Trimethoprim/sulfamethoxazole (TMP/SMX), also known as co-trimoxazole among other names, is an antibiotic used to treat a variety of bacterial infections.[1] It consists of one part trimethoprim to five parts sulfamethoxazole.[2] It is used for urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others.[1][2] It may be used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS.[1] It can be given by mouth or intravenously.[1] Common side effects include nausea, vomiting, rash, and diarrhea.[1] Severe allergic reactions and Clostridium difficile diarrhea may occasionally occur.[1] Its use near the end of pregnancy is not recommended.[1] It appears to be safe for use during breastfeeding as long as the baby is healthy.[3] TMP/SMX generally results in bacterial death.[1] It works by blocking the making and use of folate by the microorganisms.[1] TMP/SMX was first sold in 1974.[4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] It is available as a generic medication and is not very expensive.[2] In the United States, it is about US$0.40 per dose.[1] In 2016, it was the 106th most prescribed medication in the United States, with more than 6 million prescriptions.[6] Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[7] 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.[8] 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.[9] The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.[10] Organisms against which co-trimoxazole can be effective include:[11][12] The only notable nonsusceptible organisms are Pseudomonas aeruginosa, the mycoplasmae[12] and Francisella tularensis (the causative organism of tularaemia).[13][14] Its use during pregnancy is contraindicated, although it has been placed in Australian pregnancy category C and American pregnancy category D.[11] Its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects such as spina bifida, cardiovascular malformations (e.g. Ebstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies.[11] Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67).[15][16] Animal studies have yielded similarly discouraging results.[17] It is also excreted in breast milk and hence nursing during treatment with co-trimoxazole is generally advised against.[11] Its use in those less than 2 months of age is not recommended due to the risk of adverse side effects.[18][19] Contraindications include the following:[11][20] Its use is advised against in patients being concomitantly treated with:[11][17][20][21][22][23] Likely signs of toxicity include:[17] The recommended treatment for overdose includes:[17] Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.[17] The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.[25][26][27] Trimethoprim and sulfamethoxazole 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.[12] Sulfamethoxazole, 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.[12] Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.[12] Tetrahydrofolate is crucial in the synthesis of purines, thymidine, and methionine which are needed for the production of DNA and proteins[28] 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 trimethoprim 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 sulfamethoxazole comes in, its role is in depleting the excess DHF by preventing it from being synthesised in the first place.[12] Trimethoprim/sulfamethoxazole may be abbreviated as SXT, TMP-SMX, TMP-SMZ, or TMP-sulfa. Co-trimoxazole (BAN) is manufactured and sold by many different companies. The following list of brand names is incomplete: