What adverse events are associated with Bactrim (trimethoprim‑sulfamethoxazole) and what monitoring is recommended?

Adverse Events Associated with Bactrim (Trimethoprim-Sulfamethoxazole)

Most Common Adverse Reactions

The most frequent adverse events with Bactrim are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (rash and urticaria), occurring in approximately 6-8% of patients. 1, 2

• Mild cutaneous reactions, consisting of erythematous maculopapular rash, occur in approximately 16% of patients receiving prophylactic therapy 3
• Gastrointestinal upset includes nausea, emesis, abdominal pain, diarrhea, and anorexia 1
• These reactions typically develop within the first two weeks of therapy 4

Life-Threatening and Severe Adverse Reactions

Severe Cutaneous Adverse Reactions (SCARs)

Stevens-Johnson syndrome and toxic epidermal necrolysis are potentially fatal skin reactions that require immediate discontinuation of Bactrim. 3, 1

• Erythema multiforme and exfoliative dermatitis occur rarely, in approximately 1 in 200,000 courses of therapy 3
• Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) have been reported 1
• If urticarial rash or Stevens-Johnson syndrome occurs, TMP-SMX must be discontinued permanently and not readministered 3

Hematologic Toxicity

Serious hematologic reactions include agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia, which can be fatal despite aggressive supportive care. 1, 5

• Fatal reactions to TMP-SMX are rare, occurring in less than 1 in 100,000 children 3
• Hematologic reactions include neutropenia, thrombocytopenia, megaloblastic anemia, and hemolytic anemia (particularly in patients with G6PD deficiency) 3, 1
• The incidence of hematologic reactions varies from less than 0.1% to as high as 12-34% depending on the population studied 3
• Thrombotic thrombocytopenic purpura and idiopathic thrombocytopenic purpura have been reported 1
• In elderly patients receiving thiazide diuretics concurrently, an increased incidence of thrombocytopenia with purpura has been documented 1

Hepatotoxicity

Fulminant hepatic necrosis is a rare but fatal complication of Bactrim therapy. 1

• Hepatitis with cholestatic jaundice and hepatic necrosis can occur 1, 6
• Elevation of serum transaminases and bilirubin may be observed 1
• Cholestatic liver injury pattern, though less common than hepatocellular injury, has been documented and typically resolves within days of discontinuation 6

Renal Toxicity

Acute kidney injury (AKI) occurs in approximately 11% of patients treated for at least 6 days, with 5.8% of cases likely attributable to Bactrim. 7

• Renal failure, interstitial nephritis, and elevation of BUN and serum creatinine can occur 3, 1
• Crystalluria and nephrotoxicity may develop, particularly when combined with cyclosporine 1
• Oliguria and anuria progressing to toxic nephrosis have been reported 1
• AKI typically resolves promptly after discontinuation, though dialysis may rarely be required 7
• Patients with hypertension and diabetes mellitus have increased risk for renal insufficiency, especially if poorly controlled 7
• Pyuria is uncommon (appearing in only 2 of 37 patients in one study), and eosinophiluria is rarely observed 7

Respiratory Complications

Acute and delayed lung injury, including acute eosinophilic pneumonia and acute respiratory failure, can occur with Bactrim. 1

• Pulmonary infiltrates, cough, and shortness of breath have been reported 1
• Interstitial lung disease may develop 1

Cardiovascular Toxicity

QT prolongation resulting in ventricular tachycardia and torsades de pointes can occur, particularly when combined with other QT-prolonging agents. 1

• Circulatory shock and anaphylaxis have been reported 1
• Allergic myocarditis is a rare but serious complication 1

Metabolic and Electrolyte Abnormalities

Hyperkalemia is a significant concern, particularly in patients with renal insufficiency or those taking ACE inhibitors, ARBs, or potassium-sparing diuretics. 1

• Hyponatremia and metabolic acidosis can occur 1
• Three cases of hyperkalemia in elderly patients have been reported after concomitant intake with ACE inhibitors 1
• Hypoglycemia may develop, especially when combined with oral hypoglycemic agents 1

Neurologic and Psychiatric Reactions

• Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, and headache have been reported 1
• Psychiatric manifestations include hallucinations, depression, apathy, and nervousness 1

Other Significant Adverse Events

• Pseudomembranous enterocolitis, including Clostridium difficile-associated diarrhea, can occur 1
• Pancreatitis has been documented 1
• Serum sickness-like syndrome and Henoch-Schönlein purpura may develop 1
• Rhabdomyolysis, arthralgia, and myalgia are musculoskeletal complications 1

Population-Specific Considerations

HIV-Infected Adults vs. Children

Adverse reactions to TMP-SMX are significantly more frequent and severe in HIV-infected adults (40-65%) compared to HIV-infected children (approximately 15%). 3

• The majority of reactions in children are cutaneous (82%), followed by hematologic (18%) 3
• Serious reaction rates in children are dose-dependent, with prophylaxis dosages having the lowest rate 3

Elderly Patients

• Elderly patients have increased susceptibility to adverse effects, including bone marrow suppression and electrolyte disturbances 1
• Increased digoxin blood levels can occur with concomitant therapy, especially in elderly patients 1

Neonates and Infants

Bactrim is absolutely contraindicated in infants younger than 2 months due to the risk of kernicterus from bilirubin displacement. 3, 8

Monitoring Recommendations

For patients on prolonged therapy, monitor complete blood counts, renal function (BUN and creatinine), hepatic function (transaminases and bilirubin), and serum potassium levels. 8, 1

• Discontinue Bactrim if significant electrolyte abnormality, renal insufficiency, or reduction in any formed blood element is noted 1
• Ensure adequate hydration to prevent crystalluria 8
• Monitor INR in patients on warfarin, as Bactrim can prolong prothrombin time 1
• Monitor serum phenytoin levels when co-administered, as Bactrim inhibits phenytoin metabolism 1
• Monitor blood glucose more frequently in patients on oral hypoglycemic agents 1

Critical Drug Interactions

Avoid concurrent use of Bactrim with methotrexate due to bone marrow suppression and increased antifolate effects. 1

• Avoid concurrent use with cyclosporine due to marked but reversible nephrotoxicity 1
• Avoid concurrent use with dofetilide (contraindicated) due to risk of serious ventricular arrhythmias 1
• Avoid concurrent use with ACE inhibitors due to hyperkalemia risk 1
• Avoid concurrent use with amantadine due to risk of toxic delirium 1
• Monitor closely when combined with zidovudine due to potential additive myelotoxicity 1

Common Pitfalls to Avoid

• Do not use Bactrim in pregnant women, especially in the last trimester, due to potential fetal risks 3, 8
• Do not prescribe for patients with documented folate deficiency-related megaloblastic anemia 8
• Do not use in patients with prior history of immune thrombocytopenia with trimethoprim or sulfonamides 8
• Do not rely on hospital antibiograms for community-acquired infections, as they overestimate resistance rates 9
• Do not use as monotherapy for conditions requiring combination therapy 8