What are the adverse reactions of Trimethoprim-Sulfamethoxazole (TMP-SMX) with their frequencies?

Adverse Reactions of Trimethoprim-Sulfamethoxazole (TMP-SMX)

TMP-SMX is frequently associated with substantial pruritus, rash, leukopenia, transaminase elevation, and nausea, though these reactions are rarely life-threatening. 1

Common Adverse Reactions (Frequency: Frequent to Common)

Dermatologic Reactions

• Rash and pruritus occur frequently and are among the most common adverse reactions 1
• Rash occurred in 1.83% of high-dose patients vs 0.20% of standard-dose patients in ambulatory settings 2
• Overall adverse drug reactions occur in 6-8% of patients in general use 3
• In Japanese dermatology patients, adverse events occurred in 24.2% of cases, higher than typical populations 4

Hematologic Reactions

• Leukopenia occurs frequently 1
• Thrombocytopenia was the most frequent adverse event in dermatology patients at 12.5% 4
• Neutropenia can occur, though severe cases are rare 3

Gastrointestinal Reactions

• Nausea occurs frequently 1
• Gastrointestinal upset is common, with 5.30% vs 2.24% in high-dose vs standard-dose patients 2
• Vomiting is commonly reported 5
• Mild gastrointestinal distress is one of the most common adverse reactions 3

Hepatic Reactions

• Transaminase elevation occurs frequently 1
• Hepatitis with cholestatic jaundice can occur, characterized by elevation of transaminases and bilirubin 6

Metabolic/Renal Reactions

• Hyperkalemia occurred in 3.46% vs 0.81% in high-dose vs standard-dose patients 2
• Hyperkalemia risk is increased in AIDS patients receiving TMP-SMX 7
• Acute renal injury occurred in 3.67% vs 1.63% in high-dose vs standard-dose patients 2
• Crystalluria can occur without adequate fluid intake 6, 7

Central Nervous System Reactions

• CNS adverse reactions occurred in 2.65% vs 0.81% in high-dose vs standard-dose patients 2
• Aseptic meningitis is a rare but serious CNS complication 6

Severe/Life-Threatening Reactions (Frequency: Rare)

Severe Cutaneous Reactions

• Stevens-Johnson syndrome occurs only rarely but can be fatal 1, 7
• Toxic epidermal necrolysis is a life-threatening skin reaction 1, 6, 7
• Erythema multiforme and exfoliative dermatitis are severe hypersensitivity manifestations 6
• Severe exfoliative rashes are rare complications 1

Hematologic Toxicity

• Agranulocytosis is a potentially fatal bone marrow suppression complication 6, 7
• Aplastic anemia can occur and may be fatal 6, 7
• Thrombotic thrombocytopenic purpura and idiopathic thrombocytopenic purpura can occur 6
• Hemolytic anemia, particularly in G6PD-deficient individuals 6, 7
• Megaloblastic anemia can occur, especially with folate deficiency 6, 7

Hepatic Toxicity

• Fulminant hepatic necrosis is a fatal liver failure complication that has been reported 6, 7

Other Severe Reactions

• Anaphylaxis and anaphylactoid reactions can occur 6
• Serum sickness-like syndrome and Henoch-Schönlein purpura 6
• Pseudomembranous enterocolitis, including Clostridium difficile-associated diarrhea 6, 7
• Interstitial nephritis and renal failure, potentially progressing to toxic nephrosis with oliguria and anuria 6

Special Population Considerations

AIDS Patients

• Substantially increased incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferases compared to non-AIDS patients 7
• Approximately 15% of HIV-infected children have substantial adverse reactions to TMP-SMX 1
• Severe adverse reactions occurred in 32% vs 26% in patients with vs without prior mild TMP-SMX intolerance 1

Elderly Patients

• Increased risk of severe adverse reactions, particularly with complicating conditions like impaired kidney/liver function 7
• Severe skin reactions, generalized bone marrow suppression, thrombocytopenia with purpura, and hyperkalemia are most frequently reported 7
• Increased incidence of thrombocytopenia with purpura when receiving concurrent thiazide diuretics 7
• Hematological changes indicative of folic acid deficiency may occur 7

Pediatric Patients

• Overall frequency of adverse reactions appears lower in HIV-infected children than adults 1
• Approximately 15% of children have substantial adverse reactions 1
• Rash (including erythema multiforme and rarely Stevens-Johnson syndrome), hematologic abnormalities, gastrointestinal complaints (usually mild), hepatitis, and renal disorders can occur 1

Risk Factors for Increased Adverse Reactions

• Advanced age is an independent risk factor 2
• Concomitant ACE inhibitor therapy significantly increases hyperkalemia risk 2
• High-dose therapy (≥4 double-strength tablets daily) increases overall adverse reaction rate to 13.0% vs 5.09% for standard dosing 2
• Renal dysfunction, liver disease, or malnutrition increase risk of hypoglycemia and other complications 7
• Folate deficiency states (elderly, chronic alcoholics, anticonvulsant therapy, malabsorption, malnutrition) 7
• G6PD deficiency increases hemolysis risk, frequently dose-related 7
• Concomitant use of drugs affecting potassium (ACE inhibitors, potassium-sparing diuretics) 8, 6

Clinical Monitoring Implications

Complete blood counts should be performed frequently during therapy, with discontinuation if significant reduction in any formed blood element occurs 7. For prolonged therapy, monitor renal function (BUN, creatinine), hepatic function (transaminases, bilirubin), and serum potassium, particularly in high-risk patients 6, 7. Ensure adequate hydration to prevent crystalluria 6, 7.