Antimicrobial Therapy. David H Antimicrobial Therapy David H. Spach, MD Professor of Medicine Division of Infectious Diseases University of Washington, Seattle 1

Structure of Gram-Positive Bacteria Penicillin Binding Proteins DNA Cell Wall Cell Membrane 1

Structure of Gram-Negative Bacteria Outer Membrane Cell Wall Periplasmic Space Cell Membrane DNA Porin Channel 1

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 Cell Membrane - Daptomycin DNA Inhibitor - Fluoroquinolone - TMP-SMX - Metronidazole 1

Antimicrobial Spectrum Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Antimicrobial Spectrum Gram-Positives Gram-Negatives Highly-Resistant Gram-Positives Highly-Resistant Gram-Negatives Anaerobes Highly Resistant Anaerobes 1

Antibiotic Use and Resistance Community Use Hospital Use Agricultural Use 1

Antibiotic Resistance Antibiotic Development 1

Void in Discovery of New Classes of Antibiotics Source: Silver LL. Clin Microbiol Rev. 2011;24:71-109. Figure from The Pew Charitable Trust. ©2016 1

Systemic Antibacterials: Recent FDA Approvals 2009: Telavancin (Vibativ): SSTI 2010: Ceftaroline (Teflaro): SSTI, CAP 2011: Fidaxomicin (Difficid): Clostridium difficile 2013: Telavancin (Vibativ): HAP/VAP 2014 Tedizolid (Sivextro): SSTI Dalbavancin (Dalvance): SSTI Oritavancin (Orbactiv): SSTI Ceftolazone/tazobactam (Zerbaxa): cIAI, cUTI 2015: Ceftazidime/avibactam (Avycaz): cIAI, UTI 1

Beta-Lactams 1

Beta-Lactam Antibiotics Penicillins Cephalosporins Monobactam Carbapenems 1

Antimicrobials: Question What is the mechanism of action for beta-lactam antimicrobials? 1

Beta-Lactams: Mechanism of Action Penicillin Binding Proteins Beta-Lactam Transpeptidation Carboxypeptidation DNA Cell Wall Cell Membrane 1

Beta-Lactams: Mechanism of Action Cell Wall Synthesis DNA Cell Membrane Cell Wall Penicillin Binding Proteins 1

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 1

Piperacillin-Tazobactam (Zosyn) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Antimicrobials: Question Which of the cephalosporins typically have anti-pseudomonal activity? a. Ceftriaxone b. Ceftazidime c. Ceftaroline d. Cefotaxime 1

Ceftriaxone (Rocephin) 3rd-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Enterococcus sp. Anaerobes 1

Ceftazidime (Fortaz, Tazicef, Tazidime) 3rd-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Cefepime (Maxepime) 4th-Generation Cephalosporin Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Enterococcus sp. Anaerobes 1

Ceftaroline (Teflaro) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives E. faecium Anaerobes 1

MRSA: Resistance to Beta-Lactams Altered Penicillin Binding Protein Beta-Lactam PBP 2a PBP 2a MRSA mecA PBP 2a DNA 1

Ceftaroline and MRSA: PBP2a Binding Altered Penicillin Binding Protein Ceftaroline PBP 2a PBP 2a DNA 1

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. 1

Monobactams Aztreonam (Azactam) 1

Aztreonam (Azactam) Gram-Positives Gram-Negatives Anaerobes Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Carbapenems Imipenem + Cilastatin (Primaxin) Meropenem (Merrem) Ertapenem (Invanz) Doripenem (Doribax) 1

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. 1

Imipenem (Primaxin) & Meropenem (Merrem) & Doripenem (Doribax) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Ertapenem (Invanz) Gram-Positives Gram-Negatives Anaerobes Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Vancomycin 1

Antimicrobials: Question What is the mechanism of action for vancomycin? 1

Vancomycin: Mechanism of Action Cell Wall Synthesis DNA 1

Tripeptide Intermediate Cell Wall Pentapeptide Precursor Vancomycin: Mechanism of Action Ligase D-Ala D-Ala Tripeptide Intermediate D-Ala D-Ala Cell Wall Pentapeptide Precursor D-Ala D-Ala Vancomycin 1

Vancomycin Anaerobes Gram-Positives Gram-Negatives Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives VISA VRE Anaerobes 1

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 1

Daptomycin (Cubicin) 1

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 4-7% of patients 1

Daptomycin (Cubicin): Mechanism of Action 1. Ca2+-Dependent Binding to Cell Membrane 2. Membrane Depolarization and K+ Efflux Daptomycin 1 Ca2+ K+ 2 K+ DNA Altered Penicillin Binding Protein Cell Membrane 1

Daptomycin (Cubicin) Gram-Positives Gram-Negatives Anaerobes Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

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 1

Daptomycin (Cubicin) vs Comparator for MSSA & MRSA Bacteremia & Endocarditis Study Design Success 42 Days Post Treatment 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) Source: Fowler VG, et al. N Engl J Med 2006;355:653-65. 1

Linezolid (Zyvox) 1

Antimicrobial: Question Which of the following is TRUE regarding the antimicrobial Linezolid (Zyvox)? 1. The oral bioavailability of linezolid is excellent 2. About 40% of MRSA now resistant to linezolid 3. Neutropenia is the most common lab abnormality 4. It works by disrupting bacterial cell wall synthesis 1

Linezolid: Mechanism of Action 50 S Ribosome Linezolid 30 S Ribosome 50S fMet-tRNA 30S 70 S Initiation Complex DNA 1

Linezolid (Zyvox) Gram-Positives Gram-Negatives Anaerobes Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Nosocomial Pneumonia: Vancomycin vs. Linezolid Study Design Clinical Cure 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 P = 0.182 P = 0.009 From: Wunderink RG, et al. Chest 2003;124:1789-97. 1

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? 1

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. 1

Ceftaroline (Teflaro) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

Tigecycline (Tygacil) 1

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

Tetracyclines & Glycylcyclines: Mechanism of Action Tigecycline DNA 30S Ribosomal Subunit Binding Sites 1

Tigecycline (Tygacil) Highly Resistant Gram-Positives Highly Resistant Gram-Negatives Gram-Positives Gram-Negatives Anaerobes 1

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 1

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 Source: Babinchak T, et al. Clin Infect Dis 2005;41:S354-7. 1

Fluoroquinolones 1

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

Fluoroquinolone: Mechanism of Action DNA Topoisomerase IV DNA Gyrase DNA Cell Wall Cell Membrane 1

Fluoroquinolones Levofloxacin (Levaquin) Moxifloxacin (Avelox) Gemifloxacin (Factive) Ciprofloxacin (Cipro) Norfloxacin (Noroxin) Ofloxacin (Floxin) RTI, SSTI UTI 1

Questions? 1