Antimicrobial Therapy

1
Antimicrobial Therapy

• Chemotherapy any treatment of patient with
  chemicals to treat a condition.
• Now word associated with cancer treatment
• Our focus is on antimicrobial agents
• Antimicrobials synthetic, antibiotics, or
  semi-synthetic
• Antibiotics natural products made by microbes,
  effective against other microbes. Some drugs are
  wholly synthetic.
• Semi-synthetic antibiotics use natural
  antibiotic as base, but modified chemically most
  of our new antibiotics
• Antibiotics are small molecules, 300 - 1500 MW,
  not to be at all confused with antibodies which
  are proteins (MW 150,000)

2
Spectrum

• Some antibiotics are considered broad spectrum
• By definition, these are effective against many
  types of bacteria, both Gram negative and Gram
  positive
• Broad spectrum antibiotics can sometimes cause
  problems because of damage to normal microbiota
  of host
• Superinfection may result from this situation
• Overgrowth of normal microbes that cause disease

3
Selective Toxicity the key to antibiotic therapy

• 3 concentration ranges ineffective, effective,
  and toxic. A drug needs to have a wide effective
  (therapeutic) range.

Selective toxicity is the ability of the drug to
harm the target without harming the host.
Bacteria have many targets that are biologically
different from us that the drugs can hit. As the
target becomes more like us, there are fewer and
fewer drugs that are selectively toxic fungi,
protozoa, worms, viruses, cancer.
4
Selective Toxicity and side effects

• Drugs may fail to be selectively toxic and
  interfere with mammalian biochemistry. They may
  cause allergies. They may destroy too many
  normal bacteria.

5
Actions of antimicrobials

• Drugs work against microbes by these basic
  mechanisms
• Inhibition of cell wall synthesis
• Causes bacterium to commit suicide, but only
  during growth when cells are cutting their own
  PG.
• Disruption of membrane function
• Often toxic to humans because we have membranes
  too, cause leakage of vital molecules.
• Inhibition of protein synthesis many
  antibiotics
• Bind to ribosomal RNAs, proteins.
• Inhibition of nucleic acid synthesis
• Attack transcription, DNA unwinding enzymes
• Act as anti-metabolites competitive inhibitors,
  inhibit function of enzymes, usually
  bacteriostatic.

6
Ideal Antibiotic

• Good drug properties (e.g. soluble in body
  fluids)
• Selectively toxic, obviously
• Easily administered
• Non-allergenic
• Stable in vivo, slowly broken down and excreted
• Difficult for microbe to become resistant to.
• Long shelf life (chemically stable)
• low

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Measurement of Efficacy-1

• Disk diffusion assay
• Paper disks with antibiotic applied to lawn in
  Petri dish
• Zone of inhibition indicates susceptibility to
  drug

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Measurement of Efficacy-2

• Broth dilution test to measure MIC
• Minimum inhibitory concentration
• Drug is diluted in broth which is inoculated
• Clear broth indicates no growth or bacteria
  killed.
• That concentration of drug that first inhibits
  MIC

http//www.bmb.leeds.ac.uk/mbiology/ug/ugteach/icu
8/images/antibiotics/mic.gif
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Why bacteria might be resistant

• Innate or behavioral Evasion, bacteria may hide
  in cells or organelles Gram have OM some
  bacteria have no cell walls.
• Mutations change in transport protein, ribosome,
  enzyme, etc. Mutations that are normally harmful
  are selected FOR in the presence of antibiotic.
• New genetic information from elsewhere
• Plasmids or other DNA from
• conjugation, transduction, etc.

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yer/Stryer_F32-13.jpg
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Mechanisms of drug resistance

• Alteration of target active site of enzyme
  changes, ribosome changes.
• Alteration of membrane permeability transport
  protein changes, drug no longer enters drug that
  does enter is actively pumped out.
• Enzymatic destruction of drug penicillinases
  (beta lactamases)
• End around inhibitor bacteria learns to use
  new metabolic pathway, drug no longer effective.

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Attack by penicillinase
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ca/de_wer4.gif
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Human behavior and antibiotic resistance

• Bacteria once under control are making a comeback
  due to antibiotic resistance
• S. aureus, Enterococcus, M. tuberculosis, et al.
• Human behavior
• Most diseases caused by viruses, non-cellular,
  not treatable with antibiotics (but Doctor, do
  something)
• last bacteria left are the most resistant, if
  they arent killed, they become normal dont
  stop regimen because you feel better.
• Social behavior
• resistance in homeless/poor
• growth stimulants in agriculture

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Fighting antibiotic resistance

• Use drug as prescribed
• Use drug at correct concentration, correct amount
  of time
• Dont allow the least sensitive bacteria to
  survive
• Drugs in combination
• Odds of mutating to resist 2 drugs 1 in 106 x
  106
• Synergism e.g. amoxicillin and clavulanic acid
• Limit antibiotic use
• gt50 of infections are viral not affected by
  antibiotics
• Constant exposure breeds resistance, selects for
  resist.
• New drugs