Chloramphenicol
Clinical data | |
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Trade names | Chloromycetin, Abeed, others[1] |
Other names | C/CHL/CL[2] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608008 |
License data | |
Pregnancy category |
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QJ51BA01 (WHO) | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 75–90% |
Protein binding | 60% |
Metabolism | Liver |
Elimination half-life | 1.6–3.3 hours |
Excretion | Kidney (5–15%), faeces (4%) |
Identifiers | |
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Chloramphenicol is an
Common side effects include
Chloramphenicol was discovered after being isolated from Streptomyces venezuelae in 1947.[8] Its chemical structure was identified and it was first synthesized in 1949. It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[5]
Medical uses
The original indication of chloramphenicol was in the treatment of
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.[10]
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.[11]
In the context of preventing endophthalmitis, a complication of cataract surgery, a 2017 systematic review found moderate evidence that using chloramphenicol eye drops in addition to an antibiotic injection (cefuroxime or penicillin) will likely lower the risk of endophthalmitis, compared to eye drops or antibiotic injections alone.[12]
Spectrum
Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections such as conjunctivitis, blepharitis etc. caused by a number of bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. It is not effective against Pseudomonas aeruginosa. The following susceptibility data represent the minimum inhibitory concentration for a few medically significant organisms.[13]
- Escherichia coli: 0.015 – 10,000 μg/mL
- Staphylococcus aureus: 0.06 – 128 μg/mL
- Streptococcus pneumoniae: 2 – 16 μg/mL
Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains of
Resistance
Three mechanisms of
Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the
As of 2014 some Enterococcus faecium and Pseudomonas aeruginosa strains are resistant to chloramphenicol. Some Veillonella spp. and Staphylococcus capitis strains have also developed resistance to chloramphenicol to varying degrees.[16]
Adverse effects
Aplastic anemia
The most serious
Bone marrow suppression
Chloramphenicol may cause
Leukemia
Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhood leukemia is increased, as demonstrated in a Chinese case–control study,[22] and the risk increases with length of treatment.
Gray baby syndrome
Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.[23] 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.[24] This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.[25][26][27]
Hypersensitivity reactions
Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer's reactions have occurred during therapy for typhoid fever.[28]
Neurotoxic reactions
Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn.[28]
Pharmacokinetics
Chloramphenicol is extremely lipid-soluble; it remains relatively unbound to protein and is a small molecule. It has a large apparent volume of distribution 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.[28] The concentration achieved in brain and cerebrospinal fluid 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]
Chloramphenicol increases the absorption of iron.[29]
Use in special populations
Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (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 (an intravenous prodrug 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.[30] Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.[31]
Dose monitoring
Plasma 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 kidney failure. 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 µg/ml with toxicity > 40 µg/ml; trough levels (taken immediately before a dose) should be 5–10 µg/ml.[32][33]
Drug interactions
Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.[34]
Chloramphenicol is a potent inhibitor of the
Drug antagonistic
Chloramphenicol is antagonistic with most cephalosporins and using both together should be avoided in the treatment of infections.[37]
Drug synergism
Chloramphenicol has been demonstrated a synergistic effect when combined with fosfomycin against clinical isolates of Enterococcus faecium.[38]
Mechanism of action
Chloramphenicol is a
History
Chloramphenicol was first isolated from Streptomyces venezuelae in 1947 and in 1949 a team of scientists at Parke-Davis including Mildred Rebstock published their identification of the chemical structure and their synthesis.[8]: 26 [44][45]
In 1972, Senator Ted Kennedy combined the two examples of the Tuskegee Syphilis Study and the 1958 Los Angeles Infant Chloramphenicol experiments as initial subjects of a Senate Subcommittee investigation into dangerous medical experimentation on human subjects.[46]
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.[47]
Society and culture
Names
Chloramphenicol is available as a generic worldwide under many brandnames[48] and also under various generic names in eastern Europe and Russia, including chlornitromycin, levomycetin, and chloromycetin; the racemate is known as synthomycetin.[49]
Formulations
Chloramphenicol is available as a capsule or as a liquid. In some countries, it is sold as chloramphenicol
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.[50]
In molecular biology, chloramphenicol is prepared in ethanol.[citation needed]
Intravenous
The
Oily
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
Oily chloramphenicol was first used to treat meningitis in 1975[54] and numerous studies since have demonstrated its efficacy.[55][56][57] 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.[58]
Eye drops
Chloramphenicol is used in topical preparations (
Veterinary uses
Although its use in veterinary medicine is highly restricted, chloramphenicol still has some important veterinary uses.[60] It is currently considered the most useful treatment of chlamydial disease in koalas.[61][62] The pharmacokinetics of chloramphenicol have been investigated in koalas.[63]
References
- ISBN 9781428361065. Archivedfrom the original on 2016-03-05.
- ^ "Antibiotic abbreviations list". Retrieved 22 June 2023.
- FDA. Retrieved 22 Oct 2023.
- ^ "Chloramphenicol". PubChem. Archived from the original on 2016-11-15.
- ^ a b c d e f g h i j k "Chloramphenicol". The American Society of Health-System Pharmacists. Archived from the original on 2015-06-24. Retrieved Aug 1, 2015.
- ISBN 978-0750687782. Archivedfrom the original on 2017-03-07.
- ^ "Chloramphenicol Pregnancy and Breastfeeding Warnings". Multum Information Services. Archived from the original on 8 September 2015. Retrieved 26 August 2015.
- ^ ISBN 978-3-642-46403-4.
- hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ "WHO meningitis epidemic guidelines Africa". Archived from the original on 5 March 2016. Retrieved 29 February 2016.
- from the original on 2022-03-03. Retrieved 2021-07-02.
- PMID 28192644.
- ^ "Chloramphenicol (Chloromycetin) | the Antimicrobial Index Knowledgebase - TOKU-E". Archived from the original on 2014-04-23. Retrieved 2014-04-21.
- PMID 24361397.
- PMID 24236055.
- ^ "Chloramphenicol spectrum of bacterial susceptibility and Resistance" (PDF). Product Data Safety Sheet. TOKU-E. December 2010. Archived from the original (PDF) on 11 February 2014. Retrieved 15 May 2012.
- PMID 9590397.
- PMID 5818983.
- ^ PMID 9522792.
- PMID 2486534.
- S2CID 40234293.
- S2CID 3217082.
- S2CID 29906856.
- (PDF) from the original on 2021-08-28. Retrieved 2012-01-09.
- PMID 3529436.
- PMID 6416440.
- PMID 4000136.
- ^ a b c d "Drug Insert from DailyMed". Archived from the original on 19 April 2014. Retrieved 18 April 2014.
- ISBN 978-0-553-58892-7.
- S2CID 8701518.
- ^ "Drugs and Other Substances in Breast Milk". kidsgrowth.org. Archived from the original on 23 June 2007. Retrieved 19 June 2009.
- PMID 9590397.
- ^ "Chloramphenicol (Lexi-Drugs)". Lexi-Comp Online. Archived from the original on 26 July 2013. Retrieved 18 April 2014.
- ^ "Practice Guidance: OTC Chloramphenicol Eye Drops" (PDF). Royal Pharmaceutical Society of Great Britain (RPSGB). June 2005. Archived from the original (PDF) on 2005-10-22.
- PMID 14576103.
- ^ "Fakta för förskrivare" [Facts for prescribers] (in Swedish). FASS – Swedish National Drug Formulary. Archived from the original on 2002-06-11.
- PMID 3195999.
- S2CID 225174927.
- PMID 23650345.
- ^ "Chloramphenicol". The Merck Manual. Rahway, NJ, USA: Merck & Co., Inc. Archived from the original on 2010-03-10.
- (PDF) from the original on 2015-12-11.
- PMID 14289020.
- PMID 14353832.
- .
- .
- ^ ""Kennedy Says 45 Babies Died in a Test"". The New York Times. New York. October 12, 1972. Retrieved 18 December 2022.
- PMID 23953152.
- ^ "International listings for chloramphenicol". Drugs.com. Archived from the original on 2015-07-11. Retrieved 9 July 2015.
- ^ The Great Soviet Encyclopedia, 3rd Edition, 1970–1979 (3rd ed.). The Gale Group, Inc. Archived from the original on 11 July 2015. Retrieved 10 July 2015.
- ^ "Chloramphenicol". go.drugbank.com. June 23, 2023. Retrieved 23 June 2023.
- ^ Glazko AJ, Dill WA, Kinkel AW (1977). "Absorption and excretion of parenteral doses of chloramphenicol sodium succinate in comparison with per oral doses of chloramphenicol (abstract)". Clinical Pharmacological Therapy. 21: 104.
- S2CID 13369284.
- S2CID 42224633.
- .
- PMID 538813.
- PMID 6464136.
- S2CID 31211632.
- from the original on 2021-08-28. Retrieved 2019-09-24.
- PMID 30413681.
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
- ^ Boothe DM (March 2012). "Chloramphenicol and Congeners". Rahway, NJ, USA: Merck & Co., Inc. Archived from the original on 31 October 2014. Retrieved 31 October 2014.
- PMID 21569052.
- PMID 23106328.
- PMID 23157306.