trimethoprim/sulfamethoxazole; cotrimoxazole (Bactrim, Septra, Cotrim, Sulfatrim, Sulfoxatrim, Trisulfam, Uroplus)
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Introduction
Tradenames: Bactrim, Septra, Cotrim.
Indications
- bacterial infections due to susceptible organisms
- urogenital infection
- respiratory tract infections
- acute otitis media
- endocarditis
- gastroenteritis
- brucellosis
- pertussis
- plague prophylaxis
- drug of choice for Stenotrophomonas maltophilia & Pseudomonas cepacia
- methicillin-resistant Staphylococcus aureus (MRSA)
- skin or soft tissue infections
- osteomyelitis
- protozoan infectons
Contraindications
- not active against Pseudomonas aeruginosa or anaerobes
- many Enterococcus organisms are resistant
- pregnancy near term[5]
- generally avoided during the first trimester
- may cause hyperbilitubinemia & kernicterus in newborn[5]
* first trimester of pregnancy
- folic acid antagonist
- may be associated with fetal developmental anomalies[5]
Dosage
- dosages in mg based upon trimethoprim
- UTI: 1 DS BID for 3-14 days
- chronic bronchitis 1 DS BID for 10-14 days
- for effective tissue levels outside the urinary tract QID dosing is indicated
- Pneumocystis pneumonia (PCP):
- 5 mg/kg (based on trimethoprim) IV every 6 hours or 2 tabs DS QID
- Pneumocystis prophylaxis: 1 double strength tab PO BID
- serious infections: same as PCP dose
- 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
- creatinine clearance > 30 mL/min: use regular dose
- creatinine clearance 15-10 mL/min: use 50% of dose
- relatively contraindicated with creatinine clearance of < 15 mL/min
Pharmacokinetics
- well absorbed orally
- well distributed to most tissues & fluid spaces
- highly concentrated in the prostate, bile & sputum
- CSF concentrations are 50% of serum concentrations
- crosses placenta & distributes into breast milk
- protein-binding 45% (TMP), 68% (SMX)
- peak serum concentrations 1-4 hours after oral dose
- hepatic metabolism
- trimethoprim is metabolized to oxide & hydroxylated metabolites
- sulfamethoxazole is N-acetylated & conjugated with glucuronide
- trimethoprim & sulfamethoxazole are secreted in the urine
- elimination 1/2life is about 10 hours
- sulfamethoxazole 9 hours
- trimethoprim 6-17 hours
- 1/2 life of both prolonged with renal insufficiency
- urine excretion is pH-dependent
Antimicrobial activity
- Streptococcus
- Enterococcus faecalis
- Listeria monocytogenes
- Staphylococcus aureus (MSSA)
- Staphylococcus aureus (MRSA) (+/-)
- Staphylococcus epidermidis (+/-)
- 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]
Adverse effects
- common (> 10%)
- less common (1-10%)
- blood dyscrasias, hepatoxicity (hepatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis
- 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
- 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
- Bactrim, Septra increase serum concentrations of:
- cyclosporine:
- decreased concentration of cyclosporine
- increased risk of nephrotoxicity
- mercaptopurine:
- in combination increases risk of bone marrow supression
- Bactrim, Septra increases cytotoxic effect of methotrexate
- didanosine: in combination increases risk of pancreatitis
- Bactrim, Septra inhibits cyt P450 2C9
- may increase levels of drugs metabolized by cyt P450 2C9
- increased risk of hyperkalemia & sudden death in elderly taking ACE inhibitors or ARBs[11]
- RR=1.38, absolute risk increase 0.2%[11]
- drug interaction(s) of renin-angiotensin-aldosterone inhibitors with trimethoprim-sulfamethoxazole
- drug interaction(s) of trimethoprim/sulfamethoxazole with warfarin
- drug interaction(s) of ARB with trimethoprim
- drug interaction(s) of ACE inhibitor with trimethoprim
- drug interaction(s) of spironolactone with trimethoprim
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
- generally bactericidal
- sulfamethoxazole inhibits synthesis of dihydrofolate
- trimethoprim inhibits synthesis of tetrahydrofolate by inhibiting dihydrofolate reductase
- trimethoprim acts as a K+ sparing diuretic
More general terms
Additional terms
- 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
Components
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 166
- ↑ 3.0 3.1 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
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Medical Knowledge Self Assessment Program (MKSAP) 11,17, 19 American College of Physicians, Philadelphia 1998, 2015, 2022
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 7.0 7.1 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
- ↑ 8.0 8.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20386005 <Internet> http://archinte.ama-assn.org/cgi/content/abstract/170/7/617
- ↑ 9.0 9.1 Fraser TN et al. Acute kidney injury associated with trimethoprim/sulfamethoxazole. J Antimicrob Chemother 2012 Feb 20 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22351681 <Internet> http://jac.oxfordjournals.org/content/67/5/1271
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Deprecated Reference
- ↑ 11.0 11.1 11.2 Fralick M et al Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ 2014;349:g6196 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25359996 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25360034 <Internet> http://www.bmj.com/content/349/bmj.g6242 - ↑ 12.0 12.1 12.2 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: https://www.ncbi.nlm.nih.gov/pubmed/24259630
- ↑ 13.0 13.1 NEJM Knowledge+