Trimethoprim-sulfamethoxazole Flashcards
MOA
Sulfamethoxazole: a sulfonamide that competitively inhibits the incorporation of p-aminobenzoic acid (PABA) into folic acid by inhibiting dihydropteroate synthetase, which inhibits the formation of dihydrofolic acid
Trimethoprim: competitively inhibits the activity of bacterial dihydrofolate reductase to prevent the reduction of dihydrofolate to tetrahydrofolate
Together, these two agents produce sequential inhibition of the synthesis of folate, which is necessary for microbial production of DNA, producing a synergistic bactericidal effect against many Gram-positive and Gram-negative aerobic bacteria that may not be present with each agent alone.
MOR
Bacterial resistance is mediated by point mutations in dihydropteroate synthase and/or altered production or sensitivity of bacterial dihydrofolate reductase.
Resistance to trimethoprim-sulfamethoxazole occurs, but appears to develop more slowly to the combination than to each individual agent.
Resistance has been reported in E. coli, Klebsiella spp., Proteus mirabilis, H. influenzae, Salmonella spp., and Staphylococcus aureus.
Spectrum of activity
Gram-Positive Aerobes: S. aureus (including some MRSA, especially CA-MRSA), S. pyogenes (marginal), and Nocardia
Gram-Negative Aerobes: Stenotrophomonas maltophilia most Enterobacteriaceae including Acinetobacter baumannii, Enterobacter spp., E. coli (75-80%), K. pneumoniae, P. mirabilis, Salmonella, Shigella, Serratia spp., ampicillin-resistant H. influenzae, H. ducreyi, N. gonorrhoeae
Other Organisms: Pneumocystis carinii/jirovecii (DRUG OF CHOICE)
Pharmacology
a fixed oral or intravenous combination of 1:5 (TMP:SMX).
Bactericidal
Elimination
About 60% of TMP and 25 to 50% of SMX is excreted in the urine in 24 hours.
Doses should be adjusted in patients with CrCl < 30 ml/min.
absorption
Co-trimoxazole is rapidly and well absorbed after oral administration.
Peaks are higher and more predictable after parenteral administration.
Distribution
TMP-SMX concentrates well into saliva, breast milk, urine, uninflamed prostatic tissue, seminal fluid, inflamed lung tissue, and bile.
Penetrates the CSF in the presence of inflamed meninges. CSF concentrations are 30 to 50% (TMP) and 20% (SMX) of concomitant plasma concentrations.
side effects
Hematologic: leukopenia,thrombocytopenia
Hypersensitivity reactions: rash
Others: – crystalluria, hyperkalemia, increase creatinine
Pregnancy Category C - should NOT be used in pregnant women (especially during the third trimester or at term) or lactating women because it may cause kernicterus in the newborn due to bilirubin displacement from protein binding sites
DRUG INTERACTIONS
A. Warfarin – potentiated anticoagulant effects due to inhibition of metabolism and possible displacement from protein binding sites
