Sulfamethoxazole-Trimethoprim (Bactrim, Septra)

Indications

Diseases

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

Cardiovascular Adverse Effects

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

Dermatologic Adverse Effects

Endocrinologic Adverse Effects

Gastrointestinal Adverse Effects

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

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

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

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]