2: Clindamycin + Tetracyclines + Chloramphenicol Flashcards
where does clindamycin come from?
lincomycin treated with chlorine + triphenylphosphine in acetonitrile
clindamycin MOA
- same as macrolides
- inhibits protein synthesis - binds 23S RNA at same site as erythro
*antagonism/cross resistance b/w clinda and erythro
clindamycin uses
- aerobic G(+) cocci (staph, strep)
- anaerobic G(-) bacilli (bacteroides, fusobacterium)
- bone infections w/ S. aureus
- severe acne
- bacterial vaginosis
- replaced penicillin for lung abscesses, anaerobic lung and pleural space infections
- MRSA
- IV w/ pyrimethamine + lucovorin for AIDS toxoplasma encephalitis
clindamycin admin
- capsules, oral suspension
- IV: clindamycin phosphate
- topical: clindamycin HCl/ clindamycin phosphate
clindamycin metabolism
CYPs in liver -> inactive sulfoxide + N-demethylated derivative
clindamycin PK:
- % absorbed?
- where it goes?
- excretion?
- half life?
- 90% absorbed from GI
- penetrates CNS (tx of cerebral toxoplasmosis in HIV)
- excreted in urine/bile
- t1/2 = 1.5-5h
what happens to clindamycin in hepatic failure?
accumulates
clindamycin AE
- diarrhea
- pseudomembranous colitis (C. diff inherently resistant, treat w/ metronidazole or vancomycin)
- nausea
- vomit
- abdominal cramping
- rash (hypersensitivity)
where do tetracyclines come from?
broad spec from streptomyces (mummy bones)
tetracycline contraindications
form stable chelates w/ polyvalent metal ions (Ca2+, Al3+, Cu2+, Mg2+) -> insoluble:
- don’t give w/ foods rich in Ca, antacids, hematinics w/ Fe
- give metals 1h before or 2h after tetracycline
- chelates Ca during tooth formation -> permanently gray/brown that worsens w/ time due to photo-oxidation rxn (don’t give to kids)
- pain on injection due to formation of insoluble Ca complexes so now inject w/ EDTA to chelate Ca
describe epimerization of tetracyclines
deprotonation -> followed by reprotonation, but in opposite orientation, rendering it inactive
describe dehydration of tetracyclines
- tertiary benzylic -OH at C6 is antiperiplanar w/ proton at C5a -> set up for dehydration
- results in 4-epianhydrotetracycline (inactive, toxic)
describe toxicity of 4-epianhydrotetracycline
produces Fanconi-like syndrome: failrue of reabsorption mechanism in PCT
-electrolytes not reabsorbed -> water follows electrolytes -> increased urine output, dehydration, electrolyte imbalances
what two tetracyclines do not form the toxic intermediate? why?
minocycline, doxycycline
-do not have -OH at C6 position
what happens to tetracyclines in basic solution?
cleavage -> forms a lactone product that is inactive
tetracycline MOA
- binds 30S subunit, blocks anticodon-codon interaction in A site, resulting in termination of peptide growth
- does not overlap with erythromycin binding site
- can inhibit human protein synthesis, but eukaryotes don’t have a tetracycline uptake mechanism, so usually not a problem
- binds in 6 different spots; Tet1 has highest occupancy
tetracyclines uses
- acne
- chlamydia (trachoma, psittacosis, salpingitis, urethritis, LGV)
- Rickettsia (typhus, RMSF)
- brucellosis
- spirochetes (borreliosis, syphilis, Lyme disease)
tetracyclines structures
study cheat sheet
tetracycline: contraindications
decrease oral absorption 50% if taken with food or milk
tetracycline: original organism
strep aureofaciens
demeclocycline: contraindications
decrease oral absorption 50% if taken with food or milk
demeclocycline: why slower dehydration than tetracycline?
2nd -OH at C6 -> secondary cation intermediate is less stable and has higher energy barrier to overcome
demeclocycline: original organism
strep aureofaciens
minocycline: contraindications
decrease oral absorption 20% if taken with food or milk
minocycline: bioavailability
90-100% orally
minocycline: why no toxic intermediate?
no -OH at C6
minocycline: original organism
from demeclocycline
minocycline: AE
vestibular toxicities
oxytetracycline: contraindications
decrease oral absorption 50% if taken with food or milk
oxytetracycline: bioavailability
60%, orally (not great therapeutically), but most hydrophilic tetracycline
oxytetracycline: original organism
strep rimosis
doxycycline: contraindications
decrease oral absorption 20% if taken with food or milk
doxycycline: bioavailability
90-100%, orally
doxycycline: why no toxic intermediate?
no -OH on C6
doxycycline: why is it the preferred tetracycline?
- good bioavailability
- lesser degree of absorption reduction w/ food/milk
- less GI sx
- no toxic intermediate
- t1/2 = 18-22h (once a day dosing)
where does chloramphenicol come from?
strep venezuelae
chloramphenicol MOA
- binds reversibly to 50@ at a site near the site for erythro/clinda (competitive binding interactions among these drugs)
- inhibits peptidyl transferase -> blocks peptide bond formation b/w P and A sites
chloramphenicol uses
- ointment/eye drops: bacterial conjunctivitis
- chloramphenicol Na succinate = prodrug for IV/IM admin:
- hydrolyzed to chloramphenicol in liver
- bacterial meningitis
- typhoid fever
- Rickettsial infections
- intraocular infections
why is it important that chloramphenicol is lipid soluble?
remains relatively unbound to plasma proteins -> penetrates into all tissues, including brain
chloramphenicol resistance: 3 mechanisms
- decrease membrane permeability
- mutation of 50S subunit
- elaboration of chloramphenicol acetyltransferase (don’t bind 50S)
chloramphenicol toxicity, worst one
aplastic anemia:
- rare, but generally fatal
- weeks to months post treatment
- highest risk w/ oral suspension
- lowest risk w/ eye drops
- keep blood levels
chloramphenicol toxicity, common ones
- bone marrow suppression due to impairment of mitochondrial fxn once you reach a cumulative dose of 20g (completely reversible)
- increased risk of childhood leukemia + risk increases with length of treatment
- adults: nausea, vomit, diarrhea (rare in kids)
chloramphenicol metabolism
turned into its glururonide in liver (inactive) -> excreted by kidneys
-therefore must decrease dose if decreased hepatic fxn
why should you never give neonates chloramphenicol?
they can’t metabolize it
