Vancomycin + Macrolides Flashcards
European version of Vancomycin
Teicoplanin
What is vancomycin anyway?
A nonribosomal glycopeptide antibiotic
How is vancomycin made
Fermentation of Nocardia orientalis
Vancomycin mode of action?
Inhibitor of G+ cell wall biosynthesis Binds the peptidyl D-Alanyl, D-Alanyl before cross-linking Transpeptidase can’t compete
Vancomycin What does it do
Bactericidal against G+ Bacterium with MIC below 4ug/mL
Vancomycin-resistant enterococcal infections came from where
Overuse of Avoparcin as a feed additive in European livestock
Mechanism of VRE resistance?
Mutation of the peptidoglycan cell wall from D-Ala D-Ala to D-Ala D-Lactate. Vancomycin does not have a strong affinity for this substrate.
Vancomycin toxicity?
Potential for a hypersensitivity Response Red skin rash, potential anaphylaxis
Potential Side effects of Vanco?
Nephrotoxicity (0.1-1% patients) Ototoxicity Minimized by careful dosing
Structure of Macrolides
Macrocyclic lactones (usually 14 membered lactone rings) Polyketides (made by sequential addition of proprionate groups)
How is erythronolide activated?
Converge with deoxyhexose biosynthesis Boom – Erythromycin
Secondary Macrolide metabolites are often produced by _____ bacterial stains
Streptomyces
The pKa of the amine in erythromycin is….. So what?
8.8 Can form salts that are more soluble
How do Macrolides stop bacteria?
Binding reversibly to the P site of the bacterial ribosome Inhibited translocation of peptidyl-tRNA from A to P
Macrolide binding mainly involves which bacterial ribosome subunit?
23S RNA
What cell do macrolides tend to accumulate in? So fucking what?
Macrophages Delivered to sites of infection
Four mechanisms of Macrolide resistance
- Lactone ester hydrolase hydrolyzes macrocycle 2. RNA methylase 3. Mutation of A->G at A2058 (erythro can’t bind it anymore) 4. Efflux Pump ejects drugs from the cell by active transport
What does RNA methylase do to promote Macrolide resistance
Methylates A2058 on the 23S ribosome RNA molecules of the 50S subunit. No binding to 50S subunit
Why don’t erythromycin-producing organisms have toxic effects from their byproduct?
They use the ribosomal methylation technique to protect themselves.
How do pseudomonas and enterobacter protect themself from macrolides?
Intrinsic resistance/Not allowing entry
Why is oral erythromycin administered with enteric coated tablets?
Parent molecule inactivated in acid
Problems with acid inactivated erythromycin?
Inactive, Produces GI cramping
How can you get that erythromycin to be stable in acid (by turning it into Clarithromycin)?
6-OCH3 derivative, which enhances oral absorption Blocks ketal formation You just made Clarithromycin!
How can you get erythromycin to be stable in acid (by turning it into Azithromycin)?
An N-methylated methylamino moiety replaces the C-9 ketone Can’t make a ketal anymore
