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
Main route of erythromycin metabolism?
Demethylation in the Liver Eliminated in Bile (small portion in urine)
Erythromycin half life
1.5 hours
Erythromycin and clarithromycin both bind and inhibit which CYP
CYP 3A4
Drug interactions of Azithromycin?
None
Macrolides (other than Azithro) tend to cause drug reactions with which specific drugs
Carbamazepine Cyclosporin Disopyramide Midazolam Quinidine Rifampicin Triazolam and a bunch of others. 3A4 does a lot of shit…
Macrolide side effects.
- Relatively Safe - Stimulate GI motor activity (Vomiting, Cramps, Ab Pain) - Minor/Major Allergic Rxns - Stevens-Johnson Syndrome - Cholestatic Hepatitis (Jaundice, cramping, nausea, fever) - Pyloric stenosis in children of moms taking drug
How is erythromycin given orally
Enteric Coated capsules More stable salts, esters
Erythromycin estolate is a ____ ester. It is a _______ of erythromycin
Propionyl Lauryl sulfate prodrug
Purpose of the propionyl ester on Erythromycin estolate?
Drug is more lipophilic than erythro. alone Increased oral absorption and blood levels after admin.
What happens in Erythromycin estolate cholestatic jaundice
Bile becomes granular in duct Impeded flow Salts back into circulation No more macrolides after this
Erythromycin estolate is contraindicated for..
Patients with preexisting liver disease/dysfunction
Erythromycin estolate is used to treat…
Group A beta-hemolytic strep
Primary Syph
Amebic Dysyntery
Prophylactically to stop endocardiditis from viridans
What is Erythromycin Ethyl Succinate?
An ethyl succinate ester prodrug of erythromycin
Advantage to Erythromycin Ethyl Succinate?
Ethyl succinate ester makes the drug more lipophilic and increases absorption from oral admi
How is Erythromycin Ethyl Succinate typically used?
Flavored oral suspension for pediatric patients
Relationship of Clarithromycin and Erythromycin
Cl is the C6 methyl ether of Ery Blocks ketal formation, increased stability
Fun fact about Clarithromycin metabolites…
The 14-R-hydroxy metabolite of Clarithromycin has greater antibiotic activity than Clarithromycin
The 14-R-hydroxy metabolite of Clarithromycin is especially effective against…
H. influenzae
Clarithromycin. Mechanism of administration
Oral suspension Tablets Extended-release tablets
How does Azithromycin prevent cyclic ketal formation?
Removal of Carbonyl Oxygen, Addition of N-ch3 group
Relationship between Azithromycin and Erhythromycin half lives. So what?
Azi – 68 hours Ery – 1.5 hours Infrequent doses help out with noncompliant patients
The concentration of Azithromycin in the tissue can up over ____ times higher than in the plasma
50
What might form complexes with Azithromycin that prevent absorption?
Magnesium Aluminum
Major route of Azithromycin elimination?
Biliary Over about a week, 6% appears as unchanged drug in the urine
Azithromycin is especially active against…
G- Better than erythromycin, clarithromycin
Most common side effects of Azithromycin
Diarrhea Nausea Ab Pain Vomiting
Identify.
Vancomycin
Identify
Erythromycin Estolate
Identify.
Erythromycin Ethyl Succinate
Identify.
Clarithromycin
Identify.
Azithromycin.
