Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole generally kills bacteria, by blocking the microorganisms' ability to make and to use folate.

Trimethoprim/sulfamethoxazole (TMP/SMX) is the medicine most commonly used to prevent Pneumocystis jirovecii pneumonia (PCP){{Cite web |date=13 October 2021 |title=Pneumocystis pneumonia |url=https://www.cdc.gov/fungal/diseases/pneumocystis-pneumonia/index.html |url-status=live |archive-url=https://web.archive.org/web/20210726083526/https://www.cdc.gov/fungal/diseases/pneumocystis-pneumonia/index.html |archive-date=26 July 2021 |access-date=30 December 2021 |website=U.S. Centers for Disease Control and Prevention (CDC)}} People who get Pneumocystis pneumonia have a medical condition that weakens their immune system, like HIV/AIDS, or take medicines (such as corticosteroid, monoclonal antibody and immunosuppressants) that reduce the body's ability to fight bacterial and viral infections. People with HIV/AIDS are less likely to get Pneumocystis pneumonia as a result of antiretroviral therapy (ART). However, Pneumocystis pneumonia is still a substantial public health problem. Most of what is scientifically known about Pneumocystis pneumonia and its treatment comes from studying people with HIV/AIDS.

Organisms against which trimethoprim/sulfamethoxazole can be effective include:{{Cite web |title=trimethoprim/sulfamethoxazole (Rx) |url=http://reference.medscape.com/drug/bactrim-trimethoprim-sulfamethoxazole-342543#showall |url-status=live |archive-url=https://web.archive.org/web/20140116124927/http://reference.medscape.com/drug/bactrim-trimethoprim-sulfamethoxazole-342543#showall |archive-date=16 January 2014 |access-date=13 January 2014 |website=Medscape Reference}}

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• Acinetobacter spp.
• Aeromonas spp.
• Alcaligenes/Achromobacter spp.
• Bartonella henselae
• Bordetella pertussis (pertussis)
• Brucella spp.
• Burkholderia cepacia
• Burkholderia mallei (glanders)
• Burkholderia pseudomallei (melioidosis)
• Chlamydia spp.
• Chryseobacterium meningosepticum
• Citrobacter spp.
• Enterobacter spp.
• Enterococcus spp.
• Escherichia coli
• Haemophilus spp.
• Hafnia alvei
• Kingella spp.
• Klebsiella granulomatis
• Klebsiella pneumoniae
• Legionella spp.
• Listeria monocytogenes (listeriosis)
• Moraxella catarrhalis
• Morganella morganii
• Mycobacterium tuberculosis (tuberculosis)
• Neisseria gonorrhoeae (gonorrhoea)
• Neisseria meningitidis (meningococcal disease)
• Nocardia spp.
• Plesiomonas shigelloides
• Pneumocystis jirovecii
• Proteus mirabilis
• Proteus vulgaris
• Providencia rettgeri
• Providencia stuartii
• Salmonella typhi (typhoid fever)
• Non-typhi (food poisoning) Salmonella
• Serratia spp.
• Shigella spp.
• Staphylococcus aureus
• Staphylococcus epidermidis
• Staphylococcus saprophyticus
• Stenotrophomonas maltophilia
• Streptococcus agalactiae
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Streptococcus viridans
• Toxoplasma gondii (toxoplasmosis)
• Tropheryma whippelii (Whipple's disease)
• Vibrio cholerae (cholera)
• Yersinia enterocolitica
• Yersinia pestis (bubonic plague)
• Yersinia pseudotuberculosis

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The only notable nonsusceptible organisms are Pseudomonas aeruginosa, the mycoplasmae and Francisella tularensis (the causative organism of tularaemia).{{Cite web |date=17 July 2011 |title=Tularemia |url=http://new.dhh.louisiana.gov/assets/oph/Center-PHCH/Center-CH/infectious-epi/EpiManual/TularemiaManual.pdf |url-status=live |archive-url=https://web.archive.org/web/20140223030105/http://new.dhh.louisiana.gov/assets/oph/Center-PHCH/Center-CH/infectious-epi/EpiManual/TularemiaManual.pdf |archive-date=23 February 2014 |access-date=12 February 2014 |website=Infectious Disease Epidemiology Section |publisher=Louisiana Office of Public Health}}{{Cite journal |vauthors=Harik NS |date=July 2013 |title=Tularemia: epidemiology, diagnosis, and treatment |journal=Pediatric Annals |volume=42 |issue=7 |pages=288–292 |doi=10.3928/00904481-20130619-13 |pmid=23805970}}

Its use during pregnancy is contraindicated, although it has been placed in Australian pregnancy category C. 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. 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).{{Cite journal |vauthors=Yang J, Xie RH, Krewski D, Wang YJ, Walker M, Wen SW |date=May 2011 |title=Exposure to trimethoprim/sulfamethoxazole but not other FDA category C and D anti-infectives is associated with increased risks of preterm birth and low birth weight |journal=International Journal of Infectious Diseases |volume=15 |issue=5 |pages=e336–e341 |doi=10.1016/j.ijid.2011.01.007 |pmid=21345707 |doi-access=free |title-link=doi}}{{Cite journal |vauthors=Santos F, Sheehy O, Perreault S, Ferreira E, Berard A |date=October 2011 |title=Exposure to anti-infective drugs during pregnancy and the risk of small-for-gestational-age newborns: a case-control study |journal=BJOG |volume=118 |issue=11 |pages=1374–1382 |doi=10.1111/j.1471-0528.2011.03041.x |pmid=21749628 |s2cid=21014782 |doi-access=free |title-link=doi}} Animal studies have yielded similarly discouraging results.

It appears to be safe for use during breastfeeding as long as the baby is healthy.{{Cite web |title=Sulfamethoxazole / trimethoprim Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/sulfamethoxazole-trimethoprim.html |url-status=live |archive-url=https://web.archive.org/web/20150906073951/http://www.drugs.com/pregnancy/sulfamethoxazole-trimethoprim.html |archive-date=6 September 2015 |access-date=31 August 2015 |quote=An extensive systematic review of sulfonamide usage near term and during breastfeeding found no side effects in infants; the authors concluded that use of this combination drug during breastfeeding presents no risk of neonatal kernicterus... LactMed: Use is considered acceptable when breastfeeding healthy, full-term infants after the newborn period}}

Its use in those less than 2 months of age is not recommended due to the risk of adverse side effects.{{Cite web |title=Drugs & Medications |url=https://www.webmd.com/drugs/2/drug-5530/bactrim-ds-oral/details/list-sideeffects |url-status=live |archive-url=https://web.archive.org/web/20190419210051/https://www.webmd.com/drugs/2/drug-5530/bactrim-ds-oral/details/list-sideeffects |archive-date=19 April 2019 |access-date=19 April 2019 |website=WebMD}}

{{See also|List of side effects of trimethoprim/sulfamethoxazole}}

Common side effects include nausea, vomiting, rash, and diarrhea. Severe allergic reactions and Clostridioides difficile infection may occasionally occur. Its use in pregnancy is not recommended. It appears to be safe for use during breastfeeding as long as the baby is healthy.

Contraindications include the following:

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• Known hypersensitivity to trimethoprim, sulphonamides or any other ingredients in the formulations
• Pregnancy
• Severe liver failure, marked liver parenchymal damage, or jaundice.
• Serious haematological disorders and porphyria (due to the sulfonamide component of the preparation).
• Severe chronic kidney disease (CrCl <15 ml/min) where repeated measurements of the plasma concentration cannot be performed

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Its use is advised against in people being concomitantly treated with:{{Cite book |last=Joint Formulary Committee |url=https://archive.org/details/bnf65britishnati0000unse |title=British National Formulary (BNF) |publisher=Pharmaceutical Press |year=2013 |isbn=978-0-85711-084-8 |edition=65 |location=London, UK |url-access=registration}}{{Cite book |title=Australian Medicines Handbook |publisher=The Australian Medicines Handbook Unit Trust |year=2013 |isbn=978-0-9805790-9-3 |veditors=Rossi S |edition=2013 |location=Adelaide}}

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• ACE inhibitors like captopril, enalapril, lisinopril, perindopril, and ramipril due to the potential for additive hyperkalaemic effects
• Prilocaine — additive risk of methaemoglobinaemia
• Antiarrhythmics like amiodarone (increased risk of ventricular arrhythmias) and dofetilide (increased risk of QT interval prolongation)
• Antibacterials like dapsone (increases plasma levels of both drugs), methenamine (increased risk of crystalluria) and rifampicin (as it may lead to an increased plasma level of rifampicin and lower plasma levels of trimethoprim)
• Anticoagulants like warfarin and acenocoumarol — anticoagulant effects of either drug is potentiated by this combination
• Sulfonylureas — effects enhanced
• Phenytoin, half-life of phenytoin is increased
• Antifolates like pyrimethamine, proguanil and methotrexate increase the risk of associated side effects like bone marrow toxicity, folic acid supplementation should be considered. A significant risk of megaloblastic anaemia exists with doses of pyrimethamine in excess of 25 mg/wk.
• Antivirals, more specifically, lamivudine (increased plasma concentrations of lamivudine), zalcitabine (increased plasma concentrations of zalcitabine) and zidovudine (increased risk of haematological reactions)
• Procainamide and/or amantadine may have their plasma concentrations increased bilaterally or unilaterally.
• Clozapine and other antipsychotics — increased risk of haematological side effects
• Nucleoside analogue antineoplastics like azathioprine and mercaptopurine — increased risk of haematological toxicity
• Digoxin — increase in digoxin levels in a proportion of elderly patients
• Diuretics — elderly patients receiving thiazide diuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole
• Ciclosporin — patients who have received a kidney transplant and are receiving co-trimoxazole and ciclosporin concomitantly are at an increased risk of having a reversible deterioration in their kidney function.
• Spironolactone — concurrent use can increase the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.{{Cite journal |vauthors=Juvet T, Gourineni VC, Ravi S, Zarich SW |date=September 2013 |title=Life-threatening hyperkalemia: a potentially lethal drug combination |journal=Connecticut Medicine |volume=77 |issue=8 |pages=491–3 |pmid=24156179}}
• Potassium aminobenzoate — effects of sulfonamides (like Sulfamethoxazole) inhibited.
• Laboratory tests — trimethoprim and sulfonamides have been reported to interfere with diagnostic tests, including serum-methotrexate and elevated serum creatinine levels,{{Cite journal |vauthors=Gentry CA, Nguyen AT |date=December 2013 |title=An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications |journal=The Annals of Pharmacotherapy |volume=47 |issue=12 |pages=1618–26 |doi=10.1177/1060028013509973 |pmid=24259630 |s2cid=19395548}} also urea, urinary glucose and urobilinogen tests.

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Likely signs of toxicity include:

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• Nausea
• Vomiting
• Dizziness
• Headache
• Mental depression
• Confusion
• Thrombocytopenia
• Uremia
• Bone marrow depression
• Loss of appetite
• Colic
• Drowsiness
• Unconsciousness

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The recommended treatment for overdose includes:

• Administration of activated charcoal
• Stomach pumping
• General supportive measures
• Haemodialysis, which is moderately effective in clearing co-trimoxazole from the plasma.
• Calcium folinate treatment in cases of blood dyscrasias
• Forcing oral fluids

Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.

File:THFsynthesis pathway.svg

The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.{{Cite journal |vauthors=Bushby SR, Hitchings GH |date=May 1968 |title=Trimethoprim, a sulphonamide potentiator |journal=British Journal of Pharmacology and Chemotherapy |volume=33 |issue=1 |pages=72–90 |doi=10.1111/j.1476-5381.1968.tb00475.x |pmc=1570262 |pmid=5301731}}{{Cite journal |vauthors=Böhni E |year=1969 |title=[Comparative bacteriological investigations with the combination trimethoprim/sulfamethoxazole in vitro and in vivo] |journal=Chemotherapy |volume=14 |issue=Suppl |pages=Suppl:1–Suppl21 |doi=10.1159/000220651 |pmid=4908562}}{{Cite journal |vauthors=Böhni E |date=November 1969 |title=Chemotherapeutic activity of the combination of trimethoprim and sulphamethoxazole in infections of mice |journal=Postgraduate Medical Journal |volume=45 |issue=Suppl |pages=Suppl:18–Suppl:21 |pmid=4902845}} 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.

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.

Trimethoprim 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{{Cite web |title=Tetrahydrofolic acid |url=https://pubchem.ncbi.nlm.nih.gov/compound/tetrahydrofolate#section=Drug-and-Medication-Information |url-status=live |archive-url=https://web.archive.org/web/20180226151952/https://pubchem.ncbi.nlm.nih.gov/compound/tetrahydrofolate#section=Drug-and-Medication-Information |archive-date=26 February 2018 |access-date=26 February 2018 |website=PubChem |publisher=U.S. National Library of Medicine}} during bacterial replication.

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.

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.{{Cite book |url=https://www.taylorfrancis.com/books/edit/10.1201/9781498747967/kucers-use-antibiotics-lindsay-grayson-sara-cosgrove-suzanne-crowe-lindsay-grayson-william-hope-james-mccarthy-john-mills-johan-mouton-david-paterson |title=Kucers' the Use of Antibiotics |vauthors=Trubiano JA, Grayson ML |publisher=CRC Press |year=2017 |isbn=978-1-4987-4796-7 |veditors=Grayson ML, Cosgrove S, Crowe S, Hope W, McCarthy J, Mills J, Mouton JW, Paterson D |edition=7th |pages=1625, 1634 |chapter=Trimethoprim and Trimethoprim–Sulfamethoxazole (Cotrimoxazole) |doi=10.1201/9781498747967 |chapter-url=https://www.taylorfrancis.com/chapters/edit/10.1201/9781498747967-92/trimethoprim-trimethoprim%E2%80%93sulfamethoxazole-cotrimoxazole-jason-trubiano-lindsay-grayson}}{{Cite journal |vauthors=Brumfitt W, Hamilton-Miller JM |date=December 1993 |title=Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines |journal=Journal of Chemotherapy |volume=5 |issue=6 |pages=465–469 |doi=10.1080/1120009X.1993.11741097 |pmid=8195839}}

Trimethoprim/sulfamethoxazole may be abbreviated as SXT, SMZ-TMP, TMP-SMX, TMP-SMZ, or TMP-sulfa.{{citation needed|date=December 2021}} The generic British Approved Name (BAN) Co-trimoxazole is used for trimethoprim/sulfamethoxazole manufactured and sold by many different companies.{{Cite web |title=Co-trimoxazole Medicinal forms |url=https://bnf.nice.org.uk/drugs/co-trimoxazole/medicinal-forms/#oral-tablet |access-date=4 June 2024 |publisher=NICE}}

The following list of brand names is incomplete:

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• Bactrim, Bactrimel (manufactured by Roche and distributed in Europe)
• Bactrom (Venezuela)
• Bibactin (manufactured by PPM and distributed in Cambodia and some African countries)
• Biseptol
• Sumetrolim
• Co-trimoxazole (used as generic UK name)
• Cotrim
• Deprim (AFT Pharmaceuticals)
• Diseptyl (Israel)
• Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
• Infectrin, Bactrim (Brazil)
• Novo-Trimel{{Cite web |title=Novo-Trimel Advanced Patient Information – Drugs.com |url=https://www.drugs.com/cons/novo-trimel.html |url-status=live |archive-url=https://web.archive.org/web/20180201192950/https://www.drugs.com/cons/novo-trimel.html |archive-date=1 February 2018 |access-date=1 February 2018 |website=Drugs.com}}
• Primadex (manufactured by Dexa Medica and distributed in Indonesia)
• Primotren (Lek in Slovenia and other countries)
• Resprim
• Sanprima (manufactured by Sanbe Farma and distributed in Indonesia)
• Septra (Aspen Pharmacare and formerly GlaxoSmithKline)
• Septram (Panama)
• Septran (GlaxoSmithKline){{Cite web |date=13 August 2017 |title=Septran/Sepman Double Strength – Co-Trimoxazole Oral Formulations |url=http://india-pharma.gsk.com/media/701285/septran-and-sepmax.pdf |url-status=live |archive-url=https://web.archive.org/web/20180601211744/http://india-pharma.gsk.com/media/701285/septran-and-sepmax.pdf |archive-date=1 June 2018 |access-date=1 June 2018 |publisher=GlaxoSmithKline}}
• Septrin (Spain){{Cite web |title=SEPTRIN FORTE Comp. 800/160 mg – Datos generales |url=http://www.vademecum.es/medicamento-septrin+forte_3626 |url-status=live |archive-url=https://web.archive.org/web/20150616233203/http://www.vademecum.es/medicamento-septrin+forte_3626 |archive-date=16 June 2015 |access-date=17 August 2015}}
• Sulfatrim
• Teva-Trimel
• Trisul
• Vactrim (manufactured and distributed in Laos)

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Trimethoprim/sulfamethoxazole is relatively inexpensive as of 2019.{{Cite book |url=https://books.google.com/books?id=_nTADwAAQBAJ&dq=Cefalexin+relatively+inexpensive&pg=PA1173 |title=Lewis's Medical-Surgical Nursing EBook: Assessment and Management of Clinical Problems |vauthors=Brown D, Edwards H, Buckley T, Aitken RL |date=2019 |publisher=Elsevier Health Sciences |isbn=978-0-7295-8708-2 |page=1173 |access-date=30 March 2020 |archive-url=https://web.archive.org/web/20210829095029/https://www.google.com/books/edition/Lewis_s_Medical_Surgical_Nursing_EBook/_nTADwAAQBAJ?hl=en&gbpv=1&dq=Cefalexin+relatively+inexpensive&pg=PA1173 |archive-date=29 August 2021 |url-status=live}}

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