sulfonamides/trimethoprim Flashcards

1
Q

Silver Sulfadiazine (SILVADENE)

A

topical

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2
Q

Trimethoprim-sulfamethoxazole

A

aka co-trimoxazole, TMP-SMX (BACTRIM, SEPTRA, etc): oral, IV

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3
Q

sulfonamides are used for ??

A

routine infections of the urinary, gastrointestinal, and respiratory systems, and also for specialized and life-threatening infections caused by Nocardia, Toxoplasma, Pneumocystis, etc.

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4
Q

SMX, TMP inhibit DNA synthesis by inhibiting sequential enzymes in the
??

A

folic acid pathway

FA is a necessary precursor for purine bases, so TMP-SMX results in a ‘thymine-less death’ of bacteria

separately bacteriostatic, together bactericidal

mostly combo, resistance if used on own, esp. TMP

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5
Q

Sulfonamides competitively inhibit the bacterial enzyme ?? which converts ?? into ??, an immediate precursor of folic acid.

A

dihydropteroate synthase

para-aminobenzoic acid (PABA)

dihydropteroic acid

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6
Q

sulfonamide action: selective or non-selective??

what species are naturally resistant? why?

A

selective against bacteria because, unlike mammalian cells, most bacteria cannot use pre-formed folate and so rely on intracellular pathways to synthesize it.

Enterococcus faecalis, auxotrophic for folic acid

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7
Q

Sulfonamides that are absorbed and excreted rapidly ??
half-life??
how eliminated??

A

sulfasoxizole and sulfamethoxazole

half-life ranges from 5- 11 hours, and distribution is rapid and extensive

eliminated by the kidney, lesser amounts in feces/bile; subject to hepatic metabolism that are not antibac, but potentially toxic
need to adjust dose for decreased GFR

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8
Q

Sulfonamides penetrate ??

cross BBB? placenta??

A

pleural, peritoneal, synovial, and ocular fluids

cross into the CSF and can be useful in meningitis
cross the placenta as well with potential toxicity

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9
Q

Sulfasalazine: absorbed well or not??
uses??
actions??

A

not well-absorbed from the GI
UC and IBD
not v. antibac but rather luminal flora metabolize it into breakdown products:

5-aminosalysilc acid (5-ASA): remains in lumen and has topical anti-inflammatory and immune modulating properties

and sulfapyridine: absorbed from the GI and may account for toxicities such as hemolysis in pts deficient in G6PD.

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10
Q

Silver sulfadiazine, Sulfacetamide, mafenide uses

why is silver sulfadiazine the standard for prevention of infection in burns ??

A

topical agents used for management of burns, and in ophthalmological ointments for conjunctivitis and Chlamydia trachoma

negligible absorption that limits toxicity

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11
Q

Sulfadoxine

A

oral sulfonamide with an unusually long half-life of 7-9 days
secondary role: malaria prophylaxis

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12
Q

TMP inhibits ??

selectivity?

A

a diaminopyrimidine that inhibits bacterial dihydrofolate reductase(DHFR) (converts dihydrofolic acid (DHF) into tetrahydrofolic acid (THF))

DHF reductase in bac is 100,000x more sensitive to TMP than human DHF reductase

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13
Q

TMP compared to SMX
typical ratio of TMP: SMX

excretion?

A

similar spectrum of activity, more potent

1: 5 ratio of TMP : SMX (to achieve a 1:20 ratio in serum concentrations)
- both half-lives 10-12 hours and both are eliminated primarily by the kidneys
- much TMP is excreted unchanged
- adjust dose in severe renal insufficiency

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14
Q

due to lipophilicity, trimethoprim distributes much more widely than sulfamethoxazole and better penetrates ??

A

CSF

The 1:20 serum concentration typically results in a CSF ratio of 1:15

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15
Q

TMP-SMX uses

A
uncomplicated, lower UTIs
prostatitis (TMP penetrates prostate)
respiratory pathogens
GI pathogens
soft-tissue infections (some MRSA may be susceptible!!)
unusual but serious infections
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16
Q

urinary pathogens targeted by TMP-SMX

A

E. coli, Kleb, Proteus mirabilis, Enterobacter sp. and Morganella morgan

17
Q

respiratory pathogens targeted by TMP-SMX

A

Strep pneumonia*, H.flu, Moraxella catarrhalis and Pneumocystis jirovecii (PCP)

*high rate of pneumococcal resistance

18
Q

GI pathogens targeted by TMP-SMX

A

E. coli, Salmonella spp, Vibrio cholera, and others

*formerly Shigella, which is now resistant

19
Q

unusual but serious infections targeted by TMP-SMX

A

Listeria monocytogenes, Yersinia pestis, Nocardia, Toxoplasma gondii, and Pneumocystis.

20
Q

molecular mechanisms result in clinically relevant resistance to TMP-SMX

A
  • Mutations in dihydropteroate synthase and/or dihydrofolate reductase decrease drug affinity
  • Some bac have a decreased permeability
  • some can extrude the drugs via active efflux pumps (Pseudomonas)
  • some can accumulate high concentrations of normal metabolites, which neutralize the drugs through competition for the enzyme active site
21
Q

orgs commonly resistant to TMP-SMX

A

Pseudomonas, B. fragilis (many other anaerobes)
Mtb, T. pallidum, Campy, PCN- resistant pneumococci, and rickettsiae
(naturally resistant: Enterococcus faecalis)

22
Q

TMP-SMX adverse effects (5%)

A
  • crystaluria (earliest sulfonamides)
  • hemolytic anemia (G6PD deficiency)
  • suppress bone marrow–>blood dyscrasias (anemia, common in AIDs, ca pts)
  • skin hypersensitivity (HIV) (rarely SJS, exfoliative dermatitis)
23
Q

more TMP-SMX adverse effects

A
  • N/V/GI distress
  • hyperkalemia (block Na+ re-import in the distal nephron, which inhibits K+ excretion)
  • may impair folate metab. in malnourished pts/those with pre-existing folate deficiency
24
Q

TMP-SMX: safe for pregnancy?? breastfeeding??

A

category D, avoid in early and late pregnancy

early: potential inhibition of mammalian DHFR
late: displace bilirubin by binding to serum albumins–>excess bili can enter CNS and cause kernicterus

ALSO secreted in breast milk, and should not be given to a mother nursing an infant with G6PD deficiency.

25
Q

TMP-SMX may be used in pregnant women when benefits outweigh risks, such as ??

A

prophylaxis or treatment of Pneumocystis jirovecii pneumonia, for the prophylaxis of Toxoplasmic gondii encephalitis

26
Q

Sulfonamides can displace other drugs that bind to ?? including ??

A

albumin

-warfarin, phenytoin, and sulfonylurea hypoglycemics

27
Q

pts who are hypersensitive to sulfonamides have a higher rate of hypersensitivity to ??

A

other sulfa drugs including sulfonylureas, diuretics, and diazoxide
-due to predisposition to drug- allergies of any kind in certain individuals