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?