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trimethoprim/sulfamethoxazole; cotrimoxazole (Bactrim, Septra, Cotrim, Sulfatrim, Sulfoxatrim, Trisulfam, Uroplus)

Tradenames: Bactrim, Septra, Cotrim. Indications: - bacterial infections due to susceptible organisms - urogenital infection - urinary tract infections - chancroid [10] - lymphogranuloma venereum - respiratory tract infections - sinusitis - pneumonia - acute otitis media - endocarditis - gastroenteritis - cholera - typhoid fever, paratyphoid fever - diverticulitis - intestinal lipodystrophy - brucellosis - pertussis - plague prophylaxis - drug of choice for Stenotrophomonas maltophilia & Pseudomonas cepacia - methicillin-resistant Staphylococcus aureus (MRSA) - skin or soft tissue infections - diabetic foot infection - osteomyelitis - protozoan infectons - paracoccidioidomycosis - toxoplasmosis - pneumocystis pneumonia (Pneumocystis jirovecii) - pneumocystis pneumonia prophylaxis [10] Contraindications: 1) not active against Pseudomonas aeruginosa or anaerobes 2) many Enterococcus organisms are resistant 3) pregnancy near term [5] - generally avoided during the first trimester pregnancy-category C* safety in lactation - * pregnancy near term [5]; - may cause hyperbilitubinemia & kernicterus in newborn [5] * first trimester of pregnancy - folic acid antagonist - may be associated with fetal developmental anomalies [5] Dosage: 1) dosages in mg based upon trimethoprim 2) UTI: 1 DS BID for 3-14 days 3) chronic bronchitis 1 DS BID for 10-14 days 4) for effective tissue levels outside the urinary tract QID dosing is indicated 5) Pneumocystis pneumonia (PCP): - 5 mg/kg (based on trimethoprim) IV every 6 hours or 2 tabs DS QID 6) Pneumocystis prophylaxis: 1 double strength tab PO BID 7) serious infections: same as PCP dose 8) traveler's diarrhea: 1 DS BID for 5 days 5/1 ratio of sulfamethoxazole/trimethoprim is constant in all formulations Tabs: trimethoprim 80 mg/sulfamethoxazole 400 mg Tabs (double strength): trimethoprim 160 mg/sulfamethoxazole 800 mg Suspension: trimethoprim 40 mg/sulfamethoxazole 200 mg/5 mL (100, 150, 200 mL) Infusion: trimethoprim 16 mg/sulfamethoxazole 80 mg/mL (10 & 30 mL) Dosage adjustment in renal failure: 1) creatinine clearance > 30 mL/min: use regular dose 2) creatinine clearance 15-10 mL/min: use 50% of dose 3) relatively contraindicated with creatinine clearance of < 15 mL/min Pharmacokinetics: 1) well absorbed orally 2) well distributed to most tissues & fluid spaces 3) highly concentrated in the prostate, bile & sputum 4) CSF concentrations are 50% of serum concentrations 5) crosses placenta & distributes into breast milk 6) protein-binding 45% (TMP), 68% (SMX) 7) peak serum concentrations 1-4 hours after oral dose 7) hepatic metabolism a) trimethoprim is metabolized to oxide & hydroxylated metabolites b) sulfamethoxazole is N-acetylated & conjugated with glucuronide 8) trimethoprim & sulfamethoxazole are secreted in the urine 9) elimination 1/2life is about 10 hours a) sulfamethoxazole 9 hours b) trimethoprim 6-17 hours c) 1/2 life of both prolonged with renal insufficiency 10) urine excretion is pH-dependent Antimicrobial activity: Gram positive - Streptococcus - Streptococcus group A - Streptococcus group B - Streptococcus group C - Streptococcus group G - Streptococcus pneumonia - Enterococcus faecalis - Listeria monocytogenes - Staphylococcus aureus (MSSA) - Staphylococcus aureus (MRSA) (+/-) - Staphylococcus epidermidis (+/-) Gram negative - Neisseria gonorrhoeae (+/-) Neisseria meningitidis [10] - Chlamydia - Moraxella catarrhalis - Haemophilus influenzae (+/-) - Salmonella - Shigella - Aeromonas - Escherichia coli - Klebsiella species (+/-) - Serratia marcescens (+/-) - Pseudomonas cepacia - Stenotrophomonas maltophilia - Xanthomonas maltophilia - Francisella tularensis - Brucella species - Legionella species - Haemophilus ducreyi (+/-) - Coxiella burnetii - Enterobacter [10] - Proteus [10] - Morganella morganii [10] protozoa - Pneumocystis carinii - Toxoplasma Adverse effects: 1) common (> 10%) - nausea/vomiting - anorexia - allergic skin reactions - urticaria - rash - hypersensitivity vasculitis [5] - exanthematous drug eruption (morbilliform exanthem) - photosensitivity 2) less common (1-10%) - blood dyscrasias, hepatoxicity (hepatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis 3) uncommon (< 1%) - confusion, depression, hallucinations, seizures, fever, ataxia, erythema multiforme, stomatitis, diarrhea, pseudomembranous colitis, thrombocytopenia (immune-mediated), megaloblastic anemia, granulocytopenia, aplastic anemia, hemolysis (G6PD deficiency), serum sickness, kernicterus in neonates, interstitial nephritis 4) other [3] - pancreatitis - myalgias - hyperkalemia - crystals, insoluble in urine [7] - may lead to acute renal failure), reversible with discontinuation of drug - reversible renal failure (11%) [9] - trimethoprim is known to interfere with urine creatinine excretion: increases in serum creatinine up to 0.5 mg/dL [5] - this increase is not associated with loss of renal function [5,12] - precipitation of acute intermittent porphyria [13] * Adverse effects are common in patients with AIDS. - Mild reactions may be managed with antihistamines & antipyretics - More severe reactions require discontinuation. Drug interactions: 1) Bactrim, Septra increase serum concentrations of: a) sulfonylureas b) warfarin (increased risk of bleeding) [8] c) phenytoin (Dilantin) 2) cyclosporine: a) decreased concentration of cyclosporine b) increased risk of nephrotoxicity 3) mercaptopurine: - in combination increases risk of bone marrow supression 4) Bactrim, Septra increases cytotoxic effect of methotrexate 5) didanosine: in combination increases risk of pancreatitis 6) Bactrim, Septra inhibits cyt P450 2C9 -> may increase levels of drugs metabolized by cyt P450 2C9 7) increased risk of hyperkalemia & sudden death in elderly taking ACE inhibitors or ARBs [11] - RR=1.38, absolute risk increase 0.2% [11] Test interactions: - serum creatinine: - trimethoprim inhibits tubular secretion of creatinine - trimethoprim can increase serum creatinine up to 0.5 mg/dL* * this increase is not associated with loss of renal function [5,12] Mechanism of action: 1) generally bactericidal 2) sulfamethoxazole inhibits synthesis of dihydrofolate 3) trimethoprim inhibits synthesis of tetrahydrofolate by inhibiting dihydrofolate reductase 4) trimethoprim acts as a K+ sparing diuretic

Interactions

drug interactions

Related

cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) Pneumocystis jirovecii; Pneumocystis carinii (PCP) Pseudomonas cepacia Xanthomonas (Stenotrophomonas) maltophilia

General

antibiotic combination

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 166
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 Department of Veterans Affairs, VA National Formulary
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Medical Knowledge Self Assessment Program (MKSAP) 11,17, 19 American College of Physicians, Philadelphia 1998, 2015, 2022
  6. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  7. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
  8. Fischer HD et al Hemorrhage During Warfarin Therapy Associated With Cotrimoxazole and Other Urinary Tract Anti-infective Agents Arch Intern Med. 2010;170(7):617-621 PMID: 20386005 http://archinte.ama-assn.org/cgi/content/abstract/170/7/617
  9. Fraser TN et al. Acute kidney injury associated with trimethoprim/sulfamethoxazole. J Antimicrob Chemother 2012 Feb 20 PMID: 22351681 http://jac.oxfordjournals.org/content/67/5/1271
  10. Deprecated Reference
  11. Fralick M et al Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ 2014;349:g6196 PMID: 25359996 http://www.bmj.com/content/349/bmj.g6196 - Etminan M, Brophy JM Antibiotics and sudden death in adults taking renin- angiotensin system blockers. BMJ 2014;349:g6242 PMID: 25360034 http://www.bmj.com/content/349/bmj.g6242
  12. Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications. Ann Pharmacother. 2013 Dec;47(12):1618-26. PMID: 24259630
  13. NEJM Knowledge+

Components

sulfamethoxazole [SMX] (Gantanol, Aposulfatrim, Bactoreduct) trimethoprim; TMP (Proloprim, Trimpex)