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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. - PowerPoint PPT Presentation
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Antimicrobial Therapy
David H. Spach, MDProfessor of Medicine
Division of Infectious DiseasesUniversity of Washington, Seattle
Structure of Gram-Positive Bacteria
Cell WallCell Membrane
Penicillin Binding Proteins
DNA
Structure of Gram-Negative Bacteria
Porin Channel
Outer Membrane
Cell Wall
Periplasmic Space
Cell MembraneDNA
Antimicrobials: Site of Action
Cell Wall - Beta-Lactams - Glycopeptides
Cytoplasm23 S Ribosome- Linezolid
30S Ribosome- Aminoglycosides- Tetracyclines
50S Ribosome- Macrolides/Ketolides- Clindamycin- Chloramphenicol- Quinupristin-Dalfopristin
DNA Inhibitor - Fluoroquinolone- TMP-SMX- Metronidazole
Cell Membrane - Daptomycin
Antimicrobial Spectrum
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Antimicrobial Spectrum
Highly-Resistant
Gram-
Negatives
Highly-Resistant
Gram-Positives
Highly Resistant Anaerobes
Gram-Positives Gram-Negatives
Anaerobes
Beta-Lactams
Beta-Lactam Antibiotics
Penicillins
Cephalosporins
Monobactam
Carbapenems
Antimicrobials: Question
• What is the mechanism of action for beta-lactam antimicrobials?
Beta-Lactams: Mechanism of Action
Cell WallCell Membrane
Penicillin Binding Proteins
DNA
Beta-Lactam
TranspeptidationCarboxypeptidation
Cell WallCell Membrane
Penicillin Binding Proteins
Cell Wall Synthesis
DNA
Beta-Lactam
Beta-Lactams: Mechanism of Action
Antimicrobials: Question
• Which of the following beta-lactam animicrobial is typically active against Enterococcus faecalis (assume this is not a resistant enterococcus):
a. Cefotetanb. Aztreonam c. Piperacilline. Nafcillin
Piperacillin-Tazobactam (Zosyn)
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Antimicrobials: Question
• Which of the cephalosporins typically have anti-pseudomonal activity?
Antimicrobials: Question
• Which of the 3rd Generation Cephalosporins would be appropriate for treatment of Pseudomonas meningitis:
a. Ceftriaxoneb. Ceftazidime c. Cefoperazoned. Cefotaxime
Ceftriaxone (Rocephin) 3rd-Generation Cephalosporin
Gram-Positives Gram-Negatives
Anaerobes
Enterococcus sp.
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Ceftazidime (Fortaz, Tazicef, Tazidime) 3rd-Generation Cephalosporin
Anaerobes
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives
Cefepime (Maxepime) 4th-Generation Cephalosporin
Gram-Positives Gram-Negatives
Anaerobes
Enterococcus sp.
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Antimicrobials: Question
• Which of the following organisms do you think cefixime (Suprax) would NOT routinely have good activity against?
a. Staphyloccus aureus (MSSA or MRSA)b. Streptococcus pneumoniaec. Haemophilus influenzae d. Moraxella (Branhamella) catarrhalis
Cefixime (Suprax) 2nd/3rd Generation ORAL Cephalosporin
Anaerobes
Enterococcus sp.
Staphylococcus aureus
Gram-Positives Gram-Negatives
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Monobactams
Aztreonam (Azactam)
Aztreonam (Azactam)
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Carbapenems
Imipenem + Cilastatin (Primaxin)
Meropenem (Merrem)
Ertapenem (Invanz)
Doripenem (Doribax)
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.
Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax)
Gram-Positives Gram-Negatives
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Anaerobes
Ertapenem (Invanz)
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
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
Vancomycin
Antimicrobials: Question
• What is the mechanism of action for vancomycin?
Vancomycin: Mechanism of Action
VancomycinCell Wall
Synthesis
DNA
Vancomycin: Mechanism of Action
D-Ala D-Ala
Ligase
Tripeptide Intermediate
D-Ala D-Ala
Cell Wall Pentapeptide Precursor
D-Ala D-Ala Vancomycin
Vancomycin
Anaerobes
VRE
VISA
Gram-Positives Gram-Negatives
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
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
Daptomycin (Cubicin)
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
Daptomycin (Cubicin): Mechanism of Action
Daptomycin
DNA
K+Ca2+
1. Ca2+-Dependent Binding to Cell Membrane2. Membrane Depolarization and K+ Efflux
Cell Membrane
K+
1
2
Altered Penicillin Binding Protein
Daptomycin (Cubicin)
Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives Gram-Positives
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
Daptomycin (Cubicin) vs Comparator for MSSA & MRSA Bacteremia & Endocarditis
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)
Study Design Success 42 Days Post Treatment
Source: Fowler VG, et al. N Engl J Med 2006;355:653-65.
Linezolid (Zyvox)
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
Linezolid: Mechanism of Action
50SfMet-tRNA
50 S RibosomeLinezolid
30S
70 S Initiation Complex
30 S Ribosome
DNA
Linezolid (Zyvox)
Gram-Negatives
Anaerobes
Gram-Positives
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Nosocomial Pneumonia: Vancomycin vs. Linezolid
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
Study Design Clinical Cure
From: Wunderink RG, et al. Chest 2003;124:1789-97.
P = 0.009P = 0.182
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?
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.
Ceftaroline (Teflaro)
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.
Ceftaroline (Teflaro)
Gram-Positives Gram-Negatives
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Anaerobes
Tigecycline (Tygacil)
Antimicrobials: Question
• Which organism is Tigecycline typically NOT effective against?
1. Pseudomonas aeruginosa2. Acinetobacter sp.3. Methicillin-resistant Staphylococcus aureus 4. E. coli
Tetracyclines & Glycylcyclines: Mechanism of Action
Tigecycline
30S Ribosomal Subunit Binding Sites
DNA
Tigecycline (Tygacil)
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Negatives
Highly Resistant
Gram-Positives
Tigecycline (Tygacil)
Class: Glycylcycline
Mechanism: Inhibits protein synthesis (binds to 30S ribosome)
Dose: 100 mg IV x 1, then 50 mg IV q12 hours
Activity: - Broad gram-positive: MSSA, MRSA, VRE, DRSP- Gram-negative: Enterobacteriaceae, Acinetobacter sp.- Not ideal for Pseudomonas sp. or Proteus sp.
Clinical:- Complicated skin and soft tissue infections- Complicated intra-abdominal infections
Adverse Effects: significant nausea and vomiting
Complicated Intra-Abdominal InfectionsTigecycline versus Imipenem
Methods - Pooled analysis of 2 phase 3 trials - Double-blind trial - N = 1642 Adults - Complicated intra-Abdominal Infections
Regimens - Tigecycline 100 mg x1, then 50 mg q12h - Imipenem: 500 mg q6h
Study Design Clinical Cure
Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7.
Fluoroquinolones
Antimicrobials: Question
• The fluoroquinolone Moxifloxacin (Avelox) typically has activity against all of the following except:
1. Haemophilus influenzae2. Methicillin-resistant Staphylococcus aureus
3. Legionella pneumoniae4. Streptococcus pneumoniae
Fluoroquinolone: Mechanism of Action
Cell WallCell Membrane
DNA Gyrase
DNA Topoisomerase IV
Fluoroquinolone
DNA
Fluoroquinolones
Levofloxacin (Levaquin)
Moxifloxacin (Avelox)
Gemifloxacin (Factive)
Ciprofloxacin (Cipro)
Levofloxacin (Levaquin)
Norfloxacin (Noroxin)
Ofloxacin (Floxin)
RTI, SSTI
UTI
Questions?
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