What are the typical adverse reactions to trimethoprim‑sulfamethoxazole (Bactrim)?

Typical Adverse Reactions to Trimethoprim-Sulfamethoxazole (Bactrim)

The most common adverse reactions to trimethoprim-sulfamethoxazole are dermatologic (rash, including erythematous maculopapular eruptions) and gastrointestinal disturbances (nausea, vomiting, diarrhea), with serious reactions being rare but potentially life-threatening when they occur. 1, 2

Most Common Reactions (Occur Frequently)

Dermatologic Reactions

• Mild cutaneous reactions consisting of erythematous maculopapular rash occur in approximately 16% of children receiving prophylactic therapy 1
• Pruritus and urticarial rashes are common 1
• Photosensitivity reactions can occur 1
• In HIV-infected children, approximately 15% experience adverse reactions, with 82% of these being cutaneous (maculopapular or urticarial skin rash) 1

Gastrointestinal Reactions

• Nausea, vomiting, diarrhea, and abdominal pain are the most prevalent adverse reactions 1, 3, 4
• Anorexia and epigastric distress occur commonly 1, 3
• Glossitis and stomatitis can develop 1

Serious But Rare Reactions (Life-Threatening)

Severe Dermatologic Reactions

• Stevens-Johnson syndrome and toxic epidermal necrolysis occur rarely—approximately 1 in 200,000 courses of therapy—but are potentially fatal 1, 3
• Erythema multiforme and exfoliative dermatitis are severe hypersensitivity manifestations 1, 3
• If urticarial rash or Stevens-Johnson syndrome occurs, permanently discontinue the drug 1, 5

Hematologic Reactions

• Leukopenia and thrombocytopenia are the principal hematologic reactions 1
• The incidence varies widely from <0.1% to 12-34% depending on the population and dosing 1
• Agranulocytosis, aplastic anemia, and megaloblastic anemia are rare but potentially fatal 1, 3
• Hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, though rarely reported 1, 2
• Neutropenia and methemoglobinemia have been documented 1

Hepatic Reactions

• Hepatitis with cholestatic jaundice and elevation of serum transaminases and bilirubin 1, 3
• Fulminant hepatic necrosis is rare but fatal when it occurs 3

Renal Reactions

• Interstitial nephritis and renal failure 1, 3
• Crystalluria (preventable with adequate hydration) 1, 3
• Toxic nephrosis with oliguria and anuria 1
• Elevation of blood urea nitrogen and serum creatinine 1

Neurologic and Other Serious Reactions

• Aseptic meningitis (rare but serious) 1, 3
• Convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, and headache 1
• Tremor (less common, primarily in immunocompromised patients) 6
• Hyperkalemia, particularly in patients with renal insufficiency or those on ACE inhibitors 3, 2
• Hypoglycemia (rare, usually after several days of therapy, particularly in patients with renal dysfunction, liver disease, or malnutrition) 2

Critical Population Differences

HIV-Infected Adults vs. Children

• 40-65% of HIV-infected adults experience adverse reactions to TMP-SMX, occasionally requiring discontinuation 1
• In contrast, only 15% of HIV-infected children have adverse reactions, with most being mild cutaneous reactions 1
• Hematologic reactions account for only 18% of adverse events in HIV-infected children 1

Fatal Reactions

• Fatal reactions are extremely rare, occurring in less than 1 in 100,000 children 1
• When serious toxicity occurs, severe skin lesions and thrombocytopenia/leukopenia are the most likely complications 7

Management of Adverse Reactions

Mild to Moderate Rash

• Temporarily discontinue TMP-SMX and restart when the rash resolves 1, 5
• Most adverse reactions develop within the first two weeks of therapy 4

Severe Reactions

• For urticarial rash or Stevens-Johnson syndrome, permanently discontinue and never readminister 1, 5
• For significant reduction in any formed blood element, discontinue the drug 2

Monitoring Requirements

• Complete blood counts with differential and platelet count should be performed at initiation and monthly during prolonged therapy 8, 3, 5
• Urinalyses with microscopic examination and renal function tests should be performed, particularly in patients with impaired renal function 2
• Monitor serum potassium closely in patients with underlying potassium metabolism disorders, renal insufficiency, or those on concomitant drugs that induce hyperkalemia 2
• Ensure adequate fluid intake to prevent crystalluria and stone formation 3, 2

Common Pitfalls to Avoid

• Do not use in neonates or infants <2 months of age due to kernicterus risk 3, 5
• Avoid in patients with documented folate deficiency-related megaloblastic anemia 3
• Exercise caution in elderly patients, chronic alcoholics, patients on anticonvulsants, and those with malabsorption or malnutrition (folate deficiency risk) 2
• Be aware that "slow acetylators" may be more prone to idiosyncratic reactions 2
• Monitor for drug interactions, particularly with methotrexate, warfarin, oral hypoglycemics, and phenytoin 1, 3
• In elderly patients on thiazide diuretics, increased incidence of thrombocytopenia with purpura has been reported 2