tetracyclines and lincosamides Flashcards
(131 cards)
1
Q
tetracyclines and lincosamides inhibit ____
A
protein synthesis
2
Q
what is the structure of a tetracycline
A
4 rings, parent aromatic compound is naphthacene
3
Q
what color are tetracyclines
A
yellow
4
Q
other chemistry characteristics of tetracyclines
A
bitter, crystalline, strong yellow fluorescence under UV light, amphoteric, form crystalline water soluble salts with strong acids and bases
5
Q
what 3 substitutions for tetracyclines result in variable PK and antimicrobial activity
A
C5, C6, C7
6
Q
tetracyclines have increased lipophilicity with ____ at C_
A
absence of hydroxylation at C6
7
Q
what does the absence of hydroxylation at C6 with doxy, mino, and tige lead to
A
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
8
Q
alterations at which faces of the tetracycline molecule lead to improved antimicrobial activity and PK properties
A
northern and western faces
9
Q
alterations at which faces of the tetracycline molecule produce a considerable loss in antimicrobial activity
A
southern and eastern
10
Q
tetracyclines inhibit bacterial protein synthesis by reversibly binding to the ___ ribosomal subunit of the 70S ribosome
A
30S
11
Q
tetracyclines are _______ (bacteriostatic or bactericidal)
A
bacteriostatic; they inhibit organism growth rather than directly kill
12
Q
spectrum of tetracyclines
A
broad spectrum: gram +, gram -, anaerobes, atypical bacteria, spirochete bacteria, some protozoa
13
Q
what are two broad bacterial resistance mechanisms?
A
decreased accumulation of the drug within the cell, inhibition of drug binding to the target site of action
14
Q
what are 3 ways of decreasing accumulation of the drug within the cell by bacterial resistance
A
decreased influx, increased outflux/efflux pumps, drug inactivation
15
Q
how do bacteria resist by inhibiting drug binding to the target site of action
A
target site modification: ribosomal protection proteins alter the confirmation of the ribosome to prevent drug binding.
16
Q
what mechanisms do tetracyclines use to resist?
A
efflux pumps and target site modification
17
Q
a _____ contains loops of DNA with genes that encode for resistance and are easily shared between various bacteria
A
plasmid
18
Q
a ______ contains loops of DNA with genes that encode for resistance and are easily shared within the chromosome of a given bacteria
A
transposon
19
Q
in short, plasmids are ____
A
exogenous
20
Q
in short, transposons are ___
A
internal
21
Q
efflux pumps and target site modification are typically acquired via __
A
plasmids or transposons that encode the resistance; often inducible
22
Q
resistance to tetracycline via efflux pumps typically _____ predict resistance to second or third generation
A
doesn’t
23
Q
resistance to tetracycline via drug inactivation by enzymatic or nonenzymatic mechanisms typically ____ predict resistance to second or third generation
A
does
24
Q
resistance to tetracycline by target site modification typically predicts ___
A
resistance to second generation but not third
25
common uses of tetracycline in the community setting
CAP, PUD, urethritis (genital), PID, lyme, syphilis, acne, MRSA skin/soft tissue infxn
26
less common uses of tetracycline in the community setting
malaria chemoprophylaxis and treatment, rickettsial infections, animal bites
27
special uses of doxycycline in the community
rosacea, bioterrorism pathogens
28
what are bioterrorism pathogens
anthrax, plague, tularemia, Q fever, brucellosis
29
special uses of minocycline in the community
rosacea, acne
30
special uses of tetracycline in the community
oral infections: recurrent oral aphthous ulcers, canker sores, periodontitis
31
special use of demeclocycline in the community
chronic hyponatremia associated with SIADH
32
tetracycline absorption
60-80%
33
tetracycline half life
6-12h, short acting
34
doxycycline and minocycline absorption
90-100%
35
doxycycline and minocycline half life
18-22h, long acting
36
tetracycline urinary excretion
20-55%: eliminated primarily in the kidneys, thus drug accumulates with renal insufficiency--> avoid
37
doxycycline urinary excretion
40%: fecal excretion is increased in the setting of renal insufficiency so it can be used in renal impairment
38
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
39
food ___ absorption of tetracyclines
decreases (significant for tetracycline and demeclocycline)
40
tetracyclines form stable _____ with divalent and trivalent cations
chelates; hinders GI absorption by 50-90%
41
distribution of tetracyclines
lipophilic--> highly diffusible and penetrate hard to reach tissues and fluids (CSF, eye, prostate, sebum, respiratory secretions, dentin, reticuloendothelium, bone)
42
t/f: tetracycline crosses the placenta
true
43
t/f: tetracycline is excreted in breast milk
true
44
how are tetracyclines generally excreted
in the urine and feces mainly as unchanged drug
45
tetracyclines are concentrated in __
liver and bile
46
tetracyclines undergo ____ via bile
enterohepatic recycling
47
tetracyclines are partially inactivated via ____
hepatic metabolism
48
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
49
how is minocycline metabolism an exception
metabolized extensively in the liver to at least 6 inactive metabolites
50
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
51
superinfection from tetracycline is due to ___
candida albicans (yeast)-- due to non-susceptible or resistant organisms
52
esophageal ulceration with tetracyclines is particularly seen in ___
patients with GERD, bedtime dose with little water
53
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
54
renal toxicity from tetracycline is due to ____
decomposed nephrotoxic tetracyclines-- NEVER DISPENSE DISCOLORED (DARK) TETRACYCLINES
55
renal toxicity from tetracycline causes ___
faconi-like syndrome and systemic lupus erythematosus phenomenon
56
brown-to-black colored decomposition products of tetracycline are __ and __
anhydrotetracycline and epianhydrotetracycline
57
signs and symptoms of renal toxicity due to tetracyclines
nausea and vomiting, proteinuria, acidosis, glycosuria, death
58
vestibular effects are most common with which tetracycline
minocycline
59
what are the vestibular effects from tetracyclines
dizziness, vertigo, ataxia, nausea, vomiting; occurs in first 2 days and disappears in 48 hours
60
what discoloration does tetracycline cause in teeth, bones, nails
yellow, brown, gray (UV fluorescent)
61
deposition in enamel and dentin of permanent teeth and new bone formation is due to ______ complex
tetracycline-calcium orthophosphate
62
permanent teeth are affected if tetracyclines are administered to ___
children 8 years or younger
63
when is the greatest danger to developing teeth with tetracyclines
second trimester of pregnancy to 7 years old, permanent anterior teeth
64
what is nail stain with prolonged treatment with tetracyclines
photo-onycholysis
65
which tetracycline is least likely to deposit in teeth/bones/nails
doxycycline- less intense chelation
66
what is a phototoxic reaction to tetracycline
looks like exaggerated sunburn, appears quickly within minutes to hours of exposure to the sun
67
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
68
signs of intracranial hypertension with tetracyclines
headache, blurred vision, dipolopia, vision loss
69
avoid concomitant use of _____ with tetracyclines due to intracranial hypertension
isotretinoin (accutane)
70
what is papilledema
optic disk swelling secondary to elevated intracranial pressure
71
when is there greater risk of developing papilledema from tetracyclines
females of childbearing age who are overweight
72
is papilledema reversible
usually on drug cessation, but permanent vision loss can occur
73
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
74
contraindications to tetracyclines
children 8 years or younger, pregnancy
75
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
76
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
77
what are drug interactions with tetracyclines
supplements/vitamins/antacids, warfarin, penicillins and aminoglycosides, oral contraceptives
78
what is the interaction between supplements/vitamins/antacids and tetracyclines
decrease absorption of tetracycline drugs
79
what is the mechanism of interaction between supplements/vitamins/antacids and tetracyclines
chelation of divalent or trivalent cations by tetracycline drugs
80
how to manage the interaction between supplements/vitamins/antacids and tetracyclines
separate administration 1-2 hours ac or 2 hours pc
81
what is the interaction between warfarin and tetracycline
depresses plasma prothrombin activity
82
what is the mechanism for interaction between warfarin and tetracycline
may increase risk of bleeding
83
management for the interaction between warfarin and tetracycline
increase monitoring for bleeding
84
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
85
what are third generation tetracyclines
tigecycline, eravacycline, omadacycline, sarecycline
86
substitutions at _____ in 3rd gen tetracyclines have what benefits
R9, reduce bacterial resistance, improve PK
87
what mechanisms of tetracycline resistance do the third generations overcome
efflux pumps and ribosomal protection proteins
88
why is sarecycline unique
R7 substitution leading to unique mechanism at the 50S ribosome A (acceptor) site. not approved for treatment of infections
89
omadacycline is present as its ____ salt
monotosylate
90
approved indications for omadacycline
CAP, skin/skin structure infxn
91
omadacycline dosage forms
po, iv
92
sarecycline is present as its ____ salt
monohydrochloride
93
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
94
sarecycline dosage forms
po
95
sarecycline adverse effects
nausea
96
omadacycline spectrum
gram positive, gram negative, atypical
97
sarecycline spectrum
LACKS activity against most gram negatives, has activity against gram positive
98
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
99
sarecycline with food?
not significantly affected by food
100
clindamycin is significantly more _____ than lincomycin
lipophilic
101
what does the lipophilicity of clindamycin provide advantage for
greater oral absorption, better penetration into bacterial cell membranes, higher intracellular concentration, more reliable activity
102
structure of lincosamides
amino acid linked to an amino sugar
103
where do clindamycin and lincomycin differ
r1 and r2 at c6
104
lincosamides form salts at ____
tertiary amine hydrogen
105
lincosamides form esters at ___
c2 hydroxy group in amino sugar
106
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
107
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
108
lincosamides spectrum of activity
aerobic gram +, anaerobic gram +, anerobic gram -, spore forming protozoa
109
important bacterial resistance mechanisms for lincosamides
decreased influx and target site modification
110
what is the significance of limitations to drug uptake by bacterial resistance to lincosamides
poor permeability= intrinsic gram negative resistance
111
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)
112
_____ and lincosamide binding sites overlap on the 50S subunit so resistance may indicate lincosamide resistance
macrolides
113
what is MLS(B)
macrolide lincosamide streptogramin(B) resistance: erm gene
114
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
115
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
116
common uses of lincosamides in the community setting
skin/soft tissue infections, oral cavity infection, acne vulgaris, bacterial vaginosis, bacterial endocarditis prophylaxis
117
clindamycin is __% bioavailable
90
118
lincosamide distribution
wide, into most tissues/fluids/bone, does not achieve significant CSF levels
119
lincosamide metabolism
hepatic (liver) to active and inactive metabolites; the active metabolite N-demethyl clindamycin is more active than the parent compound
120
lincosamide elimination
excreted in urine, to a lesser extent the bile as metabolites
121
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
122
drug interactions with lincosamides
CYP3A4 inhibitors/inducers, cyclosporine, macrolides
123
some formulations of clindamycin contain ____
tartrazine; aspirin allergy associated
124
patient counseling for clindamycin
take capsules with a full glass of water to avoid esophageal irritation
125
what class is mupirocin (bactroban)
pseudomonic acid A
126
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
127
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)
128
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
129
what class is retapamulin (altabax)
pleuromutilin
130
retapamulin mechanism
interacts at 50S bacterial ribosomal subunit via a mechanism different from any other antibiotic results in inhibition of protein synthesis
131
indications for retapamulin
topical treatment of impetigo due to MSSA/strep pyogenes
