Sulfamethoxazole-Trimethoprim (Bactrim, Septra)

Indications

Diseases

Bronchiectasis (see Bronchiectasis, [[Bronchiectasis]])

Organisms

Burkholderia Cepacia (Formerly Pseudomonas Cepacia) (see Burkholderia Cepacia, [[Burkholderia Cepacia]])
Escherichia Coli (see Escherichia Coli, [[Escherichia Coli]])
Nocardiosis (see Nocardiosis, [[Nocardiosis]])
- Sulfamethoxazole-Trimethoprim is the Recommended First Line Treatment
Pneumocystis Jirovecii (see Pneumocystis Jirovecii, [[Pneumocystis Jirovecii]])
- Prophylaxis: sulfamethoxazole-trimethoprim is the recommended first line prophylaxis agent
- Treatment: sulfamethoxazole-trimethoprim is the recommended first line treatment
Serratia Marcescens (see Serratia Marcescens, [[Serratia Marcescens]])
Staphylococcus Aureus (see Staphylococcus Aureus, [[Staphylococcus Aureus]])
- Methicillin-Resistant Staphylococcus Aureus (MRSA): most MRSA isolates (especially community-acquired isolates, such as the USA300 clone) are sensitive to sulfamethoxazole-trimethoprim
Stenotrophomonas Maltophilia (Formerly Xanthomonas Maltophilia) (see Stenotrophomonas Maltophilia, [[Stenotrophomonas Maltophilia]])
- Sulfamethoxazole-Trimethoprim is the Recommended First Line Treatment

Contraindications

Folate Deficiency (see Folate, [[Folate]]): since trimethoprim interferes with folate metabolism
History of Erythema Multiforme (see Erythema Multiforme, [[Erythema Multiforme]])
- However, if Sulfamethoxazole-Trimethoprim was Previously Discontinued for a Non-Life Threatening Dermatologic Adverse Effect, Desensitization Can Be Utilized if Re-Introduction of Sulfamethoxazole-Trimethoprim is Required
History of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (TEN) (see Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis, [[Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis]])
- However, if Sulfamethoxazole-Trimethoprim was Previously Discontinued for a Non-Life Threatening Dermatologic Adverse Effect, Desensitization Can Be Utilized if Re-Introduction of Sulfamethoxazole-Trimethoprim is Required

Pharmacology

General Comments

Sulfamethoxazole and Trimethoprim Each Alone are Weak Bactericidal Agents: however, the combination is highly bactericidal
- Maximum Bactericidal Activity: occurs at a 20:1 ratio of sulfamethoxazole/trimethoprim
  - Sulfamethoxazole-Trimethoprim is Supplied at a 5:1 Ratio: however, due to the wider volume of distribution of trimethoprim, peak serum ratios of 20:1 are achieved

Pharmacology of Components

Sulfamethoxazole
- Sulfonamide Antibiotic (see Sulfonamides, [[Sulfonamides]])
- Sulfamethoxazole is a Structural Analogue of Para-Aminobenzoic Acid (PABA), Which Binds to Dihydropteroate Synthetase and Competes with PABA to Inhibit Bacterial Synthesis of Dihydrofolic Acid, an Intermediate Step in the Synthesis of Tetrahydrofolate
  - Decreased Availability of Tetrahydrofolate with the the Bacteria Impairs Thymidine (and Subsequently, DNA) Synthesis
Trimethoprim
- Trimethoprim Binds to Bacterial Dihydrofolate Reductase, Inhibiting the Synthesis of Tetrahydrofolate
  - Decreased Availability of Tetrahydrofolate with the the Bacteria Impairs Thymidine (and Subsequently, DNA) Synthesis
- Epithelial Sodium Channel (ENaC) Antagonist (see Epithelial Sodium Channel Antagonists, [[Epithelial Sodium Channel Antagonists]])
  - Inhibits sodium channels on the luminal membrane of cells in the renal collecting tubule: collecting tubule is the site of action of aldosterone

Metabolism

Renal: 50% of drug is excreted within the first 24 hrs
Hepatic: sulfamethoxazole is acetylated (61%) and glucuronidated (15%) in the liver

Administration

PO (Treatment): one double-strength (DS) tablet BID
- One Double Strength Tablet: contains 160 mg of trimethoprim
PO (PCP Prophylaxis): one one double-strength (DS) 3x/wk
- One Double Strength Tablet: contains 160 mg of trimethoprim
IV (PCP Treatment): 15-20 mg/kg/day divided q6-8hrs x 21 days

Dose Adjustment

Hepatic: none
Renal
- CrCl <30 mL/min: reduce dose
- CrCl <15 mL/min (and on Hemodialysis): although prescribing information recommends avoiding use (due to risk of drug accumulation), dose adjustment is appropriate in these patients

Pregnancy

First Trimester: avoid use (due to effect on folate metabolism)
Third Trimester: avoid use (due to ability of sulfonamides to displace bilirubin which is bound to albumin, increasing free unconjugated bilirubin and increasing the risk of kernicterus in the neonate)

Drug Interactions

Angiotensin Converting Enzyme Inhibitors (ACE-I) (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]]): due to compounded risk of hyperkalemia
Angiotensin II Receptor Blockers (ARB) (see Angiotensin II Receptor Blockers, [[Angiotensin II Receptor Blockers]]): due to compounded risk of hyperkalemia
Coumadin (see Coumadin, [[Coumadin]])
Dapsone (see Dapsone, [[Dapsone]])
Methenamine (see Methenamine, [[Methenamine]])
Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
Rifampin (see Rifampin, [[Rifampin]])
Spironolactone (Aldactone) (see Spironolactone, [[Spironolactone]]): due to compounded risk of hyperkalemia

Adverse Effects

General Comments

Increased Risk of Adverse Effects in HIV Patients: rate of adverse effects may be as high as 25-50% (with more severe reactions being reported)

Allergic/Immunologic Adverse Effects

Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]])
Serum Sickness (see Serum Sickness, [[Serum Sickness]])

Cardiovascular Adverse Effects

QT Prolongation without Definite Association with Torsade (see Torsade, [[Torsade]])

Dermatologic Adverse Effects

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS Syndrome) (Drug-Induced Hypersensitivity Syndrome, DIHS) (see Drug Rash with Eosinophilia and Systemic Symptoms, [[Drug Rash with Eosinophilia and Systemic Symptoms]])
- Epidemiology: case reports (Ann Allergy Asthma Immunology, 2016) [MEDLINE]
Erythema Multiforme (see Erythema Multiforme, [[Erythema Multiforme]])
Photodermatitis
Rash
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (TEN) (see Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis, [[Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis]])
Urticaria (see Urticaria, [[Urticaria]])

Endocrinologic Adverse Effects

Drug-Induced Hypoaldosteronism (see Hypoaldosteronism, [[Hypoaldosteronism]]): see Hyperkalemia below
Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): case reports [MEDLINE]

Gastrointestinal Adverse Effects

Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]]): definite association with acute pancreatitis
Anorexia (see Anorexia, [[Anorexia]])
Diarrhea (see Diarrhea, [[Diarrhea]])
Hepatotoxicity (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])

Hematologic Adverse Effects

Anemia (see Anemia, [[Anemia]])
Drug-Induced Thrombotic Microangiopathy (see Drug-Induced Thrombotic Microangiopathy, [[Drug-Induced Thrombotic Microangiopathy]])
- Epidemiology: strong evidence for association with thrombotic microangiopathy
Increased Risk of Hemolysis in Patient with G6PD Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]] and Hemolytic Anemia, [[Hemolytic Anemia]])
Leukopenia/Neutropenia (see Leukopenia, [[Leukopenia]] and Neutropenia, [[Neutropenia]])
Pancytopenia (see Pancytopenia, [[Pancytopenia]])
- Physiology: xxx
- Diagnosis: megaloblastic
- Treatment: folinic acid supplementation may be used to decrease the anti-folate activity of sulfamethoxazole-trimethoprim (without affecting its antimicrobial activity)
Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

Neurologic Adverse Effects

Aseptic Meningitis (see Meningitis, [[Meningitis]])
Delirium/Confusion (see Headache, [[Headache]])

Pulmonary Adverse Effects

Pulmonary Infiltrates with Eosinophilia (see Drug-Induced Pulmonary Eosinophilia, [[Drug-Induced Pulmonary Eosinophilia]])

Renal Adverse Effects

Acute Interstitial Nephritis (see Acute Interstitial Nephritis, [[Acute Interstitial Nephritis]])

Epidemiology

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])

Epidemiology
- Retrospective Study of Incidence of AKI with Sulfamethoxazole-Trimethoprim Therapy (J Antimicrob Chemother, 2012) [MEDLINE]: AKI occurred in 11.2% of patients during or immediately following therapeutic course
Mechanisms
- Acute Interstitial Nephritis (see Acute Interstitial Nephritis, [[Acute Interstitial Nephritis]])
- Acute Tubular Necrosis (ATN): cases have been reported
- Sulfamethoxazole Precipitation with Intratubular Deposition and Obstruction: with crystalluria

Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])

Epidemiology
- Canadian Drug Safety and Effectiveness Research Network (CDSERN) Study of Sudden Death in Patients Co-Prescribed Sulfamethoxazole/Trimethoprim + Either ACE-I or ARB’s (BMJ, 2014) [MEDLINE]: study of 39,879 sudden deaths -> 1027 occurred within 7 days of exposure to an antibiotic
  - Study Found an Increased Risk of Sudden Death in Patients at Least 66 y/o on ACE-Inhibitors or ARB’s (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76)
    - The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84) -> this corresponds to approximately 3 sudden deaths within 14 days per 1000 co-trimoxazole prescriptions
    - Likely related to unrecognized hyperkalemia associated with the combination of these agents
Physiology: trimethoprim is an epithelial sodium channel (ENaC) antagonist -> acts to close sodium channels on the luminal membrane of cells in the collecting tubule
- Renal Collecting Tubule is the Site of Action of Aldosterone: trimethoprim results in aldosterone resistance, resulting in hypoaldosteronism (see Hypoaldosteronism, [[Hypoaldosteronism]])
Clinical
- Risk is Highest in HIV Patients Receiving High Doses of Medication
- Predisposing Factors
  - May be more severe in patients with pre-existing renal insufficiency
  - Effect may be additive when sulfamethoxazole-trimethoprim is used in combination with other agents which predispose to hyperkalemia (such as ACE inhibitors, ARB’s, etc)
- Dose-Dependent: degree of hyperkalemia is dose-dependent
  - Although this is observed predominantly at the high doses of sulfamethoxazole-trimethoprim which are used to treat PCP, it may occur in older patients at more commonly used doses
- Peak Effect: occurs at 4-5 days

Increased Creatinine (see Increased Creatinine, [[Increased Creatinine]])

Physiology: trimethoprim decreases the tubular secretion of creatinine

Type 4 Renal Tubular Acidosis (RTA) (see Type 4 Renal Tubular Acidosis, [[Type 4 Renal Tubular Acidosis]])

Physiology: trimethoprim is an epithelial sodium channel (ENaC) antagonist -> acts to close sodium channels on the luminal membrane of cells in the collecting tubule
- Renal Collecting Tubule is the Site of Action of Aldosterone: trimethoprim results in aldosterone resistance, resulting in hypoaldosteronism (see Hypoaldosteronism, [[Hypoaldosteronism]])
Mechanisms of Decreased Urinary Ammonium Excretion
- Impaired Potassium Excretion with Potassium Entry into Cells -> Consequent Movement of Sodium and Hydrogen Ion into the Extracellular Fluid (to Maintain Electroneutrality) -> Alkalosis in Kidney Decreases Ammonium Synthesis in the Proximal Tubule
- Hyperkalemia Decreases Medullary Cycling by Inhibiting Ammonium Reabsorption in Thick Ascending Limb: ammonium is normally reabsorbed into the medullary interstitium and then is re-secreted into the medullary collecting tubule
- Potassium Competition for the Collecting Duct Na-NH4 Exchanger (i.e. the Basolateral Na-K-ATPase) Which Functions to Permit Uptake of Ammonium from the Interstitium and Allow Its Secretion into the Urine: potassium impairs the capacity of this pump to carry ammonium into the cell
Clinical
- Mild Hyperchloremic Normal Anion Gap Metabolic Acidosis (see Metabolic Acidosis-Normal Anion Gap, [[Metabolic Acidosis-Normal Anion Gap]])

Toxicologic Adverse Effects

Propylene Glycol Intoxication (see Propylene Glycol, [[Propylene Glycol]])
- Epidemiology: case reports associated with the intravenous preparation of sulfamethoxazole-trimethoprim (Medicine, 2016) [MEDLINE]
- Pharmacology: each milliliter of sulfamethoxazole-trimethoprim contains 400 mg of propylene glycol

Other Adverse Effects

Fever (see Fever, [[Fever]])
Multi-Organ Dysfunction: case report in AIDS patient (BMJ Case Rep, 2012) [MEDLINE]
- Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
- Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])
- Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]])
- Hepatitis (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
- Rhabdomyolysis (see Rhabdomyolysis, [[Rhabdomyolysis]])
Thrombophlebitis

References

Crystal-induced acute renal failure. Am J Med. 1999 Apr;106(4):459-65 [MEDLINE]
Trimethoprim-sulfamethoxazole. Mayo Clin Proc. 1999;74(7):730 [MEDLINE]
Trimethoprim-sulfamethoxazole-induced hypoglycemia as a cause of altered mental status in an elderly patient. J Am Board Fam Pract. 2000;13(3):211 [MEDLINE]
Trimethoprim-sulfamethoxazole revisited. Arch Intern Med. 2003;163(4):402 [MEDLINE]
Antimicrobial-associated renal tubular acidosis. Ann Pharmacother. 2004;38(6):1031 [MEDLINE]
Am J Kidney Dis. 2011 Sep;58(3):492-3. doi: 10.1053/j.ajkd.2011.06.014. Sulfamethoxazole crystalluria [MEDLINE]
Acute kidney injury associated with trimethoprim/sulfamethoxazole. J Antimicrob Chemother. 2012 May;67(5):1271-7. doi: 10.1093/jac/dks030. Epub 2012 Feb 20 [MEDLINE]
Trimethoprim/sulfamethoxazole induced multiorgan dysfunction. BMJ Case Rep. 2012 Dec 18;2012. pii: bcr2012007460. doi: 10.1136/bcr-2012-007460 [MEDLINE]
Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196
Trimethoprim-sulfamethoxazole-induced DRESS syndrome in a 4-year-old child. Ann Allergy Asthma Immunol. 2016 Apr;116(4):366-7. doi: 10.1016/j.anai.2015.12.009. Epub 2016 Jan 9 [MEDLINE]
Trimethoprim/Sulfamethoxazole-Induced Severe Lactic Acidosis: A Case Report and Review of the Literature. Medicine (Baltimore). 2016 Apr;95(17):e3478. doi: 10.1097/MD.0000000000003478 [MEDLINE]