1. Nathan P. Samsa, Pharm.D., R.Ph.
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 Concentration-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 Glycopeptides 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 Broader spectrum over penicillin
Ampicillin (Omnipen®, Principen®)
Amoxicillin (Amoxil®, Trimox®)
Bacampicillin (Spectrobid®)
Broader spectrum over penicillin
Gram {-} aerobes
Listeria monocytogenes
Proteus mirabilis
E. coli

17. Carboxypenicillins Agents More coverage than the aminopenicillins
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 Activity 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 foxy tan 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 3rd Generation Cefuroxime Cefotaxime
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 Infusion related reactions: 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 only against 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” Trimethoprim Both are bacteriostatic
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

51. Fluoroquinolones Inhibit DNA topoisomerase II (DNA gyrase)
Bacteriostatic
Divided into generations; reverse of the reverse of cepholosporins (actual classification varies between sources)
Cephalosporins progress from Gram {+} to Gram {-} activity, but loses Gram {+}
Fluoroquinolones progress from Gram {-} to Gram {+} activity, but retains Gram {-}

52. 1st Generation FQs Nalidixic Acid (NegGram®) Gram {-} coverage only
Enterobacteraceae
E. Coli
Klebsiella
Proteus

53. 2nd Generation FQs Agents Increased Gram {-} spectrum
Cinoxacin (Cinobac®)
Enoxacin (Penetrex®)
Pulled from market
Lomefloxacin (Maxaquin®)
Norfloxacin (Noroxin®)
Increased Gram {-} spectrum

54. Advanced 2nd Generation FQs
Agents
Ciprofloxacin (Cipro®)
Ofloxacin (Floxin®)
Has increased Gram {-} coverage along with atypicals
Cipro has good Pseudomonas coverage

55. 3rd Generation FQ Agents
Gatifloxacin (Tequin®)
Grepafloxacin (Raxar®)
Pulled from market
Levofloxacin (Levaquin®)
L-isomer of Ofloxacin
Sparfloxacin (Zagam®)
Temafloxacin (Omniflox®)
Same coverage as 2nd generation with moderate Gram {+} activity
Used in community acuquired pneumonia

56. 4th Generation FQ Agents
Alatrofloxacin (Trovan® IV)
Limited market availability d/t toxicity
Gemifloxacin (Factive®)
Moxifloxacin (Avelox®)
Trovafloxacin (Trovan® PO)
Same as 3rd generation with anaerobic coverage

57. FQ Side Effects Complexes with cations Photosensitivity
CYP450 interactions
Renal elimination
QT prolongationTorsades de Pointes
Hepatic failure (Trovan®)
Tendon rupture
Do not give if <18yo

58. Ribosomal Inhibitors

59. Anti-Ribosomal Agents
Ribosomal Subunits
30s Subunit (Prokaryotic)≈40s (Eukaryotic)
Tetracyclines
Aminoglycosides
50s Subunit (Prokaryotic)≈60s (Eukaryotic)
Macrolides
Lincomycins
Chloramphenicol
Miscellaneous
Streptogramins
Oxazolidinones

60. Anti-Ribosomal Mnemonic
@30, Amina cycles
(Aminoglycocide & Tetracycline)
@50, Mac likes Nicole
(Macrolide & Lincomycin & Chloramphenicol)
Hey, they’re cheesy, but I’m desperate for ideas!

61. 30s Inhibitors Tetracyclines: Aminoglycosides
Bind to amino acyl t-RNA portion of the mRNA-ribosome complex
Bacteriostatic
Aminoglycosides
Bind to the separated 30s subunit causing misreading
Bacteriocidal

62. Tetracyclines Demeclocycline (Declomycin®) Doxycycline (Vibramycin®)
Minocycline (Minocin®)
Tetracycline (Sumycin®)

63. Tetracycline Spectrum
Gram {+} Bacilli
Gram {-} Rods
Gram {-} Bacilli
H. influenzae, Vibrio cholera
Spirochetes
Borrelia burgdorferi (Lyme dz), treponema pallidum (syphilis)
Chlamydia
Rickettsia rickettsii (Rocky Mt. Spotted Fever)

64. Tetracycline SE Chelates with cations GI upset Phototoxicity
Decreased absorption with dairy, calcium
Deposition on calcified tissues
GI upset
Phototoxicity
Demeclocycline
Never used as an antibiotic because it can induce nephrogenic diabetes insipidus
Used in treatment of SIADH

65. Aminoglycocides Amikacin (Amikin®) Gentamicin (Garamycin®)
Netilmycin (Netromycin®)
Neomycin (Mycifradin®)
Kanamycin (Kantrex®)
Streptomycin
Tobramycin (Nebcin®)

66. Aminoglycocide Spectrum
Gram {-} Bacteria
Pseudomonas aeruginosa
Vibrio cholerae
Yersinia pestis (PLAGUE! )
Enterobacter aerogenes
E. coli
Klebsiella pneumoneae
Proteus
Serratia

67. Aminoglycocide SE
Highly polar (cationic) molecules, usually prevents GI absorption
Renally eliminated
Ototoxicity
Nephrotoxicity
Neomycin-used topically, orally for hepatic failure
Streptomycin-used in TB

68. 50s Inhibitors
All 50s inhibitors binds irreversibly to 50s subunit, inhibiting translocation (peptidyl transferase
Therefore, giving ≥2 of these agents is redundant
Generally bacteriostatic high doses)

69. Macrolides Azalides: Ketolides: Macrolides: Azithromycin (Zithromax®)
Telithromycin (Ketek®)
Macrolides:
Clarithromycin (Biaxin®)
Dirithromycin (Dynabac®)
Erythromycin (Ery-Tab®)

70. Macrolide Spectrum Chlamydia (Erythro drug of choice in pregnancy)
Mycoplasma pneumoniae
Ureaplasma urealyticum
Legionella pneumophila
Treponema pallidum (Syphillis)
Gram (+) cocci
Gram (+) bacilli

71. Macrolide Spectrum Clarithro>erythro Azithro<erythro
Chlamydia, Legionella, Ureaplasma H. flu
Azithro<erythro
Staph, Strep
Azithro>erythro
H. flu, moraxella catarrhalis (why used for pneumonia)

72. Macrolide SE Erythro destroyed by gastric acid
Enteric coated or esterified forms
Azithro concentrates in neutrophils, macrophages, fibroblasts
Erythro Azithro=hepatic; clarithro=renal
SE:
NVD, cholestatic jaundice (estolate salt-erythro), Erythro & clarithro go through CYP450

73. Lincomycins
Clindamycin (Cleocin®)
Lincomycin (Lincocin®)

74. Lincomycin Spectrum Gram {+} aerobes Gram {+} anaerobes
NO gram {-} aerobic coverage
Think of these as 2nd-line penicillins

75. Lincomycin SE Rash Neutropenia Thrombocytopenia
Erythema multiforme (rare)
Pseudomembranous colitis

76. Chloramphenicol
Broad spectrum against Gram {+}, Gram {-}, and anaerobes.
Can be extremely toxic
Dose-related revesible anemia
Hemolytic anemia in G6PD deficiency
Dose-independent aplastic anemia
“Grey baby syndrome” caused by drug accumulation leading to cyanosis, cardiovascular collapse and eventual death

77. Streptogramins Quinupristin/Dalfopristin (Synercid®)
Dalfopristin inhibits early phase of protein synthesis
Quinupristin inhibits late phase of protein synthesis
Ratio 70% dalfopristin/30% quinupristin
Major use is for VRE Enterococcus faecium (NO coverage against enterococcus faecalis)

78. Oxazolidinones
Linezolid (Zyvox®)

79. Linezolid
Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex
Monoamine Oxidase Inhibition
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Used in VRE and other severe infections

80. Cell Membrane Inhibitors

81. Cell Membrane Inhibitors
Daptomycin (Cubicin®)
Unique mechanism of action that it binds to bacterial membranes and causes a rapid depolarization of membrane potential which leads to inhibition of protein, DNA, and RNA synthesis
Used in antibiotic resistant MRSA, VRE, and linezolid-resistant strains
Can cause myalgias

82. Take Home Messages
Regarding mechanism of action: Know its major effect (cell wall vs. ribosomal)
Regarding side effects: Know what will kill (or maim) a person, or something totally unique to that drug
Regarding coverage: Know broad classes (Gram, anaerobic)
Regarding drugs: You will NEVER know everything about pharmacology, so don’t try to!

83. The End