tetracyclines and lincosamides Flashcards
tetracyclines and lincosamides inhibit ____
protein synthesis
what is the structure of a tetracycline
4 rings, parent aromatic compound is naphthacene
what color are tetracyclines
yellow
other chemistry characteristics of tetracyclines
bitter, crystalline, strong yellow fluorescence under UV light, amphoteric, form crystalline water soluble salts with strong acids and bases
what 3 substitutions for tetracyclines result in variable PK and antimicrobial activity
C5, C6, C7
tetracyclines have increased lipophilicity with ____ at C_
absence of hydroxylation at C6
what does the absence of hydroxylation at C6 with doxy, mino, and tige lead to
increased stability to degradation, increased fluid and tissue penetration, longer t1/2, enhanced antibacterial activity, higher fraction of plasma protein binding, higher volume of distribution and lower renal clearance
alterations at which faces of the tetracycline molecule lead to improved antimicrobial activity and PK properties
northern and western faces
alterations at which faces of the tetracycline molecule produce a considerable loss in antimicrobial activity
southern and eastern
tetracyclines inhibit bacterial protein synthesis by reversibly binding to the ___ ribosomal subunit of the 70S ribosome
30S
tetracyclines are _______ (bacteriostatic or bactericidal)
bacteriostatic; they inhibit organism growth rather than directly kill
spectrum of tetracyclines
broad spectrum: gram +, gram -, anaerobes, atypical bacteria, spirochete bacteria, some protozoa
what are two broad bacterial resistance mechanisms?
decreased accumulation of the drug within the cell, inhibition of drug binding to the target site of action
what are 3 ways of decreasing accumulation of the drug within the cell by bacterial resistance
decreased influx, increased outflux/efflux pumps, drug inactivation
how do bacteria resist by inhibiting drug binding to the target site of action
target site modification: ribosomal protection proteins alter the confirmation of the ribosome to prevent drug binding.
what mechanisms do tetracyclines use to resist?
efflux pumps and target site modification
a _____ contains loops of DNA with genes that encode for resistance and are easily shared between various bacteria
plasmid
a ______ contains loops of DNA with genes that encode for resistance and are easily shared within the chromosome of a given bacteria
transposon
in short, plasmids are ____
exogenous
in short, transposons are ___
internal
efflux pumps and target site modification are typically acquired via __
plasmids or transposons that encode the resistance; often inducible
resistance to tetracycline via efflux pumps typically _____ predict resistance to second or third generation
doesn’t
resistance to tetracycline via drug inactivation by enzymatic or nonenzymatic mechanisms typically ____ predict resistance to second or third generation
does
resistance to tetracycline by target site modification typically predicts ___
resistance to second generation but not third
common uses of tetracycline in the community setting
CAP, PUD, urethritis (genital), PID, lyme, syphilis, acne, MRSA skin/soft tissue infxn
less common uses of tetracycline in the community setting
malaria chemoprophylaxis and treatment, rickettsial infections, animal bites
special uses of doxycycline in the community
rosacea, bioterrorism pathogens
what are bioterrorism pathogens
anthrax, plague, tularemia, Q fever, brucellosis
special uses of minocycline in the community
rosacea, acne
special uses of tetracycline in the community
oral infections: recurrent oral aphthous ulcers, canker sores, periodontitis
special use of demeclocycline in the community
chronic hyponatremia associated with SIADH
tetracycline absorption
60-80%
tetracycline half life
6-12h, short acting
doxycycline and minocycline absorption
90-100%
doxycycline and minocycline half life
18-22h, long acting
tetracycline urinary excretion
20-55%: eliminated primarily in the kidneys, thus drug accumulates with renal insufficiency–> avoid
doxycycline urinary excretion
40%: fecal excretion is increased in the setting of renal insufficiency so it can be used in renal impairment
minocycline urinary excretion
5-10%: less than 20% is eliminated by the kidneys, and 20-34% excreted in the feces: accumulation potential with renal insufficiency may preclude use
food ___ absorption of tetracyclines
decreases (significant for tetracycline and demeclocycline)
tetracyclines form stable _____ with divalent and trivalent cations
chelates; hinders GI absorption by 50-90%
distribution of tetracyclines
lipophilic–> highly diffusible and penetrate hard to reach tissues and fluids (CSF, eye, prostate, sebum, respiratory secretions, dentin, reticuloendothelium, bone)
t/f: tetracycline crosses the placenta
true
t/f: tetracycline is excreted in breast milk
true
how are tetracyclines generally excreted
in the urine and feces mainly as unchanged drug
tetracyclines are concentrated in __
liver and bile
tetracyclines undergo ____ via bile
enterohepatic recycling
tetracyclines are partially inactivated via ____
hepatic metabolism
how can doxycycline be given to patients with renal impairment
extrarenal mode of elimination: in renal impairment, it diffuses into the intestinal lumen and chelates with Ca or Mg, the complex is incapable of reabsorption
how is minocycline metabolism an exception
metabolized extensively in the liver to at least 6 inactive metabolites
adverse reactions with tetracyclines
superinfection, esophageal ulceration, renal, vestibular, deposition in growing teeth, bones, nails, photosensitivity/phototoxicity, intracranial hypertension, papilledema, discoloration of skin/teeth, thyroid
superinfection from tetracycline is due to ___
candida albicans (yeast)– due to non-susceptible or resistant organisms
esophageal ulceration with tetracyclines is particularly seen in ___
patients with GERD, bedtime dose with little water
counseling to prevent esophageal ulceration from tetracyclines
take last dose 1hr before bed or recumbency with 100 mL water, and remain standing for at least 90 seconds
renal toxicity from tetracycline is due to ____
decomposed nephrotoxic tetracyclines– NEVER DISPENSE DISCOLORED (DARK) TETRACYCLINES
renal toxicity from tetracycline causes ___
faconi-like syndrome and systemic lupus erythematosus phenomenon
brown-to-black colored decomposition products of tetracycline are __ and __
anhydrotetracycline and epianhydrotetracycline
signs and symptoms of renal toxicity due to tetracyclines
nausea and vomiting, proteinuria, acidosis, glycosuria, death
vestibular effects are most common with which tetracycline
minocycline
what are the vestibular effects from tetracyclines
dizziness, vertigo, ataxia, nausea, vomiting; occurs in first 2 days and disappears in 48 hours
what discoloration does tetracycline cause in teeth, bones, nails
yellow, brown, gray (UV fluorescent)
deposition in enamel and dentin of permanent teeth and new bone formation is due to ______ complex
tetracycline-calcium orthophosphate
permanent teeth are affected if tetracyclines are administered to ___
children 8 years or younger
when is the greatest danger to developing teeth with tetracyclines
second trimester of pregnancy to 7 years old, permanent anterior teeth
what is nail stain with prolonged treatment with tetracyclines
photo-onycholysis
which tetracycline is least likely to deposit in teeth/bones/nails
doxycycline- less intense chelation
what is a phototoxic reaction to tetracycline
looks like exaggerated sunburn, appears quickly within minutes to hours of exposure to the sun
what is a photoallergic/photosensitivity reaction to tetracycline
mimics contact dermatitis, may spread to areas not exposed to the sun, delayed onset over 24 hours after exposure to the sun
signs of intracranial hypertension with tetracyclines
headache, blurred vision, dipolopia, vision loss
avoid concomitant use of _____ with tetracyclines due to intracranial hypertension
isotretinoin (accutane)
what is papilledema
optic disk swelling secondary to elevated intracranial pressure
when is there greater risk of developing papilledema from tetracyclines
females of childbearing age who are overweight
is papilledema reversible
usually on drug cessation, but permanent vision loss can occur
what are uncommon adverse effects more common with minocycline
black discoloration of tongue or thyroid, brown-to-black pigmentation in chronic acne patients, discoloration of soft contact lenses, thyroid cancer
contraindications to tetracyclines
children 8 years or younger, pregnancy
what are the risks to tetracyclines for children 8 years or younger
permanent discoloration of the teeth and enamel, hypoplasia, retardation of skeletal development and bone growth
what are pregnancy risks with tetracyclines
micromelia (disproportionately short limbs), cusp deformities on teeth and discoloration, cataracts (loss of lens transparency), cleft lip, cleft palate
what are drug interactions with tetracyclines
supplements/vitamins/antacids, warfarin, penicillins and aminoglycosides, oral contraceptives
what is the interaction between supplements/vitamins/antacids and tetracyclines
decrease absorption of tetracycline drugs
what is the mechanism of interaction between supplements/vitamins/antacids and tetracyclines
chelation of divalent or trivalent cations by tetracycline drugs
how to manage the interaction between supplements/vitamins/antacids and tetracyclines
separate administration 1-2 hours ac or 2 hours pc
what is the interaction between warfarin and tetracycline
depresses plasma prothrombin activity
what is the mechanism for interaction between warfarin and tetracycline
may increase risk of bleeding
management for the interaction between warfarin and tetracycline
increase monitoring for bleeding
patient counseling for tetracyclines
take on empty stomach w/ full glass of water 1 hour before a meal or 2 hours after a meal. avoid simultaneous ingestion of dairy, antacids, iron, mineral supplements. avoid recumbency after ingestion. avoid prolonged exposure to sunlight or sunlamps
what are third generation tetracyclines
tigecycline, eravacycline, omadacycline, sarecycline
substitutions at _____ in 3rd gen tetracyclines have what benefits
R9, reduce bacterial resistance, improve PK
what mechanisms of tetracycline resistance do the third generations overcome
efflux pumps and ribosomal protection proteins
why is sarecycline unique
R7 substitution leading to unique mechanism at the 50S ribosome A (acceptor) site. not approved for treatment of infections
omadacycline is present as its ____ salt
monotosylate
approved indications for omadacycline
CAP, skin/skin structure infxn
omadacycline dosage forms
po, iv
sarecycline is present as its ____ salt
monohydrochloride
approved indications for sarecycline
therapy of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age or older—- NOT EVALUATED TO TREAT INFECTIONS
sarecycline dosage forms
po
sarecycline adverse effects
nausea
omadacycline spectrum
gram positive, gram negative, atypical
sarecycline spectrum
LACKS activity against most gram negatives, has activity against gram positive
omadacycline with food?
food affects rate and extent, administer 4 hours AC or 2 hours PC, avoid dairy, multivitamins or antacids for 4 hours AC
sarecycline with food?
not significantly affected by food
clindamycin is significantly more _____ than lincomycin
lipophilic
what does the lipophilicity of clindamycin provide advantage for
greater oral absorption, better penetration into bacterial cell membranes, higher intracellular concentration, more reliable activity
structure of lincosamides
amino acid linked to an amino sugar
where do clindamycin and lincomycin differ
r1 and r2 at c6
lincosamides form salts at ____
tertiary amine hydrogen
lincosamides form esters at ___
c2 hydroxy group in amino sugar
what is the significance of clindamycin forming an ester
it is a biologically inactive prodrug: clindamycin phosphate, clindamycin palmitate hydrochloride, hydrolyzes to the parent base in vivo in the bloodstream
mechanism of action of lincosamides
bind to 23s rRNA component of the 50S bacterial ribosomal subunit to interrupt the process of peptide chain initiation, bacteriostatic/bactericidal
lincosamides spectrum of activity
aerobic gram +, anaerobic gram +, anerobic gram -, spore forming protozoa
important bacterial resistance mechanisms for lincosamides
decreased influx and target site modification
what is the significance of limitations to drug uptake by bacterial resistance to lincosamides
poor permeability= intrinsic gram negative resistance
how do bacteria alter the 23S rRNA of 50S ribosomal subunit to resist lincosamides
methylation: plasmid mediated providing MLS(B) resistance (ermA gene) or methytransferse enzyme (cfr gene)
_____ and lincosamide binding sites overlap on the 50S subunit so resistance may indicate lincosamide resistance
macrolides
what is MLS(B)
macrolide lincosamide streptogramin(B) resistance: erm gene
what is erm gene
erythromycin ribosome methylase gene: encodes enzymes that confer inducible or constitutive resistance to MLS agents via methylation of the 23s rRNA binding site
what does a positive D test indicate
erythromycin has induced clindamycin resistance, do not use clindamycin, presence of an erm gene that could result in clindamycin failure
common uses of lincosamides in the community setting
skin/soft tissue infections, oral cavity infection, acne vulgaris, bacterial vaginosis, bacterial endocarditis prophylaxis
clindamycin is __% bioavailable
90
lincosamide distribution
wide, into most tissues/fluids/bone, does not achieve significant CSF levels
lincosamide metabolism
hepatic (liver) to active and inactive metabolites; the active metabolite N-demethyl clindamycin is more active than the parent compound
lincosamide elimination
excreted in urine, to a lesser extent the bile as metabolites
adverse effects with lincosamides
cutaneous reactions, common cause of antibiotic associated diarrhea, may cause severe or even fatal colitis usually due to overgrowth of C. diff because it is resistant
drug interactions with lincosamides
CYP3A4 inhibitors/inducers, cyclosporine, macrolides
some formulations of clindamycin contain ____
tartrazine; aspirin allergy associated
patient counseling for clindamycin
take capsules with a full glass of water to avoid esophageal irritation
what class is mupirocin (bactroban)
pseudomonic acid A
what is the mechanism of mupirocin
inhibits bacterial protein synthesis via a specific and reversible binding to bacterial isoleucyl transfer-RNA synthetase–> prevents incorporation of isoleucine into growing protein chains, bacteriostatic
indications for mupirocin
topical only: impetigo (ointment) or secondary infected traumatic skin lesions (cream) due to staph/strep, eradication of nasal colonization with MRSA in adult patients and health care workers (nasal ointment)
warnings for mupirocin
potentially toxic amounts of PEG in the vehicle may be percutaneously absorbed in patients w/ open wounds or extensive burns, not for the treatment of pressure sores, avoid prolonged use may result in the overgrowth of non-susceptible organisms
what class is retapamulin (altabax)
pleuromutilin
retapamulin mechanism
interacts at 50S bacterial ribosomal subunit via a mechanism different from any other antibiotic results in inhibition of protein synthesis
indications for retapamulin
topical treatment of impetigo due to MSSA/strep pyogenes
