Antimicrobial Therapy

1
Antimicrobial Therapy

• Vocabulary
• Chemotherapy (Erlich)
• Antibiotic
• Synthetic and semi-synthetic

2
Antimicrobial Therapy

• Very Brief History
• Erlich - Salvarsan
• Domagk - Prontosil (sulfa) prodrug
• Fleming, Chain, Florey - penicillin
• 1969 - government - all over

3
Selective Toxicity
Therapeutic Dose Toxic Dose Therapeutic Index
(TI) Toxic/Therapeutic
4
Whats a good antibiotic?

• soluble, not protein bound
• stable and unaltered in tissues
• good TI
• non-allergenic
• no resistance issues

5
Side Effects

• Toxicity
• Allergy
• Disruption of normal flora - a Z-pak with a
  Diflucan chaser - hospital settings

6
Modes of Action

• Inhibit cell wall synthesis
• Disrupt the cell membrane
• Inhibit protein synthesis
• Inhibit nucleic acid synthesis
• Act as antimetabolites

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Spectrum of Activity
Broad spectrum vs Narrow spectrum
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Penicillin
9
Penicillins
10
Remember Peptidoglycan?
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Penicillins
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Penicillins

• blocks transpeptidase that crosslinks
  peptidoglycan in the cell wall
• often used for Streptococci (pneumonia,
  meningitis), spirochetes
• semisynthetics used if PenG resistance
• 5 of adults are allergic
• prophylactic for surgery

13
Cephalosporins
penicillins cephalorsporins
14
Cephalosporins
15
Cephalosporins

• broad spectrum good oral absorption
• expensive
• maybe a problem if penicillin allergic
• prophylactic for surgery

16
Other cell wall inhibitors

• carbapenems - very broad spectrum
• bacitracin - peptide, topical

17
Other cell wall inhibitors
vancomycin - Gram ()s, MRSA, IV
18
Cell membrane disrupters

• polymyxins - often topical, Pseudomonas,
  fairly toxic internally

19
Protein synthesis inhibitors

• aminoglycosides
• tetracyclines
• macrolides

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Aminoglycosides

• aminoglycosides - bind ribosomes -
  streptomycin - neomycin - kanamycin -
  gentamicin - tobramycin
• synergistic use, often with penicillin
• special apps - hospital infections, joint
  infections
• toxicity with prolonged use

21
Tetracyclines

• tetracyclines - bind 30s ribosome -
  tetracycline - doxycycline (Vibramycin)
• widest spectrum - also causes problems
• good distribution in body including
  intracellular
• kidney and liver toxicity

22
Tetracyclines
Bad for a patients teeth Good for
bone research
http//pathology2.jhu.edu/bonelab
www.drjohnrutland.com
23
Macrolides

• macrolides - bind 50s ribosome -
  erythromycin - azithromycin (Zithromax)
• used especially on respiratory infections
• reaches high levels in tissues - long half-life
• emerging Zmax resistance

24
Quinolones

• quinolones - inhibit DNA synthesis DNA
  gyrase - ciprofloxacin - moxafloxacin
• last resort drugs - relatively wide spectrum
• urinary tract infections
• anthrax

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Antimetabolites

• sulfa drugs - block folic acid synthesis --
  sulfamethoxazole often in combo with
  trimethoprim Bactrim or Septra
• specific uses - CNS, Pneumocystis pneumonia

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Antifungals

• imidazoles/triazoles - block membrane
  sterol synthesis -- most used
  topically miconazole (Monostat)
  clortrimazole (Lotramin) -- some systemic
  ketoconazole fluconazole (Diflucan)
• skin fungal infections Candidiasis

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Antivirals

• base analogs - mutations, feedback inhibition
  -- ribavirin
• uncoating -- rimantadine
• neurominidase inhibitors -- oseltamivir
  (Tamiflu)
• protease inhibitors (HIV) -- nelfinavir

nice link for mechanism of actionTamiflu
Mechanism of Action
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Antibiotic Resistance in Hospitals
MG. Taubes, Science 321, 356 -361 (2008)
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Resistance

• Physical Evasion
• Genetic Changes (mutations) - chromosomal -
  plasmid mediated

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Resistance Mechanisms

• target alterations
• membrane alterations
• enzyme action
• enzyme changes
• metabolic pathway changes

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Penicillin Resistance
?-lactamase
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Tetracycline Resistance

• tetracycline resistance - efflux pump

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?-lactamases
Davies and Davies, MMBR 74, 417 -433 (2010)
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Carbopenase and KP
http//www.cdc.gov/
35
Cipro Resistance in GC
MIC gt1 ?g/ml MIC 0.125 - 1 ?g/ml
Percentage of Neisseria gonorrhoeae isolates with
ciprofloxacin resistance
http//www.cdc.gov/std/gisp2007/default.htm
36
Cipro Resistance in GC
Distribution of Neisseria gonorrhoeae
ciprofloxacin MICs
http//www.cdc.gov/std/gisp2007/default.htm
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Zithromax Resistance in GC
Distribution of Neisseria gonorrhoeae
azithromycin MICs
http//www.cdc.gov/std/gisp2007/default.htm
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Limiting Resistance
39
Limiting Resistance
40
Limiting Resistance
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Limiting Resistance

• use synergistic drugs - penicillin
  streptomycin pentration - Augmentin
  clavulanic acid (anti-?-lactamase
  amoxicillin
• dont use antagonistic drugs - tetracycline
  penicillin tet slows growth
• use drugs only in essential cases - NO
  ANTIBIOTICS FOR COLDS!

42
Limiting Resistance
www.ehponline.org
43
FDA Antibiotics Approval
MG. Taubes, Science 321, 356 -361 (2008)
44
Innovation Gap in Antibiotics
M. A. Fischbach et al., Science 325, 1089
-1093 (2009)
45
Really New Stuff
Hacking Bacterial Communications