Clindamycin and Tetracyclines Flashcards
how is clindamycin synthesized?
from naturally occurring antibiotic Lincomycin
- treatment with chlorine and triphenylphosphine in acetonitrile
- inversion configuration
MOA of clindamycin
same has erythromycin
inhibits protein synthesis by binding to bacterial 50S ribosome
-binds same site as erythromycin
what is clindamycin most effective against?
- aerobic G+ cocci, including most staph/strep
2. anaerobic G- bacilli, including bacteroids and fusobacterium genera
what has clindamycin replaced that normally penicillin would be used for?
lung abscesses and anaerobic lung and pleural space infections
-can treat MRSA as well
clindamycin can treat systemic ______ infections from _______?
bone infections with staph. aureus or topically to treat severe acne
-vaginal cream for vaginitis
how is clindamycin administered to treat AIDS or toxo?
by IV with pyrimethamine and leucovorin to treat AIDS patients with encephalitis caused by toxoplasma gondii
clindamycin dosage forms
capsules, oral suspensions, IV (clindamycin phosphate), topical forms
metabolism of clindamycin
cytochrome P450 in liver
-metabolites: sulfoxide and N-demethylated derivative (both inactive)
how much of clindamycin is absorbed in GI tract?
90%
-widely distributed
does clindamycin penetrate CNS?
yes
-can be useful to treat cerebral toxoplasmosis in human immunodeficiency virus infected patients
half life of clindamycin
1-1.5 hours
elimination of clindamycin
clindamycin and metabolites excreted in urine abd bile
side effects of clindamycin
diarrhea, pseudomembranous colitis, V&N, abdominal cramps, rash
-topical application can cause dermatitis
lethal complication from clindamycin
pseudomembranous colitis
- overgrowth of C. difficile (resistant to clindamycin), results in production of a toxin that causes a range of adverse side effects like diarrhea to colitis and toxic megacolon
- treat with metronidazole or vancomycin
what do tetracyclines form?
chelation, form stable chelates with polyvalent metal ions such as calcium, Al, Cu, Mg
-chelates are usually insoluble
tetracyclines should NOT be administered with what kinds of food?
- calcium rich b/c calcium chelates are not absorbed by GI tract,
- antacids that contain multivalent metals
- hematinics containing iron
what if therapy with tetracyclines and multivalent metals cannot be avoided?
metals should be administered 1 hour before or 2 hours after tetracycline
why shouldn’t tetracycline be give to children while forming their permanent teeth?
will chelate with calcium during formation of teeth and cause permanent teeth to turn brown or grey.
why are injectable tetracycline formations contain EDTA?
pain on injection as been attributed to formation of insoluble calcium complexes, so EDTA is added to chelate calcium and they are buffered to acidic pH where chelation is suppressed
what is epimerization
hydrogen on amine bearing carbon atom is acidic and can undergo enolization and epimerization
-epitetracycline is inactive, but can cause tetracycline to lose potency because can occur in solid state as well as in solution, but slow in solid state and most rapid at pH4
how does dehydration occur with tetracycline?
teritary benzylic hydroxyl group at C6 has an antiperiplanar relationship with proton C5a, so set up for elimination
why should discolored tetracyclines be thrown out?
4-epitetra. is toxic to kidney and can produce Fanconi-like syndrome (failure of reabsorption mechanism in proximal convoluted tubule)
what pH do tetra. undergo cleavage?
pH8.5 or above-> inactive
MOA of tetra.
bind 30S subunit and inhibit bacterial protein synthesis by blocking attachment of the aminoacyl-tRNA to A site of ribosome-> termination of peptide chain growth
-inhibits of codon anticodon interaction
why is it less likely for tetra to inhibit host protein synthesis?
eukaryotic cells don’t have an uptake mechanism for tetracycline
most common use of tetracycline
acne -but also for: c hlamydia, rickettsia, brucellosis, spirochetal infections (lyme, borreliosis, syphilis) anthrax tularemia legionnaires disease
what lowers tetracycline absorption?
milk and food, by 50%
dehydration rate difference in tetracycline versus demeclocycline
dehydration in demeclocycline is slower because of hydroxyl and C6 position is secondary-> forms secondary intermediate
what lowers demeclocycline absorption?
food and milk, by 50%
does Minocycline undergo dehydration?
No, does NOT contain C-6 hydroxyl group
-NO potential for 4-epitetra. toxicity either
what lowers minocycline absorption?
food and milk, by 20%
-also has 90-100% oral bioavailability
what side effects does minocycline have that other tetracyclines don’t?
vestibular toxicities: vertigo, ataxia, nausea
oxytetracycline
bioavailability of 60%
-reduced by 50% when taken with food or milk
doxycycline
doesn’t undergo dehydration
- 90-100% bioavailability
- absorption lowered by 20% when taken with food or milk
- half life 18-22 hours, permits one day dosing
chloramphenicol
not as used because of toxicities
MOA of chloramphenicol
binds reversibly to 50S ribosomal subunit at site that is near the site for erythromycin and clindamycin
- competitive binding interactions
- inhibits peptidyl transferase activity of ribosome and thus blocks peptide bond formation between P and A sites
main therapeutic use of chloramphenicol
ointment or eye drops to treat bacterial conjunctivitis
-chloramphenicol sodium succinate-> prodrug for IV and IM-> hydrolyzed in liver: treats typhoid fever, rickettsial, intraocular infections, etc.
chloramphenicol characteristics
- lipid soluble
- remains relatively unbound to plasma proteins
- penetrates effectively into all tissues of the body, including brain
what are the three ways resistance formed for chloramphenicol
- mutation of 50S ribosomal subunit
- reduced membrane permeability
- elaboration of chloramphenicol acetyltransferase-> acetylates one or both hydroxy groups to form metabolites that do not bind to 50S ribosomal subunit
toxicity with chloramphenicol
aplastic anemia
- high risk orally, low risk with eye drops
- recommended to monitor blood levels when taking chloramphenicol to keep it less than 25 micrograms/mL
bone marrow suppression-> impairment of mitochondrial function from protein synthesis inhibition
childhood leukemia
N&V and diarrhea in adults but rarely children
MOA of chloramphenicol
metabolized to glucuronide in liver-> inactive and excreted by kidneys
- reaction is catalyzed by glucuronyl transferase and therefore chloramphenicol dosage should be reduced in those with hepatic function impairment
- neonates cannot metabolize chloramphenicol
