Sulfonamides & Antifols

Mechanisms of resistance
o o o
o

expression of efflux transporters production of competitive substrates (PABA, DHFA) Mutation in genes encoding target enzymes (DHPA synthetase for sulfonamides and DHF reductase for trimethoprim) Resistance to TMP-SMZ (esp. E. coli (30%) and S. pneumoniae)

Kinetics ALL
Sulfonamides: -Good oral bioavailability -Short half lives (except sulfadoxine, multiple doses) -Liver metabolism & some renal elimination(urine variable, crystalluria occur) -Bind strong to plasma proteins (displace other drugs enhancing their effects) Trimethoprim: Good oral biolavailability & tissue penetration -Renal elimination

Rx uses

Toxicity
-Hypersensitivity: 2
nd

Contraindications to penicillin,
Pregnancy category C, rd avoid and in 3 trimester

Drug Interactions
-Displace many drugs from plasma proteins including sulfonylureas (used in diabetes), methotrexate (anticancer & immunosuppressant), phenytoin (anticonvulsant) and warfarin (blood thinner) from plasma proteins

assume cross allergy, mainly skin reactions but possibly anaphylaxis & StevensJohnson syndrome (life threatening) -Hematotoxicity: thrombocytopenia (consider supp folinic acid) -Hemolysis: glucose-6-phosophate dehydrogenase (G6PD) deficiency -Nephrotoxicity: crstyalluria, hematuria

-Phototoxicity -Kernicterus: neuro damage due to

displacement of bilirubin from plasma proteins which enters the CNS, especially likely in neonates

Sulfisoxazole
Sulfamethoxazole (Gantanol)

-PO, topical -PO -UT infections -Topical -Chlamydial eye infections -PO, topical -Nocardial infections -Topical -Topical -Burn dressings (active vs. Pseudomonas sp) -DOC for toxoplasmosis
(T. gondii opportunistic infection in AIDS (TMP-SMX also used)

Sulfacetamide Sulfadiazine Silver sulfadiazine (Silvadene) Sulfamylon (Mafenide) Sulfadiazine + pyrimethamine

Drugs inhibiting Folic Acid Synthesis: -Necessary for protein & nucleic acid synthetic pathways -(HUMANS) Dihydrofolate is converted by the enzyme dihydrofolate reductase (DHF reductase) to tetrahydrofolic acid -(MICROORGANISMS) Synthesize from scratch using 2 enzyme steps prior to DHF reducatase st -Sulfonamides inhibit dihydropteroate synthetase (enzyme that catalyze 1 step in folic acid synthesis) in microorganisms Sequential Blockade of Folic Acid Synthesis -Combination of sulfonamide (sulfamethoxazole) with trimethoprim = sequential block of folic acid synthesis super-additive antimicrobial effects -Individual sulfas and trimethoprim = BACTERIOSTATIC, used together (TMP-SMX) = BACTERICIDAL (<resistance emerging)