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

Structure of Gram-Positive Bacteria DHS/PP Cell Wall Cell Membrane Penicillin Binding Proteins DNA

Structure of Gram -Negative Bacteria Porin Channel Outer Membrane Cell Wall Periplasmic Space Cell Membrane DNA DHS/PP

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

Antimicrobial Spectrum DHS/PP Gram-PositivesGram-Negatives Anaerobes Resistant Gram-Positives Resistant Gram-Negatives

Antimicrobial Spectrum DHS/PP Highly-Resistant Gram-Negatives Highly-Resistant Gram-Positives Highly Resistant Anaerobes Gram-PositivesGram-Negatives Anaerobes

DHS/PP Beta-Lactams

Beta-Lactam Antibiotics  Penicillins  Cephalosporins  Monobactam  Carbapenems DHS/PP

Antimicrobials: Question What is the mechanism of action for beta-lactam antimicrobials? DHS/PP

Beta-Lactams: Mechanism of Action DHS/PP Cell Wall Cell Membrane Penicillin Binding Proteins DNA Beta-Lactam

Beta-Lactam: Mechanism of Action DHS/PP Cell Wall Cell 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. Cefotetan b. Aztreonam c. Piperacillin e. Nafcillin DHS/PP

Piperacillin-Tazobactam (Zosyn) DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-Negatives Highly Resistant Gram-Negatives Anaerobes

Antimicrobials: Question Which of the cephalosporins typically have anti-pseudomonal activity? DHS/PP

Antimicrobials: Question Which of the 3rd Generation Cephalosporins would be appropriate for treatment of Pseudomonas meningitis: a. Ceftriaxone b. Ceftazidime c. Cefoperazone d. Cefotaxime DHS/PP

Ceftriaxone (Rocephin) 3rd-Generation Cephalosporin DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-Negatives Highly Resistant Gram-Negatives Anaerobes Enterococcus sp.

Ceftazidime (Fortaz, Tazicef, Tazidime) 3rd-Generation Cephalosporin DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-Negatives Highly Resistant Gram-Negatives Anaerobes

Cefepime (Maxepime) 4th-Generation Cephalosporin DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-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 pneumoniae c. Haemophilus influenzae d. Moraxella (Branhamella) catarrhalis DHS/PP

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

DHS/PP Monobactams  Aztreonam (Azactam)

Aztreonam DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-Negatives Highly Resistant Gram-Negatives Anaerobes

DHS/PP 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 activity 2. Imipenem has much greater anaerobic activity 3. Ertapenem has much better gram-positive activity 4. Ertapenem has better activity against Acinetobacter sp. DHS/PP

Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax) DHS/PP Gram-PositivesGram-Negatives Anaerobes Highly Resistant Gram-Positives Highly Resistant Gram-Negatives

Ertapenem (Invanz) DHS/PP Highly Resistant Gram-Positives Gram-PositivesGram-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 Ampicillin 2. Change to Imipenem 3. Add Clindamycin 4. Change to Cefazolin DHS/PP

Vancomycin

Antimicrobials: Question What is vancomycin’s mechanism of action? DHS/PP

Vancomycin: Mechanism of Action Vancomycin DHS/PP Cell Wall Synthesis DNA

Vancomycin: Mechanism of Action DHS/PP D-Ala Ligase Tripeptide Intermediate D-Ala Cell Wall Pentapeptide Precursor D-Ala Vancomycin

DHS/PP Gram-Negatives Highly Resistant Gram-Negatives Anaerobes Highly Resistant Gram-Positives Gram-Positives VRE VISA

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 < 5 2. Trough Trough Trough 15-20

DHS/PP Daptomycin (Cubicin)

DHS/PP Antimicrobial: Question  Which of the following is TRUE regarding the antimicrobial Daptomcyin (Cubicin)? 1. Daptomycin is a bacterial cell wall inhibitor 2. Based on recent data, daptomycin is the drug of choice for MRSA pneumonia 3. 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 DHS/PP DNA K+K+ Ca Ca 2+ -Dependent Binding to Cell Membrane 2. Membrane Depolarization and K+ Efflux Cell Membrane K+K+ 1 2 Altered Penicillin Binding Protein

Daptomycin DHS/PP 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 DHS/PP

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 DesignSuccess 42 Days Post Treatment Source: Fowler VG et al. N Engl J Med 2006;355: DHS/PP

DHS/RTI/PP Linezolid (Zyvox)

DHS/PP Antimicrobial: Question  Which of the following is TRUE regarding the antimicrobial Linezolid (Zyvox)? 1. The oral bioavailability of linezolid is excellent 2. About 30% of MRSA now resistant to linezolid 3. Neutropenia is the most common lab abnormality 4. It works by disrupting bacterial cell wall synthesis

Linezolid: Mechanism of Action DHS/PP 50 S fMet-tRNA 50 S Ribosome Linezolid 30 S 70 S Initiation Complex 30 S Ribosome DNA

Linezolid (Zyvox) DHS/PP Gram-Negatives Highly Resistant Gram-Negatives Anaerobes Highly Resistant Gram-Positives 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 with documented S. aureus with documented MRSA  Regimens - Vancomycin + Aztreonam - Linezolid + Aztreonam Study Design Clinical Cure From: Wunderink RG, et al. Chest 2003;124: DHS/PP P = 0.009P = 0.182

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?

Linezolid (Zyvox) & Serotonin Syndrome  29 cases in postmarketing data  Age Range:  Most common class of drug was SSRI  3/29 resulted in death; 7/29 resulted in hospitalization  No clear recommendations for prevention DHS/PP From: Lawrence KR, et al. Clin Infect Dis 2006;42:

Tigecycline (Tygacil)

Antimicrobials: Question Which organism is Tigecycline typically NOT effective against? 1. Pseudomonas aeruginosa 2. Acinetobacter sp. 3. Methicillin-resistant Staphylococcus aureus 4. E. coli DHS/PP

Tigecycline: Mechanism of Action DHS/PP Tigecycline 30S Ribosomal Subunit Binding Sites DNA

Tigecycline (Tygacil) DHS/PP 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 DHS/PP

Complicated Intra-Abdominal Infections Tigecycline 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 DesignClinical Cure From: Babinchak T, et al. Clin Infect Dis 2005;41:S DHS/PP

Fluoroquinolones DHS/PP

Antimicrobials: Question The new fluoroquinolone Moxifloxacin typically has activity against all of the following except: 1. Haemophilus influenzae 2. Methicillin-resistant Staphylococcus aureus 3. Legionella pneumoniae 4. Streptococcus pneumoniae DHS/PP

Fluoroquinolone: Mechanism of Action DHS/PP Cell Wall Cell Membrane DNA Gyrase DNA Topoisomerase IV Fluoroquinolone DNA

Fluoroquinolones  Levofloxacin (Levaquin)  Moxifloxacin (Avelox)  Gemifloxacin (Factive)  Ciprofloxacin(Cipro)  Norfloxacin (Noroxin)  Ofloxacin (Floxin) DHS/PP

Questions? DHS/PP