'Chloramphenicol' is a
bacteriostatic antimicrobial originally derived from the
bacterium ''
Streptomyces venezuelae'', isolated by
David Gottlieb, and introduced into clinical practice in 1949.
It was the first antibiotic to be manufactured synthetically on a large scale. Chloramphenicol is effective against a wide variety of microorganisms; it is still very widely used in low income countries because it is exceedingly cheap, but has fallen out of favour in the West due to a very rare but very serious side effect:
aplastic anemia.
In the West, the main use of chloramphenicol is in
eye drops or
ointment for bacterial
conjunctivitis.
Dosage
The usual dose is 50 mg/kg/day in four divided doses: the usual dose in an adult male is therefore around 750 mg four times daily; this dose is doubled in severe illness. Half the dose is used in premature babies or neonates, because they do not metabolise the drug as effectively.
Chloramphenicol is available as 250 mg capsules or as a liquid (125 /5 ). In some countries, chloramphenicol is sold as chloramphenicol
palmitate ester. Chloramphenicol palmitate ester is inactive, and is
hydrolysed to active chloramphenicol in the
small intestine. There is no difference in
bioavailability between chloramphenicol and chloramphenicol palmitate.
The (IV) preparation of chloramphenicol is the
succinate ester, because pure chloramphenicol does not dissolve in water. This creates a problem: chloramphenicol succinate ester is an inactive
prodrug and must first be hydrolysed to chloramphenicol; the hydrolysis process is incomplete and 30% of the dose is lost unchanged in the urine, therefore serum concentrations of chloramphenicol are only 70% of those achieved when chloramphenicol is given orally.
[1] For this reason, the chloramphenicol dose needs to be increased to 75 mg/kg/day when administered IV in order to achieve levels equivalent to the oral dose.
[2] The oral route is therefore preferred to the intravenous route.
Manufacture of oral chloramphenicol in the U.S. stopped in 1991, because the vast majority of chloramphenicol-associated cases of aplastic anaemia are associated with the oral preparation. There is now no oral formulation of chloramphenicol available in the U.S., although there is no theoretical reason why the intravenous preparation should not be equally effective (or perhaps even more effective) when taken by mouth.
Dose monitoring
Plasma levels of chloramphenicol must be monitored in neonates and in patients with abnormal liver function. It is recommended that plasma levels be monitored in all children under the age of 4, the elderly and patients with renal failure.
Peak levels (1 hour after the dose is given) should be 15–25 /; trough levels (taken immediately before a dose) should be less than 15 mg/l.
Chloramphenicol and the liver
Chloramphenicol is metabolised by the liver to chloramphenicol
glucuronate (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. There is no standard dose reduction for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations.
Chloramphenicol and the kidneys
The majority of the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged. It is suggested that plasma levels be monitored in patients with renal impairment, but this is not mandatory. Chloramphenicol succinate ester (the inactive intravenous form of the drug) is readily excreted unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason why levels of chloramphenicol in the blood are much lower when given intravenously than orally.
Oily chloramphenicol
Dose: 100 / (maximum dose 3 ) as a single intramuscular injection. The dose is repeated if there is no clinical response after 48 hours. A single injection costs approximately
US$5.
Oily chloramphenicol (or chloramphenicol oil suspension) is a long-acting preparation of chloramphenicol first introduced by Roussel in 1954; marketed as Tifomycine®, it was originally used as a treatment for
typhoid. Roussel stopped production of oily chloramphenicol in 1995; the
International Dispensary Association has manufactured it since 1998, first in
Malta and then in
India from December 2004.
Oily chloramphenicol is recommended by the
World Health Organization (WHO) as the first line treatment of
meningitis in low-income countries and appears on the
essential drugs list. It was first used to treat meningitis in 1975
[3] and there have been numerous studies since demonstrating its efficacy.
[4][5][6] 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.
[7]
Oily chloramphenicol is not currently available in the U.S. or Europe.
Chloramphenicol eye drops
In the West, chloramphenicol is still widely used in topical preparations (
ointments and
eye drops) for the treatment of bacterial
conjunctivitis. Isolated cases report of
aplastic anaemia following chloramphenicol eyedrops exist, but the risk is estimated to be less than 1 in 224,716 prescriptions.
[8]
Pharmacology
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.
Uses
Because it functions by inhibiting bacterial
protein synthesis, chloramphenicol has a very broad spectrum of activity: it is active against
Gram-positive bacteria (including most strains of
MRSA),
Gram-negative bacteria and
anaerobes.
[ Antimicrobial Chemotherapy:Antimicrobial Inhibitors of Ribosome Function.. ''In:'' Baron's Medical Microbiology ''(Baron S ''et al'', eds.), Neu HC, Gootz TD, , , Univ of Texas Medical Branch, 1996, (via NCBI Bookshelf) ISBN 0-9631172-1-1 ] It is not active against ''
Pseudomonas aeruginosa'' or ''
Enterobacter'' species. It has some activity against ''
Burkholderia pseudomallei'', but is no longer routinely used to treat infections caused by this organism (it has been superseded by
ceftazidime and
meropenem). In the West, chloramphenicol is mostly restricted to topical uses because of the worries about the risk of
aplastic anaemia.
The original indication of chloramphenicol was in the treatment of
typhoid, but the now almost universal presence of multi-drug resistant ''
Salmonella typhi'' has meant that it is seldom used for this indication except when the organism is known to be sensitive. Chloramphenicol may be used as a second-line agent in the treatment of
tetracycline-resistant
cholera.
Because of its excellent
CSF 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 it being considered for treatment of
vancomycin-resistant enterococci.
Adverse effects
Aplastic anemia
The most serious
side effect of chloramphenicol treatment is
aplastic anaemia.
[9] This effect is rare and is generally fatal: there is no treatment and there is no way of predicting who may or may not get this side effect. The effect usually occurs weeks or months after chloramphenicol treatment has been stopped and there may be a genetic predisposition.
[10] It is not known whether monitoring the
blood counts of patients can prevent the development of aplastic anaemia, but it is recommended that patients have a blood count checked twice weekly while on treatment. The highest risk is with oral chloramphenicol
[11] (affecting 1 in 24,000–40,000)
[12] and the lowest risk occurs with eye drops (affecting less than 1 in 224,716 prescriptions).
is a related compound with a similar spectrum of activity that is available in Italy and China for human use, and has never been associated with aplastic anaemia. Thiamphenicol is available in the U.S. and Europe as a
veterinary antibiotic, and is not approved for use in humans.
Bone marrow suppression
It is common for chloramphenicol to cause
bone marrow suppression during treatment: this is a direct toxic effect of the drug on human
mitochondria. This effect manifests first as a fall in
haemoglobin levels and occurs quite predictably once a cumulative dose of 20 g has been given. This effect is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia.
Leukaemia
There is an increased risk of childhood
leukaemia as demonstrated in a Chinese
case-controlled study,
[13] and the risk increases with length of treatment.
Gray baby syndrome
Intravenous chloramphenicol use has been associated with the so called
gray baby syndrome.
[ Drug toxicity in the neonate., McIntyre J, Choonara I, , , Biol Neonate, 2004 ]
This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes, and so chloramphenicol remains unmetabolized in the body.
[ Liver., Piñeiro-Carrero V, Piñeiro E, , , Pediatrics, 2004 ]
This causes several adverse effects, including
hypotension and
cyanosis. The condition can be prevented by using chloramphenicol at the recommended doses and monitoring blood levels.
[14][15][16]
Mechanism and resistance
Chloramphenicol is
bacteriostatic (that is, it stops bacterial growth). It functions by inhibiting
ribosomal activity and protein synthesis via prevention of the binding of amino acyl-
tRNA to the A site on the 50S subunit.
[17] While chloramphenicol and the macrolide class of antibiotics both interact with the 50S ribosomal subunit, chloramphenicol is not a macrolide. Furthermore, their mechanisms are slightly different. While chloramphenicol directly interferes with substrate binding, macrolides sterically block the progression of the growing peptide.
There are three mechanisms of
resistance to chloramphenicol: reduced membrane permeability, mutation of the 50S ribosomal subunit and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permability to chloramphenicol ''in vitro'' by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High level resistance is conferred by the ''cat''-gene; this
gene codes for an
enzyme called
chloramphenicol acetyltransferase which inactivates chloramphenicol by covalently linking one or two
acetyl groups, derived from acetyl-S-coenzyme A, to the
hydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.
Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the
ACCoT plasmid (A=
ampicillin, C=chloramphenicol, Co=
co-trimoxazole, T=
tetracycline) which mediates multi-drug resistance in typhoid (also called
R factors).
Trade names
Chloramphenicol has a long history and therefore a multitude of alternative names in many different countries:
★ Alficetyn
★ Amphicol
★ Biomicin
★ Chlornitromycin
★ Chloromycetin (U.S., intravenous preparation)
★ Chlorsig (U.S., Australia, eye drops)
★ Fenicol
★ Kemicetine (UK, intravenous preparation)
★ Laevomycetin
★ Optrex Infected Eyes (UK, eye drops)
★ Phenicol
★ Nevimycin
★ Silmycetin (Thailand, eye drops)
★ Synthomycine (Israel, eye ointment)
★ Tifomycine (France, oily chloramphenicol)
★ Vernacetin
★ Veticol
References
1. Absorption and excretion of parenteral doses of chloramphenicol sodium succinate in comparison with per oral doses of chloramphenicol (abstract), Glazko AJ, Dill WA, Kinkel AW, ''et al.'', , , Clin Pharmacol Ther, 1977
2. Chloramphenicol clearance in typhoid fever: implications for therapy., Bhutta Z, Niazi S, Suria A, , , Indian J Pediatr, 1992
3. Traitement minute de la méningite
cérébrospinale épidémique par injection intramusculaire unique de
chloramphénicol (suspension huileuse), Rey M, Ouedraogo L, Saliou P, Perino L, , , Médecine et Maladies Infectieuses, 1976
4. Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol., Wali S, Macfarlane J, Weir W, Cleland P, Ball P, Hassan-King M, Whittle H, Greenwood B, , , Trans R Soc Trop Med Hyg, 1979
5. A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis., Puddicombe J, Wali S, Greenwood B, , , Trans R Soc Trop Med Hyg, 1984
6. Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis., Pécoul B, Varaine F, Keita M, Soga G, Djibo A, Soula G, Abdou A, Etienne J, Rey M, , , Lancet, 1991
7. Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study, Nathan N, Borel T, Djibo A, ''et al.'', , , Lancet, 2005
8. Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database, Lancaster T, Stewart AM, Jick H, , , Brit Med J, 1998
9. A fatal case of aplastic anemia following chloramphenicol (chloromycetin) therapy., Rich M, Ritterhoff R, Hoffmann R, , , Ann Intern Med, 1950
10. Concordance for drug-induced aplastic anemia in identical twins., Nagao T, Mauer A, , , N Engl J Med, 1969
11. The bacterial degradation of chloramphenicol, Holt R, , , Lancet, 1967
12. Statewide study of chloramphenicol therapy and fatal aplastic anemia., Wallerstein R, Condit P, Kasper C, Brown J, Morrison F, , , JAMA, 1969
13. Chloramphenicol use and childhood leukaemia in Shanghai., Shu X, Gao Y, Linet M, Brinton L, Gao R, Jin F, Fraumeni J, , , Lancet, 1987
14. Chloramphenicol: what we have learned in the last decade., Feder H, , , South Med J, 1986
15. Chloramphenicol toxicity in neonates: its incidence and prevention., Mulhall A, de Louvois J, Hurley R, , , Br Med J (Clin Res Ed), 1983
16. [Need for the determination of chloramphenicol levels in the treatment of bacterial-purulent meningitis with chloramphenicol succinate in infants and small children], Forster J, Hufschmidt C, Niederhoff H, Künzer W, , , Monatsschr Kinderheilkd, 1985
17. Pestka, S. (1971). Inhibitors of ribosome functions. Annual Review of Microbiology 25:1580.
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