Formulary
Cotrimoxazole (Trimethoprim-Sulfamethoxazole / TMP-SMX): Uses, Dosing, Side Effects and Indian Brand Names
Cotrimoxazole combines trimethoprim and sulfamethoxazole for synergistic sequential folate pathway blockade, remaining the drug of choice for Pneumocystis jirovecii pneumonia and a cornerstone of HIV prophylaxis.
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Cotrimoxazole (Trimethoprim-Sulfamethoxazole / TMP-SMX): Uses, Dosing, Side Effects and Indian Brand Names
Cotrimoxazole combines trimethoprim and sulfamethoxazole for synergistic sequential folate pathway blockade, remaining the drug of choice for Pneumocystis jirovecii pneumonia and a cornerstone of HIV prophylaxis.
NEET PG High-Yield: Sequential folate blockade (DHPS + DHFR) = synergistic bactericidal. Drug of choice for PCP and Nocardia. SJS/TEN (sulfonamide -- most common drug cause). Hyperkalaemia from trimethoprim (amiloride-like ENaC block). Contraindicated in G6PD deficiency. High-dose for PCP treatment. Warfarin interaction (CYP2C9 inhibition). First-line PCP prophylaxis (CD4 <200). Megaloblastic anaemia (treat with leucovorin, NOT folic acid -- folic acid would bypass the block and help the bacterium too).
Clinical overview
Cotrimoxazole is a fixed-dose combination of trimethoprim and sulfamethoxazole in a 1:5 ratio that produces sequential blockade of bacterial folate synthesis, making the combination bactericidal despite each component being merely bacteriostatic alone. This synergistic mechanism is a favourite pharmacology examination topic. Cotrimoxazole has historically been one of the most versatile antibiotics, effective against a wide range of Gram-positive and Gram-negative organisms, but resistance has become widespread globally, particularly in India where E. coli resistance rates exceed 60-70% in many centres. It retains critical importance as the drug of choice for Pneumocystis jirovecii pneumonia (PCP) -- both prophylaxis and treatment in HIV/AIDS -- and is a cornerstone of opportunistic infection prophylaxis in HIV patients with CD4 <200 cells/microL. Cotrimoxazole is also first-line for Nocardia infections, Stenotrophomonas maltophilia, and Isospora belli. Adverse effects are common, particularly in HIV patients (up to 50-60% incidence), and include hypersensitivity reactions, bone marrow suppression (megaloblastic anaemia due to folate antagonism), hyperkalaemia (trimethoprim blocks ENaC in the collecting duct, mimicking amiloride), and severe cutaneous reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis, which are more common with sulfonamides than any other antibiotic class). Cotrimoxazole is contraindicated in the first trimester (folate antagonism) and near term (kernicterus risk from sulfonamide displacement of bilirubin).
Pharmacological class
Cotrimoxazole (Trimethoprim-Sulfamethoxazole / TMP-SMX) belongs to the Folate Synthesis Inhibitors (Dihydrofolate Reductase Inhibitor + Sulfonamide) class. Sequential blockade of the folate synthesis pathway. Sulfamethoxazole competitively inhibits dihydropteroate synthase (DHPS), blocking conversion of PABA to dihydrofolic acid. Trimethoprim inhibits dihydrofolate reductase (DHFR), blocking conversion of dihydrofolic acid to tetrahydrofolic acid. The combination is synergistic and bactericidal because it blocks two sequential steps. Human cells use preformed folate from diet (they lack DHPS), providing selective toxicity.
Indian brand names and formulations
Available as: Septran (GSK), Bactrim (Roche/Abbott), Oriprim (Cipla), Cotrimox (various generic).
Tablets: Single-strength (TMP 80 mg + SMX 400 mg), Double-strength/DS (TMP 160 mg + SMX 800 mg). Suspension: TMP 40 mg + SMX 200 mg per 5 mL. IV infusion: TMP 80 mg + SMX 400 mg per 5 mL ampoule (dilute before infusion).
Regulatory status
Cotrimoxazole (Trimethoprim-Sulfamethoxazole / TMP-SMX) is classified under Schedule H in India under the Drugs and Cosmetics Act, 1940. Prescription-only. Listed on NLEM. Widely available. Critical drug for HIV programmes (free under NACO).
Indications
- Pneumocystis jirovecii pneumonia (PCP) -- treatment and prophylaxis
- PCP prophylaxis in HIV (CD4 <200/microL or oropharyngeal candidiasis)
- Urinary tract infections (where local resistance permits)
- Nocardiosis (drug of choice)
- Stenotrophomonas maltophilia infections (drug of choice)
- Isospora belli diarrhoea in HIV
- Toxoplasmosis prophylaxis in HIV
- MRSA skin and soft tissue infections (community-acquired)
Dosing
UTI: TMP 160 mg + SMX 800 mg (double-strength tablet) twice daily for 3-5 days. PCP treatment: TMP 15-20 mg/kg/day + SMX 75-100 mg/kg/day in 3-4 divided doses for 21 days (high-dose). PCP prophylaxis: 1 DS tablet daily or 1 SS tablet daily. Nocardiosis: TMP 10-15 mg/kg/day in 2-4 divided doses for months. Renal impairment (CrCl 15-30): half dose; CrCl <15: avoid.
Contraindications
- Megaloblastic anaemia due to folate deficiency (would be worsened)
- Severe hepatic or renal impairment
- Neonates and infants <6 weeks (kernicterus risk from sulfonamide)
- First trimester of pregnancy (folate antagonism -- neural tube defects)
- G6PD deficiency (sulfonamide component causes haemolysis)
- Known hypersensitivity to sulfonamides or trimethoprim
Adverse effects
- GI disturbances (nausea, vomiting, anorexia)
- Hypersensitivity rash (very common in HIV patients, up to 50-60%)
- Stevens-Johnson syndrome and toxic epidermal necrolysis (sulfonamide -- most common drug cause of SJS/TEN)
- Bone marrow suppression (megaloblastic anaemia, neutropaenia, thrombocytopaenia -- due to folate antagonism; give leucovorin if severe)
- Hyperkalaemia (trimethoprim blocks epithelial sodium channels in collecting duct -- mimics amiloride)
- Crystalluria (sulfonamide -- maintain hydration; alkalinise urine)
- Hepatitis
Drug interactions
- Warfarin: cotrimoxazole inhibits CYP2C9, markedly increasing INR and bleeding risk (one of the most clinically significant warfarin interactions)
- Methotrexate: both are folate antagonists; additive bone marrow toxicity
- Phenytoin: trimethoprim inhibits CYP2C9, increasing phenytoin levels
- ACE inhibitors and ARBs: additive hyperkalaemia risk with trimethoprim component
- Dapsone: both can cause haemolysis in G6PD deficiency; additive bone marrow toxicity
Pregnancy and lactation
Contraindicated in the first trimester (folate antagonism -- neural tube defects) and near term (sulfonamide crosses placenta and displaces bilirubin from albumin, causing kernicterus in the neonate). If used during pregnancy (e.g., PCP prophylaxis in HIV), supplement with high-dose folic acid 5 mg/day.
Exam-style clinical scenario
An HIV-positive patient with CD4 count 120 cells/microL presents with dry cough, progressive dyspnoea, bilateral ground-glass opacities on HRCT, and elevated LDH. What is the diagnosis and treatment? Pneumocystis jirovecii pneumonia (PCP). Treatment: high-dose IV cotrimoxazole (TMP 15-20 mg/kg/day) for 21 days + adjunctive prednisolone if PaO2 <70 mmHg.
Cost in India
Rs 10-30 for a strip of 10 DS tablets (TMP 160 mg + SMX 800 mg). Suspension: Rs 20-40 for 60 mL bottle. Free under NACO for HIV patients.
Clinical governance
Author: MedNext Editorial Team. Clinical reviewer: Awaiting clinical review. Jurisdiction: India (Drugs and Cosmetics Act, 1940). Sources: CIMS India, Indian Pharmacopoeia. Publication state: Awaiting clinical review. Correction: Report errors at support@mednext.academy.
Frequently Asked Questions
Why is the synergism of cotrimoxazole a favourite exam question?
It illustrates a key pharmacological principle: sequential blockade of the same metabolic pathway produces synergistic killing. Sulfamethoxazole blocks step 1 (PABA dihydrofolate via DHPS) and trimethoprim blocks step 2 (dihydrofolate tetrahydrofolate via DHFR). Each alone is bacteriostatic; together they are bactericidal. Human cells are spared because they lack DHPS and obtain preformed folate from the diet.
Why does trimethoprim cause hyperkalaemia?
Trimethoprim has structural similarity to amiloride and blocks the epithelial sodium channel (ENaC) in the collecting duct principal cells. This reduces sodium reabsorption and the lumen-negative potential that drives potassium secretion through ROMK channels, resulting in potassium retention. The effect is clinically significant at high doses (PCP treatment), in CKD, and when combined with other potassium-retaining drugs (ACEI, ARBs, spironolactone).
Why do HIV patients have such high rates of cotrimoxazole reactions?
The exact mechanism is not fully understood but is thought to relate to altered drug metabolism in HIV-infected individuals. One theory is that glutathione depletion (common in HIV) impairs detoxification of the sulfonamide hydroxylamine metabolite, which acts as a hapten and triggers immune responses. The incidence of adverse reactions (particularly rash) is 50-60% in HIV patients vs 3-5% in the general population.
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