Acinetobacter (not Pseudomonas,) E coli and Klebs

  26. 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

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

  28. 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,

  29. 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 at the price of more renal toxicity • If MRSA MIC >= 1 should probably change vancomycin to daptomycin, linezolid or tigecycline • Few THD MRSA have MIC >1 • The trough of 15 or higher is not needed for streptococci or MRSA with MIC <=0.5

  30. Higher Serum/tissue levels are associated with faster killing • Aminoglycosides • Peak/MIC ratio of >10-12 optimal • Achieved by “Once Daily Dosing” • Post Antibiotic Effect (PAE) helps • Fluoroquinolones • 10-12 ratio achieved for enteric GNR • PAE helps • Achieved forPseudomonas only if MIC <=0.5 • Daptomycin • Dose based on actual body weight

  31. AUC/MIC = AUIC • *For Streptococcus pneumoniae, FQ should have AUIC >= 30 (achieved with respiratory FQ (levo, moxi) • For gram negative rods then FQ AUIC should >= 125 • For staphylococci, vancomycin AUIC needs to be >=400. Not achieved when MIC >=1.0. Strept have much lower MICs. • Look up AUC in “References” • Sanford Table 9A • Look up Antibiogram in “References”

  32. Mechanisms of Antimicrobial ActivityFC TenoverAmer J Med 2006;119: S3-10

  33. 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

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

  35. ESKAPE Organisms (mechanism) Enterococcus faecium VRE (Van A) Staphylococcus aureus MRSA (Mec A) Klebsiella pneumoniae/E coli (ESBL – KPC) Acinetobacter baumanii (KPC, NDM1, MCR*) Pseudomonas aeruginosa(AmpC, KPC, NDM-1) Enterobacter species (AmpC, also ESBL)

  36. A Primer of Bad Beta Lactamases • ESBL: Contact Isolation • Klebsiella and E coli • Usually require carbapenems • although for u-UTI Pip/tazo might work • Advanced cephalosporins may be effective (ceftaz/avibactam and ceftolozane/tazobactam). Only ID can order • AMP C • SPICE organisms (Serratia, Pseudomonas, Indole Positive Proteus, Citrobacter, Enterobacter) • Inducible/derepressed beta lactamase • Requires carbapenems when AMP C expressed • Cefepime and advanced cephalosporins may be effective in urine • Do not require Contact Isolation

  37. Really Bad Beta Resistance Enzymes • Carbapenem Resistant Enterobacteraciae (CRE) • Resistant to everything but colistin and sometimes tigecycline • New Delhi Metalloproteinases (NDM) • Pseudomonas and enterobacteraciae • Resistant to all but colistin • MCR-1 (not a beta lactamase) confers resistance to colistin and can be plasmid associated = transmissible to other bacteria = UNTREATABLE WITH ABX!! • These patients require Contact Isolation and Cohorting

  38. 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

  39. Acceptance of Recommendations

  40. Individual Drug Usage: “The Good”

  41. Individual Drug Usage: “The Bad”

  42. And “The Ugly”

  43. The Surprise

  44. The C-Suite Overjoyed!

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