Betalactams

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Betalactams

  1. 1. β-Lactam Antibiotics dr shabeel pn www.hi-dentfinishingschool.blogspot.com
  2. 2. Objectives <ul><li>Review basic pharmacology of β-lactam antibiotics </li></ul><ul><li>Discuss the four main classes of β-lactam antibiotics </li></ul><ul><li>Organize agents according to various criteria </li></ul><ul><li>Address indications and side effects </li></ul><ul><li>Provide helpful mnemonics </li></ul>
  3. 3. Bacterial Cell Walls <ul><li>Bacterial cell walls (especially Gram {+}) contain a peptidoglycan layer made up of repeating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units </li></ul><ul><li>Each NAM is linked to an 5-peptide chain: L -ala— D -glu— L -lys— D -ala— D -ala </li></ul><ul><li>Penicillin binding proteins (PBP) crosslink the peptidoglycan strands </li></ul>
  4. 4. Mechanism Of β-Lactams <ul><li>Spatial arrangement of the β-lactam ring system closely resembles the conformation of the D -ala— D -ala segment of the peptidoglycan strand </li></ul><ul><li>PBPs recognize the β-lactam as the natural substrate </li></ul><ul><li>The β-lactam ring “pops open,” thereby destroying the PBP and halting further crosslinking  cell wall weakens  lysis </li></ul><ul><li>Time-dependent killing </li></ul>
  5. 5. Bacterial Defenses <ul><li>β-lactamases </li></ul><ul><ul><li>Proteins that catalyze hydrolysis of the β-lactam ring  inactivation </li></ul></ul><ul><li>Decreased affinity of PBPs </li></ul><ul><li>Reduced penetrance to the site of action </li></ul>
  6. 6. β-Lactam Subtypes <ul><li>Penicillins </li></ul><ul><li>Cephalosporins </li></ul><ul><li>Monobactams </li></ul><ul><li>Carbapenems </li></ul>
  7. 7. β-Lactam Hypersentivity <ul><li>Immediate reactions (<72 hours after initiation) can be IgE-mediated </li></ul><ul><ul><li>IgE mediated reactions thought to be caused by the β-lactam ring </li></ul></ul><ul><li>Delayed reactions (>3 days) in patients with first exposure are not IgE- mediated </li></ul>
  8. 8. Cross Sensitivity <ul><li>Cephalosporins share the β-lactam structure of penicillin; this is the proposed mechanism for cross-sensitivity </li></ul><ul><li>A rash (type IV sensitivity) from penicillin does not guarantee a reaction to cephalosporins (<10% cross-reactivty) </li></ul>Penicillin Cephalosporin
  9. 9. Penicillamine <ul><li>Penicillamine (Cuprimine ® ) </li></ul><ul><ul><li>Chelates copper in Wilson’s disease </li></ul></ul><ul><ul><li>Decreases IgM Rheumatoid Factor </li></ul></ul><ul><ul><li>Decreases excretion of cystine in cystinuria </li></ul></ul><ul><li>Shares a common non β-lactam component structure with penicillin, the cause of cross-sensitivity </li></ul>Penicillin Penicillamine
  10. 10. β-Lactam Side Effects <ul><li>Seizures </li></ul><ul><ul><li>Especially the carbapenems </li></ul></ul><ul><li>Gastrointestinal </li></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><ul><li>Pseudomembranous collitis </li></ul></ul><ul><ul><ul><li>Caused by overgrowth of C. Difficile </li></ul></ul></ul><ul><li>Positive direct Coomb’s Test </li></ul>
  11. 11. Penicillin Classifications <ul><li>Narrow-spectrum penicillins </li></ul><ul><li>Penicillinase-resistant penicillins </li></ul><ul><li>Extended-spectrum penicillins </li></ul>
  12. 12. Narrow-Spectrum Agents <ul><li>Natural penicillin comes as two variants </li></ul><ul><ul><li>Penicillin G (Pfzierpen ® ) </li></ul></ul><ul><ul><ul><li>A.K.A. benzylpenicillin </li></ul></ul></ul><ul><ul><li>Penicillin V (Pen-Vee K ® , Veetids ® ) </li></ul></ul><ul><ul><ul><li>A.K.A. phenoxymethyl penicillin </li></ul></ul></ul><ul><li>Short half-lives </li></ul><ul><li>As K + or Na + salts; follow in renal patients </li></ul><ul><ul><li>1.7 mEq K + per 1 million units </li></ul></ul><ul><ul><li>2 mEq Na + per 1 million units </li></ul></ul>
  13. 13. Penicillin G Versus V <ul><li>Penicillin G (IV, PO, IM) </li></ul><ul><ul><li>Destroyed extremely rapidly by gastric acid </li></ul></ul><ul><ul><li>More active against Neiserra and anaerobes </li></ul></ul><ul><li>Penicillin V (PO) </li></ul><ul><li>Keep it straight: V is not IV </li></ul><ul><li>In a severe infection, this is one of the few times you would not want to give an oral medication over IV </li></ul><ul><ul><li>Due to erratic absorption of penicillin V </li></ul></ul>
  14. 14. Narrow-Spectrum Coverage <ul><li>Good activity against Gram {+} cocci (except penicillinase-producing staph) </li></ul><ul><li>Anaerobic activity (except Bacteroides ) </li></ul><ul><li>Drug of choice for syphilis, gas gangrene, and meningococcus </li></ul><ul><li>No activity against aerobic Gram {-} </li></ul>
  15. 15. Prolonging Penicillin G <ul><li>Benzathine salt (Bicillin LA ® ) </li></ul><ul><ul><li>Average duration is 26 days </li></ul></ul><ul><ul><li>Benzathine adds anesthetic aspect as well </li></ul></ul><ul><li>Procaine salt (Wycillin ® ) </li></ul><ul><ul><li>Average duration 24 hours </li></ul></ul><ul><ul><li>Potential for procaine allergy </li></ul></ul><ul><ul><li>Large doses can cause procaine toxicity </li></ul></ul><ul><li>Benzathine/procaine salt (Bicillin CR ® ) </li></ul><ul><ul><li>Contains both salts for early and late peaks </li></ul></ul><ul><ul><li>Usually used for syphilis </li></ul></ul>
  16. 16. Prolonging Penicillin V <ul><li>Probenecid (Benemid ® ) </li></ul><ul><ul><li>Competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule; used for gout, especially under excretors </li></ul></ul><ul><ul><li>At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids, including β-lactams </li></ul></ul><ul><ul><li>Not typically used anymore for penicillins </li></ul></ul>
  17. 17. Penicillinase-Resistant Agents <ul><li>Cloxacillin (Cloxapen ® ) </li></ul><ul><li>Dicloxacillin (Dynapen ® ) </li></ul><ul><li>Methacillin (Staphcillin ® ) </li></ul><ul><ul><li>Discontinued in US </li></ul></ul><ul><li>Nafcillin (Nafcil ® ) </li></ul><ul><li>Oxacillin (Prostaphlin ® ) </li></ul>
  18. 18. Penicillinase-Resistant PCNs <ul><li>Originally designed solely for coverage against S. aureus (methicillin-susceptable S. aureus [MSSA]) </li></ul><ul><li>Decreased activity against other bugs </li></ul><ul><li>S. aureus becoming increasingly resistant to this class (MRSA), as well as Staphylococcus epidermidis </li></ul><ul><ul><li>Vancomycin treatment of choice for MRSA </li></ul></ul><ul><li>Eliminated hepatically </li></ul>
  19. 19. Extended-spectrum PCNs <ul><li>Aminopenicillins </li></ul><ul><li>Carboxypenicillins </li></ul><ul><li>Ureidopenicillins </li></ul>
  20. 20. Aminopenicillins <ul><li>Agents </li></ul><ul><ul><li>Ampicillin (Omnipen ® , Principen ® ) </li></ul></ul><ul><ul><li>Amoxicillin (Amoxil ® , Trimox ® ) </li></ul></ul><ul><ul><li>Bacampicillin (Spectrobid ® ) </li></ul></ul><ul><li>Broader spectrum over penicillin </li></ul><ul><ul><li>Gram {-} aerobes </li></ul></ul><ul><ul><li>Listeria monocytogenes </li></ul></ul><ul><ul><li>Proteus mirabilis </li></ul></ul><ul><ul><li>E. coli </li></ul></ul>
  21. 21. Carboxypenicillins <ul><li>Agents </li></ul><ul><ul><li>Carbenicillin (Geopen®) </li></ul></ul><ul><ul><li>Ticarcillin (Ticar®) </li></ul></ul><ul><li>More coverage than the aminopenicillins </li></ul><ul><ul><li>Increased Gram {-} coverage </li></ul></ul><ul><ul><li>Peudeomonas aeruginosa </li></ul></ul><ul><ul><ul><li>Ticarcillin 2-4× > Carbenicillin </li></ul></ul></ul><ul><ul><li>Enterobacter </li></ul></ul><ul><li>Carbenicillin concentrates rapidly in urine </li></ul>
  22. 22. Ureidopenicillins <ul><li>Agents </li></ul><ul><ul><li>Azlocillin (Azlin ® ) </li></ul></ul><ul><ul><ul><li>Discontinued in the US </li></ul></ul></ul><ul><ul><li>Mezlocillin (Mezlin ® ) </li></ul></ul><ul><ul><li>Pipercillin (Pipracil ® ) </li></ul></ul><ul><li>Activity </li></ul><ul><ul><li>Maintains Gram {+} coverage </li></ul></ul><ul><ul><li>Added Gram {-} </li></ul></ul><ul><ul><li>Anti-pseudomonal activity </li></ul></ul>
  23. 23. β-Lactamase Inhibitors <ul><li>Irreversibly inactivate β-lactamase </li></ul><ul><li>Given in combination with β-lactamase susceptible penicillins; this allows the penicillins to do their job without being destroyed </li></ul><ul><li>Have no innate antibacterial activity themselves </li></ul>
  24. 24. Combination Drugs <ul><li>Sulbactam </li></ul><ul><ul><li>With ampicillin (Unasyn ® ) </li></ul></ul><ul><li>Tazobactam </li></ul><ul><ul><li>With pipercillin (Zosyn ® ) </li></ul></ul><ul><li>Clavulanate/Clavulanic acid </li></ul><ul><ul><li>With amoxicillin (Augmentin ® ) </li></ul></ul><ul><ul><li>With ticarcillin (Timentin ® ) </li></ul></ul>
  25. 25. Cephalosporins Classifications <ul><li>Spectra of activity (generation) </li></ul><ul><li>Carbacephem structure </li></ul><ul><li>Anaerobic activity (Cephamycin structure) </li></ul><ul><li>Anti-pseudomonal activity </li></ul><ul><li>Methyltetrazolethiomethyl side-chain </li></ul><ul><li>Metabolism/elimination </li></ul><ul><li>Cerebrospinal fluid penetrance </li></ul>
  26. 26. 1 st Generation Agents <ul><li>Cefazolin (Ancef ® , Kefzol ® ) </li></ul><ul><li>Cefadroxil (Duricef ® ) </li></ul><ul><ul><li>Cephalosporin analog of amoxicillin </li></ul></ul><ul><li>Cephalexin (Keflex ® ) </li></ul><ul><ul><li>Cephalosporin analog of ampicillin </li></ul></ul><ul><li>Cephalothin (Keflin ® ) </li></ul><ul><li>Cephapirin (Cefadyl ® ) </li></ul><ul><li>Cephradine (Anspor ® , Velosef ® ) </li></ul>
  27. 27. 1 st Generation Cephalosporins <ul><li>Great Gram {+} activity </li></ul><ul><li>No activity against enterococci or Listeria monocytogenes </li></ul><ul><li>Mainstay of choice for uncomplicated community acquired infections </li></ul><ul><li>PEcK activity </li></ul><ul><ul><li>Proteus </li></ul></ul><ul><ul><li>E. coli </li></ul></ul><ul><ul><li>Klebsiella </li></ul></ul>
  28. 28. 2 nd Generation Agents <ul><li>Cefaclor (Ceclor ® ) </li></ul><ul><li>Cefamandole (Mandol ® ) </li></ul><ul><li>Cefmetazole (Zefazone ® ) </li></ul><ul><li>Cefoxitin (Mefoxin ® ) </li></ul><ul><li>Cefotetan (Cefotan ® ) </li></ul><ul><li>Cefonicid (Monocid ® ) </li></ul><ul><li>Cefprozil (Cefzil ® ) </li></ul><ul><li>Cefuroxime (Ceftin ® , Zinacef ® , Kefurox ® ) </li></ul>
  29. 29. 2 nd Generation Cephalosporins <ul><li>More Gram {-} activity than 1 st generation agents </li></ul><ul><li>Often used for UTIs and URIs </li></ul><ul><li>HENPEcK activity </li></ul><ul><ul><li>H. influenzae </li></ul></ul><ul><ul><li>Enterobacter * (rapid resistance occurs) </li></ul></ul><ul><ul><li>Neisseria </li></ul></ul><ul><ul><li>Proteus </li></ul></ul><ul><ul><li>E. coli </li></ul></ul><ul><ul><li>Klebsiella </li></ul></ul>
  30. 30. 3 rd Generation Agents <ul><li>Cefdinir (Omnicef ® ) </li></ul><ul><li>Cefditoren (Spectracef ® ) </li></ul><ul><li>Cefixime (Suprax ® ) </li></ul><ul><li>Cefoperazone (Cefobid ® ) </li></ul><ul><li>Cefotaxime (Claforan ® ) </li></ul><ul><li>Cefpodoxime (Vantin ® ) </li></ul><ul><li>Ceftazidime (Fortaz ® , Tazidime ® ) </li></ul><ul><li>Ceftibuten (Cedax ® ) </li></ul><ul><li>Ceftizoxime (Cefizox ® ) </li></ul><ul><li>Ceftriaxone (Rocephin ® ) </li></ul>
  31. 31. 3 rd Generation Cephalosporins <ul><li>Have even better Gram {-} coverage than second generation agents </li></ul><ul><li>Loses more Gram {+} coverage </li></ul><ul><li>Extra coverage against Serratia and Moraxella catarrhalis </li></ul>
  32. 32. 4 th Generation Agents <ul><li>Cefepime (Maxipime ® ) </li></ul>
  33. 33. 4 th Generation Cephalosporins <ul><li>Has most of the Gram {-} coverage with Gram {+} coverage </li></ul><ul><li>Anti-pseudomonal activity </li></ul><ul><li>No anaerobic activity </li></ul>
  34. 34. The Generation Progression <ul><li>As one moves up in cephalosporin generation, more Gram {-} activity is seen </li></ul><ul><li>Consequently, Gram {+} activity is decreased advancing in generation </li></ul><ul><li>4 th generation has Gram {-} activity without sacrificing Gram {+} activity </li></ul>
  35. 35. Keeping Generations Straight <ul><li>How can one keep them all straight? </li></ul><ul><li>1 st generation: </li></ul><ul><ul><li>If the “f” sound is spelled “ph”, it HAS to be a 1 st generation ( ph irst) </li></ul></ul><ul><li>3 rd generation: </li></ul><ul><ul><li>If an “f” is followed immediately by a “d” or “t”, it HAS to be a 3 rd generation ( t hir d ) </li></ul></ul><ul><li>4 th generation: </li></ul><ul><ul><li>“ Cefepime is supreme!” </li></ul></ul>
  36. 36. Carbacephems <ul><li>Carbacephems substitute a carbon in place of sulfur </li></ul><ul><li>Otherwise has same activity as a cephalosporin </li></ul><ul><li>Loracarbef (Lorabid ® ), the only clinically used carbacephem, is typically classified as a 2 nd generation cephalosporin (due to its activity) </li></ul>
  37. 37. Cephamycins <ul><li>Cephamycins are a special subset of 2 nd generation cephalosporins with excellent anaerobic activity </li></ul><ul><ul><li>Cefotetan </li></ul></ul><ul><ul><li>Cefoxitin </li></ul></ul><ul><li>Mnemonic: Get a foxy tan on your back ! </li></ul><ul><ul><li>Back is for bacteroides , a common anaeobic bacteria </li></ul></ul>
  38. 38. Anti-Pseudomonal Cephalosporins <ul><li>3 rd Generation </li></ul><ul><ul><li>Cefoperazone </li></ul></ul><ul><ul><li>Ceftazidime </li></ul></ul><ul><li>4 th Generation </li></ul><ul><ul><li>Cefepime </li></ul></ul><ul><li>The 3 rd generation anti-pseduomonal agents lose even more Gram {+} activity than other 3 rd generation agents </li></ul>
  39. 39. MTT Side-Chain <ul><li>Methyltetrazolethiomethyl (MTT) </li></ul><ul><ul><li>Hypoprothrombinemia and bleeding by disturbing synthesis of vitamin K-dependent clotting factors </li></ul></ul><ul><ul><ul><li>Risk factors are renal or hepatic disease, poor nutrition, the elderly, and cancer </li></ul></ul></ul><ul><ul><li>Disulfiram-like reaction </li></ul></ul><ul><ul><ul><li>Disulfiram is an agent that inhibits alcohol dehydrogenase, causing an increase of acetaldehyde, the agent that causes hangovers </li></ul></ul></ul>
  40. 40. MTT-Containing Cephalosporins <ul><li>Agents </li></ul><ul><ul><li>Cefamandole </li></ul></ul><ul><ul><li>Cefmetazole </li></ul></ul><ul><ul><li>Cefoperazone </li></ul></ul><ul><ul><li>Cefotetan </li></ul></ul><ul><li>Mnemonic: I met a man with a per fect tan </li></ul>
  41. 41. Cephalosporin Elimination <ul><li>For the most part, all are renal with few exceptions </li></ul><ul><li>The “zones” are hepatic </li></ul><ul><ul><li>Cefoperazone </li></ul></ul><ul><ul><li>Ceftriaxone </li></ul></ul>
  42. 42. CSF penetrance <ul><li>2 nd Generation </li></ul><ul><ul><li>Cefuroxime </li></ul></ul><ul><ul><ul><li>Generally not used due to decreased efficacy </li></ul></ul></ul><ul><li>3 rd Generation </li></ul><ul><ul><li>Cefotaxime </li></ul></ul><ul><ul><ul><li>Q6-8° dosing </li></ul></ul></ul><ul><ul><ul><li>Agent of choice in neonatal meningitis (along with ampicillin) </li></ul></ul></ul><ul><ul><li>Ceftriaxone </li></ul></ul><ul><ul><ul><li>Q12-24° dosing </li></ul></ul></ul><ul><ul><ul><li>Agent of choice for adult meningitis </li></ul></ul></ul><ul><ul><ul><li>Causes kernicterus in neonates </li></ul></ul></ul>
  43. 43. Monobactams <ul><li>Aztreonam (Azactam ® ) </li></ul><ul><li>Resistant to most Gram {-} β-lactamases </li></ul><ul><li>Activity </li></ul><ul><ul><li>Only Gram {-} coverage (spectrum resembles aminoglycosides) </li></ul></ul><ul><ul><li>Excellent activity against P. aeruginosa </li></ul></ul><ul><ul><li>Superb Enterobacteriaceae activity </li></ul></ul><ul><ul><li>No Gram {+} or anaerobic activity </li></ul></ul>
  44. 44. Carbapenems <ul><li>More resistant to hydrolysis from β-lactamases </li></ul><ul><li>Very broad spectrum with coverage of Gram {+} (not MRSA), Gram {-}, anaerobes, and Pseudomonas aeruginosa </li></ul><ul><li>Higher incidence of seizure than other β-lactam agents </li></ul>
  45. 45. Carbapenem Agents <ul><li>Agents </li></ul><ul><ul><li>Ertapenem (Invanz®) </li></ul></ul><ul><ul><li>Imipenem (Primaxin®) </li></ul></ul><ul><ul><li>Meropenem (Merrem®) </li></ul></ul><ul><li>Ertapenem lacks coverage against Pseudomonas acinetobacter , two common nosocomial agents </li></ul>
  46. 46. Cilistatin <ul><li>Inhibits renal dehydropeptidase 1, an enzyme which degrades imipenem in the kidney brush border cells </li></ul><ul><li>Given only with imipenem (Primaxin ® ) </li></ul><ul><li>Has neither β-lactamase inhibitory effects nor antibacterial activity </li></ul><ul><li>Totally unrelated from the “statin” cholesterol drugs (HMG-CoA Inhibitors) </li></ul>
  47. 47. Conclusion <ul><li>β-lactam antibiotics can treat a wide variety of bacterial infections </li></ul><ul><li>Choosing an agent must be done with care as each specific drug has its own strengths and weaknesses </li></ul><ul><li>However, members of each class share similar characteristics that would allow for a fairly equivalent substitution </li></ul>
  48. 48. References <ul><li>Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9 th & 10 th Ed. </li></ul><ul><li>http://www.aafp.org/afp/20000801/611.html </li></ul><ul><li>Mayo Clin Proc 1999:74;187-195 </li></ul><ul><li>Mayo Clin Proc 1999:74;290-307 </li></ul>

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