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
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
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
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]
Treatment: folinic acid supplementation may be used to decrease the anti-folate activity of sulfamethoxazole-trimethoprim (without affecting its antimicrobial activity)
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
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
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
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]
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]
