Antimicrobial Agents 101 SWACM 2011 Christopher Doern, Ph.D., D(ABMM)
β -Lactams Penicillins Cephalosporins Carbapenems Monobactams β -Lactamase Inhibitors Clavulanate Amox/Clav Ticar/Clav Sulbactam Amp/Sulb Tazobactam Pip/Tazo Back to Basics: Cell Wall Acting Antibiotics Bactericidal Inhibit cell wall synthesis by blocking transpeptidase (Penicillin binding protein or PBP) activity. Weak antibacterial activity Potent inhibitors of some β-lactamases
Beta-lactam Video http://www.youtube.com/watch_popup?v=qbdynrhdwcq&vq=medium
Beta-Lactam Spectrum of Activity Active* Aerobic and anaerobic Gram positive cocci and bacilli Aerobic and anaerobic Gram negative bacilli Beta-Lactamase inhibitors used to inhibit beta-lactamases produced by anaerobes Other organisms Pasteurella Streptobacillus Treponema pallidum Erysypelothrix Inactive Carbapenemase producing Gram negative bacilli Ampicillin resistant Enterococci Mycoplasma Stenotrophomonas maltophilia MRSA *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Common Clinical Indications for Beta-Lactams Penicillin or Ampicillin Severe Enterococcal infection (plus gentamicin for synergy) GAS and GBS Actinomyces Syphillis Beta-lactam + inhibitor Bite wounds Infections expected to include anaerobes Uncomplicated UTI GAS pharyngitis Otitis media Pip/Tazo P. aeruginosa Kucers : The Use of Antibiotics, 6 th Edition Cefazolin and Cefalothin* (1 st gen cephs) MSSA infection *Itself rarely used but predicts susceptibility to oral 1 st gen cephs Cefotaxime and Ceftriaxone Empiric treatment for meningitis Ampicillin added to those <2 months if Listeria suspected Pneumococcal infection N. gonorrhoeae and meningitidis Serious Gram negative infection Ceftazidime Empiric treatment of fever and neutropenia P. aeruginosa infection Carbapenems Serious, resistant Gram negative infections Medical Letter, Inc. June 2010
Back to Basics: Other Cell Wall Acting Antibiotics Glycopeptides Vancomycin Teicoplanin Lipopeptides Daptomycin Polymyxins Colistin Inhibits assembly of peptidoglycan precursors (murein) Slowly bactericidal Binds to cell membrane and disrupts bacterial cell membrane potential Rapidly bactericidal Penetrate and disrupt cell membranes Rapidly bactericidal
Spectrum of Activity Active* Glycopeptides and Lipopeptides Gram positive cocci and bacilli Inactive Glycopeptides and Lipopeptides Gram negatives Polymyxins Gram negative Polymyxins Gram positives Anaerobes Burkholderia Proteus Serratia Providencia *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Common Clinical Indications for Use Vancomycin Empiric coverage for Gram positive infection MRSA Recurrent C. difficile infection Daptomycin VRE MRSA non-respiratory Colistin Hospital acquired ventilator associated pneumonia MDR Acinetobacter MDR Gram negatives Can be nebulized for respiratory infections Medical Letter, Inc. June 2010
Back to Basics: Protein Synthesis Inhibitors Oxazolidinones Linezolid Tetracyclines and Chloramphenicol Doxy-, Mino-, Tetra-, Tigecycline Chloramphenicol www.accessmedicine.net http://pharmaxchange.info/press/wp-content/uploads/2011/06/oxazolidinone-115x115.png
Back to Basics: Protein Synthesis Inhibitors MLSb Antibiotics Macrolides Erythromycin, Clarithromycin and Azithromycin Lincosamides Clindamycin Streptogramins www.accessmedicine.net Synercid Bind 50S subunit and inhibit peptide chain elongation Bind 50S and inhibit both addition of peptides and chain elongation
Macrolide Video http://www.youtube.com/watch_popup?v=oc21vlftsjo&vq=medium
Spectrum of Activity Linezolid Gram positives Nocardia Mycobacteria Active* Tetracyclines and Chloramphenicol Aerobic and anaerobic Gram positives Aerobic and anaerobic Gram negatives Spirochetes Rickettsiae, chlamydiae, mycoplasmas and protozoans Inactive Linezolid Gram negatives Mycoplasmas and ureaplasmas *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Spectrum of Activity Macrolides Active* Aerobic and anaerobic Gram positives and Gram negatives Treponemes, mycoplasmas, Chlamydia and rickettsiae Lincosamides Aerobic and anaerobic Gram positives and Gram negatives Streptogramins Aerobic and anaerobic Gram positives Some Gram negatives Inactive Lincosamides Enterobacteriaceae Streptogramins Enterococcus faecalis Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Common Clinical Indications for Use Azithromycin Legionella Chlamydia Acute otitis media Acute exacerbations of chronic bronchitis CAP in low MDR risk patients Pertusiss Shigella in children Immunomodulating agent in CF Linezolid MRSA Skin and soft-tissue infection Pneumonia VRE Clindamycin (not exhaustive) S. aureus infections (MRSA and MSSA) Skin and connective tissue infections Bites, acne, cellulitis, necrotizing fasciitis to name a few Bone and joint infections Bacterial pneumonia Abscesses Skin, head and neck, retro and parapharyngeal Toxin producing infections caused by Gram positives Doxycycline Tick-borne disease Ehrlichia, Lyme disease, Typhus, RMSF Chlamydia Pelvic inflammatory disease Bartonella Prophylaxis for agents of bioterrorism Kucers : The Use of Antibiotics, 6 th Edition Medical Letter, Inc. June 2010
Back to Basics: Protein Synthesis Inhibitors Aminoglycosides Gentamicin, Amikacin, Tobramycin, Spectinomycin and many more Interfere with proofreading mechanism resulting in premature termination Interfere with protein synthesis by blocking ribosomal tranlocation Can disrupt integrity of cell membrane Some bind to 50S and other 30S subunit
Aminoglycoside Spectrum of Activity Active* Aerobic Gram positives and Gram negatives Mycobacteria Inactive Anaerobes MRSA S. pneumoniae Stenotrophomonas maltophilia Burkholderia cepacia *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Common Clinical Indications for Use Aminoglycosides Synergy with beta-lactam Viridans group streptococci (Gentamicin) Listeria (Gentamicin) Pseudomonas aeruginosa (Pip/Tazo) Enterococcus spp. (high level) Tularemia, plague and Brucella Complicated UTI Serious Gram negative infections Kucers : The Use of Antibiotics, 6 th Edition Medical Letter, Inc. June 2010
Back to Basics: DNA Synthesis Inhibitors Quinolones and Fluorquinolones Numerous Nalidixic acid, Ciprofloxacin, Levofloxacin, Gatifloxacin and Moxifloxacin
Quinolone Video http://www.youtube.com/watch_popup?v=ikkz_gxaoxi&vq=medium
Quinolone Spectrum of Activity Active* Inactive Aerobic Gram negatives and Gram positives Anaerobic Gram negatives and Gram positives Mycobacteria Mycoplasma, Chlamydia and Treponema *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Back to Basics: RNA Synthesis Inhibitors Rifamycins Rifampicin (rifampin), rifabutin, rifapentine Interferes with DNAdependent RNA polymerase to inhibit RNA synthesis Sassetti and Rubin. 2007. Nat. Med.
Rifamycin Spectrum of Activity Active* Inactive Mycobacterium tuberculosis Non-tuberculous mycobacteria Gram positive cocci Gram negative bacilli Some anaerobes Neisseria meningitidis (oropharyngeal clearance) Other organisms Chlamydia Bartonella Legionella H. pylori Ehrlichia Brucella *In many cases susceptibility testing necessary to confirm activity of specific class of beta-lactam against individual isolates.
Common Clinical Indications for Use Rifampin Haemophilus influenzae type B and N. meningitis contact prophylaxis TB, MAI and other mycobacteria Combination therapy Serious staphylococcal infection Brucella infections Bartonella infection Coxiella infection Medical Letter, Inc. June 2010
Recommendations for Top 6 Infections 1. Skin and soft tissue Uncomplicated: MRSA, MSSA, Group A Streptococcus Recommendation: MRSA - Drainage alone, bactrim, doxy, clinda or linezolid Non-MRSA 1 st gen ceph, if hospitalized nafcillin or cefazolin, clinda or vanc. Complicated: Above plus Gram negative bacilli (E. coli and P. aeruginosa) Recommendation: Vanc, dapto and linezolid If polymicrobic w/out MRSA amp/sulb, pip/tazo, carbapenem (not erta) If GAS or Clostridium likely clinda plus penicillin
Recommendations for Top 6 Infections 2. Bone and Joint Acute Osteomyelitis: Common S. aureus, Group A Streptococcus Rare Salmonella, E. coli, PA Recommendation: MRSA Empiric = vanc, Confirmed = Dapto, Vanc or Lzd GC = Ceftriaxone Streptococci = Pen or Ceftriaxone Chronic Osteomyelitis: Recommendation : SURGICAL DEBRIDEMENT followed by bactrim, metronidazole, linezolid or moxifloxacin Septic arthritis: S. aureus, Group A Streptococcus, Pneumococcus, GC Prosthetic joint Coag. Neg Staph., S. aureus Recommendation: MRSA Empiric = vanc, Confirmed = Dapto, Vanc or Lzd GC = Ceftriaxone Streptococci = Pen or Ceftriaxone
Recommendations for Top 6 Infections 3. Meningitis Adults and Children: Common Pneumococcus and N. meningitidis Rare HIB Recommendation: Ceftriaxone and vancomycin for resistant pneumococcu Neonates and Elderly: Group B Streptococcus, Listeria, Enterobacteriaceae Recommendation : Ampcillin plus ceftriaxone +/- gentamicin
Recommendations for Top 6 Infections 4. Upper Respiratory Tract Acute Sinusitis: Common Pneumococcus, H. influenzae, M. catarrhalis Recommendation: amoxicillin or amox/clav, cefuroxime, cefpodoxime or levofloxacin. Doxy or Bactrim for pen-allergic Exacerbations of sinusitis: Same as above plus Pseudomonas in COPD Recommendation : Same as above plus cipro or ceftazidime for Pseudomonas Pharyngitis: Group A Streptococci Recommendation : Penicillin, amoxicillin or macrolide
Recommendations for Top 6 Infections 5. Pneumonia CAP: Common Pneumococcus, S. aureus, H. influenzaeatypicals (Mycoplasma, Chlamydophila, Legionella) Recommendation: AMBULATORY: Azithromycin or Doxycycline or Fluoroquinolone HOSPITALIZED: Ceftriaxone plus macrolide or fluoroquinolone IF SEVERE MRSA: Vanc, bactrim, linezolid Hospital Acquired or VAP: GNR s (Enterics, P. aeruginosa, Acinetobacter), S. aureus Recommendation : If no risk factors for MDR = ceftriaxone, levo or moxi, pip/tazo If risk for MDR = pip/tazo, cefepime, carbapenem (not erta), vancomycin, linezolid, colistin or tigecycline (when options limited)
Recommendations for Top 6 Infections 6. UTI Uncomplicated: Common E. coli, S. saprophyticus, other GNRs and enterococci Recommendation: Fluoroquinolones, bactrim, nitrofurantoin, amoxicillin or cephalosporin Complicated: Resistant GNR s, S. aureus, enterococci Recommendation : OUTPATIENT - fluoroquinolone, amox/clav, oral 3 rd gen ceph (cefpodoxime, cefdinir, ceftibuten) INPATIENT 3 rd gen ceph, fluoroquinolone, pip/tazo, carbapenem (not erta)
Things you should know about susceptibility testing. Brief (re)-introduction to primary classes of antibiotics Things to know and not test Intrinsic resistance patterns Don t go there Drug/site penetration discussion What doesn t belong?
When a doctor calls and asks
Will you release this drug?
When a doctor calls and asks YOU DOCTOR
Things to know and not test Organism Salmonella spp. Shigella spp. MRSA Enterococcus spp. Agents that Must not be reported as susceptible 1 st and 2 nd generation cephalosporins, cephamycins and aminoglycosides 1 st and 2 nd generation cephalosporins, cephamycins and aminoglycosides Penicillins, beta-lactam/beta-lactamase inhibitor combinations, cephalosporins** and carbapenems Aminoglycosides (except high concentrations), cephalosporins, clindamycin and trim/sulfa Location in CLSI M100-S21 Table 2A, Page 42 Table 2A, Page 42 Table 2C, Page 68 Table 2D, Page 84 ** Newer fifth generation cephalosporins (ceftobiprole and ceftaroline) have activity against MRSA WARNING: These antimicrobial agent/organism combinations may appear active in vitro but are not effective clinically and should be reported as susceptible
Other interesting intrinsic resistance characteristics Vancomycin Resistant Gram positives Enterococcus faecium Not intrinsically resistant but high percentage are VRE. Erysipelothrix Leuconostoc Pediococcus Lactobacillus Vancomycin Susceptible Gram negatives Chryseobacterium Sphingomonas Elizabethkingia
Other important intrinsic resistance characteristics GRAM NEGATIVES Stenotrophomonas maltophilia (metallo beta-lactamase) All beta-lactam antibiotics (except aztreonam) Klebsiella pneumoniae (class A betalactamase) Ampicillin Proteus mirabilis Nitrofurantoin Proteus vulgaris, Proteus penneri and Morganella Piperacillin, ampicillin cefoperazone (3 rd ), cefuroxime (2 nd ), cefazolin (1 st ) Pseudomonas aeruginosa Bactrim Burkholderia cepacia, Pandorea, Ralstonia pickettii, GC, Neisseria meningitidis, Moraxella catarrhalis, Brucella, Proteus, Providencia and Serratia Colistin Aeromonas Ampicillin Achromobacter spp. Aminoglycosides
Drug-Site Contraindications: Should not be routinely reported for bacteria isolated from these sites Oral agents CSF 1 st and 2 nd generation cephalosporins (except cefuroxime) Cephamycins Clindamycin Macrolides Tetracyclines Fluoroquinolones Respiratory Daptomycin Urine Macrolides
Good resources Medical letter - http://www.medicalletter.org/downloads/t94-1.pdf Sanford Guide CLSI document- M100 - Appendix Manual of Clinical Microbiology Antimicrobial Susceptibilities sections Clinical Microbiology Practices Handbook Section 5 procedure 5.16 http://labtestsonline.org
Glossary I and II Class, subclass, generic name Abbreviations / PO, IM, IV
Part 1 Part 2 CLSI M100-21 Page Glossary of Antimicrobial Agents
Questions?
Let s review: Salmonella from blood culture Drug Ampicillin Cefazolin Cefoxitin Cefotaxime Ciprofloxacin Gentamicin Interpretation Susceptible Susceptible Susceptible Susceptible Susceptible Susceptible What is wrong with this report? Cefazolin Cefoxitin Gentamicin
Let s review: MRSA from blood culture Drug Penicillin Cefazolin Oxacillin Meropenem Vancomycin Clindamycin Bactrim Interpretation Resistant Resistant Resistant Susceptible Susceptible Susceptible Susceptible What is wrong with this report? Meropenem
Let s review: Listeria monocytogenes from CSF Drug Ampicillin Gentamicin Cefotaxime Doxycline Clindamycin Interpretation Susceptible Susceptible Susceptible Susceptible Susceptible What is wrong with this report? Cefotaxime Doxycycline Clindamycin
Let s review: Enterococcus faecium from CSF Drug Ampicillin Gentamicin (High Level) Cefotaxime Bactrim Clindamycin Vancomycin Interpretation Resistant Susceptible Susceptible Susceptible Susceptible Resistat What is wrong with this report? Cefotaxime Clindamycin Bactrim
Let s review: ESBL producing Klebsiella pneumoniae from Urine Drug Ampicillin Cefazolin Cefalothin Gentamicin Cefotaxime Tigecycline Ciprofloxacin Cefepime Meropenem Clindamycin Interpretation Resistant Resistant Resistant Resistant Resistant Susceptible Resistant Resistant Resistant Susceptible What is wrong with this report? Meropenem Clindamycin