2: Vancomycin + Macrolides Flashcards
what type of drug is vancomycin? how many of this type of drug are there?
non-ribosomal glycopeptide
-only 2 (this and teicoplanin)
vancomycin MOA
inhibits G(+) cell wall synthesis by covering D-Ala-D-Ala terminus, so PG can’t react w/ neighboring PG
what dose of vancomycin is bacteriocidal
1-5 ug/mL
resistance to vancomycin associated with what?
VRE connected to avoparcin use (livestock feed additive), but reversible (decreased resistance when stopped avoparcin use)
mechanism of vancomycin resistance?
D-Ala-D-Ala replaced by D-Ala-D-Lac (1000x reduced affinity)
toxicity/side effects of vancomycin
- hypersensitivity: red skin rash + some anaphylaxis
- rare: nephrotoxicity/ototoxicity (associated with high [circulating drug])
macrolide structure
macrocyclic lactone, 14-member ring, polyketide
how are polyketides produced? what pattern does it produce?
sequential addition of propionate groups to growing chain -> results in methyl groups on alternating C’s
where does erythromycin A come from?
most from Streptomyces fermentation -> erythronolide intermediate
how can you make erythromycin more soluble?
pka is 8.8, so can form more soluble salts:
- glucoheptonic acid
- lactobiononic acid
macrolide MOA
- inhibit bacterial protein synthesis: bind reversibly to P site, preventing peptidyl-tRNA translocation (or bind b/w A and P sites, inhibiting peptide bond formation)
- binds on 23S RNA of 50S subunit
bacteriostatic or bacteriocidal?
bacteriostatic mostly, but can be bacteriocidal in high concentration
where do macrolides accumulate and why is this important?
in leukocytes -> transported directly to infection
4 mechanisms of macrolide resistance
- lactone ester hydrolase (hydrolyzes ring)
- methylated A2058 on 23S RNA (inhibits binding to 23S)
- A2058 -> G2058 (10,000x reduction in binding)
- efflux pump
what hypothesis did the discovery of methylation of A2058 as a macrolide resistance mechanism provide?
resistance may originate in the producing organism and then transfer to other bacteria
resistance to what other bug is associated with macrolide use?
S. pneumoniae
what two bugs have inherent macrolide resistance? what is the mechanism of their resistance?
Pseudomonas and Enterobacter
-don’t allow entry of drug
describe acid inactivation of macrolides - how does this affect oral administration of macrolides?
intramolecular acid-catalyzed ketal formation at 6-OH -> causes GI cramping
-oral erythromycin must be enteric coated or as a stable salt/ester
2 ways in which acid inactivation is overcome?
- Clarithromycin: 6-OCH3 instead of 6-OH blocks ketal formation
- Azithromycin: N-methylated methyleneamino instead of C9 ketone blocks ketal formation
describe macrolide metabolism
mainly demethylation in liver by CYP3A4
half life of erythromycin
1.5h
elimination of macrolides
mostly bile, small bit in urine
DDIs with each of the following macrolides:
- erythromycin
- clarithromycin
- azithromycin
erythro, clarithro inhibit CYP3A4 -> probs w/:
- carbamazepine
- cyclosporin
- disopyramide
- midazolam
- quinidine
- rifampicin
- rifabutin
- theophylline
- triazolam
- zidovudine
no reported cases with azithromycin
others: ergotamine, digoxin, methylprednisone
macrolide side effects:
- general
- rare
- long term use
- preg/nursing moms
- stimulate GI -> vomit, nausea, diarrhea, cramps, pain
- rashes (minor to severe)
- rare Stevens Johnson syndrome, toxic epidermal necrolysis
- long term use: reversible cholestatic hepatitis (jaundice + cramps, nausea, fever)
- late preg/nursing moms: increase risk of pyloric stenosis in kids
Erythromycin estolate (Ilosone): structure
propionyl ester, lauryl sulfate prodrug of erythro - makes it more lipophilic -> increases oral absorption, serum levels
Erythromycin estolate (Ilosone): side effects
some cholestatic jaundice: granular bile blocks duct -> bile salts in serum
Erythromycin estolate (Ilosone): contraindications
pre-existing liver disease
Erythromycin estolate (Ilosone): activity
- GABHS
- primary syphilis
- amebic dysentery
- endocarditis (surgery prophylaxis for viridans)
erythromycin ethyl succinate: structure
ethyl succinate ester prodrug of erythro - makes it more lipophilic -> increase oral absorption
erythromycin ethyl succinate: admin
flavored oral suspension or coated tabs
clarithromycin: structure
C6 methyl ether of erythro - blocks ketal formation, better oral absorption, less GI upset
clarithromycin: metabolism
bioactivation: 14-(R)-hydroxy metabolite has increased activity
clarithromycin: admin
- oral suspensions
- tablets
- extended release pills
azithromycin (zithromax, z pak): structure
15 member lactone ring w/ N-CH3 b/w C9 and C10 - blocks ketal formation
azithromycin (zithromax, z pak): half life, cause of this length?
68h -> once a day admin (due to extensive uptake and subsequent release of drug from tissues)
azithromycin (zithromax, z pak): contraindications
coordinates with Mg or Al (antacids) -> prevents absorption
azithromycin (zithromax, z pak): excretion
biliary excretion, predominately unchanged
azithromycin (zithromax, z pak): activity
G(-)
azithromycin (zithromax, z pak): side effects
GI:
- diarrhea
- nausea
- abdominal pain
- vomit
