1. Ax
    Microbial metabolite and it must kill bacteria; these are natural products because they are produced naturally from micro-organisms. These all work in conjunction with the immune system, it is very difficult to Tx and infection if the immune system is compromised.
  2. Semi-synthetic Ax vs. Antibacterial
    they are no longer produced exclusively from the organism but are produced in the lab. Generally we refer to anything human made or made in the lab as antibacterials (these could be Ax). They may not be in Ax in the sense it won't kill bacteria but it could inhibt the growth of bacteria. Ax KILL bacteria*
  3. Bacteriocidal vs Bacteriostatic
    Bacteriostatic Ax inhibit the growth and reproduction of bacteria without killing them while bacteriocidal Ax kill the bacteria.
  4. MBC vs. MIC
    • Min. bacteriocidal [ ] vs. Min. inhibitory [ ]
    • MBC= lowest [ ] of the Ax required to kill the germ
    • MIC= lowest [ ] of an antimicrobial that will inhibit the visible growth of a microorganism over night (referring to static*)
  5. Clinical significance of MBC and MIC
    MIC is important in diagnostic labs to confirm resistance of microorganims to an antimicrobial agent and to also monitor the activity of a new antimicrobial agent. Antibacterials are usually considered -cidal if there MBC is no more than 4 times the MIC.
  6. Bacteriocidal / -static clinical significance
    If we were to take these internally and depending on the dose, we need to know if we'll get a beneficial effect of killing the bacteria or an AE of harming the patient (we need to get a balanced effect to avoid harming the patient). We can always increase the [ ] of the Ax to a zone of inhibition when we are in the lab so when we test for Ax, it was always be bacteriocidal (because we are in the lab and we can always kill bacteria). The question is, can we achieve these [ ]'s in a human without harming the patient or causing AE's? If it's bacteriocidal in the lab, is it also in you patient? Sometimes drugs may be bacteriocidal in a lab but -static in a patient.

    • ie. Tetracycline = cannot double this dose, we would have to increase by a 20-30 fold and this would harm the patient
    • ie. Gentamycin = both static and cidal
  7. PAE
    • Post-Ax effect
    • When you check the levels of an Ax in the blood we might see levels that are lower than what's needed to Tx the infection. However, we may still be getting inhibition even though we don't detect therapeutic levels-->this is known as the PAE and it's due to many factors such as duration of exposure to the Ax, bacterial species, culture medium, and class of Ax and a possibility of alteration of DNA function.
    • Most inhibitors of nucleic acid and protein synthesis induce long term PAE's against susceptible bacteria such as aminoglycosides, fluoroquinolones, tetracyclines, clindamycin, certain newer macrolides/ketolides, and rifampicin and rifabutin
  8. Classes of Ax
    • This is based upon chemical structure and on the mode of action.
    • 1.beta lactams
    • 2.aminoglycosides
    • 3.macrolides
    • 4.polypeptides
    • 5.vancomycin
    • 6.tetracyclines
    • 7.fluoroquinolones
    • 8.sulfonamides & trimethoprim
    • 9.miscellaneous
  9. Beta Lactams
    penicillins and cephalosporins

    cell wall inhibitors
  10. Aminoglycosides

    protein synthesis inhibitor
  11. Macrolides

    protein synthesis inhibitor
  12. Polypetides
    Bacitracin, Polymixin

    protein synthesis inhibitors
  13. Vancomycin
    Quinupristin, Dalfopristin

    cell wall / protein synthesis inhibitors
  14. Tetracyclins

    protein synthesis inhibitor
  15. Fluoroquinolones

    DNA gyrase inhibitor
  16. Sulfonamides and Trimethoprim
    bacteriostatic agents, inhibits the synthesis of dihydrofolate and tetrahydrofolate respectively
  17. Miscellaneous
    Chloramphenicol, Lincosamines, etc.
  18. Penicillins
    These were the 1st class of Ax to be discovered by Alexander Fleming. These contain a fused 4 membered beta lactam ring with a 5 membered thiazolidine heterocyle. The 4 membered lactam contains the biologic activity in this class.Image Upload 1
  19. Major problems with the penicillin class (4)
    • 1.narrow spectrum of activity (gram+ organisms)
    • 2.acid unstable (poor oral bioavailability)
    • 3.ineffective against beta lactamase (penicillinase) producing organisms
    • 4.allergic reactions (by acting as a "hapten)
  20. Mode of action
    Bind to penicillin binding proteins in the cell wall (carboxy peptidases and transpeptidases) which are needed to for the complex 3D structure of the cell wall. These Ax resemble the D-ala D-ala linkage of the terminal residues of the peptide pendants (from the proteoglycans) which are required for cross linking (to Gly) to form the 3D structure of the cell wall. The inhibit the synthesis of bacteria cell walls
  21. SAR: Penicillins
    • 6-Aminopenicillanic Acid (6-APA)
    • Precursor to semi-synthetic penicillins
    • Image Upload 2
  22. Natural Penicillins (2)
    • Penicillin G
    • Penicillin V

    These were the first Ax used for gram + organisms such as staph, strep, etc.and ones that DON'T produce penicillinase (beta lactamase). These tend to be underutilized due to drug companies marketing more profitable Ax. To overcome problems of the natural analogs, the semi-synthetic dervatives were developed from 6-APA- containing the core beta lactam ring seen in all penicillins
  23. Penicillin G
    Benzylpenicillin, Pentid
  24. Penicillin G salts (2)
    • Procaine Penicillin G = Duracillin
    • Benzathine Penicillin G = Bicillin, Permapen
  25. Penicillin V
    Phenoxymethyl Penicillin, Pen Vee K
  26. Semi-synthetic Penicillins (4)
    • aminopenicillins
    • penicillinase resistant penicillins
    • caroxypenicillins
    • ureidopenicillins
  27. Aminopenicillins (3)
    • Ampicillin (omnipen)
    • Amoxicillin (amoxil)
    • Cyclacillin (cyclapen-W)
  28. Aminopenicillin Esters (2)
    • (with 3-carboxylic acid)--more bioavailable*
    • Pivampicillin
    • Bacampicillin
  29. Aminopenicillins Tx
    Good for gram + with extended spectrum to limited gram -. These are used orally in simple or complicated UTI's or upper respiratory tract infections (ear, sinus, etc.). Ampicillin is less bioavailable than amoxicillin and thus causes more GI upsets (diarrhea) and is dosed more frequently. Beta lactamase producing organisms are still resistant to these.
  30. Penicillinase Resistant Penicillins (6)
    • methicillin (staphcillin)
    • nafcillin (unipen)
    • oxacillin
    • cloxacillin
    • dicloxacillin
    • floxacillin
  31. Penicillinase Resistant Penicillins Tx
    Gram+ (staph and strep) which produce penicillinase. Generally if the organism is methicillin resistant (MRSA), the organism, the organism will be resistant to all the members in this class
  32. Carboxypenicillins (3)
    • carbenicillin disodium (geopen)
    • ticarcillin (ticar) - thiole isostere of benzene
    • geocillin - prodrug form of ticar
  33. Carboxypenicillin Tx
    • ONLY for gram - (no activity for gram +)
    • these are penicillinase sensitive
    • these were the original anti-pseudomonas penicillins
    • used in combo with beta lactamase inhibitors (timentin) although limited use
    • carbenicillin is a lg "horse pill" used in some specialized nursing facilities to Tx chronic pseudomonas aeruginosa UTI's
    • fluoroquinolones have largely replaced carbenicillin*
  34. Ureidopenicillins (3)
    • azlocillin
    • mezlocillin
    • piperacillin
  35. Ureidopenicillin Tx
    extended spectrum of activity covering gram + and many gram - INCLUDING pseudomonas aeruginosa
  36. Monobactams (1)
    • aztreonam (azactam)
    • contain only the beta lactam ring, a single ring as opposed to the natural fused rings of the 4 membered beta lactam + 5 membered thiazolidine
  37. Monobactams Tx
    covers gram - ONLY including pseudomonas aeruginosaresistant to penicillinasesimilar in spectrum to aminoglycosides but w/out oto-/nephrotoxicityused in patients who can't tolerate aminoglycosidesONLY beta lactam with no history of allergies
  38. Carbapenams (1)
    • imipenan (meropenam and primaxin)
    • bio-isostere analog of the thiazolidine where a carbon atom replaces the sulfur in the 5 membered heterocycle
  39. Carbapenam Tx
    • when used in combo with cilastatin sulfate = renal dehydropeptidase inhibitor
    • broad spectrum of activity and sometimes called "gorillacillin" or "gorilamycin"
    • used in severe infections of enterobacteriacae and pseudomonas aeruginosa and gram + cocci (except enterococci*)
    • patients w/ renal failure allow for buildup of imipenam-->seizures
    • meropenam causes less seizures and is safer for pediatric use
  40. Fermentation derived penicillins (3)
    • 6-APA
    • Image Upload 3
    • Penicillin G
    • Image Upload 4
    • Penicillin V
    • Image Upload 5
  41. Semi-synthetic penicillinase resistant parenteral penicillins (2)
    • methicillin
    • Image Upload 6
    • nafcillin
    • Image Upload 7
  42. Semi-synthetic penicillinase resistant oral penicillins (3)
    • oxacillin
    • Image Upload 8
    • cloxaxillin
    • Image Upload 9
    • dicloxacillin
    • Image Upload 10
  43. Semi-synthetic penicillinase sensitive, broad spectrum, parenteral penicillins (3)
    • carbenicillin
    • Image Upload 11
    • ticarcillin
    • Image Upload 12
    • mezlocillin
    • Image Upload 13
    • piperacillin
    • Image Upload 14
  44. Semi-synthetic penicillinase sensitive broad spectrum oral penicillins (2)
    • ampicillin
    • Image Upload 15
    • amoxicillin
    • Image Upload 16
  45. Penicillin Salts (2)
    • benzyl penicillin + procaine = used as depot parenteral formulation
    • benzyl penicillin + benzathine = depot parenteral
  46. Penicillin Prodrugs
    Carboxyester derivatives = allows for increased oral bioavailability
  47. Ampicillin esters (2)
    Image Upload 17
    • pivampicillin
    • Image Upload 18
    • bacampicillin
    • Image Upload 19
    • allows for increased oral bioavailability of ampicillin
  48. Carbenicillin ester (1)
    Image Upload 20
    • Geocillin
    • Image Upload 21
  49. Beta Lactamase Inhibitors (3)
    • clavulanic acid
    • Image Upload 22
    • sulbactam
    • Image Upload 23
    • tazobactam
    • Image Upload 24
  50. Beta Lactamase Inhibitor Tx
    • Though these contain a beta lactam they have NO antibacterial activity* but they prevent penicillinase from breaking down (hydrolyzing) the active penicillins
    • used in combo products for susceptible organisms which produce beta lactamase
  51. Combo product's : Beta Lactamase Inhibitors (4)
    • augmentin = amoxicillin + clauvulinic acid
    • timentin = ticarcillin + clauvulinic acid
    • unasyn = ampicillin + sulbactam
    • zosyn = piperacillin + tazobactam
  52. Carbapenams
    • Carbon isostere of penicillin where the 4-sulfur is replaced by a carbon ad the sulfur is taken out of the 5 membered ring system
    • these are BROAD SPECTRUM AGENTS (thienamycin, imipenam, meropenam)
    • Imipenam aka "gorillacillin" because of its broad spectrum activity and is used in combo w/ cilastatin Na (renal peptidase inhibitor) to improve systemic levels of the drug (combo product = premaxim)
  53. Thienamycin
    Image Upload 25
  54. Impenem
    Image Upload 26
  55. Cilastatin Na
    Image Upload 27
  56. Meropenem (Merrem)
    Image Upload 28
  57. Monobactams (Aztreonam)
    Image Upload 29
    • has only one ring which is the beta lactam
    • only used for gram = with little to no activity for gram +
    • only beta lactam not yet displayed any allergy Sx
  58. CephalosporinsImage Upload 30
    • these are also beta lactams but contain 6 membered ring (dihydrothiazine) fused to the 4 membered beta lactam (instead of the thiazolidine in penicillins)
    • classified according to the chronological order in which they were introduced into the market (1st-4th generation)
  59. First Generation (6)
    • they are primarily gram + and have similar activity to the aminopenicillins
    • cephalothin (keflin)
    • cephalexin (keflex)
    • cefazolin (kefzol or ancef)
    • cephradine (anspor or velocef)
    • cephaperin (cefadyl)
    • cefadroxil (duracef)
  60. Cephalexin (keflex)
    Image Upload 31
    these are used in penicillin allergic (only for rash and not for anaphylactic event) patients and lower respirtatory infections
  61. Parenteral First Generation Cephalosporins (2)
    • cephapirin
    • Image Upload 32
    • cefazolin
    • Image Upload 33
  62. Oral First Generation Cephalosporins (2)
    • cephalexin
    • Image Upload 34
    • cefadroxil
    • Image Upload 35
  63. Oral + Parenteral First Generation Cephalosporin (1)
    • Cephradine
    • Image Upload 36
  64. Cephalothin (keflin)
    1st generation cephalosporin
  65. Cephalexin (keflex)
    1st generation cephalosporin
  66. Cefazolin (kefzol or velocef)
    first generation cephalosporin
  67. cephradine (anspor or velocef)
    first generation cephalosporin
  68. Cephaperin (Cefadyl)
    first generation cephalosporin
  69. Cefadroxil (duracef)
    first generation cephalosporin
  70. 2nd Generation Cephalosporins (11)
    • These agents cover gram + as well as gram -
    • cefamandole (mandol)
    • cefaclor (ceclor)
    • cefuroxime axetil (ceftin)
    • cefuroxime (zinacef or kefurex)
    • cefonocid (monocid)
    • cefoxitin (mefoxitin)
    • cefmetazole (zefazone)
    • cefotetan (cefotan)
    • cefprozil (cefzil)
    • cefpodoxime proxetil (vantin)
    • loracarbef (lorabid)
  71. Cefamandole (mandol)
    2nd generation cephalosporin
  72. Cefaclor (ceclor)
    2nd generation cephalosporin
  73. Cefuroxime (zinacef or kefurex)
    Image Upload 37
    • 2nd generation cephalosporin
    • good for empiric pnuemonia*
  74. Cefuroxime Axetil (Ceftin)
    Image Upload 38
    • 2nd generation cephalosporin
    • oral form of cefuroxime
  75. Cefonicid (Monocid)
    2nd generation cephalosporin
  76. Cefotoxin (Mefoxitin)
    2nd generation cephalosporin
  77. Cefmetazole ( Zefazone)
    2nd generation cephalosporin
  78. Cefotetan (Cefotan)
    2nd generation cephalosporin
  79. Cefprozil (Cefzil)
    2nd generation cephalosporin
  80. Cefpodoxime proxetil ( Vantin)
    • 2nd generation cephalosporin
    • oral agent similar to cefaclor
  81. Loracarbef (Lorabid)
    2nd generation cephalosporin
  82. 2nd Generation Parenteral Agents (6)
    • Cefamandole
    • Cefonicid
    • Cefoxitin
    • Cefotetan
    • Cefmetazole
  83. 2nd Generation Oral Agents (3)
    • Cefaclor
    • Loracarbef
    • Cefprozil
  84. 3rd Generation Cephalopsporins (8)
    • mainly active on gram - organisms and on some gram + (streptococcus pneumonia)
    • generally used in empiric therapy upon patient presenting with infection on admission to hospital
    • ceftiaxone (rocephin)
    • ceftizoxime (cefizox)
    • cefotaxime (claforan)
    • *these 3 are the most popular
    • cefoperazone (cefobid)
    • ceftazidime (fortazm tazicef, tazidime)
    • cefixime (suprax)
    • ceftibuten (cedax)
    • cefdinir (omnicef)
  85. Ceftriaxone (Rocephin)
    • 3rd generation cephalosporin
    • parenteral
  86. Ceftizoxime (cefizox)
    • 3rd generation cephalosporin
    • parenteral
  87. Cefotaxime (Claforan)
    • 3rd generation cephalosporin
    • parenteral
  88. Cefoperazone (Cefobid)
    • 3rd generation cephalosporin
    • parenteral
  89. Ceftazidime (Fortaz, Tazicef, Tazidime)
    • 3rd generation cephalosporin
    • parenteral
  90. Cefixime (Suprax)
    • 3rd generation cephalosporin
    • oral
  91. Ceftibuten (Cedex)
    • 3rd generation cephalosporin
    • oral
  92. Cefdinir (Omnicef)
    • 3rd generation cephalosporin
    • oral
  93. 4th Generation Cephalosporin's (2)
    • mainly active against gram - (esp those resistant to 3rd generation and a few gram +)
    • cefepime (maxipime)
    • cefpirome (cefrom)
  94. Cefepime (Maxipime)
    • 4th generation cephalosporin
    • also active against some gram + (staph aureus [methicillin susceptibile], strep pneumoniae and strep pyrogenes)
  95. Cefpirome (Cefrom)
    4th generation cephalosporin
  96. 5th Generation Cephalosporin (1)
  97. Ceftobiprole
    • 5th generation cephalosporin
    • new broad spectrum agent given via injection for use against MRSA complicated skin infections--approval pending due to concerns over clinical trial data
  98. Aminoglycosides
    Image Upload 39
    • these are amines linked to sugars and are extremely polar and water soluble at all achievable pH's and given by injection (IM or IV)
    • broad spectrum but primarily used for aerobic gram - bacilli (pseudomonas aeroginosa)
  99. Aminoglycosides MOA
    • inhibitors of protein synthesis and affect bacterial outer membranes
    • affect bacterial membranes by creating holes / fissures resulting in leakage and also by diffusing through bacterial membrane porins (gram - outer mem) into cells where they bind to ribosomes causing mistranslation of RNA producing "nonsense" proteins
    • include mistranslation of the porins allowing for increased entry of the drug which then completely shuts down protein syntheis
  100. Prototype for Aminoglycosides
    • Streptomycin-first member of the group isolated
    • Image Upload 40
  101. Gentamicin (Garamycin)
    Natural aminoglycoside
  102. Kanamycin (Kantrex)
    natural aminoglycoside
  103. Neomycin (Mycifradin)
    natural aminoglycoside
  104. Paramomycin (Bumatin)
    natural aminoglycoside
  105. Tobramycin (Nebcin)
    natural aminoglycoside
  106. Amikacin (Amikin)
    Semi-synthetic aminoglycoside
  107. Netilmicin (Netromycin)
    Semi-synthetic aminoglycoside
  108. Aminoglycoside AE's
    • nephrotoxic, ototoxic which needs to be monitored (creatinine function) because of delayed onset
    • at high [ ]'s also causes neuromuscular blockade
    • DI w/ beta lactam Ax (inactivates both Ax)
  109. Resistance Patterns w/ Aminoglycosides
    • phosphorylation
    • adenylation
    • acetylation of certain hydroxyl and amino groups present on the molecule which leads to loss of binding to the ribosomal proteins
  110. Macrolides (3)
    Image Upload 41
    • lg membered lactones attached to sugars and are weakly basic
    • not very water soluble but can be made into salts with weak acids to increase water solubilty
    • broad spectrum
  111. Erythromycin (erythrocin)
    • prototype for macrolides
    • Image Upload 42
  112. Clarithromycin (Biaxin)
    • 6-methoxy semi synthetic derivative; macrolide
    • Image Upload 43
  113. Azithromycin (Zithromax)
    • ring expanded derivative; macrolide
    • Image Upload 44
  114. Telithromycin (Ketek)
    Image Upload 45
    • ketolide rather than a macrolide
    • oxidation of 3-OH to a ketone (>C=O) and used for certain macrolide resistant strains
    • less GI effects than macrolides because 3-O-cladinose sugar is absent
  115. Macrolide MOA
    inhibits protein synthesis by inhibiting translocation of tRNA in the ribosomes resulting in short peptides and dissociation of the growing peptide chain from the ribosome
  116. Macrolide Major Problems/Properties
    • bitter taste and GI upsets (cramping, diarrhea)
    • GI upset thought to be due to the 3-O-cladinose sugar substituent as well as an acid catalyzed ketalization resulting from 6-hydroxy and 9-keto groups
    • to avoid bitter taste insoluble esters/salts were made (erythromycin estolate, ethylsuccinate /EES, stearate)
    • parenteral products were made as well (lactobionate)
  117. Erythromycin Estolate
    • C-2'-propionate ester and N-laurylsulfate salt
    • macrolide
    • made to avoid bitter taste
  118. Ethylsuccinate (EES)
    • macrolide ester/salt
    • made to avoid bitter taste
  119. Stearate
    • macrolide ester/salt
    • made to avoid bitter taste
  120. Lactobionate
    • Macrolide
    • parenteral product
  121. Macrolide DI's
    tend to be inhibitors of CYP-450 enzymes and can increase T1/2 of other drugs (warfarin, theophyllin, digoxin, and oral contraceptives)
  122. Macrolides; Other Uses
    • because of GI effects, erythromycin has been used as a prokinetic agent to advance feeding tubes from stomach to duodenum
    • erythromycin has the greatest SE's compared to the others and is the most frequently dosed
    • biaxin is more stable and is dosed QD while azithromycin is the most stable of the three and has the longest duration of action (QD dosing) with a loading dose and then given x5d
  123. Macrolide Resistance
    • due to efflux of drugs
    • modification of ribosomal RNA residues (methylation of guanosine) to decrease affinity to the ribosome
    • esterase activity to hydrolyze the lactone
  124. Polypeptide Ax
    Image Upload 46
    • cyclic peptides w/ unusual chemistry
    • act as surface active agents by binding to bacterial membranes interfering with permeability
    • used mainly in topical formulations (eye)
    • tend to be quite toxic and are used systemically only in serious infections when few alternatives are present*
    • usually unstable to heat or light so solutions should be protected from these!!!
    • (usually seen in antibacterial ointments where they are not well absorbed systemically)
  125. Polymixin B Sulfate (Aerosporin)
    • Polypeptide Ax; topical & systemic
    • used for gram - organisms to Tx serious UTI's, meningitis, and septicemia caused by pseudomonas aeroginosa
    • oral preps have been used for diarrhea
    • both neuro and nephrotoxic
    • used only when other drugs fail*
  126. Colistin Sulfate (Coly-Mycin S) & Colistimethate Sodium (Coly-Mycin M)
    • Polypeptide Ax; topical & systemic
    • similar to polymixin
    • used orally for diarrhea
  127. Bacitracin
    • Polypeptide Ax; topical & systemic
    • for gram + esp for resistant staph
    • used orally for diarrhea and for pre-operative bowel sanitization
  128. Vancomycin
    • Polypeptide Ax; systemic
    • glycopeptide (glycosylated hexapeptide with unusual amino acids containing aromatic rings)
    • Tx MRSA
    • if used orally it's not absorbed and used for GI infections controlling over growth of gram + organisms in the GIT
  129. Polypetide Ax MOA
    target is the gram + bacterial cell wall, D-ala D-ala residues where it prevents cross linking
  130. Polypeptide Ax SE's
    • thrombophlebitis & nephrotoxicity
    • also causes rash (red man syndrome)
    • "Ax of last resort"
  131. Vancomycin Resistance
    • instances of vancomycin resistance have been observed and presently there are VRSA (vanco resistant staph aur, MIC is > 16 micrograms/mL) and VISA (vanco intermediate [resistant] staph aur, MIC 4-8)
    • two patterns of resistance
    • 1.due to mutation in the cell wall peptide pendant where the terminal D-ala D-ala is mutated to a D-ala-D-lactate residue. this prevents vanco from binding to the cell wall as effectively (VRSA organisms)
    • 2.resistant organisms (VISA) make an extremely thick cell wall which effectively "sponges" up the drug
  132. Quinupristin and Dalfopristin
    • Polypeptide Ax; systemic
    • Synercide (combo of 30/70 quin/dalfo for vanco resistant strains such as enterococus facium and MRSA)
    • belong to the family of "streptogramins" and work in synergy
    • dalfo binding to the ribosome creates high affinity binding site for quin at the ribosome
    • binding site is similar for that seen for the macrolides on the ribosome and hence resistance to macrolides infer resistance to Synercide
  133. Polypeptide Ax MOA
    • involves inhibition of early and late protein synthesis on the bacterial ribosome
    • it's a CYP3A4 inhibitor and hence causation when used with other durgs (esp low TI drugs) metabolized through this pathway
  134. Polypeptide Ax Topical Combo's(3)
    • neosporin
    • cortisporin
    • polysporin
  135. Neosporin
    • Polypeptide Ax; topical combo
    • neomycin+polymixin B+bacitracin
  136. Cortisporin
    • Polypeptide Ax; topical combo
    • neomycin+polymixin B+hydrocortisone
  137. Polysporin
    • Polypeptide Ax; topical combo
    • polymixin B+bacitracin
  138. Tetracyclines(7)
    Image Upload 47
    • contain 4 linearly fused rings- partially saturated napthacene system with varying functionalities
    • tend to be yellow in color
    • amphoteric molecules with 3 ionizable groups having pKa values of 3 (conjugated vinyl EtOH),7.5 (conjugated phenol), and 9.4 (dimethylamino)
    • broad spectrum
    • clinically used as bacteriostatic
    • presently used to Tx some of the more "wierd" organisms (rickettsia, chlamydia, anthrax, lyme disease [borrelia burgdorferi])
  139. Cholertetracycline (Aureomycin)
    Tetracycline; low potency and bioavailability
  140. Oxytetracycline (Terramycin)
    Tetracycline; low potency and bioavailability
  141. Tetracycline (Anchromycin, Tetracyn, Sumycin)
    Tetracycline; intermediate potency and bioavailability
  142. Demeclocycline (Declomycin)
    Tetracycline; intermediate potency and bioavailability
  143. Methacycline (Rondomycin)
    Tetracycline; intermediate potency and bioavailability
  144. Doxycycline (Vibramycin)
    Tetracycline; high potency and bioavailability
  145. Minocycline (Minocin)
    Tetracycline; high potency and bioavailability
  146. Tetracyclines MOA
    • bacterial protein synthesis inhibitors where they bind to the 30S ribosome and inhibit the binding of the amino-acyl-t-RNA to the acceptor site on the ribosome complex
    • amino acids can't be added to the growing peptide chain
  147. Tetracycline Resistance Patterns
    • increase efflux of the drug
    • decreased influx of drug through modification of the porin proteins
    • ribosomal protection (through elaboration of ribosomal proteins) which provides protection from the Ax
    • NOTE: bacterial efflux proteins are often PLASMID mediated and hence resistance to tetracyclines (through efflux mech) is a marker for resistance to other Ax*
  148. Chemical Stability and Incompatibility of Tetracyclines (3)
    • epimerization of tetracycline
    • dehydration of tetracycline(formation of anhydrotetracycline)
    • chelation properties of tetracyclines
  149. Epimerization of Tetracyclines
    • the steriochemistry at the 4 position (a-dimethylamino) is essential for Ax activity
    • bc of acidity of the 4-beta-hydrogen these derivatives have the potential to undergo epimerization at the 4-position leading to 4-epitetracycline, an INACTIVE DRUG
    • because of this many tetracycline caps are filled w/ up to 15% excess drug to compensate for destabilization
  150. Dehydration of Tetracyclines
    • tetracycline derivatives (older ones having 6-hydroxy functionality) may also undergo dehydration at the 6-position leading to anhydro-tetracycline (this product can also undergo epimerization)
    • if both reactions take placce then 4-epianhydrotetracycline forms which is both inactive and highly toxic to the kidney (Fanconi syndrome)
    • older shelf life tetracycline should be avoided bc there is the potential for the formation of this toxic molecule
    • derivatives that lack 6-OH will be stable to the anhydro reaction and epi-anhydro reaction
  151. Chelation Properties of Tetracyclines
    • all of these derivatives have the potential to chelate poly/multi-valent metal ions such as Ca2+,Al 3+,Mg2+,Fe 2+,Fe3+,etc. and form insoluble metal chelates
    • these drugs aren't compatible with dairy products,ant-acids, mineral supplements, etc.
    • not prescribed to children who are still in the process of forming their permanent teeth (6-12yrs) since they will cause a permanent yellow tooth stain
  152. Semi-Synthetic Tetracyclines (3)
    • demeclocycline
    • doxycycline
    • minocycline
    • minocycline + doxycycline are the more stable, potent and have the greatest oral absorption in this class
    • low dose doxycycline (20mg) has also been used as an agent to Tx periodontal diseases (Periostat)
  153. Tygecycline (Tigacil)
    • classified as a glycylcycline (rather than a tetracycline) and useful for tetracycline resistance
    • given parenterally
  154. Micellaneous Ax
    this group consists of diverse chemical structures
  155. Chloramphenicol
    • Micellaneous Ax
    • unusual Ax containing a nitrobenzene with a dichloroacetic acid derivative
    • broad spectrum agent
    • used widely in developing countries bc it's cheap and effective esp with typhoid and meningitis
    • not popular in developed countries bc of its effects on blood cells causing aplastic anemia (inhibiting mitochondrial protein synthesis) and effects on pediatrics causing "grey baby syndrome" duck to lack of glucuronidation in newborns leading to toxic levels and inhibition of RBC's
  156. Chloramphenicol MOA
    inhibiton of protein synthesis by preventing binding of the t-RNA at the A-site of the ribosome
  157. Resistance Patterns of Chloramphenicol
    primarily due to acetylation of the hydroxy groups leading to decreased binding to the ribosome
  158. Products of Chloramphenicol
    products include the unmodified drug, hemisuccinate ester salt (parenteral), and prodrug palmitate ester (oral)
  159. Lincosamides (2)
    • miscellaneous Ax
    • sm polar glycoside containing a thiomethyl amino-octoside moiety
    • Lincomycin (natural)
    • Clindamycin (semi-synthetic chloro derivative)
    • used or gram + bacteria and for patients with penicillin allergies
  160. Lincomycin
    natural lincosamide; miscellaneous Ax
  161. Clindamycin
    • semi-synthetic chloro derivative of lincosamides
    • miscellaneous Ax
  162. Lincosamide MOA
    protein synthesis inhibitor preventing the translocation of peptidyl-t-RNA (similar to macrolides)
  163. Lincosamide Resistance Patterns
    • ribosome modification
    • efflux
    • cross resistance to macrolides
  164. Linezolid (Zyvox)
    • miscellaneous Ax
    • belongs to the class of oxazolidinones
    • used for gram + and vanco resistance and MRSA
  165. Linezolid (Zyvox) MOA
    protein synthesis inhibitor with a unique action by inhibiting the N-formylmethionyl-tRNA of initiation complex
  166. Linezolid(Zyvox) Resistance Patterns
    mutation in the ribosome which prevents binding
  167. Linezolid (Zyvox) SE's
    blood dyscrasias-package insert warning- weekly blood count monitoring
  168. Daptomycin (Cubicin)
    • miscellaneous Ax
    • cyclic "lipopeptide" useful for gram + infections
    • given parenterally
    • causes depolarization in bacterial cell which interfere with protein and nucleic acid (RNA and DNA) synthesis
  169. Flagyl (Metronidazole)
    • miscellaneous Ax
    • exerts antimicrobial effects in an anaerobic environment by the following possible mechanism : once metronidazole enters the organism, the drug is reduced by IC electron transport proteins. Bc of this alteration. a [gradient] is maintained which promotes the drugs IC transport. Presumably, free radicals are formed which, in turn, react w/ cellular components resulting in death of the microorganism
  170. Flagyl Indications and Usage
    • Gram + anaerobes = clostridium species; eubacterium species, peptococcus niger peptostreptococcus species
    • Gram - anaerobes = bacteroides; fragilis group (B. fragilis, B. distasonis, B. ovatus, B.thetaiotaomicron, B.vulgatus); fusobacterium species
    • protozoal parasites = entamoeba histolytica; trichomonas vaginalis
Card Set
Virology Exam Numero 1; Kerr's information