Trimethoprim-Sulfamethoxazole Revisited

Abstract

During the past 3 decades, the combination of trimethoprim and sulfamethoxazole has occupied a central role in the treatment of various commonly encountered infections and has also been particularly useful for several specific clinical conditions. However, changing resistance patterns and the introduction of newer broad-spectrum antibiotics have led to the need to carefully redefine the appropriate use of this agent in clinical practice. While trimethoprim-sulfamethoxazole's traditional role as empirical therapy for several infections has been modified by increasing resistance, it remains a highly useful alternative to the new generation of expanded-spectrum agents if resistance patterns and other clinical variables are carefully considered. It also seems to have an increasing role as a cost-effective pathogen-directed therapy with the potential to decrease or delay development of resistance to newer antibiotics used for empirical treatment. In addition, trimethoprim-sulfamethoxazole continues to be the drug of choice for several clinical indications.

Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population

“…While antibiotics during pregnancy are often needed (for example, for urinary tract infection), 18 the use of trimethoprim/sulfamethoxazole could be avoided because it is not the only choice of antibiotics for urinary tract infection; there are alternative antibiotics with equal effects. 19 Trimethoprim/sulfamethoxazole is a folic acid antagonist that may cause birth defects and other adverse outcomes in the infants. 20,21 Antiasthmatic drugs (category C drugs) were also frequently used.…”

46-Year-Old Man With Fevers, Chills, and Pancytopenia

“…8 Trimethoprim also interferes with and reduces renal tubular secretion of creatinine, which can lead to an elevation in serum creatinine. 9 Hyperkalemia and elevation in serum creatinine levels resolve after trimethoprim-sulfamethoxazole therapy is discontinued and do not result in permanent renal dysfunction.…”

Autoinducer2 affects trimethoprim‐sulfamethoxazole susceptibility in avian pathogenic Escherichia coli dependent on the folate synthesis‐associate pathway

“…The rationale for the combination of trimethoprim with sulfamethoxazole is that each component blocks a different step in the folate biosynthetic pathway (Wormser, Keusch, & Heel, 1982). Sulfamethoxazole, a sulfonamide drug, is a structural analog of para‐aminobenzoic acid and competitively inhibits the synthesis of the intermediary dihydrofolic acid from its precursors, and trimethoprim is a structural analog of the pteridine portion of dihydrofolic acid that competitively inhibits dihydrofolate reductase and, consequently, decreases the production of the physiologically active tetrahydrofolic acid from dihydrofolic acid (Action, 2003; Church et al., 2015; Epstein, Amodio‐Groton, & Sadick, 1997). Although each agent alone is bacteriostatic, their blockade of two sequential enzymes results in bactericidal activity when combined (Action, 2003; Church et al., 2015).…”

“…Sulfamethoxazole, a sulfonamide drug, is a structural analog of para‐aminobenzoic acid and competitively inhibits the synthesis of the intermediary dihydrofolic acid from its precursors, and trimethoprim is a structural analog of the pteridine portion of dihydrofolic acid that competitively inhibits dihydrofolate reductase and, consequently, decreases the production of the physiologically active tetrahydrofolic acid from dihydrofolic acid (Action, 2003; Church et al., 2015; Epstein, Amodio‐Groton, & Sadick, 1997). Although each agent alone is bacteriostatic, their blockade of two sequential enzymes results in bactericidal activity when combined (Action, 2003; Church et al., 2015). The synergy between trimethoprim and sulfamethoxazole together provides effective inhibition of enzymes involved in the bacterial synthesis of tetrahydrofolic acid, which is a necessary cofactor in bacterial nucleic acid synthesis (Grim, Rapp, Martin, & Evans, 2005; Sköld, 2011; Wormser et al., 1982).…”

“…AI‐2 signals derive from spontaneous rearrangement of (4S)‐4, 5‐dihydroxy‐2, 3‐pentanedione (DPD) and are synthesized by a highly conserved AI synthase, LuxS, which is present in a variety of gram‐negative and gram‐positive bacteria species. In addition, AI‐2 supports cell population‐dependent behavior by interacting with central metabolism through the intracellular activated methyl cycle, which is related to the synthesis of tetrahydrofolic acid (Action, 2003; Bushby, 1973; Fuqua, Winans, & Greenberg, 1994; Vendeville, Winzer, Heurlier, Tang, & Hardie, 2005). It has been reported that AI‐2 increases the susceptibility in Streptococcus anginosus to ampicillin and erythromycin and decreases the susceptibility in Staphylococcus aureus to vancomycin, and AI‐2 is also involved in increased biofilm formation in Streptococcus intermedius (Ahmed et al., 2009; Xue, Zhao, & Sun, 2013).…”