Flashcards in sulfonamides/trimethoprim Deck (27):
Silver Sulfadiazine (SILVADENE)
aka co-trimoxazole, TMP-SMX (BACTRIM, SEPTRA, etc): oral, IV
sulfonamides are used for ??
routine infections of the urinary, gastrointestinal, and respiratory systems, and also for specialized and life-threatening infections caused by Nocardia, Toxoplasma, Pneumocystis, etc.
SMX, TMP inhibit DNA synthesis by inhibiting sequential enzymes in the
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
Sulfonamides competitively inhibit the bacterial enzyme ?? which converts ?? into ??, an immediate precursor of folic acid.
para-aminobenzoic acid (PABA)
sulfonamide action: selective or non-selective??
what species are naturally resistant? why?
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
Sulfonamides that are absorbed and excreted rapidly ??
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*
Sulfonamides penetrate ??
cross BBB? placenta??
pleural, peritoneal, synovial, and ocular fluids
cross into the CSF and can be useful in meningitis
cross the placenta as well with potential toxicity
Sulfasalazine: absorbed well or not??
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.
*Silver sulfadiazine*, Sulfacetamide, mafenide uses
why is silver sulfadiazine the standard for prevention of infection in burns ??
topical agents used for management of burns, and in ophthalmological ointments for conjunctivitis and Chlamydia trachoma
negligible absorption that limits toxicity
oral sulfonamide with an unusually long half-life of 7-9 days
secondary role: malaria prophylaxis
TMP inhibits ??
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
TMP compared to SMX
typical ratio of TMP: SMX
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
due to lipophilicity, trimethoprim distributes much more widely than sulfamethoxazole and better penetrates ??
(The 1:20 serum concentration typically results in a CSF ratio of 1:15)
uncomplicated, lower UTIs
prostatitis (TMP penetrates prostate)
soft-tissue infections (some MRSA may be susceptible!!)
unusual but serious infections
urinary pathogens targeted by TMP-SMX
E. coli, Kleb, Proteus mirabilis, Enterobacter sp. and Morganella morgan
respiratory pathogens targeted by TMP-SMX
Strep pneumonia*, H.flu, Moraxella catarrhalis and Pneumocystis jirovecii (PCP)
*high rate of pneumococcal resistance
GI pathogens targeted by TMP-SMX
E. coli, Salmonella spp, Vibrio cholera, and others
(*formerly Shigella, which is now resistant)
unusual but serious infections targeted by TMP-SMX
Listeria monocytogenes, Yersinia pestis, Nocardia, Toxoplasma gondii, and Pneumocystis.
molecular mechanisms result in clinically relevant resistance to TMP-SMX
-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
orgs commonly resistant to TMP-SMX
Pseudomonas, B. fragilis (many other anaerobes)
Mtb, T. pallidum, Campy, PCN- resistant pneumococci, and rickettsiae
(naturally resistant: Enterococcus faecalis)
TMP-SMX adverse effects (5%)
-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)
more TMP-SMX adverse effects
-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
TMP-SMX: safe for pregnancy?? breastfeeding??
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.
TMP-SMX may be used in pregnant women when benefits outweigh risks, such as ??
prophylaxis or treatment of Pneumocystis jirovecii pneumonia, for the prophylaxis of Toxoplasmic gondii encephalitis
Sulfonamides can displace other drugs that bind to ?? including ??
-warfarin, phenytoin, and sulfonylurea hypoglycemics