Antibiotic Overview

1. Antibiotic Overview Nathan P. Samsa,Pharm.D., R.Ph.

2. Objectives • Briefly discuss pharmacokinetics • Review basic pharmacology of the various antibiotics • Address indications and side effects • Provide helpful mnemonics • Correlate infectious diseases with appropriate pharmacological therapy

3. “Basic” Pharmacokinetics • “ADME” • Adsorption • Distribution • Metabolism • Excretion • Pharmacokinetics: • “How the body acts on the drug” • Pharmacodynamics: • “How the drug acts on the body”

4. How Can We Inhibit Bacteria? • Bacteristatic • Inhibits a vital pathway used in the growth of the bacteria, but does not directly cause death • Bactericidal • Disrupts bacterial function so much that death will occur

5. What Manner Can We Kill? • Time-dependent • Drug concentration must remain constantly above the minimum inhibitory concentration (MIC) • β-lactams, vancomycin • Concentration-dependent • Drug concentration must reach a certain concentration, many times based on the area under the curve (AUC) • Fluoroquinolones

6. What Can We Disrupt? • Cell Wall • Folic Acid Synthesis • Nucleic Acid Synthesis • Ribosome • Cell Membrane

7. Cell Wall Inhibitors

8. Cell Wall Agents • β-Lactams • Penicillins • Cephalosporins • Monbactams • Carbapenems • Glycopeptides

9. β-Lactams • Bacterial cell walls have 5-peptide chains (L-ala—D-glu—L-lys—D-ala—D-ala) cross- linked by penicillin binding proteins (PBP) • The β-lactam ring system looks like D-ala—D-ala, where the PBPs will use the β-lactam instead • The β-lactam “pops open,” destroying the PBP and halting further crosslinkingcell wall weakenslysis

10. β-Lactam Subtypes • All share a β-lactam ring, thereby having the same mechansim of action (and explaining the cross-sensitivity between classes) • Penicillins • Cephalosporins • Monobactams • Carbapenems

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

12. Narrow-Spectrum Penicillins • Penicillin G (Pfzierpen®)-IM, IV, PO • More active against Neiserra and anaerobes • Penicillin V (Pen-Vee K®, Veetids®)-PO • Keep it straight: V is not IV • Good activity against Gram {+} cocci • Anaerobic activity (except Bacteroides) • Drug of choice for syphilis, gas gangrene, and meningococcus • No activity against aerobic Gram {-}

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

14. 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

15. Extended-spectrum PCNs • Aminopenicillins • Carboxypenicillins • Ureidopenicillins

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

17. 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

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

19. β-Lactamase Inhibitors • Chemicals with no antibacterial activity that irreversibly inactivate β-lactamase • Sulbactam • With ampicillin (Unasyn®) • Tazobactam • With pipercillin (Zosyn®) • Clavulanate/Clavulanic acid • With amoxicillin (Augmentin®) • With ticarcillin (Timentin®)

20. Cephalosporins • Spectra of activity (generation) • Anaerobic activity (Cephamycins) • Anti-pseudomonal activity • Methyltetrazolethiomethyl side-chain • Metabolism/elimination • Cerebrospinal fluid penetrance

21. 1st Generation Agents • Cefazolin (Ancef®, Kefzol®) • Cefadroxil (Duricef®) • Cephalosporin analog of amoxicillin • Cephalexin (Keflex®) • Cephalosporin analog of ampicillin • Cephalothin (Keflin®) • Cephapirin (Cefadyl®) • Cephradine (Anspor®, Velosef®)

22. 1st 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

23. 2nd Generation Agents • Cefaclor (Ceclor®) • Cefamandole (Mandol®) • Cefmetazole (Zefazone®) • Cefoxitin (Mefoxin®) • Cefotetan (Cefotan®) • Cefonicid (Monocid®) • Cefprozil (Cefzil®) • Cefuroxime (Ceftin®, Zinacef®, Kefurox®)

24. 2nd Generation Cephalosporins • More Gram {-} activity than 1st generation agents • Often used for UTIs and URIs • HENPEcK activity • H. influenzae • Enterobacter* (rapid resistance occurs) • Neisseria • Proteus • E. coli • Klebsiella

25. 3rd Generation Agents • Cefdinir (Omnicef®) • Cefditoren (Spectracef®) • Cefixime (Suprax®) • Cefoperazone (Cefobid®) • Cefotaxime (Claforan®) • Cefpodoxime (Vantin®) • Ceftazidime (Fortaz®, Tazidime®) • Ceftibuten (Cedax®) • Ceftizoxime (Cefizox®) • Ceftriaxone (Rocephin®)

26. 3rd Generation Cephalosporins • Have even better Gram {-} coverage than second generation agents • Loses more Gram {+} coverage • Extra coverage against Serratia and Moraxella catarrhalis

27. 4th Generation Cephalosporins • Cefepime (Maxipime®) • Has most of the Gram {-} coverage with Gram {+} coverage • Anti-pseudomonal activity • No anaerobic activity

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

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

30. Cephamycins • Cephamycins are a special subset of 2nd generation cephalosporins with great anaerobic activity • Cefotetan • Cefoxitin • Mnemonic: Get a foxytan on your back! • Back is for bacteroides, a common anaeobic bacteria

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

32. 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

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

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

35. CSF penetrance • 2nd Generation • Cefuroxime • Generally not used due to decreased efficacy • 3rd 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

36. 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

37. 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

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

39. 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)

40. Glycopeptides • Vancomycin (Vancocin®) • Teicoplanin (Targocid®)

41. Vancomycin • Vancomycin makes five hydrogen bonds to the D-Ala-D-Ala amino acids at the end of the peptide cross-bridges • It prevents them from being accessible to the active site of the transpeptidases (where the β-lactams work)

42. Vancomycin Spectrum • Gram {+} aerobes • MRSA • Penicillin-resistant pneumococcus

43. Vancomycin SE • Renal clearance • Ototoxicity • Nephrotoxicity • These are points of contention as they are normally seen in conjunction with aminoglycosides…is it the aminoglycoside, or additive effect? • Infusion related reactions: • “Red Man Syndrome” • Fever/chills • Phlebitis

44. VRE • Vancomycin Resistant Enterococcus • Few options left: • Quinopristin/Dalfopristin (Sinercid®) • Coverage onlyagainst Enterococcus faecium, none against Enterococcus faecalis • Tip: Faecalis has a “hard c”, so it is harder to treat • Linezolid (Zyvox®) • Covers both faecium and faeacalis

45. Folic Acid Synthesis Inhibitors

46. Folic Acid Inhibitors • “Sulfas” • Inhibit dihydropteroate synthetase, an enzyme involved in the synthesis of bacterial folic acid • Trimethoprim • Inhibit dihydrofolate reductase, an enzyme necessary for thymidine synthesis • Both are bacteriostatic

47. Folic Acid Inhibitor Spectrum • Enterobacter • Chlamydia • Nocardia • Pneumocystis carnii

48. Folic Acid Inhibitor SE • Rashes • Stevens-Johnson syndrome • Angioedema • Hemolytic anemia • Nephrotoxicity • Via precipitation of crystals of the inactive metabolite • Crosses the placenta • Kernicturus • Should be avoided in pregnancy and in children under 2 months of age

49. Nucleic Acid Synthesis Inhibitors

50. Nucleic Acid Inhibitors • Fluoroquinolones