Difference between revisions of "Co-trimoxazole"
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==Synergistic action== | ==Synergistic action== | ||
| − | The [[synergy]] between [[trimethoprim]] and [[sulphamethoxazole]] was first described in a series of ''[[in vitro]]'' and ''[[in vivo]]'' experiments published in the | + | The [[synergy]] between [[trimethoprim]] and [[sulphamethoxazole]] was first described in a series of ''[[in vitro]]'' and ''[[in vivo]]'' experiments published in the late 1960s.<ref>{{cite journal|author=Bushby SRM, Hitchings GH|title=Trimethoprim, a sulphonamide potentiator|journal=Brit J Pharmacol|volume=33|pages=72|year=1968|pmid=5301731|issue=1|pmc=1570262}}</ref><ref>{{cite journal|author=Böhni E|title=Vergleichende bakteriologische untersuchungen mit der Kombination Trimethoprim/Sulfamethoxazole in vitro und in vivo|journal=Chemotherapy|volume=14|issue=Suppl|pages=1|year=1969|doi=10.1159/000220651|pmid=4908562}}</ref><ref>{{cite journal|author=Böhni E|title=Chemotherapeutic activity of the combination of trimethoprim and sulfamethoxazole in infections of mice|journal=Postgrad Med J|year=1969|volume=45|issue=Suppl|pages=18|pmid=4902845}}</ref> Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately; the reason is because they inhibit successive steps in the [[folic acid|folate]] synthesis pathway (see diagram below). |
| − | It is unclear whether this synergy occurs at doses used in humans,<ref>{{cite journal |author=Brumfitt W, Hamilton-Miller JM |title=Limitations of and indications for the use of co-trimoxazole | journal=J Chemother |year=1994 |month=February |volume=6 |issue=1 |pages=3–11 |pmid=8071675}}</ref> because at the concentrations seen in blood and tissues, the ratio of trimethoprim to sulphamethoxazole is 1:20,<ref>{{cite journal|author=Kremers P, Duvivier J, Heusghem C|title=Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses|journal=J Clin Pharmacol|year=1974|volume=14|pages=112–117}}</ref> which is less than the 1:5 ratio needed ''in vitro'' for synergy to occur. | + | It is unclear whether this synergy occurs at doses used in humans,<ref>{{cite journal |author=Brumfitt W, Hamilton-Miller JM |title=Limitations of and indications for the use of co-trimoxazole | journal=J Chemother |year=1994 |month=February |volume=6 |issue=1 |pages=3–11 |pmid=8071675}}</ref> because, at the concentrations seen in blood and tissues, the ratio of trimethoprim to sulphamethoxazole is 1:20,<ref>{{cite journal|author=Kremers P, Duvivier J, Heusghem C|title=Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses|journal=J Clin Pharmacol|year=1974|volume=14|pages=112–117}}</ref> which is less than the 1:5 ratio needed ''in vitro'' for synergy to occur. |
<center>[[Image:THFsynthesispathway.png|frame|none|Tetrahydrofolate synthesis pathway]]</center> | <center>[[Image:THFsynthesispathway.png|frame|none|Tetrahydrofolate synthesis pathway]]</center> | ||
| − | Sulfamethoxazole acts as a false-substrate inhibitor of [[dihydropteroate synthetase]]. [[Sulfonamides]] such as sulfamethoxazole are analogues of [[para-Aminobenzoic acid|''p''-aminobenzoic acid]] (PABA) and are [[competitive inhibitor]]s of the enzyme | + | Sulfamethoxazole acts as a false-substrate inhibitor of [[dihydropteroate synthetase]]. [[Sulfonamides]] such as sulfamethoxazole are analogues of [[para-Aminobenzoic acid|''p''-aminobenzoic acid]] (PABA) and, thus, are [[competitive inhibitor]]s of the enzyme, inhibiting the production of [[dihydropteroic acid]]. |
Trimethoprim acts by interfering with the action of bacterial [[dihydrofolate reductase]], inhibiting synthesis of tetrahydrofolic acid. | Trimethoprim acts by interfering with the action of bacterial [[dihydrofolate reductase]], inhibiting synthesis of tetrahydrofolic acid. | ||
| − | [[Folic acid]] is an essential precursor in the ''[[de novo synthesis|de novo]]'' synthesis of the DNA [[nucleoside]]s [[thymidine]] and [[uridine]]. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) thus are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for [[DNA replication]] and [[transcription (genetics)|transcription]]. | + | [[Folic acid]] is an essential precursor in the ''[[de novo synthesis|de novo]]'' synthesis of the DNA [[nucleoside]]s [[thymidine]] and [[uridine]]. Bacteria are unable to take up folic acid from the environment (i.e., the infection host) and, thus, are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for [[DNA replication]] and [[transcription (genetics)|transcription]]. |
==Clinical indications== | ==Clinical indications== | ||
| Line 46: | Line 46: | ||
===HIV=== | ===HIV=== | ||
Being an antibiotic, co-trimoxazole does not have any activity against HIV itself, but it is often prescribed to immunocompromised patients as [[Pneumocystis carinii]] pneumonia prophylaxis. | Being an antibiotic, co-trimoxazole does not have any activity against HIV itself, but it is often prescribed to immunocompromised patients as [[Pneumocystis carinii]] pneumonia prophylaxis. | ||
| − | |||
| − | |||
===Bacterial=== | ===Bacterial=== | ||
| Line 60: | Line 58: | ||
*[[Isosporiasis]]<ref name="pmid18257775">{{cite journal |author=Lagrange-Xélot M, Porcher R, Sarfati C, ''et al'' |title=Isosporiasis in patients with HIV infection in the highly active antiretroviral therapy era in France |journal=HIV Med. |volume=9 |issue=2 |pages=126–30 |year=2008 |month=February |pmid=18257775 |doi=10.1111/j.1468-1293.2007.00530.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1464-2662&date=2008&volume=9&issue=2&spage=126}}</ref> | *[[Isosporiasis]]<ref name="pmid18257775">{{cite journal |author=Lagrange-Xélot M, Porcher R, Sarfati C, ''et al'' |title=Isosporiasis in patients with HIV infection in the highly active antiretroviral therapy era in France |journal=HIV Med. |volume=9 |issue=2 |pages=126–30 |year=2008 |month=February |pmid=18257775 |doi=10.1111/j.1468-1293.2007.00530.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1464-2662&date=2008&volume=9&issue=2&spage=126}}</ref> | ||
*prophylaxis of cerebral [[toxoplasmosis]] in [[HIV]] patients | *prophylaxis of cerebral [[toxoplasmosis]] in [[HIV]] patients | ||
| + | * [[Cyclospora cayetanensis]] | ||
===Fungal=== | ===Fungal=== | ||
| − | *treatment and prophylaxis of pneumonia caused by ''[[Pneumocystis jirovecii]]'' (formerly identified as ''P. carinii'' and commonly seen in immunocompromised patients including those suffering from [[HIV]]/[[AIDS]]) | + | *treatment and prophylaxis of pneumonia caused by ''[[Pneumocystis jirovecii]]'' (formerly identified as ''P. carinii'' and commonly seen in immunocompromised patients including those suffering from cancer or [[HIV]]/[[AIDS]]) |
{{Refimprove|date=September 2008}} | {{Refimprove|date=September 2008}} | ||
==Safety== | ==Safety== | ||
| − | There has been some concern about its use, however, since it has been associated with both frequent mild allergic reactions and serious adverse effects including [[Stevens-Johnson syndrome]], [[myelosuppression]], [[mydriasis]], [[agranulocytosis]], as well as severe liver damage (cholestatic hepatosis, hepatitis, liver necrosis, fulminant liver failure).{{Fact|date=September 2008}} Due to displacement of bilirubin from albumin there is an increased risk of [[kernicterus]] in the newborn during the last 6 weeks of pregnancy. Also renal impairment up to acute renal failure and anuria have been reported. These side effects are seen especially in the elderly and may be fatal. (Joint Formulary Committee, 2004). | + | There has been some concern about its use, however, since it has been associated with both frequent mild allergic reactions and serious adverse effects including [[Stevens-Johnson syndrome]], [[myelosuppression]], [[mydriasis]], [[agranulocytosis]], as well as severe liver damage (cholestatic hepatosis, hepatitis, liver necrosis, fulminant liver failure).{{Fact|date=September 2008}} Due to displacement of bilirubin from albumin, there is an increased risk of [[kernicterus]] in the newborn during the last 6 weeks of pregnancy. Also renal impairment up to acute renal failure and anuria have been reported. These side-effects are seen especially in the elderly and may be fatal. (Joint Formulary Committee, 2004). Both Folic acid and Folinic acid were found equally effective in reducing the adverse effects of TMP-SMX, so unless new evidence is found for Folinic acid that shows it is more effective than the costlier Folinic acid, Folic acid will continue to be the preferred treatment method. |
| − | Folic acid | + | |
In some countries, co-trimoxazole has been withdrawn due to these toxic effects.{{Fact|date=September 2008}} | In some countries, co-trimoxazole has been withdrawn due to these toxic effects.{{Fact|date=September 2008}} | ||
| Line 84: | Line 82: | ||
*Septrin®, Septra® ([[GlaxoSmithKline]] and formerly [[Burroughs Wellcome]]) | *Septrin®, Septra® ([[GlaxoSmithKline]] and formerly [[Burroughs Wellcome]]) | ||
*Sulfatrim® | *Sulfatrim® | ||
| + | *Biseptol | ||
==References== | ==References== | ||
| Line 98: | Line 97: | ||
[[Category:World Health Organization essential medicines]] | [[Category:World Health Organization essential medicines]] | ||
| + | [[cs:Kotrimoxazol]] | ||
[[de:Cotrimoxazol]] | [[de:Cotrimoxazol]] | ||
[[es:Trimetoprim-sulfametoxazol]] | [[es:Trimetoprim-sulfametoxazol]] | ||
Latest revision as of 15:43, 27 September 2010
| File:Co-trimoxazole.JPG | |
| Combination of | |
|---|---|
| Trimethoprim | Dihydrofolate reductase inhibitor (16.7%) |
| Sulfamethoxazole | Sulfonamide antibiotic (83.3%) |
| Clinical data | |
| Pregnancy category | |
| Routes of administration | Oral |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 8064-90-2 |
| ATC code | J01EE01 (WHO) |
| PubChem | CID 358641 |
| ChemSpider | 318412 |
Co-trimoxazole (abbreviated SXT, TMP-SMX, TMP-SMZ or TMP-sulfa) is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections. The name co-trimoxazole is the British Approved Name, and has been marketed worldwide under many trade names including Septra (GSK), Bactrim (Roche), and various generic preparations. Sources differ as to whether co-trimoxazole usually is bactericidal or bacteriostatic.
Contents
Synergistic action
The synergy between trimethoprim and sulphamethoxazole was first described in a series of in vitro and in vivo experiments published in the late 1960s.[1][2][3] Trimethoprim and sulfamethoxazole have a greater effect when given together than when given separately; the reason is because they inhibit successive steps in the folate synthesis pathway (see diagram below).
It is unclear whether this synergy occurs at doses used in humans,[4] because, at the concentrations seen in blood and tissues, the ratio of trimethoprim to sulphamethoxazole is 1:20,[5] which is less than the 1:5 ratio needed in vitro for synergy to occur.
Sulfamethoxazole acts as a false-substrate inhibitor of dihydropteroate synthetase. Sulfonamides such as sulfamethoxazole are analogues of p-aminobenzoic acid (PABA) and, thus, are competitive inhibitors of the enzyme, inhibiting the production of dihydropteroic acid.
Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid.
Folic acid is an essential precursor in the de novo synthesis of the DNA nucleosides thymidine and uridine. Bacteria are unable to take up folic acid from the environment (i.e., the infection host) and, thus, are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for DNA replication and transcription.
Clinical indications
Co-trimoxazole was claimed to be more effective than either of its components individually in treating bacterial infections, although this was later disputed.[6] Along with its associated greater incidence of adverse effects including allergic responses (see below), its widespread use has been restricted in many countries to very specific circumstances where its improved efficacy is 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. The global problem of advancing antimicrobial resistance has led to a renewed interest in the use of co-trimoxazole in various settings more recently.[8]
Specific indications for its use include:
HIV
Being an antibiotic, co-trimoxazole does not have any activity against HIV itself, but it is often prescribed to immunocompromised patients as Pneumocystis carinii pneumonia prophylaxis.
Bacterial
- infections caused by Listeria monocytogenes, Nocardia spp., Stenotrophomonas maltophilia (Zanthomonas maltophilia)
- Staphylococcus saprophyticus infections presenting as urinary tract infection or cystitis
- melioidosis
- shigellosis
- Whipple's disease
- traveller's diarrhea
Protozoan
- Isosporiasis[9]
- prophylaxis of cerebral toxoplasmosis in HIV patients
- Cyclospora cayetanensis
Fungal
- treatment and prophylaxis of pneumonia caused by Pneumocystis jirovecii (formerly identified as P. carinii and commonly seen in immunocompromised patients including those suffering from cancer or HIV/AIDS)
 | This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (September 2008) |
Safety
There has been some concern about its use, however, since it has been associated with both frequent mild allergic reactions and serious adverse effects including Stevens-Johnson syndrome, myelosuppression, mydriasis, agranulocytosis, as well as severe liver damage (cholestatic hepatosis, hepatitis, liver necrosis, fulminant liver failure).[citation needed] Due to displacement of bilirubin from albumin, there is an increased risk of kernicterus in the newborn during the last 6 weeks of pregnancy. Also renal impairment up to acute renal failure and anuria have been reported. These side-effects are seen especially in the elderly and may be fatal. (Joint Formulary Committee, 2004). Both Folic acid and Folinic acid were found equally effective in reducing the adverse effects of TMP-SMX, so unless new evidence is found for Folinic acid that shows it is more effective than the costlier Folinic acid, Folic acid will continue to be the preferred treatment method.
In some countries, co-trimoxazole has been withdrawn due to these toxic effects.[citation needed]
Thus the current British Committee on Safety of Medicines (CSM) guidelines recommend limiting its use to:[citation needed]
- Pneumocystis pneumonia
- Toxoplasmosis and nocardiosis
- acute exacerbations of chronic bronchitis and infections of the urinary tract where there is good rationale for use
- acute otitis media in children where there is good rationale
Trade names
Co-trimoxazole is manufactured and sold by many different companies. Some of the brand names are listed here, but this list is not complete.
- Bactrim®, Bactrimel® (Roche)
- Cotrim®
- Septrin®, Septra® (GlaxoSmithKline and formerly Burroughs Wellcome)
- Sulfatrim®
- Biseptol
References
- Rossi S, editor. Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.
- British National Formulary, 51st edition (April 20, 2006). London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2006. ISBN 0-85369-668-3
- briandeer.com Newspaper campaign over adverse events; 1994-
Footnotes
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parameter "group" is allowed only.
<references />, or <references group="..." />de:Cotrimoxazol es:Trimetoprim-sulfametoxazol fa:کوتریموکسازول fr:Co-trimoxazole it:Cotrimossazolo nl:Co-trimoxazol pl:Kotrimoksazol ru:Ко-тримоксазол
sk:Kotrimoxazol- ↑ Bushby SRM, Hitchings GH (1968). "Trimethoprim, a sulphonamide potentiator". Brit J Pharmacol. 33 (1): 72. PMC 1570262 Freely accessible. PMID 5301731.
- ↑ Böhni E (1969). "Vergleichende bakteriologische untersuchungen mit der Kombination Trimethoprim/Sulfamethoxazole in vitro und in vivo". Chemotherapy. 14 (Suppl): 1. doi:10.1159/000220651. PMID 4908562.
- ↑ Böhni E (1969). "Chemotherapeutic activity of the combination of trimethoprim and sulfamethoxazole in infections of mice". Postgrad Med J. 45 (Suppl): 18. PMID 4902845.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Kremers P, Duvivier J, Heusghem C (1974). "Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses". J Clin Pharmacol. 14: 112–117.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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