Transcript lecture 03a-1

Antimicrobial Therapy
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• 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
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
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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 can’t get in or can’t 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.
http://dwp.fcroc.nl/microbiologie/images/antibiotica/de_wer4.gif
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Human behavior and antibiotic resistance
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• 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 aren’t killed, they become “normal”;
don’t stop regimen because you feel better.
• Social behavior
– resistance in homeless/poor
– growth stimulants in agriculture
http://www.dkp-ml.dk/images/homeless.jpg
Fighting antibiotic resistance
• Use all drug at sufficiently high concentration
– Don’t 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
– >50% of infections are viral; not affected by antibiotics
– Constant exposure breeds resistance
• New drugs
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Penicillins
amoxicillin
Amoxil
ampicillin
Penbritin
co-amoxiclav
Augmentin
flucloxacillin
Floxapen
Common
antibiotics
inhibiting cell wall
synthesis
phenoxymethylpenicillin Penicillin V
Cephalosporins
cefaclor
Distaclor
cefalexin
Ceporex, Keflex
cefotaxime
Claforan
vancomycin
bacitracin
Other
Vancocin
Common antibiotics inhibiting protein synthesis
Macrolides
clarithromycin
erythromycin
azithromycin
Tetracyclines
doxycycline
oxytetracycline
tetracycline
Aminoglycosides
gentamicin
neomycin
Others
chloramphenicol
clindamycin
Klaricid
Erymax, Erythrocin, Erythroped
Zithromax
Vibramycin
Oxymycin, Oxytetramix
Cidomycin
Nivemycin
Dalacin C
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Common antibiotics: nucleic acid targets
Quinolones
ciprofloxacin
levofloxacin
Others
metronidazole
rifampicin
Ciproxin
Levaquin
Flagyl
Disruption of membrane function
Others
polymyxin B
Anti-fungal drugs (several)
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Antimetabolites
trimethoprim
sulfamethoxazole
Monotrim
Combinations
Amoxacillin and clavulanic acid
Trimethoprim and sulfamethoxazole
Neomycin, bacitracin & polymyxin
Augmentin
Bactrim
Neosporin