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Antimicrobial Therapy

David H. Spach, MDProfessor of Medicine

Division of Infectious DiseasesUniversity of Washington, Seattle

Structure of Gram-Positive Bacteria

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Cell WallCell Membrane

Penicillin Binding Proteins

DNA

Structure of Gram-Negative Bacteria

Porin Channel

Outer Membrane

Cell Wall

Periplasmic Space

Cell MembraneDNA

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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

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Antimicrobial Spectrum

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Gram-Positives Gram-Negatives

Anaerobes

Resistant Gram-Positives Resistant Gram-Negatives

Antimicrobial Spectrum

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Highly-Resistant

Gram-Negatives Highly-Resistant

Gram-Positives

Highly Resistant Anaerobes

Gram-Positives Gram-Negatives

Anaerobes

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Beta-Lactams

Beta-Lactam Antibiotics

Penicillins

Cephalosporins

Monobactam

Carbapenems

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Antimicrobials: Question

• What is the mechanism of action for beta-lactam antimicrobials?

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Beta-Lactams: Mechanism of Action

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Cell WallCell Membrane

Penicillin Binding Proteins

DNA

Beta-Lactam

Beta-Lactam: Mechanism of Action

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Cell WallCell Membrane

Penicillin Binding Proteins

Cell Wall Synthesis

DNA

Beta-Lactam

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

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Piperacillin-Tazobactam (Zosyn)

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Antimicrobials: Question

• Which of the cephalosporins typically have anti-pseudomonal activity?

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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

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Ceftriaxone (Rocephin) 3rd-Generation Cephalosporin

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Enterococcus sp.

Ceftazidime (Fortaz, Tazicef, Tazidime) 3rd-Generation Cephalosporin

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Cefepime (Maxepime) 4th-Generation Cephalosporin

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Enterococcus sp.

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

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Cefixime (Suprax) 2nd/3rd Generation ORAL Cephalosporin

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Highly Resistant

Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Enterococcus sp.

Gram-Positives

Staphylococcus aureus

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Monobactams

Aztreonam (Azactam)

Aztreonam

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

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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 much greater anaerobic activity3. Ertapenem has much better gram-positive activity4. Ertapenem has better activity against Acinetobacter sp.

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Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax)

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Gram-Positives Gram-Negatives

Anaerobes

Highly Resistant

Gram-Positives Highly Resistant

Gram-Negatives

Ertapenem (Invanz)

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Highly Resistant

Gram-Positives Gram-Positives Gram-Negatives

Anaerobes

Highly Resistant

Gram-Negatives

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

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Vancomycin

Antimicrobials: Question

• What is vancomycin’s mechanism of action?

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Vancomycin: Mechanism of Action

Vancomycin

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Cell Wall Synthesis

DNA

Vancomycin: Mechanism of Action

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D-Ala D-Ala

Ligase

Tripeptide Intermediate

D-Ala D-Ala

Cell Wall Pentapeptide Precursor

D-Ala D-Ala Vancomycin

Vancomycin

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Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Highly Resistant

Gram-Positives Gram-Positives

VRE

VISA

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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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Daptomycin (Cubicin)

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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

Daptomycin (Cubicin): Mechanism of Action

Daptomycin

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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

Daptomycin

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Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Highly Resistant

Gram-Positives Gram-Positives

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

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Daptomycin (Cubicin) vs Comparator for MSSA & MRSA Bacteremia & Endocarditis

44 4245

4944

32

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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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Linezolid (Zyvox)

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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

Linezolid: Mechanism of Action

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50SfMet-tRNA

50 S RibosomeLinezolid

30S

70 S Initiation Complex

30 S Ribosome

DNA

Linezolid (Zyvox)

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Gram-Negatives Highly Resistant

Gram-Negatives

Anaerobes

Highly Resistant

Gram-Positives Gram-Positives

Nosocomial Pneumonia: Vancomycin vs. Linezolid

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60

80

100

Clin

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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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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

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

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

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Tigecycline: Mechanism of Action

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Tigecycline

30S Ribosomal Subunit Binding Sites

DNA

Tigecycline (Tygacil)

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Gram-Positives Gram-Negatives

Anaerobes

Highly Resistant

Gram-Positives

Highly Resistant

Gram-Negatives

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

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Complicated Intra-Abdominal InfectionsTigecycline versus Imipenem

86 8680 82

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20

40

60

80

100

Pat

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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

Fluoroquinolones

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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

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Fluoroquinolone: Mechanism of Action

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Cell WallCell Membrane

DNA Gyrase

DNA Topoisomerase IV

Fluoroquinolone

DNA

Fluoroquinolones

Levofloxacin (Levaquin)

Moxifloxacin (Avelox)

Gemifloxacin (Factive)

Ciprofloxacin (Cipro)

Norfloxacin (Noroxin)

Ofloxacin (Floxin)

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Questions?

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