Antibiotics 2 - Vancomycin and Macrolides Flashcards
Vancomycin is what type of compound
Glycopeptide
Vancomycin is an inhibitor of…
Gram+ cell wall biosynthesis
*BInding of the peptidyl side chain D-ala-D-ala in the peptidoglycan precursor
**Inhibits the transpeptidation required for PG crosslinking
Vancomycin effects and spectrum
Bactericidal, effective against Gram + bacteria
What is the threshold for a “susceptible strain” in Vancomycin treatment?
Staph strains that are methicillin resistant are usually inhibited with…
MIC of 4 μ/mL
…with MIC of 1-5 μ/mL
VRE is connected to the use of ____
Avoparcin
(a glycopeptide AB)
Mechanism of resistance (VRE)
Mutation in precursor to PG cell wall
D-ala-D-ala –> D-ala-D-lactate
(1000x less affinity for the lactate one)
Vancomycin potential sides (3)
Hypersensitivity response
Nephrotoxicity (.1-1%)
Ototoxicity (rare)
Macrolide AB’s are ________
and _______
Macrocyclic lactones
Polyketides (sequential addn of proprionate groups to a growing chain)
Macrolide site of protonation
The N on the desosamine sugar
Production of Erythromycin
Propriony-CoA
(saccharopolyspora erythrea)
Erythronolide
(Converge with deoxyheose)
Erythromycin
pHa of the amine in erythromycin
8.8
The amine in erythromycin can form salts that are more soluble, including ___ and ____
Glucoheptonic acid
Lactobiononic acid
During peptide bond formation (transpeptidation), the polypeptide attached to the tRNA in the ____ is transferred to _____
polypeptide in the P site is transferred to the amino group of the aminoacyl-tRNA in the A site
Macrolides inhibit protein synthesis by binding _______
irreversibly to the P site – inhibiting the translocation from A to P
Macrolide binding involves the bacterial _____ and not _____
the bacterial 23S RNA and not the protein
Macrolide may be _____ or _____ depending on _______
bacteriostatic
bactericidal
concentration
Macrolides accumulate within ______
leukocytes
*transported to site of infection
Four mechanisms of macrolide resistance:
- Induction of lactone ester hydrolase (degrades by hydrolysis)
- Drug induced production of RNA methylase (methylated A2058 prevents eryth from binding to 50S)
- Adenine-> Guanine at A2058 (same as above)
- Efflux pump (active transport)
Resistance management for macrolides is especially important in regards to…
respiratory infections
Intrinsic macrolide resistance organisms
Pseudomonas
Enterobacter
Acidic inactivation of the parent molecule (macrolide) is a formation of _________________
intramolecular acid-catalyzed ketal formation
Oral erythromycin is administered as ____ or ______
enteric coated tablets or more stable salts or esters
(Macrolide) Acid stability can be achieved with the ______
6-OCH3 derivative
=blocks ketal formation at low pH
–> enhances oral absorption
**this is CLARITHROMYCIN
Amine analog that is acid stable
Azithromycin
Azithromycin structural difference
N-methylated methylene-amino moiety replaces the C9 ketone
Main route of erythromycin metabolism
demethylation in the liver
—> main elimination route is in the bile
Erythromycin half life
1.5 hours
DDI for Erythromycin and clarithromycin
Lower DDI drug?
They bind and inhibit 3A4
Dirithromycin has reduced capacity to inhibit p450’s
Drugs that interact with macrolides
- Carbamazepine
- Cyclosporin
- Disopyramide
- Midazolam
- Quinidine
- Rifampacin
- Rifabutin
- Theophylline
- Triazolam
- Zidovudine
___ and ____ reduce the activity of erythromycin
rifampacin
rifabutin
Other drugs that can have DDIs with macrolides
ergotamine
digoxin
methylprednisone
14-membered macrolides stimulate ______
GI motor activity
Serious allergic/immune responses from macrolides include ___ and ____
Steven-Johnson syndrome
Toxic epidermal necrolysis
Long term macrolide use can induce…
reversible cholestateic hepatitis
Erythromycin can increase the probability of ____ in kids whose mothers took the med during pregnancy or breastfeeding
pyloric stenosis
Erythromycin is inactivated by gastric acids, so all formulations are…
given as enteric coated capsules
Erythromycin is rapidly absorbed and accumulates in high concentrations within…
phagocytes
During active ____, large amounts of Erythromycin are released
phagocytosis
the propionyl ester, lauryl sulfate prodrug of erythromycin
Erythromycin estolate
2 functions of the propionyl ester group in erythromycin estolate
- makes the drug more lipophilic than erythromycin itself
- increases oral absorption and blood levels of erythromycin after oral administration
Pathophys of the erythromycin induced Cholestatic jaundice
- The bile becomes granular in the bile duct
- Granules impedes bile flow
- Bile salts back up into the circulation
What must you do if a patient develops cholestatic jaundice while being given erythromycin
drug must be replaced by a nonmacrolide antibiotic
Erythromycin estolate is contraindicated in
patients with preexisting liver disease or dysfunction
Erythromycin Estolate is used to treat… (4)
- Beta hemolyric strep
- Primary siphilis
- amebic dysentery
- Viridans endocarditis prophylaxis
Erythromycin Ethyl Succinate
- It is a ______
- It is more ______ than erythromycin
- It is used as a ________
- It’s an ethyl succinate ester prodrug
- It is more lipophilic and orally available
- it is used as flavored oral suspension for kids
Clarithromycin is the ________ of erythromycin
What does this do?
the C-6 methyl ether of erythromycin
It blocks ketal formation and makes it more stabile in acid
Clarithromycin results in ________ due to reduction of ketals
reduced gastric upset
(gastric upset is usually caused by ketal degradation products)
Clarith forms a _____ compound
Which is especially good against _____
14-(R)-Hydroxy metabolite
H. influenzae
Structure of azith: its a ____ ring (why?)
15 membered lactone ring
because an N-CH3 group has been inserted between C9 and C10, and the carbonyl Oxygen has been removed
Azith half life compared to eryth
Longer - terminal half life 68 hours
Magnesium / aluminum and Azithromycin?
Forms coordination complexes - prevents absorption
Major route of elimiation of azithromycin
Azithromycin has a greater activity against ____ than erythromycin or clarithromycin
Gram negatives
Most common side effects of azith
Diarrhea, nausea, abd. pain
