Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole (TMP/SMX), also known as co-trimoxazole among other names, is an antibiotic used to treat a variety of bacterial infections.^[1] It consists of one part trimethoprim to five parts sulfamethoxazole.^[2] It is used for urinary tract infections, MRSA skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others.^[1][2] It may be used both to treat and prevent pneumocystis pneumonia in people with HIV/AIDS. It can be given by mouth or intravenously.^[1]

Common side effects include nausea, vomiting, rash, and diarrhea. Severe allergic reactions and Clostridium difficile diarrhea may occasionally occur. Its use near the end of pregnancy is not recommended.^[1] It appears to be okay during breastfeeding as long as the baby is healthy.^[3] TMP/SMX generally results in bacterial death. It works by blocking the making of folate by the bacteria.^[1]

TMP/SMX was first sold in 1974.^[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.^[5] It is available as a generic medication and is not very expensive.^[2] In the United States it is about 0.40 USD per dose.^[1]

Medical uses

Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.^[6] 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.^[7] 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. Co-trimoxazole in retinochoroiditis shows a reduction in the risk of recurrent retinochoroiditis.^[8] The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole more recently.^[9]

Susceptibility

Organisms against which co-trimoxazole can be effective include:^[10][11]

The only notable nonsusceptible organisms are the mycoplasmae^[11] and Francisella tularensis (the causative organism of tularaemia).^[12][13]

Pregnancy and breast feeding

Its use during pregnancy is contraindicated, although it has been placed in Australian and American pregnancy category C.^[10] 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. Ebstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies.^[10] 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).^[14][15] Animal studies have yielded similarly discouraging results.^[16] It is also excreted in breast milk and hence nursing during treatment with co-trimoxazole is generally advised against.^[10]

Adverse effects

Contraindications

Contraindications include the following:^[10][17]

• 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

Its use is advised against in patients being concomitantly treated with:^{[10][16][17][18][19][20]}

• ACE inhibitors like captopril, enalapril, lisinopril, perindopril, and ramipril due to the potential for additive hyperkalaemic effects^[17]
• 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 bone marrow toxicity, 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 diuretics are at a heightened risk for developing thrombocytopaenia while on co-trimoxazole
• Ciclosporin — patients who 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.
• Spironolactone — concurrent use can increase the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.^[21]
• 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

Likely signs of toxicity include:^[16]

The recommended treatment for overdose includes:^[16]

• 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.^[16]

Pharmacology

Tetrahydrofolate synthesis pathway

The synergy between trimethoprim and sulfamethoxazole was first described in the late 1960s.^[22][23][24] 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.^[11]

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.^[11]

Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.^[11]

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.^[11]

Society and culture

Approval

Indications for co-trimoxazole

Indication	FDA-labelled indication?	TGA-labelled indication?	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.[25]
Otitis media	Paediatric population only	No	Yes	Clinical trials have confirmed its efficacy in chronic active otitis media[26] and acute otitis media.[27]
Travellers' diarrhoea, treatment & prophylaxis	Yes	No	No	Clinical trials have confirmed its efficacy as a treatment for travellers' diarrhoea.[28][29][30]
Urinary tract infection	Yes	No	Yes	Clinical trials have confirmed its efficacy in this indication.[11]
Bacterial infections
Acne vulgaris	No	No	No	At least one clinical trial supports its use in this indication.[31]
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.[32][33][34]
Pertussis (whooping cough)	No	No	No	One cochrane review supports its efficacy in preventing the spread of pertussis.[35]
Shigellosis	Yes	Yes	No	Generally accepted treatment for shigellosis.[36] 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.[37]
Staphylococcus aureus infections	No	No	No	In vitro and in vivo activity against both non-resistant and methicillin-resistant Staphylococcus aureus (MRSA) infections.[38][39][40][41][42][43][44]
Tuberculosis	No	No	No	In vitro and in vivo activity against both nonresistant and MDR strains of TB.[45][46][47]
Whipple's disease	No	No	No	Co-trimoxazole is the recommended standard treatment for whipple's disease in some treatment protocols.[48][49][50]
Fungal and protozoal infections
Isosporiasis	No	No	No	Clinical trials have confirmed its use in this indication.[51]
Malaria	No	No	No	Clinical trials have confirmed its efficacy in both the treatment and prevention of malaria.[52]
Pneumocystis jirovecii pneumonia	Yes	Yes	Yes	Its use as a prophylactic treatment is supported by one clinical trial involving children with acute lymphoblastic leukaemia.[53] Other than this and one other clinical trial into its efficacy as a treatment for pneumocystis pneumonia,[54] 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.[55][56][57][58][59][60]
Other indications
Granulomatosis with polyangiitis (formerly Wegener's)	No	No	No	Two clinical trials have supported its efficacy in this indication.[61][62]

Trade names

Trimethoprim/sulfamethoxazole may be abbreviated as SXT, TMP-SMX, TMP-SMZ, or TMP-sulfa.

Co-trimoxazole (BAN) 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
• Diseptyl (Israel)
• Graprima Forte Kaplet (manufactured by PT Graha Farma and distributed in Indonesia)
• Infectrin (Brazil)
• Primotren (Lek in Slovenia and other countries)
• Polytrim
• Trisul
• Resprim
• Sanprima (manufactured by PT Sanbe Farma and distributed in Indonesia)
• Septra (Aspen Pharmacare and formerly GlaxoSmithKline)
• Septram (Panama)
• Septrin (Spain)^[63]
• Sulfatrim
• Trisul
• Vactrim (manufactured and distributed in Laos)

References