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DHS/PP

Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle. DHS/PP. Structure of Gram-Positive Bacteria. Penicillin Binding Proteins. DNA. Cell Wall. Cell Membrane. DHS/PP. Structure of Gram -Negative Bacteria.

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DHS/PP

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  1. Antimicrobial TherapyDavid H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/PP

  2. Structure of Gram-Positive Bacteria Penicillin Binding Proteins DNA Cell Wall Cell Membrane DHS/PP

  3. Structure of Gram-Negative Bacteria Outer Membrane Cell Wall Periplasmic Space Cell Membrane DNA Porin Channel DHS/PP

  4. Antimicrobials: Site of Action Cell Wall- Beta-Lactams - Glycopeptides Cytoplasm23 S Ribosome- Linezolid30S Ribosome- Aminoglycosides- Tetracyclines 50S Ribosome- Macrolides/Ketolides- Clindamycin- Chloramphenicol- Quinupristin-Dalfopristin Cell Membrane - Daptomycin DNA Inhibitor - Fluoroquinolone- TMP-SMX- Metronidazole DHS/PP

  5. Antimicrobial Spectrum Gram-Positives Resistant Gram-Negatives Resistant Gram-Positives Gram-Negatives Anaerobes DHS/PP

  6. Antimicrobial Spectrum Gram-Negatives Gram-Positives Highly-Resistant Gram-Negatives Highly-Resistant Gram-Positives Anaerobes Highly Resistant Anaerobes DHS/PP

  7. Beta-Lactams DHS/PP

  8. Beta-Lactam Antibiotics • Penicillins • Cephalosporins • Monobactam • Carbapenems DHS/PP

  9. Antimicrobials: Question • What is the mechanism of action for beta-lactam antimicrobials? DHS/PP

  10. Beta-Lactams: Mechanism of Action Penicillin Binding Proteins Beta-Lactam DNA Cell Wall Cell Membrane DHS/PP

  11. Beta-Lactam: Mechanism of Action Beta-Lactam Cell Wall Synthesis DNA Cell Membrane Cell Wall Penicillin Binding Proteins DHS/PP

  12. Antimicrobials: Question • Which of the following beta-lactam animicrobial is typically active against Enterococcusfaecalis (assume this is not a resistant enterococcus):a. Cefotetanb. Aztreonam c. Piperacilline. Nafcillin DHS/PP

  13. Piperacillin-Tazobactam (Zosyn) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  14. Antimicrobials: Question • Which of the cephalosporins typically have anti-pseudomonal activity? DHS/PP

  15. Antimicrobials: Question • Which of the 3rd Generation Cephalosporins would be appropriate for treatment of Pseudomonas meningitis:a. Ceftriaxoneb. Ceftazidime c. Cefoperazoned. Cefotaxime DHS/PP

  16. Ceftriaxone (Rocephin)3rd-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Enterococcus sp. Anaerobes DHS/PP

  17. Ceftazidime (Fortaz, Tazicef, Tazidime)3rd-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  18. Cefepime (Maxepime)4th-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Enterococcus sp. Anaerobes DHS/PP

  19. Antimicrobials: Question • Which of the following organisms do you think cefixime (Suprax) would NOT routinely have good activity against?a. Staphyloccusaureus (MSSA or MRSA)b. Streptococcuspneumoniaec. Haemophilusinfluenzaed. Moraxella (Branhamella) catarrhalis DHS/PP

  20. Cefixime (Suprax)2nd/3rd Generation ORAL Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Negatives Gram-Positives Staphylococcus aureus Enterococcus sp. Anaerobes DHS/PP

  21. Monobactams • Aztreonam (Azactam) DHS/PP

  22. Aztreonam Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  23. Carbapenems • Imipenem + Cilastatin (Primaxin) • Meropenem (Merrem) • Ertapenem (Invanz) • Doripenem (Doribax) DHS/PP

  24. Antimicrobials: Question • What is the major difference between Imipenem and Ertapenem?1. Imipenem has significantly better gram-negative activity2. Imipenem has much greater anaerobic activity3. Ertapenem has much better gram-positive activity4. Ertapenem has better activity against Acinetobacter sp. DHS/PP

  25. Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax) Gram-Positives Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Negatives Anaerobes DHS/PP

  26. Ertapenem (Invanz) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  27. Antimicrobials: Question • A 63-year-old woman with CLL is admitted to the hospital with fever. She is started on Ceftriaxone, but 2 days later has no improvement. LP now shows 2,600 WBCs (65% polys) and gram-positive rods. You recommend: 1. Add Ampicillin2. Change to Imipenem 3.Add Clindamycin4.Change to Cefazolin DHS/PP

  28. Vancomycin DHS/PP

  29. Antimicrobials: Question • What is vancomycin’s mechanism of action? DHS/PP

  30. Vancomycin: Mechanism of Action Vancomycin Cell Wall Synthesis DNA DHS/PP

  31. Ligase Vancomycin: Mechanism of Action D-Ala D-Ala Tripeptide Intermediate D-Ala D-Ala Cell Wall Pentapeptide Precursor D-Ala D-Ala Vancomycin DHS/PP

  32. Vancomycin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives VISA VRE Anaerobes DHS/PP

  33. Antimicrobial: Question • For ICU patients with nosocomial pneumonia, what Vancomycin trough level should you aim for (based on IDSA/ATS Guidelines)? 1. Trough < 52. Trough 5-103. Trough 10-15 4. Trough 15-20 DHS/PP

  34. Daptomycin (Cubicin) DHS/PP

  35. Antimicrobial: Question • Which of the following is TRUE regarding the antimicrobial Daptomcyin (Cubicin)? 1. Daptomycin is a bacterial cell wall inhibitor2. Based on recent data, daptomycin is the drug of choice for MRSA pneumonia3. Daptomycin’s mechanism of action takes place at the bacterial cell membrane 4. Daptomycin causes renal failure in 10-20% of patients DHS/PP

  36. Daptomycin (Cubicin): Mechanism of Action 1. Ca2+-Dependent Binding to Cell Membrane Daptomycin 2. Membrane Depolarization and K+ Efflux 1 Ca2+ K+ 2 K+ DNA Altered Penicillin Binding Protein Cell Membrane DHS/PP

  37. Daptomycin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  38. Daptomycin • Class: Lipopeptide • Mechanism: Disrupts plasma membrane function (depolarization of membrane) • Dose: 4 or 6 mg/kg IV q24 hours • Activity: MSSA, MRSA, VRSA, coag -Staph, S. pyogenes,S. pneumoniae, E. faecium and E. faecalis (including VRE) • Clinical: VRE, Complicated skin and soft tissue infections; MSSA & MRSA bacteremia and right-sided endocarditis; not for use for pneumonia • Adverse Effects: well tolerated • Renal Insufficiency: Reduce dose to 4 mg/kg q48 hours if Cr clearance <30 mL/min DHS/PP

  39. Daptomycin (Cubicin) vs Comparator for MSSA & MRSA Bacteremia & Endocarditis Study Design Success 42 Days Post Treatment • Methods - Adults with known/suspected bacteremia or endocarditis (n = 236) - Randomized, open-label • Regimens: MSSA - Daptomycin: 6 mg/kg IV qd - Nafcillin + Gentamicin (first 4 days or until blood cultures negative x 48h) • Regimens: MRSA - Daptomycin: 6 mg/kg IV qd - Vancomycin + Gentamicin (first 4 days or until blood cultures negative x 48h) DHS/PP Source: Fowler VG et al. N Engl J Med 2006;355:653-65.

  40. Linezolid (Zyvox) DHS/RTI/PP

  41. Antimicrobial: Question • Which of the following is TRUE regarding the antimicrobial Linezolid (Zyvox)? 1. The oral bioavailability of linezolid is excellent2. About 30% of MRSA now resistant to linezolid3. Neutropenia is the most common lab abnormality 4. It works by disrupting bacterial cell wall synthesis DHS/PP

  42. Linezolid: Mechanism of Action 50 S Ribosome Linezolid 30 S Ribosome 50S fMet-tRNA 30S 70 S Initiation Complex DNA DHS/PP

  43. Linezolid (Zyvox) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes DHS/PP

  44. Nosocomial Pneumonia: Vancomycin vs. Linezolid Clinical Cure Study Design • Methods - Retrospective analysis of 2 prospective, randomized, case-control studies - N =1019 Adults - Nosocomial pneumonia - Suspected gram-positive pneumonia - 339 with documented S. aureus - 160 with documented MRSA • Regimens - Vancomycin + Aztreonam - Linezolid + Aztreonam P = 0.182 P = 0.009 From: Wunderink RG, et al. Chest 2003;124:1789-97. DHS/PP

  45. Antimicrobial: Question • A 62-year-old woman is started on linezolid for MRSA vertebral osteomyelitis. Her medications include coumadin, atorvastatin, and citalopram. • Two days later the patient presents with confusion and fever. Exam shows a diaphoretic and confused patient with T = 38.8°C, P = 126, BP 160/110, dilated pupils, hyperactive bowel tones, and hyperreflexia in the lower extremities. • What is the likely cause of this patient’s symptoms? DHS/PP

  46. Linezolid (Zyvox) & Serotonin Syndrome • 29 cases in postmarketing data • Age Range: 17-83 • Most common class of drug was SSRI • 3/29 resulted in death; 7/29 resulted in hospitalization • No clear recommendations for prevention DHS/PP From: Lawrence KR, et al. Clin Infect Dis 2006;42:1578-83.

  47. Tigecycline (Tygacil)

  48. Antimicrobials: Question • Which organism is Tigecycline typically NOT effective against? 1. Pseudomonasaeruginosa2. Acinetobacter sp.3. Methicillin-resistant Staphylococcus aureus 4. E. coli DHS/PP

  49. Tigecycline: Mechanism of Action Tigecycline DNA 30S Ribosomal Subunit Binding Sites DHS/PP

  50. Tigecycline (Tygacil) Gram-Positives Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Negatives Anaerobes DHS/PP

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