Sulfamethoxazole + trimethoprim
Co-trimoxazole is a combined antibiotic (sulfamethoxazole + trimethoprim) used for urinary and respiratory infections and for prevention and treatment of Pneumocystis infections in immunocompromised patients. It is effective, but can cause serious allergic reactions and affect the bone marrow.
Also known as: Bactrim
Two sulfonamide-containing drugs (Sulfadoxine + Sulfamethoxazole) — additive risk of severe hypersensitivity reactions (e.g. Stevens-Johnson syndrome) and bone marrow suppression.
Co-trimoxazole (sulfamethoxazole + trimethoprim) and sulfadoxine-pyrimethamine share sulfonamide components (sulfamethoxazole and sulfadoxine) and antifolate components (trimethoprim and pyrimethamine, both dihydrofolate reductase inhibitors); the combination adds up the risk of haematological adverse reactions (megaloblastic anaemia, neutropenia, thrombocytopenia from folate depletion), severe skin reactions and hypersensitivity, with no additional antimicrobial benefit. The WHO (Guidelines for malaria) does not recommend the concomitant use of two sulfonamide/antifolate combinations. Avoid the combination and choose an alternative regimen; if unavoidable, monitor the blood count and liver function.
Co-trimoxazole + sulfadoxine-pyrimethamine: combination of sulfonamides with antifolate — additive risk of haematological reactions and hypersensitivity. Avoid.
Sulfadoxine and Sulfamethoxazole share the sulfonamide group; both are also antifolates (with Pyrimethamine and Trimethoprim).
Skin (rash, blisters), blood count and renal function.
Extensive rash, blisters/skin detachment, fever, anaemia, jaundice.
Avoid the association; use an alternative antibiotic whenever possible.
WHO — WHO Guidelines for malaria: https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria ; DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Co-trimoxazole can enhance the effect of glimepiride and lower blood sugar too much. Monitor blood glucose during treatment.
Sulphonamides potentiate the hypoglycaemic effect of sulfonylureas through multiple mechanisms: displacement from plasma protein binding, inhibition of metabolism and reduced renal excretion. The glimepiride SmPC (EMC-UK) lists long-acting sulphonamides among the drugs that potentiate the hypoglycaemic effect. This combination is common (urinary and respiratory infections in diabetics).
Sulphonamides (sulfamethoxazole in co-trimoxazole) potentiate sulfonylurea hypoglycaemia through protein displacement and reduced elimination. Monitor blood glucose and consider a dose reduction.
Protein displacement and inhibition of glimepiride metabolism by sulphonamides.
Capillary glucose; hypoglycaemia symptoms.
Severe hypoglycaemia — sweating, tremor, confusion, loss of consciousness.
Monitor blood glucose during the antibiotic; consider a temporary sulfonylurea dose reduction.
EMC-UK (MHRA) — approved Glimepiride SmPC: https://www.medicines.org.uk/emc/product/10742/smpc ; DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Co-trimoxazole can enhance the effect of glyburide and lower blood sugar too much. Monitor blood glucose during the antibiotic.
Sulfamethoxazole (a component of co-trimoxazole) is a sulphonamide that potentiates the hypoglycaemic effect of sulfonylureas through protein displacement and inhibition of metabolism — a classic, well-documented interaction (the glimepiride SmPC lists sulphonamides among the drugs that potentiate hypoglycaemia). This combination is common (urinary infections in diabetics) and requires blood glucose monitoring.
Sulphonamides (sulfamethoxazole) potentiate sulfonylurea hypoglycaemia. Monitor blood glucose during the antibiotic; consider a sulfonylurea dose reduction.
Protein displacement and inhibition of sulfonylurea metabolism by the sulphonamide.
Capillary glucose; hypoglycaemia symptoms.
Severe hypoglycaemia — sweating, confusion, coma.
Monitor blood glucose during the antibiotic; consider a temporary sulfonylurea dose reduction.
EMC-UK (MHRA) — approved Glimepiride SmPC: https://www.medicines.org.uk/emc/product/10742/smpc ; DailyMed/FDA (NIH/NLM) — approved Glyburide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=524eec41-37ee-419a-b7a1-d23e888ae6ab ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Lamivudine with Co-trimoxazole increases Lamivudine concentrations, with a risk of toxicity.
Lamivudine is predominantly eliminated by active renal secretion of organic cations, and trimethoprim (a co-trimoxazole component) inhibits those transporters (OCT), raising lamivudine plasma concentrations; the lamivudine label states this interaction is not considered clinically significant and that no lamivudine dose adjustment is needed. The co-trimoxazole label, however, recommends avoiding co-administration with OCT2 substrates whenever possible. In practice, the combination is common (HIV prophylaxis) and well tolerated; monitor for haematological or hepatic toxicity in susceptible patients.
Co-trimoxazole + lamivudine: trimethoprim inhibits OCT2 and raises lamivudine levels. No dose adjustment, but monitor for toxicity.
Trimethoprim reduces the renal tubular secretion of Lamivudine (via organic cation transport), increasing its exposure by about 40%.
Renal function and signs of Lamivudine toxicity (pancreatitis, anaemia, peripheral neuropathy).
Signs of Lamivudine toxicity (nausea, abdominal pain, anaemia, neuropathy) require reassessment.
Maintain surveillance; adjust the Lamivudine dose in renal impairment and watch for toxicity in prolonged therapy.
DailyMed/FDA (NIH/NLM) — approved Lamivudine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6bd6b9da-df69-46db-813e-4e7f3bdecf95 ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Increased risk of lactic acidosis: the trimethoprim component reduces renal clearance of Metformin, raising its levels.
Metformin is eliminated renally through the organic cation transporter OCT2, and trimethoprim (a co-trimoxazole component) is an OCT2 inhibitor, which can raise metformin concentrations and the risk of lactic acidosis, especially in patients with reduced renal function, the elderly or with other causes of acidosis; the co-trimoxazole label recommends avoiding co-administration with OCT2 substrates (metformin is explicitly mentioned) and monitoring glycaemia. During the combination, monitor renal function, signs of lactic acidosis (malaise, myalgia, abdominal pain, dyspnoea, drowsiness) and consider temporarily stopping metformin in at-risk patients.
Co-trimoxazole + metformin: trimethoprim inhibits OCT2 and raises metformin levels, with a risk of lactic acidosis. Monitor renal function and glycaemia.
Trimethoprim competes with Metformin for renal tubular secretion (OCT2 transporter), reducing its elimination.
Renal function before and during; signs of acidosis (Kussmaul breathing, drowsiness, hypotension).
Weakness, myalgia, abdominal pain, hyperventilation, drowsiness — stop and seek medical help.
Monitor for lactic acidosis in patients with reduced renal function; consider low Metformin doses during antibiotic therapy.
DailyMed/FDA (NIH/NLM) — approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Antifolate + folate antagonist: co-trimoxazole potentiates methotrexate toxicity.
The co-trimoxazole label recommends avoiding concomitant use with methotrexate: sulfonamides can displace methotrexate from plasma protein binding and compete with renal methotrexate transport, raising free methotrexate concentrations; additionally, trimethoprim is an antifolate (dihydrofolate reductase inhibitor) that adds its effect to that of methotrexate, and the methotrexate label lists sulfonamides among the drugs to avoid. The risk of myelosuppression, mucositis and haematological toxicity is particularly relevant with high-dose methotrexate (chemotherapy); even with low doses (rheumatoid arthritis), avoid or, if unavoidable, closely monitor the blood count, renal function and mucositis.
Co-trimoxazole + methotrexate: avoid the combination — additive antifolate effect, protein binding displacement and renal competition with a risk of myelosuppression.
Trimethoprim inhibits dihydrofolate reductase and reduces methotrexate renal clearance, risking severe marrow suppression.
Full blood count and renal function; reassess methotrexate dose.
Fever, infections, oral ulcers, anaemia, leucopenia, thrombocytopenia.
Avoid the combination when possible; if unavoidable, monitor full blood count and renal function frequently.
DailyMed (FDA) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757d6cef-6696-7a1c-8074-01258aaa8bdd ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Zidovudine with Co-trimoxazole increases the risk of myelotoxicity (anaemia and neutropenia) through an additive effect on the bone marrow.
Zidovudine is associated with haematological toxicity, including neutropenia and severe anaemia, especially in patients with advanced HIV; co-trimoxazole, with its antifolate component (trimethoprim) and the bone marrow effect of sulfonamides, adds the risk of myelosuppression when used concomitantly (the combination is common in Pneumocystis prophylaxis in HIV). Monitor the blood count regularly during the combination, especially in the first months of treatment and in patients with low counts; consider folinic acid if folate depletion arises and adjust or interrupt zidovudine in the face of significant neutropenia or anaemia.
Co-trimoxazole + zidovudine: additive risk of myelosuppression (neutropenia and anaemia). Monitor the blood count in HIV prophylaxis.
Both drugs can induce haematological abnormalities; co-administration potentiates marrow suppression, especially in immunodeficient patients.
Periodic blood counts: haemoglobin, white cells and neutrophils.
Significant anaemia or neutropenia requires reassessing the combination.
Use Co-trimoxazole with Zidovudine only when strictly indicated (e.g. Pneumocystis prophylaxis) and with haematological monitoring.
DailyMed/FDA (NIH/NLM) — approved Zidovudine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6df09f15-b102-431c-adde-d7aeef6f5d84 ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Trimethoprim reduces renal potassium excretion and can cause hyperkalaemia; potassium-rich foods add to this effect.
Monitor serum potassium in at-risk patients; moderate excessive intake of potassium-rich foods.
DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Alcohol may worsen the gastrointestinal effects and photosensitivity associated with co-trimoxazole.
Limit alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Co-trimoxazole is renally excreted; renal impairment increases the toxicity risk (including hyperkalaemia) and requires adjustment.
Adjust the dose; monitor renal function and serum potassium.
DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Trimethoprim interferes with folate metabolism and can worsen deficiency, with risk of megaloblastic anaemia.
Use with caution in folate deficiency, alcoholism and malnutrition; consider supplementation.
DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Trimethoprim is a folate antagonist; use in the 1st trimester is associated with an increased risk of malformations (neural tube defects).
Avoid in the 1st trimester; supplement folic acid if unavoidable.
Excreted into breast milk; avoid while breastfeeding neonates (kernicterus risk with sulphonamides).
No specific additional contraception.
DailyMed/FDA (NIH/NLM) — approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Antibacterial combination (sulfamethoxazole and trimethoprim, 5:1). Rapid oral absorption; peak blood levels 1 to 4 hours after dosing. About 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins; the free forms are the therapeutically active ones. Urinary concentrations considerably higher than blood concentrations.
Sequential blockade of two steps of bacterial folate synthesis: sulfamethoxazole inhibits the synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA); trimethoprim blocks the production of tetrahydrofolic acid by reversibly inhibiting dihydrofolate reductase. The combination delays the development of bacterial resistance.
Rapid oral absorption; peak blood levels 1 to 4 hours after dosing; steady state after 3 days with 800/160 mg every 12 hours (trimethoprim 1.72 mcg/mL; free and total sulfamethoxazole 57.4 and 68 mcg/mL).
Sulfamethoxazole is metabolised to at least 5 metabolites (formation of N4-hydroxy is mediated by CYP2C9); trimethoprim is metabolised in vitro to 11 metabolites. Excretion is mainly renal, by glomerular filtration and tubular secretion (84.5% of the sulfonamide and 66.8% of free trimethoprim within 72 hours).
Mean serum half-lives of 10 hours (sulfamethoxazole) and 8 to 10 hours (trimethoprim); prolonged in severe renal impairment, requiring regimen adjustment. Detectable blood concentrations 24 hours after administration.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
