|
|
| (10 intermediate revisions by 3 users not shown) |
| Line 1: |
Line 1: |
| {{Drugbox| | | {{Details0|Chloramphenicol succinate (injection)}} |
| | IUPAC_name = 2,2-dichlor-''N''- [(aR,bR)-b-hydroxy-a-hydroxymethyl- 4-nitrophenethyl] acetamide
| | {{Details0|chloramphenicol (ophthalmic)}} |
| | image = Chloramphenicol-2D-skeletal.png
| |
| | image2 = Chloramphenicol-3D-vdW.png
| |
| | CAS_number=56-75-7
| |
| | ATC_prefix=D06
| |
| | ATC_suffix=AX02
| |
| | ATC_supplemental = {{ATC|D10|AF03}} {{ATC|G01|AA05}} {{ATC|J01|BA01}} {{ATC|S01|AA01}} {{ATC|S02|AA01}} {{ATC|S03|AA08}}
| |
| | PubChem=298
| |
| | DrugBank=EXPT00942
| |
| | C=11 | H=12 | N=2 | O=5 | Cl=2
| |
| | molecular_weight = 323.132 g/mol
| |
| | bioavailability = 75–90%
| |
| | metabolism = [[Liver|Hepatic]]
| |
| | elimination_half-life = 1.5–4.0 hours
| |
| | excretion = [[Kidney|Renal]]
| |
| | pregnancy_category = C (A topical)
| |
| | legal_status = ocular P, else POM <small>([[United Kingdom|UK]])</small>
| |
| | routes_of_administration= [[Topical]] ([[Wiktionary:ocular|ocular]]), oral, [[intravenous therapy|IV]], [[intramuscular injection|IM]]
| |
| }}
| |
| {{CMG}}
| |
| | |
| | |
| | |
| '''Chloramphenicol''' is a [[bacteriostatic]] [[antimicrobial]] originally derived from the [[bacterium]] ''[[Streptomyces venezuelae]]'', isolated by [[David Gottlieb]], and introduced into clinical practice in 1949.
| |
| | |
| It was the first antibiotic to be manufactured synthetically on a large scale. Chloramphenicol is effective against a wide variety of microorganisms; it is still very widely used in low income countries because it is exceedingly cheap, but has fallen out of favour in the West due to a very rare but very serious side effect: [[aplastic anemia]].
| |
| | |
| In the West, the main use of chloramphenicol is in [[eye drop]]s or [[ointment]] for bacterial [[conjunctivitis]].
| |
| | |
| ==Dosage==
| |
| The usual dose is 50 mg/kg/day in four divided doses: the usual dose in an adult male is therefore around 750 mg four times daily; this dose is doubled in severe illness. Half the dose is used in premature babies or neonates, because they do not metabolise the drug as effectively.
| |
| | |
| Chloramphenicol is available as 250 mg capsules or as a liquid (125 [[Wiktionary:milligram|mg]]/5 [[Wiktionary:millilitre|ml]]). In some countries, chloramphenicol is sold as chloramphenicol [[palmitate]] [[ester]]. Chloramphenicol palmitate ester is inactive, and is [[hydrolysis|hydrolysed]] to active chloramphenicol in the [[small intestine]]. There is no difference in [[bioavailability]] between chloramphenicol and chloramphenicol palmitate.
| |
| | |
| The [[Wiktionary:intravenous|intravenous]] (IV) preparation of chloramphenicol is the [[succinate]] [[ester]], because pure chloramphenicol does not dissolve in water. This creates a problem: chloramphenicol succinate ester is an inactive [[prodrug]] and must first be hydrolysed to chloramphenicol; the hydrolysis process is incomplete and 30% of the dose is lost unchanged in the urine, therefore serum concentrations of chloramphenicol are only 70% of those achieved when chloramphenicol is given orally.<ref>{{cite journal | author=Glazko AJ, Dill WA, Kinkel AW, ''et al.'' | title=Absorption and excretion of parenteral doses of chloramphenicol sodium succinate in comparison with per oral doses of chloramphenicol (abstract) | journal=Clin Pharmacol Ther | year=1977 | volume=21 | pages=104 }}</ref> For this reason, the chloramphenicol dose needs to be increased to 75 mg/kg/day when administered IV in order to achieve levels equivalent to the oral dose.<ref>{{cite journal | author = Bhutta Z, Niazi S, Suria A | title = Chloramphenicol clearance in typhoid fever: implications for therapy. | journal = Indian J Pediatr | volume = 59 | issue = 2 | pages = 213-9 | year =1992 | month=Mar-Apr | id = PMID 1398851}}</ref> The oral route is therefore preferred to the intravenous route.
| |
| | |
| Manufacture of oral chloramphenicol in the U.S. stopped in 1991, because the vast majority of chloramphenicol-associated cases of aplastic anaemia are associated with the oral preparation. There is now no oral formulation of chloramphenicol available in the U.S., although there is no theoretical reason why the intravenous preparation should not be equally effective (or perhaps even more effective) when taken by mouth.
| |
| | |
| ===Dose monitoring===
| |
| [[Blood plasma|Plasma]] levels of chloramphenicol must be monitored in neonates and in patients with abnormal liver function. It is recommended that plasma levels be monitored in all children under the age of 4, the elderly and patients with renal failure.
| |
| Peak levels (1 hour after the dose is given) should be 15–25 [[Wiktionary:milligram|mg]]/[[Wiktionary:litre|l]]; trough levels (taken immediately before a dose) should be less than 15 mg/l.
| |
| | |
| ===Chloramphenicol and the liver===
| |
| Chloramphenicol is metabolised by the liver to chloramphenicol [[glucuronic acid|glucuronate]] (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. There is no standard dose reduction for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations.
| |
| | |
| ===Chloramphenicol and the kidneys===
| |
| The majority of the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged. It is suggested that plasma levels be monitored in patients with renal impairment, but this is not mandatory. Chloramphenicol succinate ester (the inactive intravenous form of the drug) is readily excreted unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason why levels of chloramphenicol in the blood are much lower when given intravenously than orally.
| |
| | |
| ===Oily chloramphenicol===
| |
| Dose: 100 [[Wiktionary:milligram|mg]]/[[Wiktionary:kilogram|kg]] (maximum dose 3 [[Wiktionary:gram|g]]) as a single intramuscular injection. The dose is repeated if there is no clinical response after 48 hours. A single injection costs approximately [[United States dollar|US$]]5.
| |
| | |
| Oily chloramphenicol (or chloramphenicol oil suspension) is a long-acting preparation of chloramphenicol first introduced by Roussel in 1954; marketed as Tifomycine®, it was originally used as a treatment for [[typhoid]]. Roussel stopped production of oily chloramphenicol in 1995; the [[International Dispensary Association]] has manufactured it since 1998, first in [[Malta]] and then in [[India]] from December 2004.
| |
| | |
| Oily chloramphenicol is recommended by the [[World Health Organization]] (WHO) as the first line treatment of [[meningitis]] in low-income countries and appears on the [[WHO Model List of Essential Medicines|essential drugs list]]. It was first used to treat meningitis in 1975<ref>{{cite journal | author=Rey M, Ouedraogo L, Saliou P, Perino L | title=Traitement minute de la méningite
| |
| cérébrospinale épidémique par injection intramusculaire unique de
| |
| chloramphénicol (suspension huileuse) | journal=Médecine et Maladies Infectieuses | year=1976 | volume=6 | pages=120–24 }}</ref> and there have been numerous studies since demonstrating its efficacy.<ref>{{cite journal | author = Wali S, Macfarlane J, Weir W, Cleland P, Ball P, Hassan-King M, Whittle H, Greenwood B | title = Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol. | journal = Trans R Soc Trop Med Hyg | volume = 73 | issue = 6 | pages = 698-702 | year = 1979 | id = PMID 538813}}</ref><ref>{{cite journal | author = Puddicombe J, Wali S, Greenwood B | title = A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis. | journal = Trans R Soc Trop Med Hyg | volume = 78 | issue = 3 | pages = 399-403 | year = 1984 | id = PMID 6464136}}</ref><ref>{{cite journal | author = Pécoul B, Varaine F, Keita M, Soga G, Djibo A, Soula G, Abdou A, Etienne J, Rey M | title = Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis. | journal = Lancet | volume = 338 | issue = 8771 | pages = 862-6 | year = 1991 | month=Oct 5 | id = PMID 1681224}}</ref> It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 for [[ampicillin]] and US$15 for five days of [[ceftriaxone]]). It has the great advantage of requiring only a single injection, whereas ceftriaxone is traditionally given daily for five days. This recommendation may yet change now that a single dose of ceftriaxone (cost US$3) has been shown to be equivalent to one dose of oily chloramphenicol.<ref>{{cite journal | title=Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study | journal=Lancet | author=Nathan N, Borel T, Djibo A, ''et al.'' | year=2005 | volume=366 | issue=9482 | pages=308–13 | id=PMID 16039333 }}</ref>
| |
| | |
| Oily chloramphenicol is not currently available in the U.S. or Europe.
| |
| | |
| ===Chloramphenicol eye drops===
| |
| In the West, chloramphenicol is still widely used in topical preparations ([[ointment]]s and [[eye drop]]s) for the treatment of bacterial [[conjunctivitis]]. Isolated cases report of [[aplastic anaemia]] following chloramphenicol eyedrops exist, but the risk is estimated to be less than 1 in 224,716 prescriptions.<ref name="Lancaster1998">{{cite journal | author=Lancaster T, Stewart AM, Jick H | title=Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database | journal=Brit Med J | year=1998 | volume=316 | pages=667 | id=PMID 9522792 |url=http://bmj.bmjjournals.com/cgi/content/full/316/7132/667}}</ref>
| |
| | |
| ==Pharmacology==
| |
| Chloramphenicol is extremely lipid soluble, it remains relatively [[plasma protein binding|unbound to protein]] and is a small molecule: it has a large apparent [[volume of distribution]] of 100 litres and penetrates effectively into all tissues of the body, including the brain. The concentration achieved in brain and [[cerebrospinal fluid]] (CSF) is around 30 to 50% even when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed.
| |
| | |
| Chloramphenicol increases the absorption of [[Human iron metabolism|iron]].<ref>{{cite encyclopedia |encyclopedia= Pill Book, The |title= Iron Supplements |pages= pp. 593–596 |editor= Harold M. Silverman, Pharm.D. (editor-in-chief) |publisher= Bantam Dell |location= New York |edition= 12th revised ed. |id= ISBN 978-0-553-58892-7 |year= 2006}}</ref>
| |
| | |
| ==Uses==
| |
| Because it functions by inhibiting bacterial [[protein]] synthesis, chloramphenicol has a very broad spectrum of activity: it is active against [[Gram-positive]] bacteria (including most strains of [[Methicillin-resistant Staphylococcus aureus|MRSA]]), [[Gram-negative]] bacteria and [[anaerobes]].<ref name=Baron>{{cite book | author = Neu HC, Gootz TD | title = Antimicrobial Chemotherapy:Antimicrobial Inhibitors of Ribosome Function.. ''In:'' Baron's Medical Microbiology ''(Baron S ''et al'', eds.)| edition = 4th ed. | publisher = Univ of Texas Medical Branch | year = 1996 | id = [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.688 (via NCBI Bookshelf)] ISBN 0-9631172-1-1 }}</ref> It is not active against ''[[Pseudomonas aeruginosa]]'' or ''[[Enterobacter]]'' species. It has some activity against ''[[Burkholderia pseudomallei]]'', but is no longer routinely used to treat infections caused by this organism (it has been superseded by [[ceftazidime]] and [[meropenem]]). In the West, chloramphenicol is mostly restricted to topical uses because of the worries about the risk of [[aplastic anaemia]].
| |
| | |
| The original indication of chloramphenicol was in the treatment of [[typhoid]], but the now almost universal presence of multi-drug resistant ''[[Salmonella typhi]]'' has meant that it is seldom used for this indication except when the organism is known to be sensitive. Chloramphenicol may be used as a second-line agent in the treatment of [[tetracycline]]-resistant [[cholera]].
| |
| | |
| Because of its excellent [[cerebrospinal fluid|CSF]] penetration (far superior to any of the [[cephalosporins]]), chloramphenicol remains the first choice treatment for [[Staphylococcus aureus|staphylococcal]] [[brain abscess]]es. It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known.
| |
| | |
| Chloramphenicol is active against the three main bacterial causes of [[meningitis]]: ''[[Neisseria meningitidis]]'', ''[[Streptococcus pneumoniae]]'' and ''[[Haemophilus influenzae]]''. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe [[penicillin]] or [[cephalosporin]] allergy and [[General Practitioner|GP]]s are recommended to carry intravenous chloramphenicol in their bag. In low income countries, the WHO recommend that oily chloramphenicol be used first-line to treat [[meningitis]].
| |
| | |
| Chloramphenicol has been used in the U.S. in the initial [[empirical treatment]] of children with fever and a [[petechial rash]], when the [[differential diagnosis]] includes both ''[[Neisseria meningitidis]]'' [[septicaemia]] as well as [[Rocky Mountain spotted fever]], pending the results of diagnostic investigations.
| |
| | |
| Chloramphenicol is also effective against ''[[Enterococcus faecium]]'', which has led to it being considered for treatment of [[Vancomycin-Resistant Enterococcus|vancomycin-resistant enterococci]].
| |
| | |
| ==Adverse effects==
| |
| ===Aplastic anemia===
| |
| The most serious [[adverse drug reaction|side effect]] of chloramphenicol treatment is [[aplastic anaemia]].<ref>{{cite journal | author = Rich M, Ritterhoff R, Hoffmann R | title = A fatal case of aplastic anemia following chloramphenicol (chloromycetin) therapy. | journal = Ann Intern Med | volume = 33 | issue = 6 | pages = 1459-67 | year = 1950 | month=Dec | id = PMID 14790529}}</ref> This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect. The effect usually occurs weeks or months after chloramphenicol treatment has been stopped and there may be a genetic predisposition.<ref>{{cite journal | author = Nagao T, Mauer A | title = Concordance for drug-induced aplastic anemia in identical twins. | journal = N Engl J Med | volume = 281 | issue = 1 | pages = 7-11 | year = 1969 | month Jul 3 |id = PMID 5785754}}</ref> It is not known whether monitoring the [[blood count]]s of patients can prevent the development of aplastic anaemia, but it is recommended that patients have a blood count checked twice weekly while on treatment. The highest risk is with oral chloramphenicol<ref>{{cite journal | author=Holt R | journal=Lancet | title=The bacterial degradation of chloramphenicol | year=1967 | volume=i | pages=1259 }}</ref> (affecting 1 in 24,000–40,000)<ref>{{cite journal | author = Wallerstein R, Condit P, Kasper C, Brown J, Morrison F | title = Statewide study of chloramphenicol therapy and fatal aplastic anemia. | journal = JAMA | volume = 208 | issue = 11 | pages = 2045-50 | year = 1969 | month=Jun 16 | id = PMID 5818983}}</ref> and the lowest risk occurs with eye drops (affecting less than 1 in 224,716 prescriptions).<ref name="Lancaster1998"/>
| |
| | |
| [[Thiamphenicol]] is a related compound with a similar spectrum of activity that is available in Italy and China for human use, and has never been associated with aplastic anaemia. Thiamphenicol is available in the U.S. and Europe as a [[veterinary]] antibiotic, and is not approved for use in humans.
| |
| | |
| ===Bone marrow suppression===
| |
| It is common for chloramphenicol to cause [[bone marrow suppression]] during treatment: this is a direct toxic effect of the drug on human [[mitochondria]]. This effect manifests first as a fall in [[haemoglobin]] levels and occurs quite predictably once a cumulative dose of 20 g has been given. This effect is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia.
| |
| | |
| ===Leukaemia===
| |
| There is an increased risk of childhood [[leukaemia]] as demonstrated in a Chinese [[case-controlled study]],<ref>{{cite journal | author = Shu X, Gao Y, Linet M, Brinton L, Gao R, Jin F, Fraumeni J | title = Chloramphenicol use and childhood leukaemia in Shanghai. | journal = Lancet | volume = 2 | issue = 8565 | pages = 934-7 | year = 1987 | month=Oct 24 | id = PMID 2889862}}</ref> and the risk increases with length of treatment.
| |
| | |
| ===Gray baby syndrome===
| |
| Intravenous chloramphenicol use has been associated with the so called [[gray baby syndrome]].<!--
| |
| --><ref name=McIntyre_2004>{{cite journal | author = McIntyre J, Choonara I | title = Drug toxicity in the neonate. | journal = Biol Neonate | volume = 86 | issue = 4 | pages = 218-21 | year = 2004 | id = PMID 15249753}}</ref>
| |
| This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes, and so chloramphenicol remains unmetabolized in the body.<!--
| |
| --><ref name=Piñeiro-Carrero_2004>{{cite journal | author = Piñeiro-Carrero V, Piñeiro E | title = Liver. | journal = Pediatrics | volume = 113 | issue = 4 Suppl | pages = 1097-106 | year = 2004 | id = PMID 15060205}}</ref>
| |
| This causes several adverse effects, including [[hypotension]] and [[cyanosis]]. The condition can be prevented by using chloramphenicol at the recommended doses and monitoring blood levels.<!--
| |
| --><ref>{{cite journal | author = Feder H | title = Chloramphenicol: what we have learned in the last decade. | journal = South Med J | volume = 79 | issue = 9 | pages = 1129-34 | year = 1986 | id = PMID 3529436}}</ref><!--
| |
| --><ref>{{cite journal | author = Mulhall A, de Louvois J, Hurley R | title = Chloramphenicol toxicity in neonates: its incidence and prevention. | journal = Br Med J (Clin Res Ed) | volume = 287 | issue = 6403 | pages = 1424-7 | year = 1983 | id = PMID 6416440 | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6416440 | format=Scanned copy & PDF}}</ref><!--
| |
| --><ref>{{cite journal | author = Forster J, Hufschmidt C, Niederhoff H, Künzer W | title = [Need for the determination of chloramphenicol levels in the treatment of bacterial-purulent meningitis with chloramphenicol succinate in infants and small children] | journal = Monatsschr Kinderheilkd | volume = 133 | issue = 4 | pages = 209-13 | year = 1985 | id = PMID 4000136}}</ref>
| |
| | |
| ==Mechanism and resistance==
| |
| Chloramphenicol is [[Bacteriostatic agent|bacteriostatic]] (that is, it stops bacterial growth). It functions by inhibiting [[peptidyl transferase]], preventing peptide bond formation. While chloramphenicol and the macrolide class of antibiotics both interact with the 50S ribosomal subunit, chloramphenicol is not a macrolide. Furthermore, their mechanisms are slightly different. While chloramphenicol directly interferes with substrate binding, macrolides sterically block the progression of the growing peptide.
| |
| | |
| There are three mechanisms of [[Antibiotic resistance|resistance]] to chloramphenicol: reduced membrane permeability, mutation of the 50S ribosomal subunit and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permability to chloramphenicol ''in vitro'' by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High level resistance is conferred by the ''cat''-gene; this [[gene]] codes for an [[enzyme]] called [[chloramphenicol acetyltransferase]] which inactivates chloramphenicol by covalently linking one or two [[acetyl]] groups, derived from acetyl-S-coenzyme A, to the [[hydroxyl]] groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.
| |
| | |
| Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the [[ACCoT]] plasmid (A=[[ampicillin]], C=chloramphenicol, Co=[[co-trimoxazole]], T=[[tetracycline]]) which mediates multi-drug resistance in typhoid (also called [[R factors]]).
| |
| | |
| ==Trade names==
| |
| Chloramphenicol has a long history and therefore a multitude of alternative names in many different countries:
| |
| *Alficetyn
| |
| *Amphicol
| |
| *Biomicin
| |
| *Chlornitromycin
| |
| *Chloromycetin (U.S., intravenous preparation)
| |
| *Chlorsig (U.S., Australia, eye drops)
| |
| *Fenicol
| |
| *Kemicetine (UK, intravenous preparation)
| |
| *Laevomycetin
| |
| *Optrex Infected Eyes (UK, eye drops)
| |
| *Phenicol
| |
| *Nevimycin
| |
| *Silmycetin (Thailand, eye drops)
| |
| *Synthomycine (Israel, eye ointment)
| |
| *Tifomycine (France, oily chloramphenicol)
| |
| *Vernacetin
| |
| *Veticol
| |
| | |
| ==External links==
| |
| * {{MerckManual|13|153|f}}
| |
| * {{MedlinePlusDrugInfo|uspdi|202125}}
| |
| * [http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/chloro.htm University of Pennsylvania]
| |
| | |
| {{Antibiotics and chemotherapeutics for dermatological use}}
| |
| {{Gynecological anti-infectives and antiseptics}}
| |
| {{Amphenicols}}
| |
| {{Otologicals}}
| |
| | |
| ==References==
| |
| <div class="references-small">
| |
| <references/>
| |
| </div>
| |
| | |
| [[Category:Antibiotics]]
| |
| <br>
| |
| [[de:Chloramphenicol]]
| |
| [[es:Cloranfenicol]]
| |
| [[fr:Chloramphénicol]]
| |
| [[it:Cloramfenicolo]]
| |
| [[he:כלורמפניקול]]
| |
| [[nl:Chlooramfenicol]]
| |
| [[ja:クロラムフェニコール]]
| |
| [[no:Kloramfenikol]]
| |
| [[pl:Chloramfenikol]]
| |
| [[pt:Cloranfenicol]]
| |
| [[ru:Хлорамфеникол]]
| |
| [[sk:Chloramfenikol]]
| |
| [[sv:Kloramfenikol]]
| |
| [[th:คลอแรมเฟนิคอล]]
| |
| [[tr:Kloramfenikol]]
| |
| [[zh:氯霉素]]
| |
| {{jb1}}
| |
| | |
| {{WikiDoc Help Menu}}
| |
| {{WS}}
| |