Trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole

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
Pregnancy cat.	C (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral, Intravenous[1]
Identifiers
CAS number	8064-90-2
ATC code	J01EE01
PubChem	CID 358641
ChemSpider	318412
Y (what is this?)  (verify)

Trimethoprim/sulfamethoxazole or co-trimoxazole (BAN; abbreviated SXT, TMP-SMX, TMP-SMZ, or TMP-sulfa) is an antibiotic used in the treatment of a variety of bacterial, fungal and protozoal infections. It consists of 1 part trimethoprim to 5 parts sulfamethoxazole. The drug has been marketed worldwide as generic preparations and under multiple brand names, including Septra (GSK) and Bactrim (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]

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.^[4] Because it has a higher incidence of adverse effects, including allergic responses (see below), its use has been restricted in many countries to very specific circumstances where its improved efficacy has been demonstrated.^[5] 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.^[6]

Susceptible organisms include:^[3][7]

Whereas the only notable non-susceptible organism are the mycoplasma species.^[7]

Pregnancy and lactation

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 like 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).^[8][9] Animal studies have yielded similarly discouraging results.^[10] It is also excreted in breast-milk and hence nursing during treatment with co-trimoxazole is generally advised against.^[3]

Adverse effects

Adverse effects by incidence:^{[3][10][49][50][51][52]}
Common (>1% frequency):

Infrequently (0.1-1% frequency):

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

Rare (<0.1% frequency):

Unknown frequency adverse effects:

Contraindications

Contraindications include the following:^[3][50]

• 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<15mL/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:^{[3][10][49][50][51][52]}

• ACE inhibitors like captopril, enalapril, lisinopril, perindopril and ramipril due to the potential for additive hyperkalaemic effects.^[50]
• 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) andrifampicin (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 — increased risk of associated side effects like blood dyscrasis. Folic acid supplementation should be considered. There's a significant risk of megaloblastic anaemia 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

Likely signs of toxicity include:^[10]

The recommended treatment for overdose includes:^[10]

• 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.^[10]

Pharmacology

Tetrahydrofolate synthesis pathway

The synergy between trimethoprim and sulfamethoxazole was first described in a series of in vitro and in vivo experiments published in the late 1960s.^[53][54][55] Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately, because they inhibit successive steps in the folate synthesispathway. 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 as to twenty — the exact ratio required for a peak synergistic effect between the two.^[7]

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.^[7]

Trimethoprim serves as a competitive inhibitor of dihydrofolate reductase (DHFR), hence inhibiting the de novo synthesis of tetrahydrofolate, the biologically active form of folate.^[7]

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.^[7]

Trade names

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

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

Notes

References