Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle Disclosure: Dr. Spach has no significant financial interest in any of the products or manufacturers mentioned.
Structure of Gram-Positive Bacteria Penicillin Binding Proteins DNA Cell Membrane Cell Wall
Structure of Gram-Negative Bacteria Outer Membrane Cell Wall Periplasmic Space Cell Membrane DNA Porin Channel
Antimicrobials: Site of Action Cell Wall - Beta-Lactams - Glycopeptides Cell Membrane - Daptomycin DNA Inhibitor - Fluoroquinolone - TMP-SMX - Metronidazole Cytoplasm 23 S Ribosome - Linezolid 30S Ribosome - Aminoglycosides - Tetracyclines 50S Ribosome - Macrolides/Ketolides - Clindamycin - Chloramphenicol - Quinupristin-Dalfopristin
Antimicrobial Spectrum Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Antimicrobial Spectrum Gram-Positives Gram-Negatives Highly-Resistant Gram-Positives Highly-Resistant Gram- Negatives Anaerobes Highly Resistant Anaerobes
Beta-Lactams
Antimicrobials: Question What are the four groups of beta-lactam antimicrobials?
Beta-Lactam Antibiotics Penicillins Cephalosporins Monobactam Carbapenems
Antimicrobials: Question What is the mechanism of action for betalactam antimicrobials?
Beta-Lactams: Mechanism of Action Penicillin Binding Proteins Transpeptidation Carboxypeptidation DNA Cell Membrane Cell Wall
Beta-Lactams: Mechanism of Action Penicillin Binding Proteins Beta-Lactam Transpeptidation Carboxypeptidation DNA Cell Membrane Cell Wall
Beta-Lactams: Mechanism of Action Cell Wall Synthesis Beta-Lactam DNA Cell Membrane Cell Wall Penicillin Binding Proteins
Antimicrobials: Question Which of the 3rd Generation Cephalosporins would be appropriate for treatment of Pseudomonas meningitis: a. Ceftriaxone b. Ceftazidime c. Cefoperazone d. Cefotaxime
Ceftriaxone 3rd-Generation Cephalosporin Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Enterococcus sp. Anaerobes
Ceftazidime 3rd-Generation Cephalosporin Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Highly Resistant Gram-Negatives Anaerobes
Cefepime 4th-Generation Cephalosporin Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Enterococcus sp. Anaerobes
Antimicrobials: Question Which one of the cephalosporins listed would be appropriate for treatment of a serious MRSA skin and soft tissue infection: a. Cefazolin b. Ceftaroline c. Cefuroxime d. Cefixime
Ceftaroline 4th-Generation Cephalosporin Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Ceftaroline Class: Cephalosporin ( 5 th 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 and MRSA: Mechanism of Action Altered Penicillin Binding Protein PBP 2a Ceftaroline PBP 2a DNA
Antimicrobials: Penicillin Allergy A 23-year-old woman develops gram-negative bacteremia, but has a history of anaphylaxis to penicillin. Which would be the safest to use (from a adverse drug effect standpoint)? 1. Mezlocillin 2. Imipenem 3. Aztreonam 4. Ceftazidime
Monobactams Aztreonam
Aztreonam Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Carbapenems Imipenem-Cilastatin Meropenem Ertapenem Doripenem
Antimicrobials: Question What is the major difference between Imipenem and Ertapenem? 1. Imipenem has significantly better gram-negative activity 2. Imipenem has significantly better anaerobic activity 3. Ertapenem has significantly better gram-positive activity 4. Ertapenem has better activity against Acinetobacter sp.
Imipenem & Meropenem & Doripenem Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Ertapenem Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Vancomycin
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 5-10 3. Trough 10-15 4. Trough 15-20
Vancomycin: Mechanism of Action Cell Wall Synthesis Vancomycin DNA
Vancomycin: Mechanism of Action Ligase D-Ala D-Ala Tripeptide Intermediate D-Ala D-Ala Cell Wall Pentapeptide Precursor D-Ala D-Ala Vancomycin
Vancomycin Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives VISA VRE Anaerobes
Daptomycin
Antimicrobial: Question Which ONE of the following is TRUE regarding Daptomcyin? 1. Daptomycin is a bacterial cell wall inhibitor 2. Daptomycin is inactivated by pulmonary surfactant 3. Daptomycin caused thrombocytopenia in 15% of patients 4. Daptomycin causes renal failure in 5-10% of patients
Daptomycin: Mechanism of Action 1. Ca 2+ -Dependent Binding to Cell Membrane 2. Membrane Depolarization and K+ Efflux Daptomycin Ca 2+ 1 K + 2 K + Altered Penicillin Binding Protein DNA Cell Membrane
Daptomycin Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Highly Resistant Gram-Negatives Anaerobes
Daptomycin Class: Lipopeptide Mechanism: Disrupts plasma membrane function (depolarization of membrane) Dose: 4 or 6 mg/kg IV q24 hours (some experts use higher doses) 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
Linezolid
Antimicrobial: Question A 62-year-old woman is started on linezolid for MRSA vertebral osteomyelitis. Her medications include warfarin, atorvastatin, and citalopram. Two days later the patient presents with confusion, fever, and muscle twitching. Exam shows a diaphoretic and confused patient who is shaking, 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: Mechanism of Action 50 S Ribosome Linezolid 30 S Ribosome fmet-trna 50S 30S 70 S Initiation Complex DNA
Linezolid Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Linezolid Class: Oxazolidinone Mechanism: Inhibits protein synthesis (blocks ribosomal initiation complex) Dose: 400-600 mg IV or PO q12 hours Activity: E. faecium and E. faecalis (including VRE), MSSA, MRSA, coag-staph, S. pyogenes, S. pneumoniae Clinical: VRE, Complicated skin and soft tissue infections, pneumonia caused by gram-positive organisms Adverse Effects: decreased platelets at higher doses; inhibits monamine oxidase (Serotonin Syndrome)
Patients% Nosocomial Pneumonia: Vancomycin vs. Linezolid Study Design Methods - Prospective, double-blind trial - N =448 - Hospitalized adult patients - Healthcare-associated MRSA pneumonia Regimens (7-14 days of treatment) - Vancomycin: 15 mg/kg q12h (n = 224) - Linezolid: 600 mg IV q12h (n =224) Results 100 80 60 40 20 Vancomycin Linezolid 58 47 17 16 P =0.042 0 Clinical Success Per Protocol All Cause Day 60 Mortality From: Wunderink RG, et al. Clin Infect Dis. 2012;54:621-9.
Linezolid & Serotonin Syndrome 29 cases in postmarketing data Age Range: 17-83 Most common class of drug was SSRI or SNRI 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.
Linezolid & Serotonin Syndrome SSRIs Paroxetine Fluvoxamine Fluoxetine SNRIs Venlafaxine Desvenlafaxine Duloxetine Sertraline Citalopram Escitalopram Vilazodon Source: Lawrence KR, et al. Clin Infect Dis 2006;42:1578-83.
Use of Linezolid in Patient on SSRI or SNRI Emergency situation requiring urgent linezolid treatment and Patient taking Serotonergic Medication Immediately stop SSRI/SNRI Closely monitor for symptoms of CNS toxicity for 2 weeks (5 weeks with fluoxetine), or until 24 hours after the last linezolid dose, whichever comes first. Serotonergic drug can be resumed 24 hours after last dose of linezolid Source: FDA Drug Safety Commmunication
Tigecycline
Antimicrobials: Question Which organism is Tigecycline typically NOT effective against? 1. Pseudomonas aeruginosa 2. Acinetobacter sp. 3. Methicillin-resistant Staphylococcus aureus 4. E. coli
Tetracyclines & Glycylcyclines: Mechanism of Action Tigecycline DNA 30S Ribosomal Subunit Binding Sites
Tigecycline Highly Resistant Highly Resistant Gram-Positives Gram-Positives Gram-Negatives Gram-Negatives Anaerobes
Tigecycline 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
Patients % Complicated Intra-Abdominal Infections Tigecycline versus Imipenem Study Design Clinical Cure 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 100 80 60 40 20 Tigecycline Imipenem 86 86 80 82 0 CE Test of Cure ITT Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7.
Fluoroquinolones
Antimicrobials: Fluoroquinolone Which of the fluoroquinolones is NOT recommended for the treatment of community-acquired pneumonia? 1. Ciprofloxacin 2. Levofloxacin 3. Moxifloxacin
Fluoroquinolones Levofloxacin Moxifloxacin RTI, SSTI Gemifloxacin Ciprofloxacin Levofloxacin Norfloxacin Ofloxacin UTI
Fluoroquinolone: Mechanism of Action Fluoroquinolone DNA Topoisomerase IV DNA Gyrase DNA Cell Membrane Cell Wall
Questions?