What are the contraindications for cotrimoxazole (trimethoprim‑sulfamethoxazole)?

Contraindications to Cotrimoxazole (Trimethoprim-Sulfamethoxazole)

Cotrimoxazole is absolutely contraindicated in patients with known hypersensitivity to trimethoprim or sulfonamides, documented megaloblastic anemia due to folate deficiency, pregnancy, nursing mothers, infants under 2 months of age, marked hepatic damage, and severe renal insufficiency when renal function cannot be monitored. 1

Absolute Contraindications

Hypersensitivity Reactions

• Known allergy to trimethoprim or any sulfonamide compound is an absolute contraindication due to risk of life-threatening reactions 1
• Patients with prior Stevens-Johnson syndrome or toxic epidermal necrolysis from cotrimoxazole must never receive it again, as these carry mortality rates of approximately 1% and 30% respectively 2
• Both immediate IgE-mediated reactions and delayed hypersensitivity reactions can occur to either component of the combination 3, 4

Hematologic Contraindications

• Documented megaloblastic anemia due to folate deficiency is an absolute contraindication 1
• The antifolate effects of both trimethoprim and sulfamethoxazole can worsen existing folate deficiency states 1

Age-Related Contraindications

• Infants less than 2 months of age must not receive cotrimoxazole due to risk of kernicterus from sulfonamide displacement of bilirubin from albumin 1

Pregnancy and Lactation

• All pregnant patients are contraindicated from receiving cotrimoxazole because sulfonamides cross the placenta 1
• All nursing mothers must avoid cotrimoxazole as sulfonamides are excreted in breast milk and may cause kernicterus in the infant 1
• The American College of Obstetricians and Gynecologists specifically recommends avoiding use at term 5

Hepatic and Renal Contraindications

• Marked hepatic damage is an absolute contraindication 1
• Severe renal insufficiency when renal function status cannot be monitored is contraindicated 1
• This reflects the need for dose adjustment in renal impairment and the risk of accumulation leading to toxicity 1

Special Population Considerations

G6PD Deficiency

• Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency should not receive cotrimoxazole due to risk of hemolytic anemia 5
• This is particularly important as G6PD deficiency may be undiagnosed in certain ethnic populations 5

Drug Interaction Contraindications

• Concurrent use with methotrexate at treatment doses should be avoided due to severe bone marrow suppression risk from combined antifolate effects 5, 6
• Lower prophylactic doses of methotrexate are generally tolerated but require careful monitoring 5

High-Risk Situations Requiring Extreme Caution

HIV-Positive Patients

• While not an absolute contraindication, HIV-positive patients experience hypersensitivity reactions in up to 60% of cases compared to 5% in HIV-negative patients 7
• Risk factors include history of syphilis, higher total plasma protein concentration, and paradoxically higher CD4:CD8 ratios 7
• Despite high reaction rates, cotrimoxazole may still be used in HIV patients for specific indications like PCP prophylaxis when benefits outweigh risks 7, 5

Patients with History of Severe Drug Reactions

• The American Academy of Pediatrics notes that rare severe allergic reactions, particularly Stevens-Johnson syndrome, make cotrimoxazole undesirable when alternative treatments exist 8
• Cotrimoxazole ranks in the upper third of drugs causing Lyell's syndrome (toxic epidermal necrolysis) based on German epidemiological data 2

Critical Monitoring Requirements When Contraindications Are Relative

When cotrimoxazole must be used despite relative contraindications:

• Baseline complete blood count and monthly monitoring for hematologic toxicity, particularly thrombocytopenia 5
• Serum potassium monitoring at baseline, 1-2 weeks after initiation, and every 4 months, especially in patients on ACE inhibitors or ARBs 6
• Immediate discontinuation if any rash develops given the risk of progression to Stevens-Johnson syndrome or toxic epidermal necrolysis 6