dhs/pp antimicrobial therapy david h. spach, md professor of medicine division of infectious...
TRANSCRIPT
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DHS/PP
Antimicrobial Therapy
David H. Spach, MDProfessor of Medicine
Division of Infectious DiseasesUniversity of Washington, Seattle
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Structure of Gram-Positive Bacteria
DHS/PP
Cell WallCell Membrane
Penicillin Binding Proteins
DNA
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Structure of Gram-Negative Bacteria
Porin Channel
Outer Membrane
Cell Wall
Periplasmic Space
Cell MembraneDNA
DHS/PP
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Antimicrobials: Site of Action
Cell Wall - Beta-Lactams - Glycopeptides Cytoplasm
23 S Ribosome- Linezolid
30S Ribosome- Aminoglycosides- Tetracyclines
50S Ribosome- Macrolides/Ketolides- Clindamycin- Chloramphenicol- Quinupristin-Dalfopristin
DNA Inhibitor - Fluoroquinolone- TMP-SMX- Metronidazole
Cell Membrane - Daptomycin
DHS/PP
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Antimicrobial Spectrum
DHS/PP
Gram-Positives Gram-Negatives
Anaerobes
Resistant Gram-Positives Resistant Gram-Negatives
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Antimicrobial Spectrum
DHS/PP
Highly-Resistant
Gram-Negatives Highly-Resistant
Gram-Positives
Highly Resistant Anaerobes
Gram-Positives Gram-Negatives
Anaerobes
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DHS/PP
Beta-Lactams
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Beta-Lactam Antibiotics
Penicillins
Cephalosporins
Monobactam
Carbapenems
DHS/PP
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Antimicrobials: Question
• What is the mechanism of action for beta-lactam antimicrobials?
DHS/PP
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Beta-Lactams: Mechanism of Action
DHS/PP
Cell WallCell Membrane
Penicillin Binding Proteins
DNA
Beta-Lactam
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Beta-Lactam: Mechanism of Action
DHS/PP
Cell WallCell Membrane
Penicillin Binding Proteins
Cell Wall Synthesis
DNA
Beta-Lactam
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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
DHS/PP
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Piperacillin-Tazobactam (Zosyn)
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
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Antimicrobials: Question
• Which of the cephalosporins typically have anti-pseudomonal activity?
DHS/PP
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Antimicrobials: Question
• Which of the 3rd Generation Cephalosporins would be appropriate for treatment of Pseudomonas meningitis:
a. Ceftriaxoneb. Ceftazidime c. Cefoperazoned. Cefotaxime
DHS/PP
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Ceftriaxone (Rocephin) 3rd-Generation Cephalosporin
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Enterococcus sp.
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Ceftazidime (Fortaz, Tazicef, Tazidime) 3rd-Generation Cephalosporin
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
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Cefepime (Maxepime) 4th-Generation Cephalosporin
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Enterococcus sp.
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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
DHS/PP
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Cefixime (Suprax) 2nd/3rd Generation ORAL Cephalosporin
DHS/PP
Highly Resistant
Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Enterococcus sp.
Gram-Positives
Staphylococcus aureus
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DHS/PP
Monobactams
Aztreonam (Azactam)
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Aztreonam
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
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DHS/PP
Carbapenems
Imipenem + Cilastatin (Primaxin)
Meropenem (Merrem)
Ertapenem (Invanz)
Doripenem (Doribax)
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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
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Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax)
DHS/PP
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives Highly Resistant
Gram-Negatives
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Ertapenem (Invanz)
DHS/PP
Highly Resistant
Gram-Positives Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Negatives
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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
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DHS/PP
Vancomycin
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Antimicrobials: Question
• What is vancomycin’s mechanism of action?
DHS/PP
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Vancomycin: Mechanism of Action
Vancomycin
DHS/PP
Cell Wall Synthesis
DNA
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Vancomycin: Mechanism of Action
DHS/PP
D-Ala D-Ala
Ligase
Tripeptide Intermediate
D-Ala D-Ala
Cell Wall Pentapeptide Precursor
D-Ala D-Ala Vancomycin
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Vancomycin
DHS/PP
Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives Gram-Positives
VRE
VISA
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DHS/PP
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
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DHS/PP
Daptomycin (Cubicin)
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DHS/PP
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
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Daptomycin (Cubicin): Mechanism of Action
Daptomycin
DHS/PP
DNA
K+Ca2+
1. Ca2+-Dependent Binding to Cell Membrane
2. Membrane Depolarization and K+ Efflux
Cell Membrane
K+
1
2
Altered Penicillin Binding Protein
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Daptomycin
DHS/PP
Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives Gram-Positives
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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
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Daptomycin (Cubicin) vs Comparator for MSSA & MRSA Bacteremia & Endocarditis
44 4245
4944
32
0
10
20
30
40
50
60
Su
cces
s R
ate
(%)
Total MSSA MRSA
Daptomycin Standard Therapy
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. DHS/PP
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DHS/RTI/PP
Linezolid (Zyvox)
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DHS/PP
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
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Linezolid: Mechanism of Action
DHS/PP
50SfMet-tRNA
50 S RibosomeLinezolid
30S
70 S Initiation Complex
30 S Ribosome
DNA
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Linezolid (Zyvox)
DHS/PP
Gram-Negatives Highly Resistant
Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives Gram-Positives
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Nosocomial Pneumonia: Vancomycin vs. Linezolid
4352
36
59
0
20
40
60
80
100
Clin
ical
Cur
e %
S. aureus MRSA
Vancomycin 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. DHS/PP
P = 0.009P = 0.182
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DHS/PP
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?
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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/PPFrom: Lawrence KR, et al. Clin Infect Dis 2006;42:1578-83.
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Tigecycline (Tygacil)
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Antimicrobials: Question
• Which organism is Tigecycline typically NOT effective against?
1. Pseudomonas aeruginosa2. Acinetobacter sp.3. Methicillin-resistant Staphylococcus aureus 4. E. coli
DHS/PP
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Tigecycline: Mechanism of Action
DHS/PP
Tigecycline
30S Ribosomal Subunit Binding Sites
DNA
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Tigecycline (Tygacil)
DHS/PP
Gram-Positives Gram-Negatives
Anaerobes
Highly Resistant
Gram-Positives
Highly Resistant
Gram-Negatives
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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
DHS/PP
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Complicated Intra-Abdominal InfectionsTigecycline versus Imipenem
86 8680 82
0
20
40
60
80
100
Pat
ien
ts %
CE ITT
Test of Cure
Tigecycline 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
From: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7. DHS/PP
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Fluoroquinolones
DHS/PP
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Antimicrobials: Question
• The new fluoroquinolone Moxifloxacin typically has activity against all of the following except:
1. Haemophilus influenzae2. Methicillin-resistant Staphylococcus aureus 3. Legionella pneumoniae4. Streptococcus pneumoniae
DHS/PP
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Fluoroquinolone: Mechanism of Action
DHS/PP
Cell WallCell Membrane
DNA Gyrase
DNA Topoisomerase IV
Fluoroquinolone
DNA
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Fluoroquinolones
Levofloxacin (Levaquin)
Moxifloxacin (Avelox)
Gemifloxacin (Factive)
Ciprofloxacin (Cipro)
Norfloxacin (Noroxin)
Ofloxacin (Floxin)
DHS/PP
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Questions?
DHS/PP