Trimethoprim/sulfamethoxazole

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Trimethoprim/sulfamethoxazole
Trimethoprim2DACS.svg
Sulfamethoxazole2DACS.svg
Trimethoprim (top) and sulfamethoxazole (bottom)
Combination of
Trimethoprim Dihydrofolate reductase inhibitor
Sulfamethoxazole Sulfonamide antibiotic
Clinical data
Trade names Bactrim, Bactrimel, Biseptol, Co-trimoxazole, Cotrim, Resprim, Septrin, Septra, Sulfatrim, Trisul, Polytrim
Pregnancy cat.
Legal status
Routes Oral, Intravenous[1]
Identifiers
CAS number 8064-90-2
ATC code J01EE01
PubChem CID 358641
DrugBank DB00440
ChemSpider 318412
 YesY (what is this?)  (verify)

Trimethoprim/sulfamethoxazole or co-trimoxazole (BAN) is an antibiotic used in the treatment of a variety of bacterial, fungal, and protozoal infections. It consists of one part trimethoprim to five parts sulfamethoxazole. The drug has been marketed worldwide as generic preparations and under multiple brand names, including Septra (GlaxoSmithKline plc) and Bactrim (Hoffmann-La Roche). Co-trimoxazole is generally considered bactericidal, although its components are individually bacteriostatic.[2] Its actions are antifolate in nature, inhibiting both de novo folate biosynthesis and metabolism.[3]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[4]

Trimethoprim/sulfamethoxazole is often abbreviated as SXT, TMP-SMX, TMP-SMZ, or TMP-sulfa, although the abbreviating of drug names is not best practice in medicine.

Medical uses[edit]

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[5] Because it has a higher incidence of adverse effects, including allergic responses, its use has been restricted in many countries to very specific circumstances where its improved efficacy has been demonstrated.[6] It may be effective in a variety of upper and lower respiratory tract infections, renal and urinary tract infections, gastrointestinal tract infections, skin and wound infections, septicaemias, and other infections caused by sensitive organisms. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.[7]

Susceptible organisms include:[3][8]

The only notable nonsusceptible organisms are the mycoplasmae[8] and Francisella tularensis (the causative organism of tularaemia).[9][10]

Pregnancy and breast feeding[edit]

Its use during pregnancy is contraindicated, although it has been placed in Australian and American pregnancy category C.[3] Despite this, its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects such as spina bifida, cardiovascular malformations (e.g. Epstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies.[3] Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67).[11][12] Animal studies have yielded similarly discouraging results.[13] It is also excreted in breast milk and hence nursing during treatment with co-trimoxazole is generally advised against.[3]

Indications for co-trimoxazole
Indication United States
FDA-labelled indication?
Australia
TGA-labelled indication?
United Kingdom
MHRA-labelled indication?
Literature support
Acute infective exacerbation of chronic bronchitis Yes No No Clinical trials are lacking.
Prophylaxis in HIV-infected individuals No No No Effective in one Ugandan study on morbidity, mortality, CD4-cell count, and viral load in HIV infection.[14]
Otitis media Paediatric population only No Yes Clinical trials have confirmed its efficacy in chronic active otitis media[15] and acute otitis media.[16]
Travellers' diarrhoea, treatment & prophylaxis Yes No No Clinical trials have confirmed its efficacy as a treatment for travellers' diarrhoea.[17][18][19]
Urinary tract infection Yes No Yes Clinical trials have confirmed its efficacy in this indication.[8]
Bacterial infections
Acne vulgaris No No No At least one clinical trial supports its use in this indication.[20]
Listeria No Yes No Well-designed clinical trials are lacking.
Melioidosis No Yes No Clinical trials have confirmed its efficacy, with or without adjunctive doxycycline; although, co-trimoxazole alone seems preferable.[21][22][23]
Pertussis (whooping cough) No No No One cochrane review supports its efficacy in preventing the spread of pertussis.[24]
Shigellosis Yes Yes No Generally accepted treatment for shigellosis.[25] A recent Cochrane review found that while it is an effective treatment for shigellosis it also produces more significant adverse effects than other antibiotic drugs.[26]
Staphylococcus aureus infections No No No In vitro and in vivo activity against both non-resistant and methicillin-resistant Staphylococcus aureus (MRSA) infections.[27][28][29][30][31][32][33]
Tuberculosis No No No In vitro and in vivo activity against both nonresistant and MDR strains of TB.[34][35][36]
Whipple's disease No No No Co-trimoxazole is the recommended standard treatment for whipple's disease in some treatment protocols.[37][38][39]
Fungal and protozoal infections
Isosporiasis No No No Clinical trials have confirmed its use in this indication.[40]
Malaria No No No Clinical trials have confirmed its efficacy in both the treatment and prevention of malaria.[41]
Pneumocystis jirovecii pneumonia Yes Yes Yes Its use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia.[42] Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia,[43] data on its use in both the treatment and prevention of pneumocystis pneumonia is significantly lacking.
Toxoplasmosis Yes Prevention only Yes Clinical trials have confirmed its prophylactic and therapeutic utility in cases of toxoplasmosis.[44][45][46][47][48][49]
Other indications
Wegener's granulomatosis No No No Two clinical trials have supported its efficacy in this indication.[50][51]

Adverse effects[edit]

Adverse effects by incidence:[3][13][52][53][54][55]
Common (>1% frequency):

  • Fever
  • Nausea
  • Vomiting
  • Diarrhea
  • Weight loss
  • Rash
  • Muscle aches
  • Joint pain
  • Itch
  • Sore mouth
  • Hyperkalaemia (high blood potassium)
  • Thrombocytopenia (low number of platelets in the blood)

Infrequently (0.1-1.0% frequency):

  • Headache
  • Jaundice
  • Elevated liver transaminases
  • Peripheral neuritis
  • Drowsiness
  • Constipation
  • Photosensitivity (light sensitivity)
  • Blood dyscrasias (e.g. neutropaenia)

Rare (<0.1% frequency):

Unknown frequency adverse effects:

  • Hallucinations
  • Cough
  • Glossitis
  • Stomatitis
  • Fatigue
  • Insomnia
  • Impaired kidney function
  • Pulmonary infiltration[Note 7]
  • Shortness of breath

Contraindications[edit]

Contraindications include the following:[3][53]

  • Known hypersensitivity to trimethoprim, sulphonamides or any other ingredients in the formulations
  • Pregnancy – especially in the period prior to birth
  • Severe hepatic failure, marked liver parenchymal damage or jaundice.
  • Serious haematological disorders and porphyria (due to the sulfonamide component of the preparation).
  • Severe renal insufficiency (CrCl <15 ml/min) where repeated measurements of the plasma concentration cannot be performed
  • Co-trimoxazole should not be given to neonates during the first 6 weeks, except for the treatment/prophylaxis of pneumocytosis jiroveci (P. carinii) in infants of four weeks of age or greater.

Interactions[edit]

Its use is advised against in patients being concomitantly treated with:[3][13][52][53][54][55]

  • ACE inhibitors like captopril, enalapril, lisinopril, perindopril, and ramipril due to the potential for additive hyperkalaemic effects[53]
  • Prilocaine — additive risk of methaemoglobinaemia
  • Antiarrhythmics like amiodarone (increased risk of ventricular arrhythmias) and dofetilide (increased risk of QT interval prolongation)
  • Antibacterials like dapsone (increases plasma levels of both drugs), methenamine (increased risk of crystalluria) and rifampicin (as it may lead to an increased plasma level of rifampicin and lower plasma levels of trimethoprim)
  • Anticoagulants like warfarin and acenocoumarol — anticoagulant effects of either drug is potentiated by this combination
  • Sulfonylureas — effects enhanced
  • Phenytoin, half-life of phenytoin is increased
  • Antifolates like pyrimethamine, proguanil and methotrexate increase the risk of associated side effects like blood dyscrasis, folic acid supplementation should be considered. A significant risk of megaloblastic anaemia exists with doses of pyrimethamine in excess of 25 mg/wk.
  • Antivirals, more specifically, lamivudine (increased plasma concentrations of lamivudine), zalcitabine (increased plasma concentrations of zalcitabine) and zidovudine (increased risk of haematological reactions)
  • Procainamide and/or amantadine may have their plasma concentrations increased bilaterally or unilaterally.
  • Clozapine and other antipsychotics — increased risk of haematological side effects
  • Nucleoside analogue antineoplastics like azathioprine and mercaptopurine — increased risk of haematological toxicity
  • Digoxin — increase in digoxin levels in a proportion of elderly patients
  • Diuretics — elderly patients receiving thiazide antidiuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole
  • Ciclosporin — patients that have received a kidney transplant and are receiving co-trimoxazole and ciclosporin concomitantly are at an increased risk of having a reversible deterioration in their kidney function.
  • Potassium aminobenzoate — effects of sulfonamides (like sulfamethoxazole) inhibited.
  • Laboratory tests; trimethoprim and sulfonamides have been reported to interfere with diagnostic tests, including serum-methotrexate and serum-plasma creatinine levels, also urea, urinary glucose and urobilinogen tests.

Overdose[edit]

Likely signs of toxicity include:[13]

  • Nausea
  • Vomiting
  • Dizziness
  • Headache
  • Mental depression
  • Confusion
  • Bone marrow depression
  • Loss of appetite
  • Colic
  • Drowsiness
  • Unconsciousness

The recommended treatment for overdose includes:[13]

  • Administration of activated charcoal
  • Stomach pumping
  • General supportive measures
  • Haemodialysis, which is moderately effective in clearing co-trimoxazole from the plasma.
  • Calcium folinate treatment in cases of blood dyscrasias
  • Forcing oral fluids

Alkalinisation of the urine may reduce the toxicity of sulfamethoxazole, but it may increase the toxic effects of trimethoprim.[13]

Pharmacology[edit]

Tetrahydrofolate synthesis pathway

The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.[56][57][58] Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesis pathway. They are given in a one-to-five ratio in their tablet formulations so that when they enter the body their concentration in the blood and tissues is roughly one-to-twenty — the exact ratio required for a peak synergistic effect between the two.[8]

Sulfamethoxazole, a sulfonamide, induces its therapeutic effects by interfering with the de novo (that is, from within the cell) synthesis of folate inside microbial organisms such as protozoa, fungi and bacteria. It does this by competing with p-aminobenzoic acid (PABA) in the biosynthesis of dihydrofolate.[8]

Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.[8]

The effects of trimethoprim causes a backlog of dihydrofolate (DHF) and this backlog can work against the inhibitory effect the drug has on tetrahydrofolate biosynthesis; this is where the sulfamethoxazole comes in, its role is in depleting the excess DHF by preventing it from being synthesised in the first place.[8]

Pharmacokinetics of co-trimoxazole[3][13]
Component Tmax (hrs) Vd (L) Protein binding t1/2 (hrs) Excretion
Sulfamethoxazole 1-4 20 66% 8-10 Renal
Trimethoprim 1-4 130 42-45% 10 Renal

Trade names[edit]

Co-trimoxazole is manufactured and sold by many different companies. The following list of brand names is incomplete:

  • Bactrim, Bactrimel (Roche)
  • Bactrom (Venezuela)
  • Bibactin (manufactured by PPM and distributed in Cambodia and some African countries)
  • Biseptol
  • Co-trimoxazole (Sandoz)
  • Cotrim
  • Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
  • Primotren (Lek in Slovenia and other countries)
  • Sanprima (manufactured by PT Sanbe Farma and distributed in Indonesia)
  • Septra (Aspen Pharmacare and formerly GlaxoSmithKline)
  • Septram (Panama)
  • Sulfatrim
  • Trisul
  • Vactrim (manufactured and distributed in Laos)

Notes[edit]

  1. ^ Low blood sugar; may affect consciousness and cause seizures
  2. ^ Breakdown of red blood cells. This side effect most often occurs in people with glucose-6-phosphate dehydrogenase deficiency
  3. ^ A potentially fatal skin reaction that causes the skin to slough off
  4. ^ Basically a worse form of Stevens-Johnson syndrome
  5. ^ Incoordination; most often after IV use in HIV patients
  6. ^ Swelling of the membranes surrounding the brain and spinal cord without any obvious infectious cause
  7. ^ Sign of hypersensitivity

References[edit]

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