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23 Cards in this Set
- Front
- Back
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Mechanism of macrolides
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Blocks protein synthesis by binding to domain V of 23S ribosomal subunity. 23s is part of 50s.Specifically an adenine.
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Resistance to macrolides happens how.
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Mutation of 23S rRNA (replace adenine), methylation of same thing. The methylation can be constitutive or inducible (only when exposed to macrolide). Efflux pump. All methods of resistance give cross-resistance to all macrolides.
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Erythromycin
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Model macrolide. Free base is unstable at acid pH. Large Vd. Concentrated in liver and excreted in bile and metabolized by p450.
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Potential improvements of erythromycin
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Broader spectrum. Increased acid stability. Decreased GI stimulation (binds to motilin receptor), reroute around p450, increased tissue penetration.
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Clarithromycin
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Macrolide with minor modification. Fewer GI affects than erythromycin, higher tissue concentrations, metabolized by p450 still.
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Azithromycin
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Extremely high tissue concentration (10-100x plasma conc), no GI stimulation, no p450 metabolism, expanded spectrum. More periodic dosing.
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Adverse affects of macrolides.
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Pretty safe.
Erythro- cholestatic hepatitis, epigastric disress. Clarithro-acute psychosis or mania All can give expanded QT interval. |
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Ketolides (telithromycin)
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derived from erythromycin. Binds to Domain V AS WELL AS Domain II. This makes Telithromycin active against macrolide-resistant organisms. It is also not a substrate for the efflux pump. Only used for community acquired pneumonia because of high risks of liver damage or failure.
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Lincosamides (Clindamycin)
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Binding identical to macrolides. Methylation gives resistance again. Does not induce methylase so inducible resistance does not occur. Staph and Strep and most significantly against anaerobic organisms like B. fragilis. High affinity for osseous tissues.
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D-Test
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Plates with erythromycin and clindamycin close to each other and it gives a D shape because of induced methylase by erythromycin. If they are resistane to erythromycin than they are considered resistant to clindamycin as well even if they work on an agar.
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Streptogramins (quinupristin/dalfopristin 30:70 {synercid})
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binds to 50S ribosome at two distinct sites which gives synergism. Good activity against many resistant Gm+ organisms. Not a frontline drug. Metabolized by CP3A4 which can give poor interactions. Must be given through a central line and can be relatively painful.
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Oxazolidinone (Linezolid)
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Unique binding site on ribosome. Active agasint Gm+ resistant organisms. Staph, Strep pneumo., enterococci. ~100% bioavailability. No metabolism of other drugs. Can get heahache, myelosuppresiion, peripheral neuropathy.
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Chloramphenicol
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Well absorbed PO. Not a macrolide but does bind to 50S of ribosome. Large Vd including CNS. Resistance due to chloramphenicol acetyl transferase in bacteria. Use is severely restricted to only where no other antibacterial is effective.
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Chloramphenicol bad effects
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Bone marrow suppression. Anemia, normocellular bone marrow, develops during therapy. Aplastic anemia is the really bad one that is not dose related. Pancytopenia and purpura. Can develop up to 6 months after therapy stopped. Fatal potentially.
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Gray (baby) syndrome.
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Inadequate metabolism of chloramphenicol. Cyanosis, respiratory irregularities, ashen color to skin, vasomotor collapse.
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Tetracyclines (Tetra, minocycline, doxycycline)
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Cause misreading of mRNA because of binding to 30s but they don't stop protein synthesis. Accumulate high intracellular concentrations . At a certain high level they actually inhibit protein synthesis. Get negative nitrogen balance. Resistance is because of active pumping out of the cell. Very broad spectrum. With later generations we get longer half-life.
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Adverse affects of tetracyclines.
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Normal stuff. Decreased absorption when heavy metals are present such as Ca, Al, Mg, Fe in antacids. Phototoxicity (don't get in the sun), GI irritation. Vestibular toxicity, discoloration of teeth, malformation of bones. Can get hyperpigmentation on skin as well.
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Glycylcyclines (tigecycline)
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Similar to tetracyclines but glycine residue added and gives higher affinity forthe ribosome. Usually unaffected by efflux pump.Effective in vitro against many multidrug-resistant pathogens. High incidence of nausea and vomiting.
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Aminoglycosides
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Energy dependent uptake that requires oxygen and one that does not (faster). Causes misreading of mRNA by binding 30s and interfering with initiation of complex formation. Cidal. Can get nonfunctional proteins. Main function is for Gm- organisms. Confined to extracellular fluids. Eliminated by kidneys. Dosed on the basis of lean body mass (mg/kg/day)
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Aminoglycosides resistance.
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Achieved by porins, altered binding site, and metabolism by pathogen. They have sugars that are distributed in extracellular fluids almost exclusively because of polarity.
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Aminoglycoside examples.
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Neomycin, Gentamicin, Netilmycin, Kanamycine, Streptocin, Amikacin. Major drugs for systemic disease. Streptomycin for TB. Kanamycine for sterilization pre-surgery. Neomycin is topical only because of toxicity. Paromomycin for intestinal parasites.
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Aminoglycosides Absorption and metabolism traits.
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Poorly absorbed PO. Primarily confined to extracellular fluids. Eliminated primarily by kidneys. Dosed on the basis of lean body mass. Need to give loading dose on day one and two maintenane doses. 3x daily after that of standard dose. We do have new form that only requires once daily administration but don't use in CF.
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Adverse effects for aminoglycosides.
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Ototoxicity for auditory, vestibular, or hair cells. Nephrotoxicity in proximal renal tubule. Neuromuscular blockade. If you have low trough levels on the concentration this is good because we don't have high concentrations in the ear for a long time.
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