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{{Short description|Antibiotic}}
{{Drugbox| Watchedfields = changed
{{for|the episode of '']''|Chloramphenicol (The Americans)}}
| verifiedrevid = 419857588
{{Use dmy dates|date=January 2025}}
| IUPAC_name = 2,2-dichloro-N-acetamide
{{cs1 config|name-list-style=vanc|display-authors=6}}
| image = Chloramphenicol-2D-skeletal.svg
{{Infobox drug
| image2 = Chloramphenicol-3D-vdW.png
| Watchedfields = changed
| verifiedrevid = 443513464
| image = Chloramphenicol.svg
| image_class = skin-invert-image
| alt =
| image2 = Chloramphenicol-from-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| alt2 =


<!--Clinical data--> <!-- Clinical data -->
| pronounce =
| Drugs.com = {{drugs.com|monograph|chloramphenicol}}
| tradename = Chloromycetin, Abeed, others<ref name=Wood2009>{{cite book| vauthors = Woods AL |title=Delmar nurse's drug handbook.|date=2008|publisher=Delmar|location=Clifton Park, N.Y.|isbn=9781428361065|page=296|edition=2009|url=https://books.google.com/books?id=8MoIHiUja_oC&pg=PA296|url-status=live|archive-url=https://web.archive.org/web/20160305042621/https://books.google.ca/books?id=8MoIHiUja_oC&pg=PA296|archive-date=2016-03-05}}</ref>
| pregnancy_category = C (systemic), A (topical)
| Drugs.com = {{drugs.com|monograph|chloramphenicol}}
| legal_status = Ocular P, else POM <small>(])</small>
| MedlinePlus = a608008
| routes_of_administration = ] (]), oral, ], ]
| DailyMedID = Chloramphenicol
| pregnancy_AU = A
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = ] (]), ], ], ]
| class =
| 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}}, {{ATCvet|J51|BA01}}


<!--Pharmacokinetic data--> <!-- Legal status -->
| legal_AU = S3
| bioavailability = 75–90%
| legal_AU_comment =
| metabolism = ]
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C5, D1, D2, E, F1, F2, F3, F4 -->
| elimination_half-life = 1.5–4.0 hours
| legal_BR_comment =
| excretion = ]
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = P
| legal_UK_comment = /&nbsp;POM
| legal_US = Rx-only
| legal_US_comment =
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Identifiers--> <!-- Pharmacokinetic data -->
| bioavailability = 75–90%
| CASNo_Ref = {{cascite|correct|CAS}}
| protein_bound = 60%
| CAS_number = 56-75-7
| metabolism = ]
| ATC_prefix = D06
| metabolites =
| ATC_suffix = AX02
| onset =
| ATC_supplemental = {{ATC|D10|AF03}} {{ATC|G01|AA05}} {{ATC|J01|BA01}} {{ATC|S01|AA01}} {{ATC|S02|AA01}} {{ATC|S03|AA08}} {{ATCvet|J51|BA01}}
| elimination_half-life = 1.6–3.3 hours
| ChEBI = 17698
| duration_of_action =
| PubChem = 298
| excretion = ] (5–15%), faeces (4%)
| DrugBank = DB00446
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5744
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 66974FR9Q1
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00104
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 130


<!--Chemical data--> <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| C=11 | H=12 | Cl=2 | N=2 | O=5
| CAS_number = 56-75-7
| molecular_weight = 323.132 g/mol
| PubChem = 5959
| smiles = c1cc(ccc1((CO)NC(=O)C(Cl)Cl)O)(=O)
| IUPHAR_ligand =
| InChI = 1/C11H12Cl2N2O5/c12-10(13)11(18)14-8(5-16)9(17)6-1-3-7(4-2-6)15(19)20/h1-4,8-10,16-17H,5H2,(H,14,18)/t8-,9-/m1/s1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00446
| StdInChI = 1S/C11H12Cl2N2O5/c12-10(13)11(18)14-8(5-16)9(17)6-1-3-7(4-2-6)15(19)20/h1-4,8-10,16-17H,5H2,(H,14,18)/t8-,9-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5744
| StdInChIKey = WIIZWVCIJKGZOK-RKDXNWHRSA-N
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 66974FR9Q1
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00104
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17698
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 130
| NIAID_ChemDB =
| PDB_ligand = CLM
| synonyms = C/CHL/CL<ref>{{cite web |title=Antibiotic abbreviations list |url=https://microbiologie-clinique.com/antibiotic-family-abbreviation.html |access-date=22 June 2023}}</ref>

<!-- Chemical and physical data -->
| IUPAC_name = 2,2-dichloro-''N''-acetamide<ref>{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/5959#section=Top|publisher=PubChem|title=Chloramphenicol|url-status=live|archive-url=https://web.archive.org/web/20161115131903/https://pubchem.ncbi.nlm.nih.gov/compound/5959#section=Top|archive-date=2016-11-15}}</ref>
| C = 11
| H = 12
| Cl = 2
| N = 2
| O = 5
| SMILES = c1cc(ccc1((CO)NC(=O)C(Cl)Cl)O)(=O)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C11H12Cl2N2O5/c12-10(13)11(18)14-8(5-16)9(17)6-1-3-7(4-2-6)15(19)20/h1-4,8-10,16-17H,5H2,(H,14,18)/t8-,9-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = WIIZWVCIJKGZOK-RKDXNWHRSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}
'''Chloramphenicol''' (]) is a ] ]. It is considered a prototypical ], alongside the ]s.


<!-- Definition and medical uses -->
Chloramphenicol is effective against a wide variety of ] and ] ], including most ]s. Due to resistance and safety concerns, it is no longer a ] for any indication in developed nations, although it is sometimes used topically for ]. Nevertheless, the global problem of advancing bacterial resistance to newer drugs has led to renewed interest in its use.<ref name=Falagas>{{cite journal |author=Falagas ME, Grammatikos AP, Michalopoulos A |title=Potential of old-generation antibiotics to address current need for new antibiotics |journal=Expert Rev Anti Infect Ther |volume=6 |issue=5 |pages=593–600 |year=2008 |month=October |pmid=18847400 |doi=10.1586/14787210.6.5.593 |url=http://www.future-drugs.com/doi/abs/10.1586/14787210.6.5.593?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov}}</ref> In low-income countries, chloramphenicol is still widely used because it is inexpensive and readily available.
'''Chloramphenicol''' is an ] useful for the treatment of a number of ].<ref name=AHFS2015>{{cite web|title=Chloramphenicol|url=https://www.drugs.com/monograph/chloramphenicol.html|publisher=The American Society of Health-System Pharmacists|access-date=Aug 1, 2015|url-status=live|archive-url=https://web.archive.org/web/20150624080341/http://www.drugs.com/monograph/chloramphenicol.html|archive-date=2015-06-24}}</ref> This includes use as an ] to treat ].<ref>{{cite book| vauthors = Edwards KH |title=Optometry: Science, Techniques and Clinical Management|date=2009|publisher=Elsevier Health Sciences|isbn=978-0750687782|page=102|url=https://books.google.com/books?id=dv2g8aOIhhsC&pg=PA102|language=en|url-status=live|archive-url=https://web.archive.org/web/20170307203947/https://books.google.ca/books?id=dv2g8aOIhhsC&pg=PA102|archive-date=2017-03-07}}</ref> By mouth or by ], it is used to treat ], ], ], and ].<ref name=AHFS2015/> Its use by mouth or by injection is only recommended when safer antibiotics cannot be used.<ref name=AHFS2015/> Monitoring both blood levels of the medication and blood cell levels every two days is recommended during treatment.<ref name=AHFS2015/>


<!-- Side effects and mechanism -->
The most serious ] associated with chloramphenicol treatment is ] toxicity, which may occur in two distinct forms: ], which is a direct toxic effect of the drug and is usually reversible, and ], which is ] (rare, unpredictable, and unrelated to dose) and generally fatal.<ref name="Rich1950">{{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=December | pmid = 14790529}}</ref>
Common side effects include ], nausea, and diarrhea.<ref name=AHFS2015/> The bone marrow suppression may result in death.<ref name=AHFS2015/> To reduce the risk of side effects treatment duration should be as short as possible.<ref name=AHFS2015/> People with liver or kidney problems may need lower doses.<ref name=AHFS2015/> In young infants, a condition known as ] may occur which results in a swollen stomach and ].<ref name=AHFS2015/> Its use near the end of pregnancy and during breastfeeding is typically not recommended.<ref>{{cite web|title=Chloramphenicol Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/chloramphenicol.html|website=Multum Information Services|access-date=26 August 2015|url-status=live|archive-url=https://web.archive.org/web/20150908064750/http://www.drugs.com/pregnancy/chloramphenicol.html|archive-date=8 September 2015}}</ref> Chloramphenicol is a ] that typically ] by stopping the production of proteins.<ref name=AHFS2015/>


<!-- History, society, and culture -->
==Spectrum of activity==
Chloramphenicol was discovered after being isolated from '']'' in 1947.<ref name=Pong1979>{{cite book| vauthors = Pongs O | veditors = Hahn FE |title=Mechanism of Action of Antibacterial Agents|date=1979|publisher=Springer Berlin Heidelberg|location=Berlin, Heidelberg|isbn=978-3-642-46403-4|pages=26–42|chapter=Chapter 3: Chloramphenicol |series=Antibiotics Volume V Part 1}}</ref> Its chemical structure was identified and it was first synthesized in 1949. It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a generic medication.<ref name=AHFS2015/>
Because it functions by inhibiting bacterial ] synthesis, chloramphenicol has a very broad spectrum of activity: it is active against ] bacteria (including most strains of ]), ] bacteria and ].<ref name=Baron>{{cite book | author = Neu HC, Gootz TD | chapter = Antimicrobial Chemotherapy:Antimicrobial Inhibitors of Ribosome Function | title = Baron's Medical Microbiology |editor=Baron S,''et al.'' | edition = 4th | publisher = Univ of Texas Medical Branch | year = 1996 |chapterurl=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.688 |isbn=0-9631172-1-1 }}</ref> It is not active against '']'', ], or '']'' species. It has some activity against '']'', but is no longer routinely used to treat infections caused by this organism (it has been superseded by ] and ]). In the West, chloramphenicol is mostly restricted to topical uses because of the worries about the risk of ].
{{TOC limit|3}}


==Therapeutic uses== == Medical uses ==
The original indication of chloramphenicol was in the treatment of ], but the now almost universal presence of multiple drug-resistant '']'' has meant 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 ]-resistant ].


The original indication of chloramphenicol was in the treatment of ], but the presence of multiple drug-resistant '']'' has meant it is seldom used for this indication except when the organism is known to be sensitive.{{medical citation needed|date=August 2022}}
Because of its excellent ] penetration (far superior to any of the ]), chloramphenicol remains the first choice treatment for ] ]es. It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known.


In low-income countries, the WHO no longer recommends only chloramphenicol as first-line to treat meningitis, but recognises it may be used with caution if there are no available alternatives.<ref name="WHOMeningitis">{{cite web|title=WHO meningitis epidemic guidelines Africa|url=https://www.who.int/csr/resources/publications/HSE_GAR_ERI_2010_4/en/|access-date=29 February 2016|url-status=dead|archive-url=https://web.archive.org/web/20160305134645/http://www.who.int/csr/resources/publications/HSE_GAR_ERI_2010_4/en/|archive-date=5 March 2016}}</ref>
Chloramphenicol is active against the three main bacterial causes of ]: '']'', '']'' and '']''. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe ] or ] allergy and ]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 ].


During the last decade chloramphenicol has been re-evaluated as an old agent with potential against systemic infections due to multidrug-resistant gram positive microorganisms (including vancomycin resistant enterococci). ''In vitro'' data have shown an activity against the majority (> 80%) of vancomycin resistant ''E. faecium'' strains.<ref>{{cite journal | vauthors = Čivljak R, Giannella M, Di Bella S, Petrosillo N | title = Could chloramphenicol be used against ESKAPE pathogens? A review of in vitro data in the literature from the 21st century | journal = Expert Review of Anti-Infective Therapy | volume = 12 | issue = 2 | pages = 249–264 | date = February 2014 | pmid = 24392752 | doi = 10.1586/14787210.2014.878647 | url = http://www.tandfonline.com/doi/full/10.1586/14787210.2014.878647 | access-date = 2021-07-02 | url-status = live | s2cid = 34134573 | archive-url = https://web.archive.org/web/20220303115239/https://www.tandfonline.com/doi/full/10.1586/14787210.2014.878647 | archive-date = 2022-03-03 }}</ref>
Chloramphenicol has been used in the U.S. in the initial ] of children with fever and a ], when the ] includes both '']'' ] as well as ], pending the results of diagnostic investigations.


In the context of preventing ], a complication of ] surgery, a 2017 systematic review found moderate evidence that using chloramphenicol eye drops in addition to an antibiotic injection (] or ]) will likely lower the risk of endophthalmitis, compared to eye drops or antibiotic injections alone.<ref name="Gower">{{cite journal | vauthors = Gower EW, Lindsley K, Tulenko SE, Nanji AA, Leyngold I, McDonnell PJ | title = Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 2 | pages = CD006364 | date = February 2017 | pmid = 28192644 | pmc = 5375161 | doi = 10.1002/14651858.CD006364.pub3 }}</ref>
Chloramphenicol is also effective against '']'', which has led to it being considered for treatment of ].


===Spectrum===
Although unpublished, recent research suggests chloramphenicol could also be applied to frogs to prevent their widespread destruction from fungal infections.<ref>{{cite news |author=Kim Griggs |title=Frog killer fungus 'breakthrough' |url=http://news.bbc.co.uk/2/hi/science/nature/7067613.stm |date=2007-10-30 |publisher=BBC News}}</ref> Chloramphenicol has recently been discovered to be a life-saving cure for ] in ].<ref> R. T. M. Poulter, J. N. Busby, P. J. Bishop, M. I. Butler, R. Speare, </ref> Chytridiomycosis is a fungal disease, blamed for the extinction of one-third of the 120 frog species lost since 1980.
Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections such as conjunctivitis, ] etc. caused by a number of bacteria including ''Staphylococcus aureus, Streptococcus pneumoniae'', and ]. It is not effective against ''Pseudomonas aeruginosa''. The following susceptibility data represent the ] for a few medically significant organisms.<ref>{{cite web |url=http://antibiotics.toku-e.com/antimicrobial_507.html |title=Chloramphenicol (Chloromycetin) {{pipe}} the Antimicrobial Index Knowledgebase - TOKU-E |access-date=2014-04-21 |url-status=live |archive-url=https://web.archive.org/web/20140423055139/http://antibiotics.toku-e.com/antimicrobial_507.html |archive-date=2014-04-23 }}</ref>
* ''Escherichia coli'': 0.015&nbsp;–&nbsp;10,000&nbsp;μg/mL
* ''Staphylococcus aureus'': 0.06&nbsp;–&nbsp;128&nbsp;μg/mL
* ''Streptococcus pneumoniae'': 2&nbsp;–&nbsp;16&nbsp;μg/mL
Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains of ], for example, show spontaneous emergence of chloramphenicol resistance.<ref>{{cite journal | vauthors = Carone BR, Xu T, Murphy KC, Marinus MG | title = High incidence of multiple antibiotic resistant cells in cultures of in enterohemorrhagic Escherichia coli O157:H7 | journal = Mutation Research | volume = 759 | pages = 1–8 | date = January 2014 | pmid = 24361397 | pmc = 3913999 | doi = 10.1016/j.mrfmmm.2013.11.008 | bibcode = 2014MRFMM.759....1C }}</ref><ref>{{cite journal | vauthors = Moore AM, Patel S, Forsberg KJ, Wang B, Bentley G, Razia Y, Qin X, Tarr PI, Dantas G | title = Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes | journal = PLOS ONE | volume = 8 | issue = 11 | pages = e78822 | date = 2013 | pmid = 24236055 | pmc = 3827270 | doi = 10.1371/journal.pone.0078822 | doi-access = free | bibcode = 2013PLoSO...878822M }}</ref>

===Resistance===

Three mechanisms of ] to chloramphenicol are known: reduced membrane permeability, mutation of the ], and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability 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;<ref name="m586">{{cite journal | vauthors = Gil JA, Kieser HM, Hopwood DA | title = Cloning of a chloramphenicol acetyltransferase gene of Streptomyces acrimycini and its expression in Streptomyces and Escherichia coli | journal = Gene | volume = 38 | issue = 1–3 | pages = 1–8 | date = 1985 | pmid = 3905512 | doi = 10.1016/0378-1119(85)90197-0 }}</ref> this ] codes for an ] called ], which inactivates chloramphenicol by covalently linking one or two ] groups, derived from acetyl-''S''-coenzyme A, to the ] groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.{{medical citation needed|date=August 2022}}

Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the ] plasmid (A=], C=chloramphenicol, Co=], T=]), which mediates ] in typhoid (also called ]).{{medical citation needed|date=August 2022}}

As of 2014 some '']'' and'' ]'' strains are resistant to chloramphenicol. Some '']'' spp. and '']'' strains have also developed resistance to chloramphenicol to varying degrees.<ref>{{cite web |title= Chloramphenicol spectrum of bacterial susceptibility and Resistance |url=http://www.toku-e.com/Upload/Products/PDS/20120618001452.pdf|access-date=15 May 2012|url-status=dead|archive-url=https://web.archive.org/web/20140211211304/http://www.toku-e.com/Upload/Products/PDS/20120618001452.pdf | work = Product Data Safety Sheet | publisher = TOKU-E | date = December 2010 |archive-date=11 February 2014}}</ref>

Some other resistance genes beyond ''cat'' are known, such as chloramphenicol hydrolase,<ref name="b716">{{cite journal | vauthors = Mosher RH, Ranade NP, Schrempf H, Vining LC | title = Chloramphenicol resistance in Streptomyces: cloning and characterization of a chloramphenicol hydrolase gene from Streptomyces venezuelae | journal = Journal of General Microbiology | volume = 136 | issue = 2 | pages = 293–301 | date = February 1990 | pmid = 2324705 | doi = 10.1099/00221287-136-2-293 | doi-access = free }}</ref> and chloramphenicol phosphotransferase.<ref name="u157">{{cite journal | vauthors = Mosher RH, Camp DJ, Yang K, Brown MP, Shaw WV, Vining LC | title = Inactivation of chloramphenicol by O-phosphorylation. A novel resistance mechanism in Streptomyces venezuelae ISP5230, a chloramphenicol producer | journal = The Journal of Biological Chemistry | volume = 270 | issue = 45 | pages = 27000–27006 | date = November 1995 | pmid = 7592948 | doi = 10.1074/jbc.270.45.27000 | doi-access = free }}</ref>


==Adverse effects== ==Adverse effects==
===Aplastic anemia===


===Aplastic anemia===
The most serious ] of chloramphenicol treatment is ].<ref name="Rich1950"/> This effect is rare and is generally fatal: there is no treatment and 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 | doi = 10.1056/NEJM196907032810102 | 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 |pmid = 5785754|month =Jul 3}}</ref> It is not known whether monitoring the ]s of patients can prevent the development of aplastic anaemia, but patients are recommended to have a blood count check 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 | doi=10.1016/S0140-6736(67)92720-1 | pmid=4165044}}</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 | pmid = 5818983 | doi = 10.1001/jama.208.11.2045}}</ref> and the lowest risk occurs with eye drops (affecting less than 1 in 224,716 prescriptions).<ref name="Lancaster1998"/>


The most serious ] of chloramphenicol treatment is ]. This effect is rare but sometimes fatal. The risk of AA is high enough that alternatives should be strongly considered. Treatments are available but expensive. No way exists to predict who may or may not suffer this side effect. The effect usually occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved. It is not known whether monitoring the ]s of patients can prevent the development of aplastic anaemia, but patients are recommended to have a baseline blood count with a repeat blood count every few days while on treatment.<ref>{{cite journal | vauthors = Hammett-Stabler CA, Johns T | title = Laboratory guidelines for monitoring of antimicrobial drugs. National Academy of Clinical Biochemistry | journal = Clinical Chemistry | volume = 44 | issue = 5 | pages = 1129–1140 | date = May 1998 | pmid = 9590397 | doi = 10.1093/clinchem/44.5.1129 | doi-access = free }}</ref> Chloramphenicol should be discontinued if the complete blood count drops. The highest risk is with oral chloramphenicol (affecting 1 in 24,000–40,000)<ref>{{cite journal | vauthors = Wallerstein RO, Condit PK, Kasper CK, Brown JW, Morrison FR | title = Statewide study of chloramphenicol therapy and fatal aplastic anemia | journal = JAMA | volume = 208 | issue = 11 | pages = 2045–2050 | date = June 1969 | pmid = 5818983 | doi = 10.1001/jama.208.11.2045 }}</ref> and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions).<ref name="Lancaster1998"/>
], a related compound with a similar spectrum of activity, is available in Italy and China for human use, and has never been associated with aplastic anaemia {{Citation needed|date=November 2009}}. Thiamphenicol is available in the U.S. and Europe as a ] antibiotic, and is not approved for use in humans.


===Bone marrow suppression=== ===Bone marrow suppression===
Chloramphenicol commomly causes ] during treatment; this is a direct toxic effect of the drug on human ]. This effect manifests first as a fall in ] levels, occurs quite predictably once a cumulative dose of 20&nbsp;g has been given, is fully reversible once the drug is stopped, and does not predict future development of aplastic anaemia. Chloramphenicol may cause ] during treatment; this is a direct toxic effect of the drug on human ].<ref name="pmid2486534">{{cite journal | vauthors = Yunis AA | title = Chloramphenicol toxicity: 25 years of research | journal = The American Journal of Medicine | volume = 87 | issue = 3N | pages = 44N–48N | date = September 1989 | pmid = 2486534 }}</ref> This effect manifests first as a fall in ] levels, which occurs quite predictably once a cumulative dose of 20&nbsp;g has been given. The anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia. Studies in mice have suggested existing marrow damage may compound any marrow damage resulting from the toxic effects of chloramphenicol.<ref>{{cite journal | vauthors = Morley A, Trainor K, Remes J | title = Residual marrow damage: possible explanation for idiosyncrasy to chloramphenicol | journal = British Journal of Haematology | volume = 32 | issue = 4 | pages = 525–531 | date = April 1976 | pmid = 1259934 | doi = 10.1111/j.1365-2141.1976.tb00955.x | s2cid = 40234293 }}</ref>


===Leukemia=== ===Leukemia===
There is an increased risk of childhood ], as demonstrated in a Chinese ],<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 | pmid = 2889862 | doi = 10.1016/S0140-6736(87)91420-6}}</ref> and the risk increases with length of treatment. Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhood ] is increased, as demonstrated in a Chinese ],<ref>{{cite journal | vauthors = Shu XO, Gao YT, Linet MS, Brinton LA, Gao RN, Jin F, Fraumeni JF | title = Chloramphenicol use and childhood leukaemia in Shanghai | journal = Lancet | volume = 2 | issue = 8565 | pages = 934–937 | date = October 1987 | pmid = 2889862 | doi = 10.1016/S0140-6736(87)91420-6 | s2cid = 3217082 }}</ref> and the risk increases with length of treatment.

'''Possible Related Adverse Effects'''

Chloramphenicol is particularly toxic to people sensitive to benzene-based preservatives, such as preservatives 210 and 211.
Chloramphenicol poisoning can cause sensitivity reactions to organic acids and salicylates.
It is also known to cause ] and balance problems through inner ear damage.
It also causes ] depletion, resulting in adverse effects to the thyroid, pituitary and prostate through effects on PABA levels. There may also be links to chronic lymphocytic leukemia (CLL) through folic acid "depletion" and resultant high levels of folic acid in the mutant lymphocytes that characterize CLL. Chloramphenicol stops the body's production of vitamin D and ]. This results in major hormone depletion, including DHEA and testosterone, that can result in death and also lowers the body's resistance to viral infection.
Chloramphenicol can cause testes pain, possibly through hormone effects.
Chinese research showed chloramphenicol affects motor neurones. It also affects insulin Igf1 levels and glutamate levels. Both conditions are considered indicative of a type of motor neurone disease. The adverse genetic effects of chloramphenicol are considered heritable.


===Gray baby syndrome=== ===Gray baby syndrome===
Intravenous chloramphenicol use has been associated with the so-called ].<!-- Intravenous chloramphenicol use has been associated with the so-called ].<!--
--><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 | pmid = 15249753 | doi = 10.1159/000079656}}</ref> --><ref name=McIntyre_2004>{{cite journal | vauthors = McIntyre J, Choonara I | title = Drug toxicity in the neonate | journal = Biology of the Neonate | volume = 86 | issue = 4 | pages = 218–221 | year = 2004 | pmid = 15249753 | doi = 10.1159/000079656 | s2cid = 29906856 }}</ref>
This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (i.e. UDP-glucuronyl transferase), so chloramphenicol remains unmetabolized in the body.<!-- This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (i.e. UDP-glucuronyl transferase), 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 | pmid = 15060205}}</ref> --><ref name="Piñeiro-Carrero_2004">{{cite journal | vauthors = Piñeiro-Carrero VM, Piñeiro EO | title = Liver | journal = Pediatrics | volume = 113 | issue = 4 Suppl | pages = 1097–1106 | date = April 2004 | pmid = 15060205 | doi = 10.1542/peds.113.S3.1097 | s2cid = 264867934 | url = http://pediatrics.aappublications.org/content/113/Supplement_3/1097.full.pdf | access-date = 2012-01-09 | url-status = live | archive-url = https://web.archive.org/web/20210828032546/https://pediatrics.aappublications.org/content/pediatrics/113/Supplement_3/1097.full.pdf | archive-date = 2021-08-28 }}</ref>
This causes several adverse effects, including ] and ]. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.<!-- This causes several adverse effects, including ] and ]. The condition can be prevented by using the drug 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 | pmid = 3529436}}</ref><!-- --><ref>{{cite journal | vauthors = Feder HM | title = Chloramphenicol: what we have learned in the last decade | journal = Southern Medical Journal | volume = 79 | issue = 9 | pages = 1129–1134 | date = September 1986 | pmid = 3529436 | doi = 10.1097/00007611-198609000-00022 }}</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 | pmid = 6416440 | pmc=1549666 | format=Scanned copy & PDF | doi = 10.1136/bmj.287.6403.1424}}</ref><!-- --><ref>{{cite journal | vauthors = Mulhall A, de Louvois J, Hurley R | title = Chloramphenicol toxicity in neonates: its incidence and prevention | journal = British Medical Journal | volume = 287 | issue = 6403 | pages = 1424–1427 | date = November 1983 | pmid = 6416440 | pmc = 1549666 | doi = 10.1136/bmj.287.6403.1424 }}</ref><!--
--><ref>{{cite journal | author = Forster J, Hufschmidt C, Niederhoff H, Künzer W | title = | journal = Monatsschr Kinderheilkd | volume = 133 | issue = 4 | pages = 209–13 | year = 1985 | pmid = 4000136}}</ref> --><ref>{{cite journal | vauthors = Forster J, Hufschmidt C, Niederhoff H, Künzer W | title = | language = de | journal = Monatsschrift Kinderheilkunde | volume = 133 | issue = 4 | pages = 209–213 | date = April 1985 | pmid = 4000136 }}</ref>

===Hypersensitivity reactions===
Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. ] have occurred during therapy for typhoid fever.<ref name="Drug Insert from DailyMed">{{cite web|title=Drug Insert from DailyMed|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08c16a42-1ad4-400f-b1b0-75303eb86713|access-date=18 April 2014|url-status=live|archive-url=https://web.archive.org/web/20140419012007/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08c16a42-1ad4-400f-b1b0-75303eb86713|archive-date=19 April 2014}}</ref>

===Neurotoxic reactions===
Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol. ] and peripheral ] have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn.<ref name="Drug Insert from DailyMed" /> It is theorized that this is caused by chloramphenicol's effects on the metabolism of ], specifically ]<ref>{{cite journal | vauthors = Ramilo O, Kinane BT, McCracken GH | title = Chloramphenicol neurotoxicity | language = en-US | journal = The Pediatric Infectious Disease Journal | volume = 7 | issue = 5 | pages = 358–359 | date = May 1988 | pmid = 3380586 | doi = 10.1097/00006454-198805000-00015 }}</ref>


==Pharmacokinetics== ==Pharmacokinetics==
Chloramphenicol is extremely lipid soluble; it remains relatively ] and is a small molecule. It has a large apparent ] of 100 litres, and penetrates effectively into all tissues of the body, including the brain. The concentration achieved in brain and ] (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 is extremely lipid-soluble; it remains relatively ] and is a small molecule. It has a large apparent ] and penetrates effectively into all tissues of the body, including the brain. Distribution is not uniform, with highest concentrations found in the liver and kidney, with lowest in the brain and cerebrospinal fluid.<ref name="Drug Insert from DailyMed" /> The concentration achieved in brain and ] <!-- (CSF) --> is around 30 to 50% of the overall average body concentration, even when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed.{{citation needed|date=March 2023}}


Chloramphenicol increases the absorption of ].<ref>{{cite encyclopedia |encyclopedia= Pill Book, The |title= Iron Supplements |pages= 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> Chloramphenicol increases the absorption of ].<ref>{{cite encyclopedia | encyclopedia = Pill Book, The | title = Iron Supplements | pages = 593–596 | veditors = Silverman HM | publisher = Bantam Dell | location = New York | edition = 12th revised | year = 2006 | isbn = 978-0-553-58892-7 }}</ref>


===Use in special populations=== ===Use in special populations===
Chloramphenicol is metabolized by the liver to chloramphenicol ] (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 is metabolized by the liver to chloramphenicol ] (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. No standard dose reduction exists for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations.

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. Plasma levels should 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.{{Citation needed|date=November 2009}}


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. Plasma levels should be monitored in patients with renal impairment, but this is not mandatory. Chloramphenicol succinate ester (an intravenous ] form) 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.<ref>{{cite journal | vauthors = Yogev R, Kolling WM, Williams T | title = Pharmacokinetic comparison of intravenous and oral chloramphenicol in patients with Haemophilus influenzae meningitis | journal = Pediatrics | volume = 67 | issue = 5 | pages = 656–660 | date = May 1981 | pmid = 6973130 | doi = 10.1542/peds.67.5.656 | s2cid = 8701518 }}</ref>
Chloramphenicol passes into ], so should therefore be avoided during breast feeding, if possible.<ref name=kidsgrowth> Retrieved on June 19, 2009</ref>


===Dose monitoring=== ===Dose monitoring===
] levels of chloramphenicol must be monitored in neonates and in patients with abnormal liver function. Plasma levels should be monitored in all children under the age of four, the elderly and patients with renal failure. ] levels of chloramphenicol must be monitored in neonates and patients with abnormal liver function. Plasma levels should be monitored in all children under the age of four, the elderly, and patients with ].
Because efficacy and toxicity of chloramphenicol are associated with a maximum serum concentration, peak levels (one hour after the intravenous dose is given) should be 10–20&nbsp;μg/mL with toxicity {{nowrap|> 40 μg/mL}}; trough levels (taken immediately before a dose) should be 5–10&nbsp;μg/mL.<ref name="Laboratory guidelines for monitoring of antimicrobial drugs">{{cite journal | vauthors = Hammett-Stabler CA, Johns T | title = Laboratory guidelines for monitoring of antimicrobial drugs. National Academy of Clinical Biochemistry | journal = Clinical Chemistry | volume = 44 | issue = 5 | pages = 1129–1140 | date = May 1998 | pmid = 9590397 | doi = 10.1093/clinchem/44.5.1129 | doi-access = free }}<!--|access-date=17 April 2014--></ref><ref name="Lexicomp Online Database">{{cite web|title=Chloramphenicol (Lexi-Drugs)|url=http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6582|work=Lexi-Comp Online|access-date=18 April 2014|url-status=live|archive-url=https://web.archive.org/web/20130726053121/http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6582|archive-date=26 July 2013}}</ref>
Peak levels (one hour after the dose is given) should be 15–25&nbsp;]/]; trough levels (taken immediately before a dose) should be less than 15&nbsp;mg/l.{{Citation needed|date=November 2009}}


===Drug interactions=== ===Drug interactions===
Administration of chloramphenicol concomitantly with ] drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.<ref> June 2005. Royal Pharmaceutical Society of Great Britain (RPSGB)</ref> Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.<ref>{{cite web | title = Practice Guidance: OTC Chloramphenicol Eye Drops | url = http://www.rpsgb.org.uk/pdfs/otcchlorampheneyedropsguid.pdf | date = June 2005 | publisher = Royal Pharmaceutical Society of Great Britain (RPSGB) | archive-url = https://web.archive.org/web/20051022000549/http://www.rpsgb.org.uk/pdfs/otcchlorampheneyedropsguid.pdf | archive-date = 2005-10-22 }}</ref>


Chloramphenicol is a potent inhibitor of the ] isoforms ] and ] in the liver.<ref>{{cite journal |author=Park JY, Kim KA, Kim SL |title=Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes |journal=Antimicrob. Agents Chemother. |volume=47 |issue=11 |pages=3464–9 |year=2003 |month=November |pmid=14576103 |pmc=253795 |doi= 10.1128/AAC.47.11.3464-3469.2003|url=}}</ref> Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, ], ] and ] if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, ], ], ], ], azole ], ]s, ] antibiotics, ]s, ] and ]s.<ref name=FASS> Facts for prescribers (Fakta för förskrivare)</ref> Chloramphenicol is a potent inhibitor of the ] ] ] and ] in the liver.<ref>{{cite journal | vauthors = Park JY, Kim KA, Kim SL | title = Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3464–3469 | date = November 2003 | pmid = 14576103 | pmc = 253795 | doi = 10.1128/AAC.47.11.3464-3469.2003 }}</ref> Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, ], ], ]s, and ]s if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, ]s, ], ], ]s, azole ], ]s, ] antibiotics, ]s, ]s, ], ], ]s, and ]s.<ref name="Drug Insert from DailyMed" /><ref name=FASS>{{cite web | url = http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 | trans-title = Facts for prescribers | title = Fakta för förskrivare | language = sv | publisher = FASS – Swedish National Drug Formulary | url-status = live | archive-url = https://web.archive.org/web/20020611044953/http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 | archive-date = 2002-06-11 }}</ref>

===Drug antagonistic===
Chloramphenicol is antagonistic with most ]s and using both together should be avoided in the treatment of infections.<ref name="Asmar_1988">{{cite journal | vauthors = Asmar BI, Prainito M, Dajani AS | title = Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone | journal = Antimicrobial Agents and Chemotherapy | volume = 32 | issue = 9 | pages = 1375–8 | date = September 1988 | pmid = 3195999 | doi = 10.1128/AAC.32.9.1375 | pmc = 175871 }}</ref>

===Drug synergism===
Chloramphenicol has been demonstrated a synergistic effect when combined with ] against clinical isolates of '']''.<ref>{{cite journal | vauthors = Lagatolla C, Milic J, Imperi F, Cervoni M, Bressan R, Luzzati R, Di Bella S | title = Synergistic activity of fosfomycin and chloramphenicol against vancomycin-resistant Enterococcus faecium (VREfm) isolates from bloodstream infections | journal = Diagnostic Microbiology and Infectious Disease | volume = 99 | issue = 2 | pages = 115241 | date = February 2021 | pmid = 33130503 | doi = 10.1016/j.diagmicrobio.2020.115241 | s2cid = 225174927 | hdl = 11368/2973877 | hdl-access = free }}</ref>


==Mechanism of action== ==Mechanism of action==


Chloramphenicol is a ] agent, ]. It prevents ] by inhibiting the ] activity of the bacterial ]. It specifically binds to A2451 and A2452 residues<ref>{{cite journal | vauthors = Schifano JM, Edifor R, Sharp JD, Ouyang M, Konkimalla A, Husson RN, Woychik NA | title = Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 21 | pages = 8501–8506 | date = May 2013 | pmid = 23650345 | pmc = 3666664 | doi = 10.1073/pnas.1222031110 | doi-access = free | bibcode = 2013PNAS..110.8501S }}</ref> in the ] of the 50S ribosomal subunit, preventing ] formation.<ref>{{cite web | url = http://merck.com/mmpe/sec14/ch170/ch170d.html | title = Chloramphenicol | work = The Merck Manual | publisher = Merck & Co., Inc. | location = Rahway, NJ, USA | url-status = live | archive-url = https://web.archive.org/web/20100310105845/http://www.merck.com/mmpe/sec14/ch170/ch170d.html | archive-date = 2010-03-10 }}</ref> Chloramphenicol directly interferes with substrate binding in the ribosome, as compared to ]s, which sterically block the progression of the growing peptide.<ref>{{cite journal | vauthors = Jardetzky O | title = Studies on the mechanism of action of chloramphenicol. I. The conformation of chlioramphenicol in solution | journal = The Journal of Biological Chemistry | volume = 238 | issue = 7 | pages = 2498–2508 | date = July 1963 | pmid = 13957484 | doi = 10.1016/S0021-9258(19)68000-2 | url = http://www.jbc.org/content/238/7/2498.full.pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20151211033031/http://www.jbc.org/content/238/7/2498.full.pdf | archive-date = 2015-12-11 | author-link1 = Oleg Jardetzky }}</ref><ref>{{cite journal | vauthors = Wolfe AD, Hahn FE | title = Mode of action of chloramphenicol IX. Effects of chloramphenicol upon a ribosomal amino acid polymerization system and its binding to bacterial ribosome | journal = Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis | volume = 95 | pages = 146–155 | date = January 1965 | pmid = 14289020 | doi = 10.1016/0005-2787(65)90219-4 }}</ref><ref>{{cite journal | vauthors = Hahn FE, Wisseman CL, Hopps HE | title = Mode of action of chloramphenicol. III. Action of chloramphenicol on bacterial energy metabolism | journal = Journal of Bacteriology | volume = 69 | issue = 2 | pages = 215–223 | date = February 1955 | pmid = 14353832 | pmc = 357505 | doi = 10.1128/JB.69.2.215-223.1955 }}</ref>
Chloramphenicol is ] (that is, it stops bacterial growth). It is a ] (more specifically inhibiting ]), causing inhibition of ] activity of the bacterial ], binding to A2451 and A2452 residues in the ] of the 50S ribosomal subunit, preventing peptide bond formation.<ref>http://merck.com/mmpe/sec14/ch170/ch170d.html</ref> While chloramphenicol and the ] class of antibiotics both interact with ribosomes, chloramphenicol is not a macrolide. It directly interferes with substrate binding; macrolides sterically block the progression of the growing peptide.
<ref> July 1963. The Journal of Biological Chemistry)</ref>
<ref> January 11, 1965. Biochim Biophys Acta)</ref>
<ref> February 1955. Journal of Bacteriology)</ref>


==Resistance== == History ==
Chloramphenicol was first isolated from '']'' in 1947 and in 1949 a team of scientists at ] including ] published their identification of the chemical structure and their synthesis.<ref name=Pong1979/>{{rp|26}}<ref>{{cite journal| vauthors = Mildred C, Crooks HM, John C, Quentin RB |title=Chloramphenicol (Chloromycetin).IV.Chemical Studies|journal=Journal of the American Chemical Society|date=July 1949|volume=71|issue=7|pages=2458–2462|doi=10.1021/ja01175a065|bibcode=1949JAChS..71.2458R }}</ref><ref>{{cite journal| vauthors = Controulis J, Rebstock MC, Crooks HM |title=Chloramphenicol (Chloromycetin). V. Synthesis|journal=Journal of the American Chemical Society|date=July 1949|volume=71|issue=7|pages=2463–2468|doi=10.1021/ja01175a066|bibcode=1949JAChS..71.2463C }}</ref>


In 1972, Senator ] combined the two examples of the ] and the 1958 Los Angeles Infant Chloramphenicol experiments as initial subjects of a Senate Subcommittee investigation into dangerous medical experimentation on human subjects.<ref>{{cite news |author=<!--not stated--> |date=October 12, 1972 |title="Kennedy Says 45 Babies Died in a Test" |url=https://timesmachine.nytimes.com/timesmachine/1972/10/12/91352284.html?pageNumber=22 |work=The New York Times |location=New York |access-date=18 December 2022}}</ref>
There are three mechanisms of ] to chloramphenicol: reduced membrane permeability, mutation of the 50S ribosomal subunit and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability 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 ] codes for an ] called ] which inactivates chloramphenicol by covalently linking one or two ] groups, derived from acetyl-S-coenzyme A, to the ] groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.


In 2007, the accumulation of reports associating aplastic anemia and blood dyscrasia with chloramphenicol eye drops led to the classification of "probable human carcinogen" according to World Health Organization criteria, based on the known published case reports and the spontaneous reports submitted to the National Registry of Drug-Induced Ocular Side Effects.<ref>{{cite journal | vauthors = Fraunfelder FW, Fraunfelder FT | title = Restricting topical ocular chloramphenicol eye drop use in the United States. Did we overreact? | journal = American Journal of Ophthalmology | volume = 156 | issue = 3 | pages = 420–422 | date = September 2013 | pmid = 23953152 | doi = 10.1016/j.ajo.2013.05.004 }}</ref>
Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the ] plasmid (A=], C=chloramphenicol, Co=], T=]) which mediates multiple drug resistance in typhoid (also called ]).


==Society and culture==
==Formulations==
Chloramphenicol is available as 250&nbsp;mg capsules or as a liquid (125&nbsp;]/5&nbsp;]). In some countries, it is sold as chloramphenicol ] ] (CPE). CPE is inactive, and is ] to active chloramphenicol in the ]. There is no difference in ] between chloramphenicol and CPE.


===Names===
The ] (IV) preparation of chloramphenicol is the ] ], because pure chloramphenicol does not dissolve in water. This creates a problem: chloramphenicol succinate ester is an inactive ] 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 IV chloramphenicol are only 70% of those achieved when chloramphenicol is given orally.<ref>{{cite journal | author=Glazko AJ, Dill WA, Kinkel AW | 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 dose needs to be increased to 75&nbsp;mg/kg/day when administered IV 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 | pmid = 1398851 | doi = 10.1007/BF02759987}}</ref> The oral route is therefore preferred to the intravenous route.
Chloramphenicol is available as a generic worldwide under many brandnames<ref>{{cite web | work = Drugs.com | url = https://www.drugs.com/international/chloramphenicol.html | title = International listings for chloramphenicol | archive-url = https://web.archive.org/web/20150711033900/http://www.drugs.com/international/chloramphenicol.html | archive-date=2015-07-11 | access-date = 9 July 2015 }}</ref> and also under various generic names in eastern Europe and Russia, including chlornitromycin, levomycetin, and chloromycetin; the racemate is known as synthomycetin.<ref name=levomyc-free-sovdict>{{cite book|title=The Great Soviet Encyclopedia, 3rd Edition, 1970–1979 |publisher=The Gale Group, Inc. |edition=3rd |url=http://encyclopedia2.thefreedictionary.com/Levomycetin |access-date=10 July 2015|archive-date=11 July 2015|archive-url=https://web.archive.org/web/20150711130905/http://encyclopedia2.thefreedictionary.com/Levomycetin|url-status=live}}</ref>


===Formulations===
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.


]
===Oily===
Chloramphenicol is available as a capsule or as a liquid. In some countries, it is sold as chloramphenicol ] ] (CPE). CPE is inactive, and is ] to active chloramphenicol in the ]. No difference in ] is noted between chloramphenicol and CPE.{{citation needed|date=March 2023}}
Dose: 100&nbsp;]/] (maximum dose 3&nbsp;]) as a single intramuscular injection. The dose is repeated if there is no clinical response after 48 hours. A single injection costs approximately ]5.


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. No oral formulation of chloramphenicol is available in the U.S. for human use.<ref>{{cite web |title=Chloramphenicol |url=https://go.drugbank.com/drugs/DB00446 |website=go.drugbank.com |access-date=23 June 2023 |date=June 23, 2023}}</ref>
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 ]. Roussel stopped production of oily chloramphenicol in 1995; the ] has manufactured it since 1998, first in ] and then in ] from December 2004.{{Citation needed|date=November 2009}}


====Intravenous====
Oily chloramphenicol is recommended by the ] (WHO) as the first-line treatment of ] in low-income countries, and appears on the ]. 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 | doi=10.1016/S0399-077X(76)80134-5 }}</ref> and numerous studies since have demonstrated 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 | pmid = 538813 | doi = 10.1016/0035-9203(79)90024-5}}</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 | pmid = 6464136 | doi = 10.1016/0035-9203(84)90132-9}}</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 | pmid = 1681224 | doi = 10.1016/0140-6736(91)91511-R}}</ref> It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 for ] and US$15 for five days of ]). 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 | year=2005 | volume=366 | issue=9482 | pages=308–13 | pmid=16039333 | doi=10.1016/S0140-6736(05)66792-X }}</ref>
The ] (IV) preparation of chloramphenicol is the succinate ester. This creates a problem: Chloramphenicol succinate ester is an inactive ] and must first be hydrolysed to chloramphenicol; however, the hydrolysis process is often incomplete, and 30% of the dose is lost and removed in the urine. Serum concentrations of IV chloramphenicol are only 70% of those achieved when chloramphenicol is given orally.<ref>{{cite journal | vauthors = Glazko AJ, Dill WA, Kinkel AW | title = Absorption and excretion of parenteral doses of chloramphenicol sodium succinate in comparison with per oral doses of chloramphenicol (abstract) | journal = Clinical Pharmacological Therapy | year = 1977 | volume = 21 | pages = 104 }}</ref> For this reason, the dose needs to be increased to 75&nbsp;mg/kg/day when administered IV to achieve levels equivalent to the oral dose.<ref>{{cite journal | vauthors = Bhutta ZA, Niazi SK, Suria A | title = Chloramphenicol clearance in typhoid fever: implications for therapy | journal = Indian Journal of Pediatrics | volume = 59 | issue = 2 | pages = 213–219 | date = March–April 1992 | pmid = 1398851 | doi = 10.1007/BF02759987 | s2cid = 13369284 }}</ref>


====Oily====
Oily chloramphenicol is not currently available in the U.S. or Europe.
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 ]. Roussel stopped production of oily chloramphenicol in 1995; the ] has manufactured it since 1998, first in ] and then in ] from December 2004.<ref>{{cite journal | vauthors = Lewis RF, Dorlencourt F, Pinel J | title = Long-acting oily chloramphenicol for meningococcal meningitis | journal = Lancet | volume = 352 | issue = 9130 | pages = 823 | date = September 1998 | pmid = 9737323 | doi = 10.1016/S0140-6736(05)60723-4 | s2cid = 42224633 | doi-access = free }}</ref>


Oily chloramphenicol was first used to treat meningitis in 1975<ref>{{cite journal | vauthors = 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 | language = fr | year = 1976 | volume = 6 | pages = 120–124 | doi = 10.1016/S0399-077X(76)80134-5 | issue = 4 }}</ref> and numerous studies since have demonstrated its efficacy.<ref>{{cite journal | vauthors = Wali SS, Macfarlane JT, Weir WR, Cleland PG, Ball PA, Hassan-King M, Whittle HC, Greenwood BM | title = Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 73 | issue = 6 | pages = 698–702 | year = 1979 | pmid = 538813 | doi = 10.1016/0035-9203(79)90024-5 }}</ref><ref>{{cite journal | vauthors = Puddicombe JB, Wali SS, Greenwood BM | title = A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 78 | issue = 3 | pages = 399–403 | year = 1984 | pmid = 6464136 | doi = 10.1016/0035-9203(84)90132-9 }}</ref><ref>{{cite journal | vauthors = 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 = 862–866 | date = October 1991 | pmid = 1681224 | doi = 10.1016/0140-6736(91)91511-R | hdl-access = free | s2cid = 31211632 | hdl = 10144/19393 }}</ref> It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 for ] and US$15 for five days of ]). 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 | vauthors = Nathan N, Borel T, Djibo A, Evans D, Djibo S, Corty JF, Guillerm M, Alberti KP, Pinoges L, Guerin PJ, Legros D | title = Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study | journal = Lancet | volume = 366 | issue = 9482 | pages = 308–313 | year = 2005 | pmid = 16039333 | doi = 10.1016/S0140-6736(05)66792-X | url = https://fieldresearch.msf.org/bitstream/10144/23232/1/187_Ceftriaxone_as_effective_as_long-acting_-_Lancet_9482_2005.pdf | access-date = 2019-09-24 | url-status = live | hdl-access = free | s2cid = 20885088 | archive-date = 2021-08-28 | archive-url = https://web.archive.org/web/20210828032549/https://fieldresearch.msf.org/bitstream/handle/10144/23232/187_Ceftriaxone_as_effective_as_long-acting_-_Lancet_9482_2005.pdf;jsessionid=4FA77D2A307B91A4436B8801D471FF05?sequence=1 | hdl = 10144/23232 }}</ref>
===Eye drops===
In ], chloramphenicol is still widely used in topical preparations (]s and ]s) for the treatment of bacterial ]. Isolated case reports of ] following use of 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 | pmid=9522792 |url=http://bmj.bmjjournals.com/cgi/content/full/316/7132/667 | issue=7132 | pmc=28473}}</ref> Note http://www.patient.co.uk/showdoc/40025037/ suggests the link between chloramphenicol eye drops and aplastic anemia is "not well founded". In ], this is the treatment used prophylactically in newborns.


===Trade names=== ====Eye drops====
Chloramphenicol is used in topical preparations (]s and ]s) for the treatment of bacterial conjunctivitis. Isolated case reports of ] following use of chloramphenicol eyedrops exist, but the risk is estimated to be of the order of less than one in 224,716 prescriptions.<ref name="Lancaster1998">{{cite journal | vauthors = Lancaster T, Swart AM, Jick H | title = Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database | journal = BMJ | volume = 316 | issue = 7132 | pages = 667 | date = February 1998 | pmid = 9522792 | pmc = 28473 | doi = 10.1136/bmj.316.7132.667 }}</ref> In Mexico, this is the treatment used ] in newborns for ].<ref>{{cite journal | vauthors = Kaštelan S, Anić Jurica S, Orešković S, Župić T, Herman M, Gverović Antunica A, Marković I, Bakija I | title = A Survey of Current Prophylactic Treatment for Ophthalmia Neonatorum in Croatia and a Review of International Preventive Practices | journal = Medical Science Monitor | volume = 24 | pages = 8042–8047 | date = November 2018 | pmid = 30413681 | pmc = 6240167 | doi = 10.12659/MSM.910705 | quote = According to current health policy in Mexico, preventive treatment for ophthalmia neonatorum in neonates is a medico-legal requirement and consists of the application of a single drop of ophthalmic chloramphenicol in both eyes shortly after birth }}</ref>
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)
*'''Dispersadron C''' (Greece, eye drops)
*'''Edrumycetin 250&nbsp;mg''' (Bangladesh, capsule)
*'''Fenicol'''
*'''Kemicetine''' (UK, intravenous preparation)
*'''Kloramfenikol''' (Denmark, eye drops)
*'''Laevomycetin'''
*UK as an eye treatment
**'''Brochlor''' (] Ltd)
**'''Chloromycetin Redidrops''' (Goldshield Pharmaceuticals Ltd)
**'''Golden Eye''' (Typharm Ltd)
**'''Optrex Infected Eyes'''
*'''Oftan Chlora''' (eye ointment)
*'''Optacloran''' (Bolivia, eye drops)
*'''Phenicol'''
*'''Posifenicol 1%''' (Germany, eye ointment)
*'''Medicom'''
*'''Nevimycin'''
*'''Renicol''' (India,eye drops)
*'''Silmycetin''' (Thailand, eye drops)
*'''Synthomycine''' (Israel, eye ointment and skin ointment)
*'''Tifomycine''' (France, oily chloramphenicol)
*'''Unison''' (Thailand, skin ointment)
*'''Vanmycetin''' (Hong Kong, eye drops)
*'''Vernacetin'''
*'''Veticol'''
*'''Orchadexoline''' (Orchidia pharmaceutical ind., Egypt, eye drops)
*'''Isoptophenicol''' (Egypt, eye drops)
*'''Cedoctine''' (Egypt, intravenous preparation)
*'''Chloramex''' (South Africa, eye ointment)
*'''Cloranfenicol''' (Portugal)


==History== ==Veterinary uses==
Although its use in veterinary medicine is highly restricted, chloramphenicol still has some important veterinary uses.<ref>{{cite web | date = March 2012 | vauthors = Boothe DM |title= Chloramphenicol and Congeners |url= http://www.merckmanuals.com/vet/pharmacology/antibacterial_agents/chloramphenicol_and_congeners.html|publisher=Merck & Co., Inc. | location = Rahway, NJ, USA|access-date=31 October 2014|url-status=live|archive-url=https://web.archive.org/web/20141031232305/http://www.merckmanuals.com/vet/pharmacology/antibacterial_agents/chloramphenicol_and_congeners.html|archive-date=31 October 2014}}</ref> It is currently considered the most useful treatment of chlamydial disease in ]s.<ref>{{cite journal | vauthors = Govendir M, Hanger J, Loader JJ, Kimble B, Griffith JE, Black LA, Krockenberger MB, Higgins DP | title = Plasma concentrations of chloramphenicol after subcutaneous administration to koalas (Phascolarctos cinereus) with chlamydiosis | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 35 | issue = 2 | pages = 147–154 | date = April 2012 | pmid = 21569052 | doi = 10.1111/j.1365-2885.2011.01307.x }}</ref><ref name=Griffith>{{cite journal | vauthors = Griffith JE, Higgins DP | title = Diagnosis, treatment and outcomes for koala chlamydiosis at a rehabilitation facility (1995-2005) | journal = Australian Veterinary Journal | volume = 90 | issue = 11 | pages = 457–463 | date = November 2012 | pmid = 23106328 | doi = 10.1111/j.1751-0813.2012.00963.x | doi-access = free }}</ref> The pharmacokinetics of chloramphenicol have been investigated in koalas.<ref>{{cite journal | vauthors = Black LA, McLachlan AJ, Griffith JE, Higgins DP, Gillett A, Krockenberger MB, Govendir M | title = Pharmacokinetics of chloramphenicol following administration of intravenous and subcutaneous chloramphenicol sodium succinate, and subcutaneous chloramphenicol, to koalas (Phascolarctos cinereus) | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 36 | issue = 5 | pages = 478–485 | date = October 2013 | pmid = 23157306 | doi = 10.1111/jvp.12024 }}</ref>
Chloramphenicol was originally derived from the ] '']'', isolated by ], and introduced into clinical practice in 1949, under the trade name '''Chloromycetin'''. It was the first antibiotic to be manufactured synthetically on a large scale.


==References== ==Biosynthesis==
The ] and pathway for chloroamphenicol was characterized from ''Streptomyces venezuelae'' ISP5230<ref name="u859">{{cite journal | vauthors = He J, Magarvey N, Piraee M, Vining LC | title = The gene cluster for chloramphenicol biosynthesis in Streptomyces venezuelae ISP5230 includes novel shikimate pathway homologues and a monomodular non-ribosomal peptide synthetase gene | journal = Microbiology | volume = 147 | issue = Pt 10 | pages = 2817–2829 | date = October 2001 | pmid = 11577160 | doi = 10.1099/00221287-147-10-2817 | doi-access = free }}</ref><ref name="g487">{{cite journal | vauthors = Piraee M, White RL, Vining LC | title = Biosynthesis of the dichloroacetyl component of chloramphenicol in Streptomyces venezuelae ISP5230: genes required for halogenation | journal = Microbiology | volume = 150 | issue = Pt 1 | pages = 85–94 | date = January 2004 | pmid = 14702400 | doi = 10.1099/mic.0.26319-0 | doi-access = free }}</ref> a.k.a. ATCC 17102.<ref name="s548">{{cite book | vauthors = Vining L, Stuttard C | title=Genetics and Biochemistry of Antibiotic Production | publisher=Butterworth-Heinemann | publication-place=Boston | date=1995 | isbn=978-0-7506-9095-9 | page=}}</ref> Currently the chloramphenicol biosynthetic gene cluster has 17 genes with assigned roles.<ref name="b214">{{cite journal | vauthors = Fernández-Martínez LT, Borsetto C, Gomez-Escribano JP, Bibb MJ, Al-Bassam MM, Chandra G, Bibb MJ | title = New insights into chloramphenicol biosynthesis in Streptomyces venezuelae ATCC 10712 | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 12 | pages = 7441–7450 | date = December 2014 | pmid = 25267678 | pmc = 4249514 | doi = 10.1128/AAC.04272-14 }}</ref>
{{reflist|2}}
{{cite journal |author=Jardetzky O |title=Studies on the Mechanism of Action of Chloramphenicol |journal=J. Biol. Chem. |volume=238 |issue=7 |pages=2498–508 |year=1963}}


==External links== == References ==
{{reflist}}
* {{MedlinePlusDrugInfo|uspdi|202125}}
*


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Chloramphenicol: Difference between revisions Add topic