Tetrahydrofolate synthesis pathway The synergy between<unk>  and<unk>  was first described in the late 1960s.<unk>  and<unk>  have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations so that when they enter the body their concentration in the blood and tissues is roughly one-to-twenty — the exact ratio required for a peak synergistic effect between the two.<unk> , a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate.<unk>  serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate. Tetrahydrofolate is crucial in the synthesis of purines, thymidine, and methionine which are needed for the production of DNA and proteins during bacterial replication. Thus the net effect of each of these drugs is a bacteriostatic halt in replication. When combined, TMP and SMX are bactericidal. The effects of<unk>  causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis. This is where the<unk>  comes in; its role is in depleting the excess DHF by preventing it from being synthesised in the first place. Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed. Because it has a higher incidence of adverse effects, including allergic responses, its use has been restricted in many countries to very specific circumstances where its improved efficacy has been demonstrated. It may be effective in a variety of upper and lower respiratory tract infections, kidney and urinary tract infections, gastrointestinal tract infections, skin and wound infections, sepsis, and other infections caused by sensitive organisms. Co-trimoxazole decreases the risk of recurrence of retinochoroiditis. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently. + Pharmacokinetics of co-trimoxazole Component Tmax (h) Vd (L) Protein binding t1/2 (h) Excretion<unk>  1-4 20 66% 8-10 Renal<unk>  1-4 130 42-45% 10 Renal
Trimethoprim/sulfamethoxazole
Doxycycline
Dapsone
Micafungin
Merafloxacin
Teicoplanin
Phenoxymethylpenicillin
Amikacin