chloramphenicol chloramphenicol chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. this includes use as an eye ointment to treat conjunctivitis. by mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, and typhoid fever. its use by mouth or by injection is only recommended when safer antibiotics cannot be used. monitoring both blood levels of the medication and blood cell levels every two days is recommended during treatment. chloramphenicolclinical datatrade nameschloromycetin, abeed, othersahfs/drugs.commonographmedlineplusa608008license data us dailymed: chloramphenicol us fda: chloramphenicol pregnancycategory au: a routes ofadministrationtopical (eye drops), by mouth, intravenous therapy (iv), intramuscular injection (im)atc coded06ax02 (who) d10af03 (who) g01aa05 (who) j01ba01 (who) s01aa01 (who) s02aa01 (who) s03aa08 (who) qj51ba01 (who)legal statuslegal status au: s3 (pharmacist only) ca: ℞-only uk: p (pharmacy medicines) / pom us: ℞-only pharmacokinetic databioavailability75–90%protein binding60%metabolismliverelimination half-life1.6–3.3 hoursexcretionkidney (5–15%), faeces (4%)identifiers iupac name 2,2-dichloro-n-acetamide cas number56-75-7 ypubchem cid298drugbankdb00446 ychemspider5744 yunii66974fr9q1keggd00104 ychebichebi:17698 ychemblchembl130 ypdb ligandclm (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid7020265 echa infocard100.000.262 chemical and physical dataformulac11h12cl2n2o5molar mass323.13 g·mol−13d model (jsmol)interactive image smiles c1cc(ccc1((co)nc(=o)c(cl)cl)o)(=o) 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 ykey:wiizwvcijkgzok-rkdxnwhrsa-n y (verify) common side effects include bone marrow suppression, nausea, and diarrhea. the bone marrow suppression may result in death. to reduce the risk of side effects treatment duration should be as short as possible. people with liver or kidney problems may need lower doses. in young children a condition known as gray baby syndrome may occur which results in a swollen stomach and low blood pressure. its use near the end of pregnancy and during breastfeeding is typically not recommended. chloramphenicol is a broad-spectrum antibiotic that typically stops bacterial growth by stopping the production of proteins. chloramphenicol was discovered after being isolated from streptomyces venezuelae in 1947. its chemical structure was identified and it was first synthesized in 1949. it is on the world health organization's list of essential medicines. it is available as a generic medication. medical uses the original indication of chloramphenicol was in the treatment of typhoid, but the 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. 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. 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. 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. 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. 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. resistance 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). 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. adverse effects aplastic anemia the most serious side effect of chloramphenicol treatment is aplastic anaemia. 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 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. chloramphenicol should be discontinued if the complete blood count drops. the highest risk is with oral chloramphenicol (affecting 1 in 24,000–40,000) and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions). 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. thiamphenicol is available in the u.s. and europe as a veterinary antibiotic, but is not approved for use in humans. bone marrow suppression chloramphenicol may 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 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. 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, and the risk increases with length of treatment. gray baby syndrome intravenous chloramphenicol use has been associated with the so-called gray baby syndrome. 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 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. hypersensitivity reactions fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. herxheimer's reactions have occurred during therapy for typhoid fever. 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. 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. 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. chloramphenicol increases the absorption of iron. 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.chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible. 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. 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. chloramphenicol is a potent inhibitor of the cytochrome p450 isoforms cyp2c19 and cyp3a4 in the liver. 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. drug antagonistic chloramphenicol is antagonistic with most cephalosporins and using both together should be avoided in the treatment of infections. drug synergism chloramphenicol has been demonstrated a synergistic effect when combined with fosfomycin against clinical isolates of enterococcus faecium. mechanism of action chloramphenicol is a bacteriostatic agent, 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 in the 23s rrna of the 50s ribosomal subunit, preventing peptide bond formation. chloramphenicol directly interferes with substrate binding in the ribosome, as compared to macrolides, which sterically block the progression of the growing peptide. 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.: 26 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. 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. society and culture names chloramphenicol is available as a generic worldwide under many brandnames and also under various generic names in eastern europe and russia, including chlornitromycin, levomycetin, and chloromycetin; the racemate is known as synthomycetin. formulations pure chloramphenicol chloramphenicol is available as a capsule or as a liquid. 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 available in the u.s. for human use. in molecular biology, chloramphenicol is prepared in ethanol. intravenous the intravenous (iv) preparation of chloramphenicol is the succinate ester. 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