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| Trade names | Chloromycetin, Abeed, others[1] |
| Other names | C/CHL/CL[2] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608008 |
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| Routes of administration | Topical (eye drops),by mouth,intravenous,intramuscular |
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| Pharmacokinetic data | |
| Bioavailability | 75–90% |
| Protein binding | 60% |
| Metabolism | Liver |
| Eliminationhalf-life | 1.6–3.3 hours |
| Excretion | Kidney (5–15%), faeces (4%) |
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| ECHA InfoCard | 100.000.262 |
| Chemical and physical data | |
| Formula | C11H12Cl2N2O5 |
| Molar mass | 323.13 g·mol−1 |
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Chloramphenicol is anantibiotic useful for the treatment of a number ofbacterial infections.[4] This includes use as aneye ointment to treatconjunctivitis.[5] By mouth or byinjection into a vein, it is used to treatmeningitis,plague,cholera, andtyphoid fever.[4] Its use by mouth or by injection is only recommended when safer antibiotics cannot be used.[4] Monitoring both blood levels of the medication and blood cell levels every two days is recommended during treatment.[4]
Common side effects includebone marrow suppression, nausea, and diarrhea.[4] The bone marrow suppression may result in death.[4] To reduce the risk of side effects treatment duration should be as short as possible.[4] People with liver or kidney problems may need lower doses.[4] In young infants, a condition known asgray baby syndrome may occur which results in a swollen stomach andlow blood pressure.[4] Its use near the end of pregnancy and during breastfeeding is typically not recommended.[6] Chloramphenicol is abroad-spectrum antibiotic that typicallystops bacterial growth by stopping the production of proteins.[4]
Chloramphenicol was discovered after being isolated fromStreptomyces venezuelae in 1947.[7] Its chemical structure was identified and it was first synthesized in 1949. It is on theWorld Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[4]
The original indication of chloramphenicol was in the treatment oftyphoid, but the presence of multiple drug-resistantSalmonella typhi has meant it is seldom used for this indication except when the organism is known to be sensitive.[medical citation needed]
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.[9]
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 resistantE. faecium strains.[10]
In the context of preventingendophthalmitis, a complication ofcataract surgery, a 2017 systematic review found moderate evidence that using chloramphenicol eye drops in addition to an antibiotic injection (cefuroxime orpenicillin) will likely lower the risk of endophthalmitis, compared to eye drops or antibiotic injections alone.[11]
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 includingStaphylococcus aureus, Streptococcus pneumoniae, andEscherichia coli. It is not effective againstPseudomonas aeruginosa. The following susceptibility data represent theminimum inhibitory concentration for a few medically significant organisms.[12]
Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains ofE coli, for example, show spontaneous emergence of chloramphenicol resistance.[13][14]
Three mechanisms ofresistance to chloramphenicol are known: reduced membrane permeability, mutation of the50S ribosomal subunit, and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability to chloramphenicolin vitro by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High-level resistance is conferred by thecat-gene;[15] thisgene codes for anenzyme calledchloramphenicol acetyltransferase, which inactivates chloramphenicol by covalently linking one or twoacetyl groups, derived from acetyl-S-coenzyme A, to thehydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.[medical citation needed]
Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is theACCoT plasmid (A=ampicillin, C=chloramphenicol, Co=co-trimoxazole, T=tetracycline), which mediatesmultiple drug resistance in typhoid (also calledR factors).[medical citation needed]
As of 2014 someEnterococcus faecium andPseudomonas aeruginosa strains are resistant to chloramphenicol. SomeVeillonella spp. andStaphylococcus capitis strains have also developed resistance to chloramphenicol to varying degrees.[16]
Some other resistance genes beyondcat are known, such as chloramphenicol hydrolase,[17] and chloramphenicol phosphotransferase.[18]
The most seriousside effect of chloramphenicol treatment isaplastic anaemia ('AA'). 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 theblood 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.[19] Chloramphenicol should be discontinued if the complete blood count drops. The highest risk is with oral chloramphenicol (affecting 1 in 24,000–40,000)[20] and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions).[21]
Chloramphenicol may causebone marrow suppression during treatment; this is a direct toxic effect of the drug on humanmitochondria.[22] This effect manifests first as a fall inhemoglobin 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.[23]
Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhoodleukemia is increased, as demonstrated in a Chinesecase–control study,[24] and the risk increases with length of treatment.
Intravenous chloramphenicol use has been associated with the so-calledgray baby syndrome.[25]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.[26]This causes several adverse effects, includinghypotension andcyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.[27][28][29]
Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur.Herxheimer's reactions have occurred during therapy for typhoid fever.[30]
Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol.Optic and peripheralneuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn.[30] It is theorized that this is caused by chloramphenicol's effects on the metabolism ofB-Vitamins, specificallyB-12.[31]
Although rare, Chloramphenicol exposure is associated with some cases ofMDS. There is a report of a positive response toimmunosuppressive treatment.[32]
Chloramphenicol is extremely lipid-soluble; it remains relativelyunbound to protein and is a small molecule. It has a large apparentvolume 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.[30] The concentration achieved in brain andcerebrospinal 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 ofiron.[33]
Chloramphenicol is metabolized by the liver to chloramphenicolglucuronate (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 intravenousprodrug 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.[34]
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 withkidney 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.[35][36]
Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.[37]
Chloramphenicol is a potent inhibitor of thecytochrome P450isoformsCYP2C19 andCYP3A4 in the liver.[38] Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example,antidepressants,antiepileptics,proton-pump inhibitors, andanticoagulants if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example,calcium channel blockers,immunosuppressants,chemotherapeutic drugs,benzodiazepines, azoleantifungals,tricyclic antidepressants,macrolide antibiotics,SSRIs,statins,cardiac antiarrhythmics,antivirals,anticoagulants, andPDE5 inhibitors.[30][39]
Chloramphenicol is antagonistic with mostcephalosporins and using both together should be avoided in the treatment of infections.[40]
Chloramphenicol has been demonstrated a synergistic effect when combined withfosfomycin against clinical isolates ofEnterococcus faecium.[41]
Chloramphenicol is abacteriostatic agent,inhibiting protein synthesis. It preventsprotein chain elongation by inhibiting thepeptidyl transferase activity of the bacterialribosome. It specifically binds to A2451 and A2452 residues[42] in the23S rRNA of the 50S ribosomal subunit, preventingpeptide bond formation.[43] Chloramphenicol directly interferes with substrate binding in the ribosome, as compared tomacrolides, which sterically block the progression of the growing peptide.[44][45][46]
Chloramphenicol was first isolated fromStreptomyces venezuelae in 1947 and in 1949 a team of scientists atParke-Davis includingMildred Rebstock published their identification of the chemical structure and their synthesis.[7]: 26 [47][48]
In 1972, SenatorTed Kennedy combined the two examples of theTuskegee 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.[49]
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.[50]
Chloramphenicol is available as a generic worldwide under many brandnames[51] and also under various generic names in eastern Europe and Russia, including chlornitromycin, levomycetin, and chloromycetin; theracemate is known as synthomycetin.[52]
Chloramphenicol is available as a capsule or as a liquid. In some countries, it is sold as chloramphenicolpalmitateester (CPE). CPE is inactive, and ishydrolysed to active chloramphenicol in thesmall intestine. No difference inbioavailability is noted between chloramphenicol and CPE.[citation needed]
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.[53]
Theintravenous (IV) preparation of chloramphenicol is the succinate ester. This creates a problem: Chloramphenicol succinate ester is an inactiveprodrug 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.[54] 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.[55]
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 fortyphoid. Roussel stopped production of oily chloramphenicol in 1995; theInternational Dispensary Association Foundation has manufactured it since 1998, first inMalta and then inIndia from December 2004.[56]
Oily chloramphenicol was first used to treat meningitis in 1975[57] and numerous studies since have demonstrated its efficacy.[58][59][60] It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 forampicillin and US$15 for five days ofceftriaxone). 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.[61]
Chloramphenicol is used in topical preparations (ointments andeye drops) for the treatment of bacterial conjunctivitis. Isolated case reports ofaplastic anaemia following use of chloramphenicol eyedrops exist, but the risk is estimated to be of the order of less than one in 224,716 prescriptions.[21] In Mexico, this is the treatment usedprophylactically in newborns forneonatal conjunctivitis.[62]
Although its use in veterinary medicine is highly restricted, chloramphenicol still has some important veterinary uses.[63] It is currently considered the most useful treatment of chlamydial disease inkoalas.[64][65] The pharmacokinetics of chloramphenicol have been investigated in koalas.[66]
Thebiosynthetic gene cluster and pathway for chloroamphenicol was characterized fromStreptomyces venezuelae ISP5230 (ATCC 17102).[67][68][69] Currently the chloramphenicol biosynthetic gene cluster has 17 genes with assigned roles.[70]
Chloramphenicol is often used when growingE. coli cultures intended forplasmid preparation. Chloramphenicol halts protein synthesis, but allows plasmids with a relaxed origin of replication to keep replicating, thus improving yield.
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
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