What are the adverse effects of cotrimoxazole (trimethoprim‑sulfamethoxazole) at the standard 160 mg/800 mg twice‑daily three‑day regimen for uncomplicated cystitis?

Adverse Effects of Cotrimoxazole (Trimethoprim-Sulfamethoxazole)

Cotrimoxazole at standard dosing (160 mg/800 mg twice daily for 3 days) causes adverse effects in approximately 35% of patients, most commonly gastrointestinal disturbances and skin rashes, with rare but serious reactions including Stevens-Johnson syndrome, hematologic abnormalities, and hyperkalemia. 1, 2

Common Adverse Effects (Occurring in ~35% of Patients)

Gastrointestinal and dermatologic reactions dominate the adverse effect profile:

• Nausea and vomiting are the most frequently reported gastrointestinal complaints 3, 1
• Skin rash and urticaria occur commonly and are well-described adverse effects of the sulfonamide component 3, 1, 4
• Diarrhea can develop during or after treatment, and patients should be counseled that watery or bloody stools may occur even 2+ months after completing therapy (potential C. difficile infection) 1

In comparative trials, adverse effects were reported by 35% of trimethoprim-sulfamethoxazole recipients versus 25-43% with other antibiotics, though the difference was not statistically significant 2, 5

Serious but Rare Adverse Effects

Life-threatening reactions require immediate discontinuation:

• Stevens-Johnson syndrome is a rare but potentially fatal dermatologic emergency that appears more common with cotrimoxazole than trimethoprim alone 3, 1, 4
• Hematologic abnormalities including thrombocytopenia, neutropenia, and leukopenia can occur, particularly in elderly patients or those with folate deficiency 3, 1
• Liver disorders appear more common with the combination than with trimethoprim monotherapy 4

Metabolic and Electrolyte Disturbances

Hyperkalemia is a critical concern, especially in at-risk populations:

• Trimethoprim blocks potassium excretion in the distal nephron, causing progressive but reversible hyperkalemia 3, 1
• Close monitoring of serum potassium is warranted in patients with renal insufficiency, underlying potassium metabolism disorders, or those receiving concomitant medications that increase potassium 3, 1
• Hypoglycemia occurs rarely in non-diabetic patients, usually after several days of therapy, with highest risk in patients with renal dysfunction, liver disease, malnutrition, or those receiving high doses 1

Hematologic Monitoring Requirements

Folate deficiency-related changes necessitate surveillance:

• Complete blood counts should be performed frequently during treatment 1
• Hematological changes indicative of folic acid deficiency may occur in elderly patients, those with preexisting folate deficiency, chronic alcoholics, patients on anticonvulsants, or those with kidney failure 1
• These effects are reversible with folinic acid therapy 1

Special Population Considerations

AIDS patients experience dramatically higher adverse effect rates:

• The incidence of rash, fever, leukopenia, and elevated aminotransferases is greatly increased in AIDS patients treated for Pneumocystis carinii pneumonia compared to non-AIDS patients 1
• Hyperkalemia appears more common in AIDS patients receiving cotrimoxazole 1
• Adverse effects are generally less severe when used for prophylaxis rather than active treatment 1

Other high-risk groups require caution:

• Glucose-6-phosphate dehydrogenase deficient individuals may experience hemolysis, which is frequently dose-related 1
• Elderly patients receiving thiazide diuretics concurrently have increased risk of thrombocytopenia with purpura 1
• Patients with impaired renal or hepatic function require dose adjustment and closer monitoring 3, 1

Renal and Urologic Adverse Effects

Crystalluria prevention requires adequate hydration:

• Patients must maintain adequate fluid intake (at least 1.5 liters daily) to prevent crystalluria and stone formation 3, 1
• Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly in patients with impaired renal function 1

Comparative Safety Profile

Evidence suggests cotrimoxazole has more adverse effects than trimethoprim alone:

• Gastrointestinal disturbances and skin rashes appear less common with trimethoprim monotherapy compared to the combination 4
• Serious adverse effects such as liver disorders and Stevens-Johnson syndrome appear more common with cotrimoxazole than with trimethoprim alone 4
• The sulfamethoxazole component contributes most adverse effects without clear clinical benefit in uncomplicated cystitis 4

Critical Counseling Points

Patients must be instructed to:

• Maintain adequate fluid intake throughout treatment 1
• Complete the full 3-day course even if symptoms improve early 1
• Contact their physician immediately if they develop skin rash, fever, sore throat, unusual bleeding/bruising, or any sign of adverse reaction 1
• Report watery or bloody diarrhea even if it occurs weeks after completing treatment 1