Antimicrobial Therapy

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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
• Antibiotics antibiotics, semi-synthetic, or
  synthetic
• Antibiotics natural products made by microbes,
  effective against other microbes
• Semi-synthetic antibiotics use natural
  antibiotic as base, but modified chemically most
  of our new antibiotics
• Synthetic made chemically in their entirety

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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
• Microbiota (not plants!)
• Superinfection may result from this situation
• Overgrowth of normal microbes that cause
  disease
• Increased susceptibility to newly acquired
  microbes

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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.
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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.

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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.

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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

• Disk diffusion assay
• Paper disks with antibiotic applied to lawn in
  Petri dish
• Zone of inhibition indicates susceptibility to
  drug
• Broth dilution test to measure MIC
• Minimum inhibitory concentration
• Drug is diluted in broth which is inoculated
• Clear broth indicates that bacteria did not grow
  or were killed.
• That concentration of drug that first inhibits
  MIC

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Why bacteria might be resistant

• They are that way naturally
• Gram negative cell wall prevents antibiotics from
  entering the cell and reaching their targets.
• Some bacteria have no cell wall, so no target.
• The way they infect
• Some bacteria enter cells where antibiotic conc
  is low.
• Some bacteria are mutated
• Mutation changes the target for the antibiotic.
• Bacteria acquire new genes
• The new genes provide ways to foil the drugs

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Mechanisms of drug resistance(How do they do it?)

• Alteration of target active site of enzyme
  changes, change in ribosome means drug no longer
  binds.
• Antibiotic either cant get in or cant stay in
  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
Bacterial enzymes (beta lactamases
penicillinases) destroy this ring. Penicillins no
longer work. Some penicillins were created to
resist these enzymes.
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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)
• Full time course needed 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 all drug at sufficiently high concentration
• 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
• New drugs

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Penicillins Penicillins
amoxicillin Amoxil
ampicillin Penbritin
co-amoxiclav Augmentin
flucloxacillin Floxapen
phenoxymethylpenicillin Penicillin V
Common antibiotics inhibiting cell wall synthesis
Cephalosporins Cephalosporins
cefaclor Distaclor
cefalexin Ceporex, Keflex
cefotaxime Claforan
Other
vancomycin Vancocin
bacitracin
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Common antibiotics inhibiting protein synthesis
Macrolides Macrolides
clarithromycin Klaricid
erythromycin Erymax, Erythrocin, Erythroped
azithromycin Zithromax
Tetracyclines Tetracyclines
doxycycline Vibramycin
oxytetracycline Oxymycin, Oxytetramix
tetracycline  
Aminoglycosides Aminoglycosides
gentamicin Cidomycin
neomycin Nivemycin
Others Others
chloramphenicol  
clindamycin Dalacin C
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Common antibiotics nucleic acid targets
Quinolones Quinolones
ciprofloxacin Ciproxin
levofloxacin Levaquin
Others Others
metronidazole Flagyl
rifampicin  
Disruption of membrane function
Others Others
polymyxin B Anti-fungal drugs (several)
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Antimetabolites
trimethoprim Monotrim
sulfamethoxazole
Combinations Amoxacillin and clavulanic
acid Augmentin Trimethoprim and
sulfamethoxazole Bactrim Neomycin, bacitracin
polymyxin Neosporin