Vancomycin and Macrolides Flashcards
vancomycin and teicoplanin
glycopeptides
-both in clinical use
what does vancomycin do?
inhibitor of G(+) cell wall biosynthesis
MOA of vancomycin
binding to the peptidyl side chain D-alanyl-D-alanyl terminus in the peptidoglycan precursor -> process of cross-linking
-transpeptidase reaction that is required for cross-linking is inhibited by high affinity binding of vancomycin to the substrate.
how have bacteria become resistant to vancomycin?
mutation of the peptidoglycan cell wall precursor from D-A-D-A to D-A-D-Lactate
-vancomycin does not inhibit transpeptidase with this mutation because has 1000 less affinity
what are some rare complications from vancomycin?
nephrotoxicity and ototoxicity-> associated with high concentrations of drugs
-red skin rash and potential anaphylaxis
erythromycin
mcrocyclic lactones
-14 membered lactone ring
what is essential to macrolide antibiotics?
deoxyhexose sugars
why is the pKa of erythromycin important?
pKa= 8.8
allows to form stable salts that are more soluble
MOA of macrolides
inhibit bacterial protein synthesis by binding reversibly to the P site of the bacterial ribosome-> inhibit translocation of peptidyl-tRNA from A site to P site
what ribosome to macrolides bind to?
23S RNA
macrolide action is mainly
bacteriostatic
how are macrolides transported to site of infection?
accumulate in leukocytes, there transported directly to infection
resistance: lactone ester hydrolase
is induced to degrade the macrolides by hydrolysis of the macrocycle.
resistance: drug induced production of?
RNA methylase
-methylates an adenine base on the 23 S RNA of the 50S ribosomal subunit-> inhibits binding of macrolides to 50S subunit
resistance: mutation of which base?
adenine to guanine at specific A2058 site
-10,000 fold reduction in binding of erythromycin and clarithromycin to 23 S ribosomal RNA
resistance: evolved way to get ride of drugs?
efflux pump ejects drugs from the cell by an active transport process
how can erythromycin be inactivated?
under acidic conditions by a process involving the 6-OH group
-intramolecular acit-catalyzed ketal-formation
the ketal-formation is active or inactive?
inactive
how is erythromycin orally administered?
enteric coated tablets or more stable salts or esters
how can acid stability be achieved?
with a 6-OCH3 derivative-> enhances oral absorption
what does the 6-OCH3 do to erythromycin stability?
blocks ketal formation at low pH
what is the name of the antibiotic with a 6-OCH3?
clarithromycin
what antibiotic is the amine analog that is more acid stable?
azithromycin
- reliable absorption
- N-methylated methyleneamino moiety replaces C-9 ketone-> no ketal formation
how is erythromycin degraded?
demethylation in liver
-elimination route in bile ( small % in urine)
erythromycin half life
1.5 hours
what do erythromycin and clarithromycin both do?
bind and inhibit CYP3A and related P450 enzymes
-can increase activities of certain drugs due to inhibition of their metabolism
what two drugs reduce the activity of erythromycin?
rifampicin and rifabutin
what is the common side effects with 14-membered macrolides?
stimulate GI motor activity: V, gastric cramps, abdominal pain
what are rare but serious side effects of macrolides?
steven’s johnson syndrome and toxic epidermal necrolysis
how does erythromycin cause jaundice?
long term use (10-20 days) can induce reversible cholestatic hepatitis which manifests as jaundice with cramping/ nausea and fever
-relieved upon termination of drug therapy
what is a side effect of a pregnant women or while nursing who take erythromycin?
increased probability of pyloric stenosis in child
prodrug of erythromycin?
erythromycin estolate
propionyl ester, lauryl sulfate
what does the propionyl ester do for erythromycin estolate?
makes it more lipophilic than erythromycin itself-> increases oral absorption and blood levels of erythromycin after oral administration
what can be a complication from erythromycin estolate?
cholestatic jaundice
-bile becomes granular impede bile duct flow> backed up bile salts get into circulation
erythromycin estolate is contraindicated in?
people with liver disease or dysfunction
what is erythromycin estolate used to treat?
GABH strep
syphilis
amebic dysentery
prophylactically prior to surgery to prevent: endocarditis from alpha-hemolytic strep (viridans group)
erythromycin ethyl succinate
- also makes more lipophilic and increases absorption
- used as flavored oral suspension for pediatric use to mask bitter taste, or as coated tablet
clarithromycin
ketal formation blocked by C-6 methyl ether
what has better antibiotic activity that clarithromycin itself?
its metabolite-> 14-R-hydroxy
-especially against H. influenza
why is clarithromycin better to use than erythromycin?
better oral absorption
high blood levels
produces less GI upset b/c of blocked ketal formation
how is azithromycin different from erythromycin and clarithromycin?
15 membered lactone ring-> N-CH3 been inserted between C 9 and 10, carbonyl oxygen removed
-prevents cyclic ketal formation
is azithromycin stable in acidic conditions?
yes
what is azithromycin half life?
terminal half life of 68 hours
-concentration of azithromycin in tissues can be 50 times higher than in plasma
why shouldn’t antacids be taken with azithromycin?
Mg and Al can form coordination complexes with azithromycin and prevent absorption
how is azithromycin predominantly excreted?
biliary excretion
what bacteria does azithromycin target?
gram negative
most common side effects of azithromycin?
diarrhea, azithromycin N&V, and abdominal pain
