Sulfamethoxazole: Sulfonamide Antibiotic in Fixed Cotrimoxazole Combination
Sulfamethoxazole is a sulfonamide antibiotic with intermediate half-life that is used almost exclusively in fixed combination with trimethoprim (cotrimoxazole, abbreviated TMP/SMX). Known brand names are Bactrim, Eusaprim, Cotrim Hexal, and numerous generics. The combination was approved in 1968 and has since been an important antibiotic for a broad range of indications, particularly for Pneumocystis jirovecii infections, toxoplasmosis, and certain urinary tract infections.
The fixed combination in the ratio 1:5 (trimethoprim to sulfamethoxazole) was chosen because both substances inhibit two consecutive steps in bacterial folate synthesis, leading to synergistic (sequential blockade) activity. Resistance development is slowed by the dual blockade.
Mechanism of Action
Bacteria cannot take up folate from food and must synthesize it themselves. Sulfamethoxazole competitively inhibits the enzyme dihydropteroate synthase, which catalyzes the incorporation of p-aminobenzoic acid (PABA) into folate precursors. Trimethoprim inhibits the subsequent enzyme dihydrofolate reductase. The combination blocks folate synthesis in two steps and leads to bacteriostatic activity.
Since human cells take up folate from food and do not possess dihydropteroate synthase, selectivity for bacteria is high. Trimethoprim binding to human dihydrofolate reductase is much weaker than to bacterial enzyme, which explains the safety profile. However, megaloblastic anemia can occur with folate deficiency or concurrent therapy with other folate antagonists such as methotrexate.
The spectrum of activity includes gram-positive organisms (Staphylococcus aureus including MRSA in many strains, streptococci in pneumonia) and gram-negative pathogens (E. coli, Klebsiella, Proteus, Salmonella, Shigella), as well as Pneumocystis jirovecii, Toxoplasma gondii, Nocardia, and Stenotrophomonas maltophilia. Pseudomonas aeruginosa is resistant.
Pharmacokinetically, sulfamethoxazole is absorbed orally with bioavailability of approximately 90 percent, half-life of approximately 10 hours, which allows for twice-daily dosing. Elimination is renal after hepatic acetylation.
Uses
- Acute uncomplicated urinary tract infection and pyelonephritis: when local resistance patterns are favorable (resistance rates vary considerably by region)
- Pneumocystis jirovecii pneumonia (PCP): standard for treatment and prophylaxis in HIV-positive and immunosuppressed patients
- Toxoplasmosis: particularly in HIV-positive patients
- Nocardiosis: first-line therapy
- Certain gastrointestinal infections: shigellosis, some salmonellosis
- Stenotrophomonas maltophilia infections
- Skin infections with MRSA (effective in some strains): for oral outpatient therapy
- Prophylaxis of recurrent UTIs in women
Dosage and Administration
Standard dose cotrimoxazole forte (160 mg TMP/800 mg SMX): 1 tablet twice daily. Cotrimoxazole standard (80 mg TMP/400 mg SMX): 2 tablets twice daily.
Pneumocystis jirovecii pneumonia treatment: high-dose 15 to 20 mg/kg TMP per day divided into 3 to 4 doses over 21 days, often intravenous.
Pneumocystis prophylaxis: cotrimoxazole forte once daily or three times per week.
UTI adults: cotrimoxazole forte 1 tablet twice daily for 3 to 5 days. For acute pyelonephritis 7 to 14 days.
In renal impairment: dose adjustment according to creatinine clearance; with eGFR below 30 ml/min halve the dose or avoid use; with eGFR below 15 ml/min contraindicated.
Administration: with sufficient water, with or without food. Adequate hydration is important as sulfonamides can crystallize and cause kidney damage.
Side Effects
Common: nausea, vomiting, diarrhea, rash (itchy, maculopapular), pruritus, hyperkalemia (especially in elderly and in renal impairment, due to trimethoprim inhibition of renal potassium excretion), eosinophilia.
Serious: severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), erythema multiforme (risk especially in the first 2 weeks, can be life-threatening); bone marrow suppression with neutropenia, thrombocytopenia, and anemia (with folate deficiency or comedication); hepatotoxicity; acute interstitial nephritis; hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency; hyperkalemia with risk of arrhythmia; pseudomembranous colitis from Clostridioides difficile.
Important: sulfonamide allergies are common (approximately 3 to 5 percent of the population). Patients with known sulfonamide allergy must not receive cotrimoxazole. With new rashes during therapy, immediate discontinuation is necessary due to risk of Stevens-Johnson syndrome.
Drug Interactions
- Methotrexate: additive folate antagonism, severe bone marrow suppression, combination contraindicated in MTX therapy
- Warfarin and other oral anticoagulants: elevated INR through inhibition of warfarin metabolism, INR monitoring required
- ACE inhibitors and sartans: additive hyperkalemia
- Potassium-sparing diuretics: additive hyperkalemia
- Sulfonylureas (glibenclamide): enhanced hypoglycemia
- Phenytoin and carbamazepine: elevated levels
- Ester-type local anesthetics (procaine): antagonistic activity with sulfonamide
- Hormonal contraceptives: theoretically reduced efficacy
Special Precautions
Pregnancy: contraindicated in the first trimester (folate antagonism with risk of neural tube defects) and in the third trimester (displacement of bilirubin from albumin binding with risk of kernicterus in the newborn). In the second trimester only with strict indication. Breastfeeding: contraindicated in premature infants and in the first weeks of life due to risk of kernicterus.
Folate deficiency and megaloblastic anemia: patients with folate deficiency, malnutrition, elderly patients, or those on antifolate therapy can develop megaloblastic anemia. Folate supplementation can provide protection without significantly reducing antibacterial activity.
Before starting therapy: history of sulfonamide allergy, glucose-6-phosphate dehydrogenase deficiency, renal impairment, pregnancy.
Monitoring during prolonged therapy: blood count, liver transaminases, creatinine, potassium after 1 week, then every 2 weeks.
Resistance in UTIs: in many regions of Germany, E. coli resistance to cotrimoxazole has already exceeded 30 percent, which is why it is no longer recommended as first-line therapy for UTI. Current guidelines prefer pivmecillinam, fosfomycin, or nitrofurantoin.
You Might Also Be Interested In
- Trimethoprim, the combination partner
- Dapsone, another sulfone antibiotic
- Fosfomycin, first-line for uncomplicated cystitis
- Nitrofurantoin, alternative UTI therapy
- Pivmecillinam hydrochloride, modern first-line UTI therapy
Frequently Asked Questions
What is cotrimoxazole?
Cotrimoxazole is the fixed combination of trimethoprim and sulfamethoxazole in a 1 to 5 ratio. Both substances inhibit consecutive steps of folate synthesis in bacteria, leading to synergistic activity and slower resistance development. The combination has been established since 1968 and is standard for many indications.
Why is cotrimoxazole given to HIV patients for prevention of pneumonia?
Pneumocystis jirovecii is a fungus that can cause severe pneumonia (PCP) in severely immunosuppressed patients (HIV with low CD4 count, after stem cell transplantation). Low-dose cotrimoxazole prophylaxis reliably prevents this infection and has been standard for decades. The same therapy is used for toxoplasmosis prophylaxis.
What is Stevens-Johnson syndrome?
Stevens-Johnson syndrome is a rare but life-threatening skin reaction with pronounced blistering, mucous membrane involvement, and skin separation. Sulfonamides are one of the most common causes. If new extensive rashes with mucous membrane involvement occur in the first 2 weeks of cotrimoxazole therapy, stop immediately and go to emergency. Treatment takes place in burn units.
Why is cotrimoxazole used less today for bladder infection?
In Germany and many other countries, the resistance rate of E. coli, the main cause of uncomplicated UTI, to cotrimoxazole has risen above 30 percent. The German S3 guideline therefore recommends pivmecillinam, fosfomycin, or nitrofurantoin as first-line therapy. Cotrimoxazole can be used if the resistance situation is individually assessed.
Sources
- Gelbe Liste, Cotrimoxazole active ingredient profile
- AWMF S3 guideline uncomplicated urinary tract infections and therapy of HIV opportunistic infections
- BfArM, Federal Institute for Drugs and Medical Devices
- EMA product information cotrimoxazole preparations
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