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Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington,

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

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Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington,

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

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

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

  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

  5. Antimicrobial Spectrum Gram-Positives Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Negatives Anaerobes

  6. Antimicrobial Spectrum Gram-Negatives Gram-Positives Highly-Resistant Gram-Positives Highly-Resistant Gram-Negatives Anaerobes Highly Resistant Anaerobes

  7. Beta-Lactams

  8. Beta-Lactam Antibiotics • Penicillins • Cephalosporins • Monobactam • Carbapenems

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

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

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

  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

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

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

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

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

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

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

  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

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

  21. Monobactams • Aztreonam (Azactam)

  22. Aztreonam (Azactam) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes

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

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

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

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

  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

  28. Vancomycin

  29. Antimicrobials: Question • What is the mechanism of action for vancomycin?

  30. Vancomycin: Mechanism of Action Vancomycin Cell Wall Synthesis DNA

  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

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

  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

  34. Daptomycin (Cubicin)

  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 4-7% of patients

  36. Daptomycin (Cubicin): Mechanism of Action 1. Ca2+-Dependent Binding to Cell Membrane2. Membrane Depolarization and K+ Efflux Daptomycin 1 Ca2+ K+ 2 K+ DNA Altered Penicillin Binding Protein Cell Membrane

  37. Daptomycin (Cubicin) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes

  38. Daptomycin (Cubicin) • Class: Lipopeptide • Mechanism: Disrupts plasma membrane function (depolarization of membrane) • Dose: 4 or 6 mg/kg IV q24 hours • Activity: MSSA, MRSA, VRSA, coag -Staphylococcus, 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 CrCl <30 mL/min

  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) Source: Fowler VG, et al. N Engl J Med 2006;355:653-65.

  40. Linezolid (Zyvox)

  41. Antimicrobial: Question • Which of the following is TRUE regarding the antimicrobial Linezolid (Zyvox)? 1. The oral bioavailability of linezolid is excellent2. About 40% of MRSA now resistant to linezolid3. Neutropenia is the most common lab abnormality 4. It works by disrupting bacterial cell wall synthesis

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

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

  44. Nosocomial Pneumonia: Vancomycin vs. Linezolid Study Design Clinical Cure • 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.

  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?

  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 Source: Lawrence KR, et al. Clin Infect Dis 2006;42:1578-83.

  47. Ceftaroline (Teflaro)

  48. Ceftaroline (Teflaro) • Class: Cephalosporin (“5th Generation”) • Mechanism: Inhibits cell wall synthesis (binds to PBP, including PBP2a) • Dose: 600 mg IV q12 hours • Activity: - Broad gram-positive activity: MSSA, MRSA, VISA, DRSP- Gram-negative: Enterobacteriaceae- Not active against Pseudomonas sp. or Proteus sp., or E. faecium • Clinical:- Skin and soft tissue infections (CANVAS 1 & 2 Studies)- Community-acquired pneumonia (FOCUS 1 & 2 Studies) • Adverse Effects: seroconversion to positive direct Coombs’ test Source: Saravolatz LD, et al. Clin Infect Dis. 2011;52:1156-63.

  49. Ceftaroline (Teflaro) Gram-Positives Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Negatives Anaerobes

  50. Tigecycline (Tygacil)

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