Chloramphenicol

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Chloramphenicol
Chloramphenicol-2D-skeletal.svg
Chloramphenicol-3D-vdW.png
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
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Topical (ocular), oral, IV, IM
Pharmacokinetic data
Bioavailability 75–90%
Protein binding 60%
Metabolism Hepatic
Half-life 1.6-3.3 hours
Excretion Renal (5-15%), faeces (4%)
Identifiers
CAS number 56-75-7 YesY
ATC code D06AX02 D10AF03 G01AA05 J01BA01 S01AA01 S02AA01 S03AA08 QJ51BA01
PubChem CID 298
DrugBank DB00446
ChemSpider 5744 YesY
UNII 66974FR9Q1 YesY
KEGG D00104 YesY
ChEBI CHEBI:17698 YesY
ChEMBL CHEMBL130 YesY
Chemical data
Formula C11H12Cl2N2O5 
Mol. mass 323.1320 g/mol
 YesY (what is this?)  (verify)

Chloramphenicol (INN) is an antibiotic useful for the treatment of a number of bacterial infections. It is a bacteriostatic; it 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 an antibiotic of choice in the developing world.

Chloramphenicol, also known as chlornitromycin, 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 infection in developed nations, with the notable exception of topical treatment of bacterial conjunctivitis. 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 generally fatal.[2]

Use of intravenous chloramphenicol has also been associated with gray baby syndrome, a phenomenon resulting from newborn infants' inability to metabolize chloramphenicol in the body. Other less serious reactions include fever, rashes, headache, and confusion. Prescription use is usually associated with monitoring of a patient's complete blood count. The drug should be discontinued upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or any other abnormal blood study findings attributable to chloramphenicol.[3]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[4]

Pure chloramphenicol

Medical uses[edit]

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 blood-brain barrier penetration (far superior to any of the cephalosporins), chloramphenicol remains the first-choice treatment for staphylococcal brain abscesses.[citation needed] It is also useful in the treatment of brain abscesses due to mixed organisms or when the causative organism is not known.

Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe penicillin or cephalosporin allergy and general practitioners are recommended to carry intravenous chloramphenicol in their bag. In low-income countries, the WHO recommend oily chloramphenicol as 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 and 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.[5] It has recently been discovered to be a life-saving cure for chytridiomycosis in amphibians.[6] Chytridiomycosis is a fungal disease, blamed for the extinction of one-third of the 120 frog species lost since 1980.

Spectrum of activity[edit]

Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections 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.[7]

  • 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 E. coli, for example, show spontaneous emergence of chloramphenicol resistance.[8][9]

Adverse effects[edit]

Aplastic anemia[edit]

The most serious side effect of chloramphenicol treatment is aplastic anaemia.[2] This effect is rare and is generally fatal. No treatment is available and no way exists to predict who may or may not get this side effect. The effect usually occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved.[10] 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 baseline blood count with a repeat blood count every few days while on treatment.[11] Chloramphenicol should be discontinued if the complete blood count drops below 2.5 x 10 cells/l. The highest risk is with oral chloramphenicol[12] (affecting 1 in 24,000–40,000)[13] and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions).[14]

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, but is not approved for use in humans.

Bone marrow suppression[edit]

Chloramphenicol may cause bone marrow suppression during treatment; this is a direct toxic effect of the drug on human mitochondria.[15] 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. Studies in mice have suggested existing marrow damage may compound any marrow damage resulting from the toxic effects of chloramphenicol.[16]

Leukemia[edit]

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-controlled study,[17] and the risk increases with length of treatment.

Gray baby syndrome[edit]

Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.[18] 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.[19] 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.[20][21][22]

Hypersensitivity reactions[edit]

Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer’s reactions have occurred during therapy for typhoid fever.[3]

Neurotoxic reactions[edit]

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.[3]

Pharmacokinetics[edit]

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.[3] The concentration achieved in brain and cerebrospinal fluid 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.[23]

Use in special populations[edit]

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.[citation needed]

Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.[24]

Dose monitoring[edit]

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 renal 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 mcg/ml with toxicity >40 mcg/ml; trough levels (taken immediately before a dose) should be 5-10 mcg/ml.[25][26]

Drug interactions[edit]

Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.[27]

Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver.[28] Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics, proton pump inhibitors, and anticoagulants 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, cardiac antiarrhythmics, antivirals, anticoagulants, and PDE5 inhibitors.[3][29]

Drug antagonistic[edit]

Bacteriostatic Chloramphenicol is antagonistic with bactericidal Cephalosporin and should be avoided in the treatment of infections.[30]

Mechanism of action[edit]

Chloramphenicol is a bacteriostatic by inhibiting protein synthesis. It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It specifically binds to A2451 and A2452 residues[not in citation given] in the 23S rRNA of the 50S ribosomal subunit, preventing peptide bond formation.[31] While chloramphenicol and the macrolide class of antibiotics both interact with ribosomes, chloramphenicol is not a macrolide. It directly interferes with substrate binding, whereas macrolides sterically block the progression of the growing peptide. [32] [33] [34]

Resistance[edit]

Three mechanisms of resistance to chloramphenicol are known: 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).

Currently, 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.[35]

History[edit]

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.

The topical formulation of chloramphenicol was commonly used as eye drops as first-line treatment of conjunctivitis. The first fatality from eye drops was reported in 1955.[36]

In 2007, the accumulation of reports associating aplastic anemia and blood dyscrasia with chloramphenicol eye drops lead to the classification of “probable” 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.[37]

Formulations[edit]

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. No difference in bioavailability is noted 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. No oral formulation of chloramphenicol is now available in the U.S.

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

Intravenous[edit]

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.[38] 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.[39]

Oily[edit]

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.[40]

Oily chloramphenicol is recommended by the World Health Organization 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[41] and numerous studies since have demonstrated its efficacy.[42][43][44] 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.[45]

Eye drops[edit]

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 one in 224,716 prescriptions.[14] In Mexico, this is the treatment used prophylactically in newborns.

References[edit]

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  44. ^ Pécoulm B.; Varaine, F.; Keita, M.; Soga, G.; Djibo, A.; Soula, G.; Abdou, A.; Etienne, J.; Rey, M. (October 1991). "Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis". Lancet 338 (8771): 862–866. doi:10.1016/0140-6736(91)91511-R. PMID 1681224. 
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Further reading[edit]

  • Jardetzky, O. (1963). "Studies on the Mechanism of Action of Chloramphenicol". Journal of Biological Chemistry 238 (7): 2498–2508. 

External links[edit]