Macrolide Antibiotics Flashcards
During peptide bond formation, the polypetide attached to the tRNA in the P site of the ribosome is transferred where?
transferred to the amino group of the aminoacyl-tRNA in the A site (transpeptidation) - ribosome then moves to the next codon
What happens to the empty tRNA?
ejected and the peptidyl-tRNA is shifted from the A site to the P site (translocaiton) - new aminoacyl-tRNA then binds to the A site
How do macrolides inhibit bacterial protein synthesis?
by binding reversibly to the P site of the bacterial ribosome
What does reversibly binding to the P site of the bacterial ribosome do?
inhibits translocation of peptidyl-tRNA from the A site to the P site
Macrolide binding mainly involves what?
the bacterial 23S RNA and not the protein
Where do macrolides tend to accumulate?
within leukocytes
What is significant about macrolide accumulation inside leukocytes?
They are therefore actually transported into the site of infection
Four basic mechanisms of macrolide resistance:
- lactone ester hydrolase induced
- drug-induced production of an RNA methylase
- mutation of adenine to guanine at the specific site A2058
- An efflux pump ejects drugs from the cell by an active transport process
What do efflux pumps do?
ejects drugs from the cell by an active transport process
How can you reduce the incidence of resistant S. pneumoniae strains?
reduce the use of macrolide antibiotics
What organisms exhibit intrinsic resistance by not allowing entry of macrolide antiobiotics?
Pseudomonas spp. and Enterobacter spp.
Why is oral erythromycin administered as enteric coated tablets or as more stable salts or esters?
under acidic conditions, macrolide antibiotics undergo intramolecular acid-catalyzed ketal formation and the ketal reaction product is inactive
Clarithromycin
6-OCH3 derivative
Describe Azithromycin
acid stable with reliable absorption
N-methylated methyleneamino moiety replaces the C-9 ketone (ketal formation is no longer possible)
main route of erythromycin metabolism
demethylation in the liver
main route of erythromycin elimination
in the bile, and a small portion in the urine
Erythromycin and clarithromycin can bind and inhibit?
CYP3A and related P450 isozymes
Drug interactions with dirithromycin?
has reduced capacity to inhibit P450 isozymes
Drug interactions with azithromycin?
no reported cases of significant drug interactions
Potential drug interactions can be expected with macrolides (ex. Azithromycin) and which drugs that are also metabolized by P450 enzymes?
carbamazepine, cyclosporin, disopyramide, midazolam, quinidine, rifampicin, rifabutin, theophylline, triazolam, zidovudine
What do the 14-membered macrolides strongly stimulate which induces a side effect?
strongly stimulates gastrointestinal motor activity and can cause vomiting, gastric cramps and abdominal pain
Serious side effects that may occur but are rare with macrolides.
Stevens-Johnson syndrome and toxic epidermal necrolysis
What can long term (10-20 days) use of macrolide antibiotics induce?
reversible cholestatic hepatitis which will manifest as a jaundice with cramping/nausea/fever - relieved upon termination of drug therapy
Erythromycin has been shown to increase the probability of what in children whose mothers took the drug during the late stages of pregnancy or while nursing.
pyloric stenosis
Describe cholestatic jaundice
bile becomes granular in the bile duct impeding bile flow, so bile salts back up into the circulation
What should you do when cholestatic jaundice occurs with erythromycin estolate use?
the drug should be replaced by a nonmacrolide antibiotic
When is erythromycin estolate contraindicated?
in patients with preexisting liver disease or dysfunction
What is erythromycin estolate used to treat?
group A beta-hemolytic streptococcal infections, primary synphilis, amebic dysentery, and prophylactically prior to surgery to prevent endocarditis caused by alpha-hemolytic streptococci (viridans group)
How is erythromycin ethyl succinate be used?
used as a flavored oral suspension for pediatric use to mask the bitter taste, or as coated tablets
C-6 methyl ether of erythromycin
clarithromycin
How is clarithromycin better than erythromycin?
it has better oral absorption and produces higher blood levels - also, less gastric upset
Why is azithromycin an advantage in patients who comply poorly?
azithromycin has a longer half-life than erythromycin, allowing once-a-day dosage
What can form coordination complexes with azithromycin and prevent absorption?
magnesium and aluminum present in some antacids
Major route of elimination of azithromycin?
biliary excretion of azithromycin, predominately unchanged
Azithromycin has greater activity against?
gram (-) bacteria
Common side effects of azithromycin?
diarrhea, nausea, abdominal pain, and vomiting - allergic reactions extremely rare
