Chloramphenicol

Chloramphenicol

Systematic (IUPAC) name
2,2-dichloro-N-[1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a608008
Pregnancy cat.	C (systemic), A (topical)
Legal status	Ocular P, else POM (UK)
Routes	Topical (ocular), oral, IV, IM
Pharmacokinetic data
Bioavailability	75–90%
Metabolism	Hepatic
Half-life	1.5–4.0 hours
Excretion	Renal
Identifiers
CAS number	56-75-7 Y
ATC code	D06AX02 D10AF03 G01AA05 J01BA01 S01AA01 S02AA01 S03AA08 QJ51BA01
PubChem	CID 298
DrugBank	DB00446
ChemSpider	5744 Y
UNII	66974FR9Q1 Y
KEGG	D00104 Y
ChEBI	CHEBI:17698 Y
ChEMBL	CHEMBL130 Y
Chemical data
Formula	C11H12Cl2N2O5
Mol. mass	323.1320 g/mol
SMILES	eMolecules & PubChem
InChI InChI=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 Y Key:WIIZWVCIJKGZOK-RKDXNWHRSA-N Y
Y(what is this?)  (verify)

Chloramphenicol (INN) is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world^{[citation needed]}.

Chloramphenicol is effective against a wide variety of Gram-positive and Gram-negative bacteria, including most anaerobic organisms. Due to resistance and safety concerns, it is no longer a first-line agent for any indication in developed nations, although it is sometimes used topically for eye infections. Nevertheless, the global problem of advancing bacterial resistance to newer drugs has led to renewed interest in its use.^[1] In low-income countries, chloramphenicol is still widely used because it is inexpensive and readily available.

The most serious adverse effect associated with chloramphenicol treatment is bone marrow toxicity, which may occur in two distinct forms: bone marrow suppression, which is a direct toxic effect of the drug and is usually reversible, and aplastic anemia, which is idiosyncratic (rare, unpredictable, and unrelated to dose) and in general fatal.^[2]

Spectrum of activity

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 MRSA), Gram-negative bacteria and anaerobes.^[3] It is not active against Pseudomonas aeruginosa, Chlamydiae, 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.

Therapeutic uses

The original indication of chloramphenicol was in the treatment of typhoid, but the now almost universal presence of multiple drug-resistant Salmonella typhi 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 tetracycline-resistant cholera.

Because of its excellent BBB penetration (far superior to any of the cephalosporins), chloramphenicol remains the first choice treatment for staphylococcal brain abscesses. 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 GPs 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 its being considered for treatment of vancomycin-resistant enterococcus.

Although unpublished, recent research suggests chloramphenicol could also be applied to frogs to prevent their widespread destruction from fungal infections.^[4] Chloramphenicol has recently been discovered to be a life-saving cure for chytridiomycosis in amphibians.^[5] Chytridiomycosis is a fungal disease, blamed for the extinction of one-third of the 120 frog species lost since 1980.

Adverse effects

Aplastic anemia

The most serious side effect of chloramphenicol treatment is aplastic anaemia.^[2] 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.^[6] It is not known whether monitoring the blood counts 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^[7] (affecting 1 in 24,000–40,000)^[8] and the lowest risk occurs with eye drops (affecting less than 1 in 224,716 prescriptions).^[9]

Thiamphenicol, 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]}. Thiamphenicol is available in the U.S. and Europe as a veterinary antibiotic, and is not approved for use in humans.

Bone marrow suppression

Chloramphenicol commomly causes 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 hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been given. The anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia.

Leukemia

There is an increased risk of childhood leukemia, as demonstrated in a Chinese case-controlled study,^[10] 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 tinnitus and balance problems through inner ear damage. It also causes folic acid 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 pregnenolone. 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

Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.^[11] 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.^[12] 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.^[13][14][15]

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 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 iron.^[16]

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. There is no standard dose reduction 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]}

Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.^[17]

Dose monitoring

Plasma 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. Peak levels (one hour after the dose is given) should be 15–25 mg/l; trough levels (taken immediately before a dose) should be less than 15 mg/l.^{[citation needed]}

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.^[18]

Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver.^[19] Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics and proton pump inhibitors if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic antidepressants, macrolide antibiotics, SSRIs, statins and PDE5 inhibitors.^[20]

Mechanism of action

Chloramphenicol is bacteriostatic (that is, it stops bacterial growth). It is a protein synthesis inhibitor (more specifically inhibiting protein chain elongation), causing inhibition of peptidyl transferase activity of the bacterial ribosome, binding to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit, preventing peptide bond formation.^[21] While chloramphenicol and the macrolide 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. ^{[22] [23] [24]}

Resistance

There are three mechanisms of 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 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 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 multiple-drug resistance in typhoid (also called R factors).

Formulations

Chloramphenicol is available as 250 mg capsules or as a liquid (125 mg/5 ml). In some countries, it is sold as chloramphenicol palmitate ester (CPE). CPE is inactive, and is hydrolysed to active chloramphenicol in the small intestine. There is no difference in bioavailability between chloramphenicol and CPE.

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.

In molecular biology, chloramphenicol is prepared as 25-50 mg/ml stock in ethanol.

Intravenous

The 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; 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.^[25] For this reason, the dose needs to be increased to 75 mg/kg/day when administered IV to achieve levels equivalent to the oral dose.^[26]

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 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.^[27]

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 essential drugs list. It was first used to treat meningitis in 1975^[28] and numerous studies since have demonstrated its efficacy.^[29][30][31] 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.^[32]

Eye drops

In the West, chloramphenicol is still widely used in topical preparations (ointments and eye drops) for the treatment of bacterial conjunctivitis. Isolated case reports of aplastic anaemia following use of chloramphenicol eyedrops exist, but the risk is estimated to be less than 1 in 224,716 prescriptions.^[9] In Mexico, this is the treatment used prophylactically in newborns.

Trade names

Chloramphenicol has a long history and therefore a multitude of trade 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 mg (Bangladesh, capsule)
• Fenicol
• Kemicetine (UK, intravenous preparation)
• Kloramfenikol (Denmark, eye drops)
• Laevomycetin
• UK as an eye treatment
  • Brochlor (Aventis Pharma 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

Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae, isolated by David Gottlieb, 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.

In popular culture

Author/editor Eric Flint chose the drug in his 1632 series as one which could be produced by seventeenth century technology and prevent disease deaths during the alternate history's modified Thirty Years War.^[33]

References

1. ^ Falagas ME, Grammatikos AP, Michalopoulos A (October 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Rev Anti Infect Ther 6 (5): 593–600. doi:10.1586/14787210.6.5.593. PMID 18847400. 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. 
2. ^ ^{a b} Rich M, Ritterhoff R, Hoffmann R (December 1950). "A fatal case of aplastic anemia following chloramphenicol (chloromycetin) therapy.". Ann Intern Med 33 (6): 1459–67. PMID 14790529. 
3. ^ Neu HC, Gootz TD (1996). "Antimicrobial Chemotherapy:Antimicrobial Inhibitors of Ribosome Function". In Baron S,et al.. Baron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.688. 
4. ^ Kim Griggs (2007-10-30). "Frog killer fungus 'breakthrough'". BBC News. http://news.bbc.co.uk/2/hi/science/nature/7067613.stm. 
5. ^ Chloramphenicol cures chytridiomycosis R. T. M. Poulter, J. N. Busby, P. J. Bishop, M. I. Butler, R. Speare, BBC News
6. ^ Nagao T, Mauer A (Jul 3 1969). "Concordance for drug-induced aplastic anemia in identical twins.". N Engl J Med 281 (1): 7–11. doi:10.1056/NEJM196907032810102. PMID 5785754. 
7. ^ Holt R (1967). "The bacterial degradation of chloramphenicol". Lancet i (7502): 1259–60. doi:10.1016/S0140-6736(67)92720-1. PMID 4165044. 
8. ^ Wallerstein R, Condit P, Kasper C, Brown J, Morrison F (Jun 16 1969). "Statewide study of chloramphenicol therapy and fatal aplastic anemia". JAMA 208 (11): 2045–50. doi:10.1001/jama.208.11.2045. PMID 5818983. 
9. ^ ^{a b} Lancaster T, Stewart AM, Jick H (1998). "Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database". Brit Med J 316 (7132): 667. PMC 28473. PMID 9522792. http://bmj.bmjjournals.com/cgi/content/full/316/7132/667. 
10. ^ Shu X, Gao Y, Linet M, Brinton L, Gao R, Jin F, Fraumeni J (Oct 24 1987). "Chloramphenicol use and childhood leukaemia in Shanghai". Lancet 2 (8565): 934–7. doi:10.1016/S0140-6736(87)91420-6. PMID 2889862. 
11. ^ McIntyre J, Choonara I (2004). "Drug toxicity in the neonate". Biol Neonate 86 (4): 218–21. doi:10.1159/000079656. PMID 15249753. 
12. ^ Piñeiro-Carrero V, Piñeiro E (2004). "Liver". Pediatrics 113 (4 Suppl): 1097–106. PMID 15060205. 
13. ^ Feder H (1986). "Chloramphenicol: what we have learned in the last decade". South Med J 79 (9): 1129–34. doi:10.1097/00007611-198609000-00022. PMID 3529436. 
14. ^ Mulhall A, de Louvois J, Hurley R (1983). "Chloramphenicol toxicity in neonates: its incidence and prevention" (Scanned copy & PDF). Br Med J (Clin Res Ed) 287 (6403): 1424–7. doi:10.1136/bmj.287.6403.1424. PMC 1549666. PMID 6416440. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1549666. 
15. ^ Forster J, Hufschmidt C, Niederhoff H, Künzer W (1985). "[Need for the determination of chloramphenicol levels in the treatment of bacterial-purulent meningitis with chloramphenicol succinate in infants and small children]". Monatsschr Kinderheilkd 133 (4): 209–13. PMID 4000136. 
16. ^ Harold M. Silverman, Pharm.D. (editor-in-chief), ed (2006). "Iron Supplements". Pill Book, The (12th revised ed.). New York: Bantam Dell. pp. 593–596. ISBN 978-0-553-58892-7. 
17. ^ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Retrieved on June 19, 2009
18. ^ PRACTICE GUIDANCE: OTC CHLORAMPHENICOL EYE DROPS June 2005. Royal Pharmaceutical Society of Great Britain (RPSGB)
19. ^ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes". Antimicrob. Agents Chemother. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=253795. 
20. ^ Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
21. ^ http://merck.com/mmpe/sec14/ch170/ch170d.html
22. ^ Studies on the Mechanism of Action of Chloramphenicol July 1963. The Journal of Biological Chemistry)
23. ^ MODE OF ACTION OF CHLORAMPHENICOL. IX. EFFECTS OF CHLORAMPHENICOL UPON A RIBOSOMAL AMINO ACID POLYMERIZATION SYSTEM AND ITS BINDING TO BACTERIAL RIBOSOME. January 11, 1965. Biochim Biophys Acta)
24. ^ MODE OF ACTION OF CHLORAMPHENICOL. III. Action of Chloramphenicol on Bacterial Energy Metabolism February 1955. Journal of Bacteriology)
25. ^ 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)". Clin Pharmacol Ther 21: 104. 
26. ^ Bhutta Z, Niazi S, Suria A (Mar-Apr 1992). "Chloramphenicol clearance in typhoid fever: implications for therapy". Indian J Pediatr 59 (2): 213–9. doi:10.1007/BF02759987. PMID 1398851. 
27. ^ Lewis RF, Dorlencourt F, Pinel J (1998). "Long-acting oily chloramphenicol for meningococcal meningitis". Lancet 352 (9130): 823. doi:10.1016/S0140-6736(05)60723-4. 
28. ^ Rey M, Ouedraogo L, Saliou P, Perino L (1976). "Traitement minute de la méningite cérébrospinale épidémique par injection intramusculaire unique de chloramphénicol (suspension huileuse)". Médecine et Maladies Infectieuses 6 (4): 120–24. doi:10.1016/S0399-077X(76)80134-5. 
29. ^ Wali S, Macfarlane J, Weir W, Cleland P, Ball P, Hassan-King M, Whittle H, Greenwood B (1979). "Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol". Trans R Soc Trop Med Hyg 73 (6): 698–702. doi:10.1016/0035-9203(79)90024-5. PMID 538813. 
30. ^ Puddicombe J, Wali S, Greenwood B (1984). "A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis". Trans R Soc Trop Med Hyg 78 (3): 399–403. doi:10.1016/0035-9203(84)90132-9. PMID 6464136. 
31. ^ Pécoul B, Varaine F, Keita M, Soga G, Djibo A, Soula G, Abdou A, Etienne J, Rey M (Oct 5 1991). "Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis". Lancet 338 (8771): 862–6. doi:10.1016/0140-6736(91)91511-R. PMID 1681224. 
32. ^ Nathan N, Borel T, Djibo A (2005). "Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study". Lancet 366 (9482): 308–13. doi:10.1016/S0140-6736(05)66792-X. PMID 16039333. 
33. ^ Flint, Eric, Grantville Gazette Vol-1, (November 2004), "Portraits", and other linked events and mentions in the series to date up to and including 1635: The Eastern Front (5 October 2010)—which has Gustavus Adolphus mention the affair to Stearns when making him General.

Jardetzky O (1963). "Studies on the Mechanism of Action of Chloramphenicol". J. Biol. Chem. 238 (7): 2498–508. 

External links

• MedlinePlus DrugInfo uspdi-202125
• University of Pennsylvania