1. 1 β-Lactam Antibiotics Nathan P. Samsa, Pharm.D., R.Ph., OMSII November 17, 2004

2. 2 Objectives Review basic pharmacology of β-lactam antibiotics Discuss the four main classes of β- lactam antibiotics Organize agents according to various criteria Address indications and side effects Provide helpful mnemonics

3. 3 Bacterial Cell Walls Bacterial cell walls (especially Gram {+}) contain a peptidoglycan layer made up of repeating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units Each NAM is linked to an 5-peptide chain: L -ala— D -glu— L -lys— D -ala— D -ala Penicillin binding proteins (PBP) crosslink the peptidoglycan strands

4. 4 Mechanism Of β-Lactams Spatial arrangement of the β-lactam ring system closely resembles the conformation of the D -ala— D -ala segment of the peptidoglycan strand PBPs recognize the β-lactam as the natural substrate The β-lactam ring “pops open,” thereby destroying the PBP and halting further crosslinking  cell wall weakens  lysis Time-dependent killing

5. 5 Bacterial Defenses β-lactamases –Proteins that catalyze hydrolysis of the β- lactam ring  inactivation Decreased affinity of PBPs Reduced penetrance to the site of action

6. 6 β-Lactam Subtypes Penicillins Cephalosporins Monobactams Carbapenems

7. 7 β-Lactam Hypersentivity Immediate reactions (<72 hours after initiation) can be IgE-mediated –IgE mediated reactions thought to be caused by the β-lactam ring Delayed reactions (>3 days) in patients with first exposure are not IgE- mediated

8. 8 Cross Sensitivity Cephalosporins share the β-lactam structure of penicillin; this is the proposed mechanism for cross-sensitivity A rash (type IV sensitivity) from penicillin does not guarantee a reaction to cephalosporins (<10% cross-reactivty) PenicillinCephalosporin

9. 9 Penicillamine Penicillamine (Cuprimine ® ) –Chelates copper in Wilson’s disease –Decreases IgM Rheumatoid Factor –Decreases excretion of cystine in cystinuria Shares a common non β-lactam component structure with penicillin, the cause of cross-sensitivity PenicillinPenicillamine

10. 10 β-Lactam Side Effects Seizures –Especially the carbapenems Gastrointestinal –Diarrhea –Pseudomembranous collitis Caused by overgrowth of C. Difficile Positive direct Coomb’s Test

11. 11 Penicillin Classifications Narrow-spectrum penicillins Penicillinase-resistant penicillins Extended-spectrum penicillins

12. 12 Narrow-Spectrum Agents Natural penicillin comes as two variants –Penicillin G (Pfzierpen ® ) A.K.A. benzylpenicillin –Penicillin V (Pen-Vee K ®, Veetids ® ) A.K.A. phenoxymethyl penicillin Short half-lives As K + or Na + salts; follow in renal patients –1.7 mEq K + per 1 million units –2 mEq Na + per 1 million units

13. 13 Penicillin G Versus V Penicillin G (IV, PO, IM) –Destroyed extremely rapidly by gastric acid –More active against Neiserra and anaerobes Penicillin V (PO) Keep it straight: V is not IV In a severe infection, this is one of the few times you would not want to give an oral medication over IV –Due to erratic absorption of penicillin V

14. 14 Narrow-Spectrum Coverage Good activity against Gram {+} cocci (except penicillinase-producing staph) Anaerobic activity (except Bacteroides) Drug of choice for syphilis, gas gangrene, and meningococcus No activity against aerobic Gram {-}

15. 15 Prolonging Penicillin G Benzathine salt (Bicillin LA ® ) –Average duration is 26 days –Benzathine adds anesthetic aspect as well Procaine salt (Wycillin ® ) –Average duration 24 hours –Potential for procaine allergy –Large doses can cause procaine toxicity Benzathine/procaine salt (Bicillin CR ® ) –Contains both salts for early and late peaks –Usually used for syphilis

16. 16 Prolonging Penicillin V Probenecid (Benemid ® ) –Competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule; used for gout, especially under excretors –At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids, including β-lactams –Not typically used anymore for penicillins

17. 17 Penicillinase-Resistant Agents Cloxacillin (Cloxapen ® ) Dicloxacillin (Dynapen ® ) Methacillin (Staphcillin ® ) –Discontinued in US Nafcillin (Nafcil ® ) Oxacillin (Prostaphlin ® )

18. 18 Penicillinase-Resistant PCNs Originally designed solely for coverage against S. aureus (methicillin-susceptable S. aureus [MSSA]) Decreased activity against other bugs S. aureus becoming increasingly resistant to this class (MRSA), as well as Staphylococcus epidermidis –Vancomycin treatment of choice for MRSA Eliminated hepatically

19. 19 Extended-spectrum PCNs Aminopenicillins Carboxypenicillins Ureidopenicillins

20. 20 Aminopenicillins Agents –Ampicillin (Omnipen ®, Principen ® ) –Amoxicillin (Amoxil ®, Trimox ® ) –Bacampicillin (Spectrobid ® ) Broader spectrum over penicillin –Gram {-} aerobes –Listeria monocytogenes –Proteus mirabilis –E. coli

21. 21 Carboxypenicillins Agents –Carbenicillin (Geopen®) –Ticarcillin (Ticar®) More coverage than the aminopenicillins –Increased Gram {-} coverage –Peudeomonas aeruginosa Ticarcillin 2-4× > Carbenicillin –Enterobacter Carbenicillin concentrates rapidly in urine

22. 22 Ureidopenicillins Agents –Azlocillin (Azlin ® ) Discontinued in the US –Mezlocillin (Mezlin ® ) –Pipercillin (Pipracil ® ) Activity –Maintains Gram {+} coverage –Added Gram {-} –Anti-pseudomonal activity

23. 23 β-Lactamase Inhibitors Irreversibly inactivate β-lactamase Given in combination with β-lactamase susceptible penicillins; this allows the penicillins to do their job without being destroyed Have no innate antibacterial activity themselves

24. 24 Combination Drugs Sulbactam –With ampicillin (Unasyn ® ) Tazobactam –With pipercillin (Zosyn ® ) Clavulanate/Clavulanic acid –With amoxicillin (Augmentin ® ) –With ticarcillin (Timentin ® )

25. 25 Cephalosporins Classifications Spectra of activity (generation) Carbacephem structure Anaerobic activity (Cephamycin structure) Anti-pseudomonal activity Methyltetrazolethiomethyl side-chain Metabolism/elimination Cerebrospinal fluid penetrance

26. 26 1 st Generation Agents Cefazolin (Ancef ®, Kefzol ® ) Cefadroxil (Duricef ® ) –Cephalosporin analog of amoxicillin Cephalexin (Keflex ® ) –Cephalosporin analog of ampicillin Cephalothin (Keflin ® ) Cephapirin (Cefadyl ® ) Cephradine (Anspor ®, Velosef ® )

27. 27 1 st Generation Cephalosporins Great Gram {+} activity No activity against enterococci or Listeria monocytogenes Mainstay of choice for uncomplicated community acquired infections PEcK activity –Proteus –E. coli –Klebsiella

28. 28 2 nd Generation Agents Cefaclor (Ceclor ® ) Cefamandole (Mandol ® ) Cefmetazole (Zefazone ® ) Cefoxitin (Mefoxin ® ) Cefotetan (Cefotan ® ) Cefonicid (Monocid ® ) Cefprozil (Cefzil ® ) Cefuroxime (Ceftin ®, Zinacef ®, Kefurox ® )

29. 29 2 nd Generation Cephalosporins More Gram {-} activity than 1 st generation agents Often used for UTIs and URIs HENPEcK activity –H. influenzae –Enterobacter * (rapid resistance occurs) –Neisseria –Proteus –E. coli –Klebsiella

30. 30 3 rd Generation Agents Cefdinir (Omnicef ® ) Cefditoren (Spectracef ® ) Cefixime (Suprax ® ) Cefoperazone (Cefobid ® ) Cefotaxime (Claforan ® ) Cefpodoxime (Vantin ® ) Ceftazidime (Fortaz ®, Tazidime ® ) Ceftibuten (Cedax ® ) Ceftizoxime (Cefizox ® ) Ceftriaxone (Rocephin ® )

31. 31 3 rd Generation Cephalosporins Have even better Gram {-} coverage than second generation agents Loses more Gram {+} coverage Extra coverage against Serratia and Moraxella catarrhalis

32. 32 4 th Generation Agents Cefepime (Maxipime ® )

33. 33 4 th Generation Cephalosporins Has most of the Gram {-} coverage with Gram {+} coverage Anti-pseudomonal activity No anaerobic activity

34. 34 The Generation Progression As one moves up in cephalosporin generation, more Gram {-} activity is seen Consequently, Gram {+} activity is decreased advancing in generation 4 th generation has Gram {-} activity without sacrificing Gram {+} activity

35. 35 Keeping Generations Straight How can one keep them all straight? 1 st generation: –If the “f” sound is spelled “ph”, it HAS to be a 1 st generation (phirst) 3 rd generation: –If an “f” is followed immediately by a “d” or “t”, it HAS to be a 3 rd generation (third) 4 th generation: –“Cefepime is supreme!”

36. 36 Carbacephems Carbacephems substitute a carbon in place of sulfur Otherwise has same activity as a cephalosporin Loracarbef (Lorabid ® ), the only clinically used carbacephem, is typically classified as a 2 nd generation cephalosporin (due to its activity)

37. 37 Cephamycins Cephamycins are a special subset of 2 nd generation cephalosporins with excellent anaerobic activity –Cefotetan –Cefoxitin Mnemonic: Get a foxy tan on your back! –Back is for bacteroides, a common anaeobic bacteria

38. 38 Anti-Pseudomonal Cephalosporins 3 rd Generation –Cefoperazone –Ceftazidime 4 th Generation –Cefepime The 3 rd generation anti-pseduomonal agents lose even more Gram {+} activity than other 3 rd generation agents

39. 39 MTT Side-Chain Methyltetrazolethiomethyl (MTT) –Hypoprothrombinemia and bleeding by disturbing synthesis of vitamin K- dependent clotting factors Risk factors are renal or hepatic disease, poor nutrition, the elderly, and cancer –Disulfiram-like reaction Disulfiram is an agent that inhibits alcohol dehydrogenase, causing an increase of acetaldehyde, the agent that causes hangovers

40. 40 MTT-Containing Cephalosporins Agents –Cefamandole –Cefmetazole –Cefoperazone –Cefotetan Mnemonic: I met a man with a perfect tan

41. 41 Cephalosporin Elimination For the most part, all are renal with few exceptions The “zones” are hepatic –Cefoperazone –Ceftriaxone

42. 42 CSF penetrance 2 nd Generation –Cefuroxime Generally not used due to decreased efficacy 3 rd Generation –Cefotaxime Q6-8° dosing Agent of choice in neonatal meningitis (along with ampicillin) –Ceftriaxone Q12-24° dosing Agent of choice for adult meningitis Causes kernicterus in neonates

43. 43 Monobactams Aztreonam (Azactam ® ) Resistant to most Gram {-} β-lactamases Activity –Only Gram {-} coverage (spectrum resembles aminoglycosides) –Excellent activity against P. aeruginosa –Superb Enterobacteriaceae activity –No Gram {+} or anaerobic activity

44. 44 Carbapenems More resistant to hydrolysis from β- lactamases Very broad spectrum with coverage of Gram {+} (not MRSA), Gram {-}, anaerobes, and Pseudomonas aeruginosa Higher incidence of seizure than other β-lactam agents

45. 45 Carbapenem Agents Agents –Ertapenem (Invanz®) –Imipenem (Primaxin®) –Meropenem (Merrem®) Ertapenem lacks coverage against Pseudomonas acinetobacter, two common nosocomial agents

46. 46 Cilistatin Inhibits renal dehydropeptidase 1, an enzyme which degrades imipenem in the kidney brush border cells Given only with imipenem (Primaxin ® ) Has neither β-lactamase inhibitory effects nor antibacterial activity Totally unrelated from the “statin” cholesterol drugs (HMG-CoA Inhibitors)

47. 47 Conclusion β-lactam antibiotics can treat a wide variety of bacterial infections Choosing an agent must be done with care as each specific drug has its own strengths and weaknesses However, members of each class share similar characteristics that would allow for a fairly equivalent substitution

48. 48 References Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9 th & 10 th Ed. http://www.aafp.org/afp/20000801/611.html Mayo Clin Proc 1999:74;187-195 Mayo Clin Proc 1999:74;290-307