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Antibiotics 101

Antibiotics 101. Puja Van Epps 1/20/14. Beta-lactams. Core PCN structure. Core Cephalosporin structure. Beta-lactams. Beta-lactamases are enzymes produced by some bacteria that provide resistance against beta lactams through hydrolysis of the β- lactam ring. Natural Penicillins.

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Antibiotics 101

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  1. Antibiotics 101 Puja Van Epps 1/20/14

  2. Beta-lactams Core PCN structure Core Cephalosporin structure

  3. Beta-lactams • Beta-lactamases are enzymes produced by some bacteria that provide resistance against beta lactams through hydrolysis of the β-lactam ring

  4. Natural Penicillins • Bicillin L-A (Penicillin G benzathine) – IM only • Penicillin G (IV) • Penicillin V = PO

  5. Natural Penicillins- Spectra

  6. Natural Penicillins Bicillin: Primary, secondary, latent and late latent syphillis PCN G: Neurosyphillis; systemic infection due to susceptible bacteria (Streptococci) PCN V: Group A strep pharyngitis

  7. Anti-staphylococcal Penicillins • Nafcillin, oxacillin, methicillin, dicloxacillin (PO) • Penicillinase is a specific type of β-lactamase, showing specificity for Penicillins • First β-lactamase to be identified; PCN R in S. aureus • Major Uses: Methicillin-susceptible S. aureus or Coagulase Negative Staph; PCN-susceptible strains of Streptococci • No gram negative activity

  8. Aminopenicillins • Ampicillin/amoxicillin; Augmentin (Amox-Clav); Unasyn (Amp-Sulbactam) • Amp/amox – Great for susceptible streps and enterococcus; very limited GN activity; cover anaerobes • Addition of Clavulanate or Sulbactam enhances Gram negative activity • No activity against MSSA without the beta-lactamase inhibitor.

  9. Aminopenicillins • Important holes in coverage • Pseudomonas sp. • Atypical gram negatives – mycoplasma pneumoniae, chlamydia pneumoniae, legionella sp. • Enterobacter sp. • If susceptible Ampicillin is the DOC for Enterococcus and Listeria

  10. Anti-Pseudomonal Penicillins • Ticarcillin, Ticar-Clav, Piperacillin, Pip-Tazo • Generally good gram positive, gram negative and anaerobic coverage • Ticarcillin and Piperacillin without their beta-lactamase inhibitor DO NOT cover MSSA • Important holes in coverage: MRSA (ESBL+, KPC+, or other resistant GN) • Stenotrophomonas maltophilia – Ticar-Clav is second line, Pip/Tazo does not cover.

  11. Cephalosporins • 5 generations, increasing gram negative coverage with each generation

  12. First Generation Cephalosporins • Cefadroxil, Cephalexin (PO) • Cefazolin (IV)

  13. First Generation Cephalosporins • Important holes in coverage – • MRSA, Enterococcus, Pseudomonas, anerobes

  14. SecondGeneration Cephalosporins • Cefuroxime (IV, PO), Cefotetan (IV), Cefoxitin (IV) • In addition to the coverage of 1st generation -H. influenzae, M. catarrhalis, Neisseria sp., and anearobic coverage (variable) • Important holes in coverage: - MRSA, Enterococcus, Pseudomonas

  15. Third Generation Cephalosporins • Ceftriaxone, Cefotaxime, Ceftazadime (IV) • Cefixime, Cefdinir (PO) • In general less active against gram-positive aerobes than previous generations, but have greater activity against gram-negatives • Cefotaxime and Ceftriaxone have the best gram + coverage in the group • Only Ceftazadime covers Pseudomonas

  16. Third Generation Cephalosporins • Major holes in coverage – - Enterococcus, MRSA, Pseudomonas (except Ceftazidime), +/- Acinetobacter, Listeria • Ceftazidime crosses BBB, Ceftriaxone in inflamed meninges

  17. Fourth Generation Cephalosporins • Cefepime (IV) • gram-positives: similar to first generation • gram-negatives: broad, including Pseudomonas • Major holes: MRSA, poor anaerobic coverage, listeria • Crosses BBB

  18. Fifth Generation Cephalosporin • Ceftaroline (IV) • Major advantage: - MRSA Major holes in coverage: - Pseudomonas, enterococcus and anaerobes • CAP, SSTI

  19. Cephalosporin Review • Antipseudomonal – Ceftazadime and Cefepime • Anti-MRSA – Ceftaroline • Anti-Enterococcal – None (Ceftaroline has in-vitro activity against E. faecalis) • Enterobacter sp. can develop resistance to cephalosporins during treatment, therefore not the treatment of choice

  20. Carbapenems • Ertapenem, Doripenem, Imipenem, Meropenem • Broadest spectrum of activity • Have activity against gram-positive and gram-negative aerobes and anaerobes • Bacteria not covered by carbapenems include MRSA, VRE, MR coagulase-negative staph • Additional ertapenem exceptions: • Pseudomonas, Acinetobacter, Enterococcus

  21. Carbapenems • Major holes in coverage: - Atypicals (Legionella, Mycoplasma) , MRSA, VRE, Stenotrophomonasmaltophilia, KPC+ • Ertapenem does not cover: - Pseudomonas, Acinetobacter, Enterococcus

  22. Monobactam • Aztreonam: binds preferentially to PBP 3 of gram-negative aerobes • No gram positive or anaerobic activity • Major uses – Hospital acquired infections in patients with anaphylaxis to any beta lactams (does not have cross reactivity) • Important gram neg holes: Acinetobacter, ESBL+, KPC+

  23. Fluoroquinolones • Ciprofloxacin, Levofloxacin, Moxifloxacin • Broad spectrum of activity, excellent bioavailability, tissue penetration • Cipro has poor gram + coverage • Disadvantages: resistance, expense, C diff • Advantages: Atypical coverage, Antipseudomonal (Cipro, Levo)

  24. Aminoglycosides • Gentamicin, Tobramycin, Amikacin • inhibit protein synthesis by irreversibly binding to 30S ribosome, bactericidal • For gram + use in combination with cell wall agents • Broad spectrum gram neg coverage including Pseudomonas and Acinetobacter • Also have mycobacterial coverage

  25. Aminoglycosides – adverse effects • Nephrotoxicity • Nonoligouric renal failure from damage to the proximal tubules • Underlying CKD, Age, other nephrotixins, duration, high troughs • Ototoxicity • 8th cranial nerve damage - vestibular and auditory toxicity; irreversible • Related to duration of therapy (>2wks)

  26. Macrolides • Clarithromycin, Erythromycin, Azithromycin • Inhibit protein synthesis by reversibly binding to the 50s ribosomal unit

  27. Macrolides • Gram-Positive Aerobes – Clarithro>Erythro>Azithro • Gram-Negative Aerobes – Azithro>Clarithro>Erythro No activity against any Enterobacteriaceae or Pseudomonas • Anaerobes – activity against upper airway anaerobes • Atypical Bacteria – Excellent • Also cover – Mycobacterium avium complex, Campylobacter, Borrelia, Bordetella, Brucella.

  28. Anti-MRSA drugs

  29. Vancomycin • Inhibits synthesis and assembly of the second stage of peptidoglycan polymers • Gram-positive bacteria: excellent coverage • Major uses: MRSA, MSSA (in PCN all), PCN R streptococci • No activity against gram-negatives or anaerobes • If MIC to Vancomycin in MRSA is ≥ 2, Do not use

  30. Vancomycin Red-Man Syndrome • flushing, pruritus, rash • related to rate of infusion • resolves spontaneously • may lengthen infusion NOT AN ALLERGY

  31. Daptomycin • Lipopeptide; binds to components of the cell membrane and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein • Major uses - SAB, Right-sided IE caused by S. aureus, VRE • Indicated for SSTI, R sided IE Do not use for lung infections including MRSA PNA – pulmonary surfactant inhibits Daptomycin

  32. Linezolid • Binds to the 50S ribosomal subunit near the surface interface of 30S subunit – causes inhibition of 70S initiation complex which inhibits protein synthesis • Active against wide range of Gram + bacteria, limited to no Gram negative or anearobic activity • Major uses – MRSA, VRE. • Major problem thrombocytopenia with prolonged use (>2wks), bacteriostatic (cidal against Enterococcus)

  33. Tigecyline • Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis. • Broad spectrum of activity including – - MRSA, VRE, gram negatives (including resistant GN) • Major holes- The 3 P’s – Pseudomonas, Proteus and doesn’t get in the urine • Indicated for complicated SSTI, intra-abdominal infections, CAP • Major problems: GI issues, and shown to have increased mortality in serious infections – monotherapy only as a last resort.

  34. Clindamycin Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit Major uses - MRSA (some isolates), anaerobic coverage

  35. Clindamycin A positive D test indicates the presence of macrolide-inducible resistance to clindamycin produced by an inducible methylase that alters the common ribosomal binding site for macrolides, clindamycin

  36. Tetracylines • Doxycyline, Minocyline • Good gram pos, neg and anaerobic coverage • Major uses MRSA, anti-malarial prophylaxis, rickettsial infections, Borreliaburgdorferi

  37. Trimethoprim, TMX-Sulfa • Inhibit various steps within the folic acid biosynthetic pathway • Good gram pos and gram neg coverage (CA-MRSA) • Important uses: Pneumocystis, Stenotrophomonasmaltophilia, Nocardia • Major holes • Pseudomonas, anaerobes

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