Basic information Description Chemical Properties Uses Antimicrobial Spectrum Mechanism of action Pharmacokinetics Indications resistance Drug interactions Adverse reactions and precautions Methods of production Safety Related Supplier
Chloramphenicol Chemical Properties
- Melting point:148-150 °C(lit.)
- alpha 19.5 º (c=6, EtOH)
- Boiling point:644.9±55.0 °C(Predicted)
- Density 1.6682 (rough estimate)
- refractive index 20 ° (C=5, EtOH)
- Flash point:14 °C
- storage temp. 2-8°C
- solubility absolute ethanol: soluble5-20mg/mL (as a stock solution)
- form powder
- color white
- Water Solubility 2.5 g/L (25 º C)
- Merck 14,2077
- BRN 2225532
- CAS DataBase Reference56-75-7(CAS DataBase Reference)
- NIST Chemistry ReferenceChloramphenicol(56-75-7)
- EPA Substance Registry SystemChloramphenicol (56-75-7)
Chloramphenicol Usage And Synthesis
- DescriptionChloramphenicol, also known as chlornitromycin, is a broad-spectrum, bacteriostatic antibiotic derived from Streptomyces venezuelae. It is first isolated from cultures of Streptomyces venequelae in 1947 but now produced synthetically. The synthetic product is racemic, also called synthomycin. Syntomycin is a mixture of chloramphenicol L-isomer and d-isomer. Because of dextroisomer antibacterial effect, the effect of synthomycin is only half of the natural products. It has a relatively simple structure and was the first broad-spectrum antibiotic to be discovered. It is effective against several gram-positive and gram-negative bacteria and commonly used in researching protein synthesis and to select for chloramphenicol-resistant transformed cells or the bacterial CAT gene.
Chloramphenicol is a semisynthetic, broad-spectrum antibiotic derived from Streptomyces venequelae with primarily bacteriostatic activity. Chloramphenicol diffuses through the bacterial cell wall and reversibly binds to the bacterial 50S ribosomal subunit. The binding interferes with peptidyl transferase activity, thereby prevents transfer of amino acids to the growing peptide chains and blocks peptide bond formation. As a result bacterial protein synthesis is blocked and impede bacterial cell proliferation.
- Chemical PropertiesIt is white or yellowish green needle like crystals. The melting point is 150.5-151.5℃ (149.7-150.7℃). Under the high vacuum it can be sublimated, slightly soluble in water (2.5mg/ml at 25℃), slightly soluble in propylene glycol (150.8mg/ml), soluble in methanol, ethanol, butanol, ethyl acetate, acetone, insoluble in ether, benzene, petroleum ether, vegetable oil. Taste is very bitter.
- Chloramphenicol is used for the treatment caused by typhoid bacillus, dysentery bacillus, Escherichia coli, bacillus, influenza and pneumococcal infections such as brucellosis.
- Chloramphenicol is used in the treatment of infections caused by bacteria. It works by killing bacteria or preventing their growth.
- Chloramphenicol is used to treat serious infections in different parts of the body. It is sometimes given with other antibiotics. However, chloramphenicol should not be used for colds, flu, other virus infections, sore throats or other minor infections, or to prevent infections.
- Chloramphenicol should only be used for serious infections in which other medicines do not work. This medicine may cause some serious side effects, including blood problems and eye problems. Symptoms of the blood problems include pale skin, sore throat and fever, unusual bleeding or bruising, and unusual tiredness or weakness.
Chloramphenicol is available only with your doctor's prescription.
- Antimicrobial SpectrumChloramphenicol is bacteriostatic and a broad-spectrum antibiotic active against both gram-positive and gram-negative bacteria including rickettsia (cause of rocky-mountain spotted fever) and chlamydia. It is also found effective against Haemophilus influenzae causing meningitis.
- Gram-positive: Streptococcus spp., Staphylococcus spp., Enterococcus spp., Bacillus anthracis, Listeria monocytogenes.
- Gram-negative: Hemophilus influenzae, M. catarrhalis, N. meningitides, E. coli, P. mirabilis, Salmonella spp., Shigella spp., Stenotrophomonas maltophilia.
- Mechanism of actionInhibition of protein synthesis, Chloramphenicol irreversibly binds to a receptor site on the 50S subunit of the bacterial ribosome, inhibiting peptidyl transferase. This inhibition consequently results to the prevention of amino acid transfer to growing peptide chains, ultimately leading to inhibition of protein formation.
- PharmacokineticsAfter oral administration, it is rapidly and completely absorbed, can be widely distributed in body tissues and body fluids. In the cerebrospinal fluid concentration distribution were higher than other antibiotics, oral bioavailability was 75%~90%. After oral half hour of in the blood can reach the effective concentration, It can reach the peak in 2 to 3 hours. Take oral 0.5g, 1g and 2g, blood drug concentration was 4mg/L, 8~10mg/L and 16~21mg/L in 2 hours, 1~2g, 4 times a day, can make the blood to maintain long-term effective concentration of 10mg/L~5. After intravenous injection, the average is similarity with oral blood drug concentration of the same dose. After intramuscular absorption is slow and irregular, blood concentration is only oral amounts of 50%, but the maintenance time is long. The plasma protein binding rate is 50%~60%., the half-life of 2 to 3 hours, the half-life of newborns was significantly higher than that of adults, under the age of 2 is about 24 hours, 2 to 4 years is about 12 hours. This product is absorbed and widely distributed in the body each Reduce the concentrations of blood concentration in the blood to body fluids and tissues of liver and kidney was the highest, followed by the lung, spleen, heart, intestine and brain. Bile content is low, about 20%~50%, but also can enter the pleural effusion and ascites, milk, fetal circulation and ocular tissue. Through the blood brain barrier to reach the cerebrospinal fluid (CSF), in normal cerebrospinal fluid (CSF) in concentrations is up to 20%~50%, inflammation is up to 50%~100%. It is mainly in the liver metabolism, binding with glucuronic acid to inactivation, about 75%~90% of the metabolites in 24 hours urine, of which 5%~15% for the prototype drug. 1 g orally, urine concentration is 70~150mg/L. serious liver disease patients, the half-life may be extended due to hepatic metabolism and poisoning caused by accumulation.
- IndicationsThis product is fat soluble, synthetic peptide can inhibit the formation and prevent protein. Is a bacteriostatic agent, high concentration or effect highly sensitive to the bacteria to this product showed bactericidal action. This product is applicable to the general application of typhoid and paratyphoid salmonella, and other Bacteroides fragilis.
1. Chloramphenicol is the preferred treatment of typhoid and paratyphoid fever, and can be used for typhoid Salmonella infections.
2. Used for pneumococcal in patients allergic to penicillin, ampicillin B Hib meningitis or tolerance, meningococcal meningitis, sensitive to the change of gram negative bacilli meningitis.
3. Used for aerobic and anaerobic bacteria mixed infection of otogenic brain abscess.
4. Used for serious anaerobic infections, such as Bacteroides fragilis infection.
5. Used as aminoglycoside drugs in the treatment of infection caused by sensitive bacteria and other microorganisms, such as influenza bacillus, Salmonella and other gram negative bacilli to sepsis, pulmonary infection.
6. Used for the local treatment of flu from Escherichia coli, bacillus, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus and eye, ear superficial infection.
7. It is effective for Rickettsia, mycoplasma, and infection.
8. Coli and Serratia of Pseudomonas aeruginosa is infections.
9. Chloramphenicol eye drops for the treatment of infections caused by sensitive bacteria caused by the eye, such as trachoma, conjunctivitis, keratitis, blepharitis etc..
10. This medicine local ear drops can be used for treating sensitive bacteria infections caused by otitis externa, acute and chronic otitis media, the drug ear plugs can also be for inflammation of the ear canal and radical mastoidectomy postoperative oozing pus.
- resistanceDrug resistance of gram negative bacilli on chloramphenicol acetyltransferase, mostly due to drug inactivation, the enzyme is mediated by the R factor. Drug resistance of gram positive bacteria, may also be due to similar mechanisms, but not fully clear. Some strains of Pseudomonas aeruginosa and Proteus, Klebsiella, are another way to generate drug resistance, which prompted the permeability change, and chloramphenicol cannot enter the cell.
Bacterial resistance to chloramphenicol resistant strains both in vitro and in vivo, increased gradually in recent years. Escherichia coli, Salmonella and other gram negative bacilli can be due to drug resistance factor factor (R) transfer and acquire resistance. It has been proven that with R factor of Escherichia coli can produce acetyl transferase, chloramphenicol acetylation of failure; chloramphenicol resistant Staphylococcus aureus can also produce some inducible enzyme, under the participation of acetyl CoA, the acetylation of chloramphenicol.
- Drug interactionsChloramphenicol inhibits hepatic microsomal enzyme of phenytoin and tolbutamide (Jia Tangning) and chlorpropamide and dicoumarol (and possibly other drug metabolism, and the prolonged in vivo half-life, increased concentrations of serum. Poisoning aggravate that death is also reported. On the other side, phenobarbital, phenytoin, rifampin (are, 1985) can decrease the serum concentration of chloramphenicol, which was estimated to be due to the inductive effect of drugs on the liver enzymes. Therefore, at the same time, the application effect of chloramphenicol pharmacokinetics of drugs, should be paid attention to the monitoring of serum concentration of chloramphenicol.
Chloramphenicol can delay the iron, folic acid and vitamin B12 on anemia treatment response. It can interfere with the host to tetanus toxoid anamnestic response. Therefore, at the same time, the application situation chloramphenicol and active immune agents should be avoided.
Antagonistic effects of chloramphenicol on penicillin bactericidal effect, which is verified in vitro and animal experiments, but its clinical significance is not clear. This kind of combination, only in the proof of such treatment is benefit, began to be used.
- Adverse reactions and precautions1. Inhibition of bone marrow hematopoietic function: for the most serious toxicity of chloramphenicol, such as red blood cells, granulocyte and platelet reduce. There are two types: one is the reversible inhibition, manifested as neutropenia and thrombocytopenia, and anemia, related to dose and duration can be gradually recovered after drug withdrawal; Second is irreversible aplastic anemia, with dosage and duration without direct relationship, low incidence, once often occur difficult to reverse, high mortality rate and a few survivors can development for granulocytic leukemia, women, children, and liver and kidney function not entire occurrence rate is high. This is the main reason to limit the clinical application.
2. In the liver, metabolism rate of this product is very high, on the function of the liver, it has impaired the appropriate quantity (adult day not more than 1 g) or not as much as possible.
3. Chloramphenicol is only 5%~10% prototype drug discharge from the kidney, it is not appropriate for the treatment of urinary tract infection.
4. Premature infants and neonatal as much as possible.
5. I see the spirit of neurological symptoms, should be promptly discontinued.
6. During late pregnancy and lactation are not suitable for this application, because this product in vivo is conjugated with glucuronic acid and detoxification, conjugates excreted by the kidneys. And this product can be through the placenta to the fetus, fetal and neonatal, due to not perfect of enzyme system in the liver, glucuronic acid combined with the ability is poor and excretory function of the kidney is weak. Therefore, it is very easy to cause drug accumulation, the newborn gray baby syndromes. Gray cyanosis, dyspnea, vomiting, abdominal distension and circulatory failure with unique performance, high fatality rate. In addition, this product can damage the hematopoietic system, can make the pregnant women aplastic anemia, neonatal thrombocytopenia and other consequences.
- Methods of productionMethods for producing countries in the world to chloramphenicol had a lot of research, summed up: (1) p-nitroacetophenone method; (2) styrene method; (3) Cinnamyl alcohol method; (4) The nitro cinnamic alcohol method; (5) P-nitrobenzaldehyde method. China use p-nitroacetophenone method, the method is by ethylbenzene via nitration, oxidation, bromide, salt, hydrolysis, acetylation, addition, reduction, decomposition, split second chloride acetylation and chloramphenicol.
- Chemical PropertiesWhite to grey-white crystalline powder
- Chemical PropertiesChloramphenicol is a white to grayish-white or yellowish-white crystalline solid.
- Usesantibacterial, antirickettsial, inhibits protein synthesis
- UsesChloramphenicol is unusual nitroaromatic metabolite produced by Streptomyces venezuelae, first published in 1947. Chloramphenicol is a broad spectrum antibiotic with good activity against Gram negative and anaerobic bacteria. Although restricted to ocular use, antibiotic resistance to other classes has refocused attention on this class. Chloramphenicol acts by binding to the 23S sub-unit of the 50S ribosome, inhibiting protein synthesis. Chloramphenicol has been extensively studied with over 35,000 literature citations.
- UsesBroad spectrum antibiotic obtained from cultures of the soil bacterium Streptomyces venezuelae. It has a broad spectrum of activity against Gram-positive and gram-negative bacteria. Antibacterial; antirickettsial
- DefinitionChEBI: An organochlorine compound that is dichloro-substituted acetamide containing a nitrobenzene ring, an amide bond and two alcohol functions.
- brand nameChloromycetin (Parke-Davis);Acne-sol;Acnoxin;Actimac;Actinac;Alficetyn susp.;Altabactin;Ambrasynth;Amphemycin-prednisonum;Ampliomicetin;Amseclim;Angimidone;Angiters;Antibiopto;Aquapred;Armacol;Arrlicetin;Aviatrin;Balkamycin;B-cpct;Bemacol;Berlicetin;Biofeniol;Biophtas;Biotocap;Bismophenyl;Bitencyl;C. o fluo-fenicol;C. o hidrocor-clora;Cafenolo;Calmina;Campiol;Caosol;Cavumycetina;Ccombinado balsamico;Ccorticol;Cebenicol;Chemibal;Chemyzin;Chloramfenicol;Chloramol;Chloramphenicol intervetra;Chloramphenicol-pos;Chloramphycin;Chloramplast;Chloramson;Chloranfeni-mck;Chloranfeni-opipno;Chloranfeni-otico;Chloranfeni-ungena;Chloreptic;Chlorical;Chloroantibion;Chlorocortal;Chlorofair;Chloroject s;Chloromex;Chloromik;Chloromimyxin;Chloromycetin kapseals;Chloromycetin palmitate;Chloroptic p. oint.;Chlorostrep;Clorbiotina;Clorbis supp.;Cloromicetin;Cloromycetin;Cloroptic farmicetina;Clorosyntex;Colidene;Colimy-c;Cortican;Cortidermale;Cortimisin;Cortiphenicol;Cortison-quemicet;Cortivert;Cutispray no. 4;Cyphenicol;Cysticat;Davuron sedante;Dectamicina;Delta optil;Devamycetin;Dexa-biofinicol;Dorsec;Duphenicol;Econoclor;Ejificol strept;Ejificol sulfa;Elase chloromycel;Enttocetrin;Erittronicol;Erteilen;Esterofenil;Estevecicina cloranfenico;Extracicilina;Fago-praxin;Fluorobioptal;Furacol l;Furamecetil alpha magna;Furamecetil magna;Furatrimon;Furokatin;Gammaphenicol;Ginetris;Gino-dectacil;Gliscol;Globveticol;Goticas;Nova-phenicol;Novoclorocap;Oftan;Ophthaphenicol;Opthalon;Oralmisetin;Otiprin;Otopred ear drops;Pantofenicol;Parcyclin;Pedimycetin;Pentocetina;Pertaril;Pimabiciron;Pinimentac;Plastoderma;Prednomycetine;Procusulf;Protercicline;Prurivet;Pulmo vinco;Quitrase antibiotico;Ranphenicol;Ranstrepcol;Reclor;Redidropsol;Renegen;Reocetin;Reostop;Rheofin;Rivomycin sulfa;Rolintrex;Roncovita;Ronphenil;Roscomycin;Rovictor;Samaphenicol;Scanicoline;Scieramycetin;Sergo-amigdalar;Serviclofen;Sigmicilina;Sintomitsin;Snophenicol;Soludectancil;Sopamycetin;Spasmo-paraxin;Spersanicol;Strepticine;Streptoglobenicol;Streptophenicol;Subital supp.;Suismycetin;Sulfaglobenicol;Sulfamycetin;Synthomycetina;Synthophtone;Tardomyocel;Tega-cetin;Tetrachlorasone;Tetracol;Tetranfen;Tetraphenicol;Tetra-phenicol oculos;Tiframilk;Tiromycetin;Toramin;Transicetina;Transpulmycin;Tribiotic;Trophen;Troymycetin;Tusolone;Tycloran;Uro-gliscal 500;Uroletten-s;Uroplex 4;Ut forte;Uvomycin;Variolan;V-crayolan;Vetical;Vetophenicol;Viceton;Viklorin;Virogin;Vitaklorin;Vsmpozim;Wintetil;Zoppib spray blu;Gotimycetin;Ichthoseptal;Iruxolum;Isicetina;Isopto fenicol;Kavipe;Kloramfex.
- World Health Organization (WHO)Chloramphenicol, an antibiotic isolated from Streptomyces venezuelae in 1947, first became available for general clinical use in 1948. By 1950 it was evident that its use could cause serious, sometimes fatal, blood dyscrasias. However, it remains one of the most effective antibiotics for treating invasive typhoid fever and salmonellosis, some rickettsioses and serious infections caused by Haemophilus influenzae or anaerobic organisms. This is considered to justify its retention in the WHO Model List of Essential Drugs. (Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert Committee, 722, , 1985)
- Antimicrobial activityIt is active against a very wide range of organisms. Minimum inhibitory concentrations (MICs) (mg/L) for other
organisms are: Staphylococcus epidermidis, 1–8; Corynebacterium
diphtheriae, 0.5–2; Bacillus anthracis, 1–4; Clostridium perfringens,
2–8; Mycobacterium tuberculosis, 8–32; Legionella pneumophila,
0.5–1; Bordetella pertussis, 0.25–4; Brucella abortus,
1–4; Campylobacter fetus, 2–4; Pasteurella spp., 0.25–4; Serratia
marcescens, 2–8; Burkholderia pseudomallei, 4–8. Most Gramnegative
bacilli are susceptible, but Pseudomonas aeruginosa
is resistant. Leptospira spp., Treponema pallidum, chlamydiae,
mycoplasmas and rickettsiae are all susceptible, but Nocardia
spp. are resistant. It is widely active against anaerobes, including
Actinomyces israelii (MIC 1–4 mg/L), Peptostreptococcus
spp. (MIC 0.1–8 mg/L), and Fusobacterium spp. (MIC 0.5–2
mg/L), but Bacteroides fragilis is only moderately susceptible
(MIC about 8 mg/L).
It is strictly bacteristatic against almost all bacterial species, but exerts a bactericidal effect at 2–4 times the MIC against some strains of Gram-positive cocci, Haemophilus influenzae and Neisseria spp. The minimum bactericidal concentrations (MBCs) for penicillin-resistant pneumococci are often significantly higher than those for penicillin- susceptible strains, although this cannot be detected by conventional disk susceptibility testing or MIC determination. Its bacteristatic effect may inhibit the action of penicillins and other β-lactam antibiotics against Klebsiella pneumoniae and other enterobacteria in vitro, but the clinical significance of this is doubtful. The presence of ampicillin does not affect the bactericidal effect of chloramphenicol on H. influenzae.
- Acquired resistanceThe prevalence of resistant strains in many Gram-positive
and Gram-negative organisms reflects usage of the antibiotic.
Over-the-counter sales are believed to have compounded the
problem in some countries. For example, it has long been the
drug of choice for the treatment of typhoid and paratyphoid
fevers, but widespread use led to a high prevalence of resistant
Salmonella enterica serotype Typhi. Outbreaks of infection
caused by chloramphenicol-resistant S. Typhi have been
seen since the early 1970s. Use of co-trimoxazole and fluoroquinolones
in typhoid has resulted in a decline in chloramphenicol
resistance in some endemic areas. Many hospital
outbreaks caused by multiresistant strains of enterobacteria,
notably Enterobacter, Klebsiella and Serratia spp., have been
Plasmid-borne resistance was first noted in shigellae in Japan and subsequently spread widely in Central America, where it was responsible for a huge outbreak. Strains of S. Typhi resistant to many antibiotics including chloramphenicol are particularly common in the Indian subcontinent. Resistance in shigellae is also relatively common in some parts of the world.
Resistant strains of H. influenzae (some also resistant to ampicillin), Staph. aureus and Streptococcus pyogenes are also encountered. Most N. meningitidis strains remain susceptible,but high-level resistance (MIC >64 mg/L) due to the production of chloramphenicol acetyltransferase has been described; the nucleotide sequence of the resistance gene was indistinguishable from that found on a transposon in Cl. perfringens. Resistant strains of Enterococcus faecalis are relatively common, and resistance to chloramphenicol is found in some multiresistant pneumococci.
Resistance in Staph. aureus is caused by an inducible acetyltransferase; additionally, the cfr (chloramphenicol– florfenicol resistance) gene encodes a 23S rRNA methyltransferase that also confers resistance to linezolid. In Escherichia coli, the capacity to acetylate chloramphenicol (at least three enzymes are involved) is carried by R factors. Replacement of the 3-OH group, which is the target of acetylation, accounts for the activity of fluorinated analogs against strains resistant to chloramphenicol and thiamphenicol. The resistance of B. fragilis and some strains of H. influenzae is also due to elaboration of a plasmid-encoded acetylating enzyme; in others it is due to reduced permeability resulting from loss of an outer membrane protein. Some resistant bacteria reduce the nitro group or hydrolyze the amide linkage. Resistance of Ps. aeruginosa is partly enzymic and partly due to impermeability.
- HazardHas deleterious and dangerous side effects. Must conform to FDA labeling requirements. Use is closely restricted. Probable carcinogen.
- Contact allergensThis broad spectrum phenicol group antibiotic has been implicated in allergic contact dermatitis. Cross-sensitivity to thiamphenicol is possible, but not systematic.
- PharmacokineticsOral absorption: 80–90%
Cmax 500 mg oral: 10–13 mg/L after 1–2 h
Plasma half-life: 1.5–3.5 h
Volume of distribution: 0.25–2 L/kg
Plasma protein binding: c. 25–60%
The plasma concentration achieved is proportional to the dose administered. Suspensions for oral administration to children contain chloramphenicol palmitate, a tasteless and bacteriologically inert compound, which is hydrolyzed in the gut to liberate chloramphenicol. Following a dose of 25 mg/kg, peak plasma levels around 6–12 mg/L are obtained, but there is much individual variation.
Pancreatic lipase is deficient in neonates and, because of poor hydrolysis, the palmitate should be avoided. In very young infants, deficient ability to form glucuronides, and low glomerular and tubular excretion greatly prolong the plasma half-life. For parenteral use, chloramphenicol sodium succinate, which is freely soluble and undergoes hydrolysis in the tissues with the liberation of chloramphenicol, can be injected intravenously or in small volumes intramuscularly. The plasma concentrations after administration by these routes are unpredictable, and approximate to only 30–70% of those obtained after the same dose by the oral route. Protein binding is reduced in cirrhotic patients and neonates, with correspondingly elevated concentrations of free drug.
Free diffusion occurs into serous effusions. Penetration occurs into all parts of the eye, the therapeutic levels in the aqueous humor being obtained even after local application of 0.5% ophthalmic solution. Concentrations obtained in cerebrospinal fluid (CSF) in the absence of meningitis are 30–50% of those of the blood and greater in brain. It crosses the placenta into the fetal circulation and appears in breast milk.
It is largely inactivated in the liver by conjugation with glucuronic acid or by reduction to inactive arylamines; clearance of the drug in patients with impaired liver function is depressed in relation to the plasma bilirubin level. It has been suggested that genetically determined variance of hepatic glucuronyl transferase might determine the disposition and toxicity of the drug.
It is excreted in the glomerular filtrate, and in the newborn elimination may be impaired by the concomitant administration of benzylpenicillin, which is handled early in life by the same route. Inactive derivatives are eliminated partly in the glomerular filtrate and partly by active tubular secretion. Over 24 h, 75–90% of the dose appears in the urine, 5–10% in biologically active forms and the rest as metabolites, chiefly as a glucuronide conjugate. Excretion diminishes linearly with renal function and at a creatinine clearance of <20 ml/min, maximum urinary concentrations are 10–20 mg/L rather than the 150–200 mg/L found in normal subjects. Because of metabolism, blood levels of active drug are only marginally elevated in renal failure, but microbiologically inactive metabolites accumulate. The plasma half-life of the products in the anuric patient is around 100 h, and little is removed by peritoneal or hemodialysis. Dosage modification is normally unnecessary in renal failure as the metabolites are less toxic than the parent compound. About 3% of the administered dose is excreted in the bile, but only 1% appears in the feces, and this mostly in inactive forms.
Induction of liver microsomal enzymes, for example by phenobarbital (phenobarbitone) or rifampicin (rifampin), diminishes blood levels of chloramphenicol; conversely, chloramphenicol, which inhibits hepatic microsomal oxidases, potentiates the activity of dicoumarol (dicumarol), phenytoin, tolbutamide and those barbiturates that are eliminated by metabolism. It also depresses the action of cyclophosphamide, which depends for its cytotoxicity on transformation into active metabolites. It is uncertain whether this interaction may lead to a clinically significant level of inhibition of the activity of cyclophosphamide. The half-life of chloramphenicol is considerably prolonged if paracetamol (acetaminophen) is given concurrently, and co-administration of these drugs should be avoided.
- Clinical UseTyphoid fever and other severe infections due to salmonellae
Invasive infection caused by H. influenzae
Destructive lung lesions involving anaerobes
Eye infections (topical)
Reference is made to its use in cholera, plague, tularemia and bartonellosis, melioidosis, Whipple’s disease and relapsing fever. In enteric fever in adults, fluoroquinolones are associated with a lower clinical relapse rate. Treatment for other serious infections should be restricted to organisms that are resistant or much less susceptible to other antibiotics. A study in low resource countries found ampicillin plus gentamicin superior to injectable chloramphenicol for the treatment of very severe communityacquired pneumonia in children.
It has been used with varying success to treat infections caused by glycopeptide-resistant enterococci. Meningitis caused by penicillin-resistant pneumococci responds poorly, apparently due to failure to achieve bactericidal concentrations in CSF. It should never be given systemically for minor infections. Topical use in the treatment of eye infections is controversial given the unsubstantiated risk of bone marrow aplasia. A placebo-controlled study in children with infective conjunctivitis in the community found no clinical benefit in the use of chloramphenicol eye drops.
The daily dose should not normally exceed 2 g, and the duration of the course should be limited (e.g. 10 days). Although patients may show toxic manifestations after receiving very little drug, the danger is almost certainly increased by excessive or repeated dosage or by the treatment of patients with impaired hepatic or renal function, including those at the extremes of life. The wide pharmacokinetic variability of the antibiotic in neonates makes monitoring of serum concentrations advisable. Determination of full blood counts should be carried out twice weekly.
- Side effectsGlossitis, associated with overgrowth of Candida albicans,
is fairly common if the course of treatment exceeds 1 week.
Stomatitis, nausea, vomiting and diarrhea may occur,
but are uncommon. Hypersensitivity reactions are very
uncommon. Jarisch–Herxheimer-like reactions have been
described in patients treated for brucellosis, enteric fever
Bone marrow effects
Chloramphenicol exerts a dose-related but reversible depressant effect on the marrow of all those treated, resulting in vacuolization of erythroid and myeloid cells, reticulocytopenia and ferrokinetic changes indicative of decreased erythropoiesis. Evidence of bone-marrow depression is regularly seen if the plasma concentration exceeds 25 mg/L, and leukopenia and thrombocytopenia may be severe. There is no evidence that this common marrow depression is the precursor of potentially fatal aplasia, which differs in that it is fortunately rare, late in onset, usually irreversible and may follow the smallest dose. Aplasia can follow systemic, oral and even ophthalmic administration and may be potentiated by cimetidine. Liver disease, uremia and pre-existing bone marrow dysfunction may increase the risk. It is unusual for manifestations to appear during treatment, and the interval between cessation of treatment and onset of dyscrasia can be months. A few patients survive with protracted aplasia, and myeloblastic leukemia then often supervenes.
It is thought that the toxic agent is not chloramphenicol itself but an as yet unidentified metabolite. Chloramphenicol is partially metabolized to produce oxidized, reduced and conjugated products. The toxic metabolite may be a shortlived product of reduction of the nitro group, which damages DNA by helix destabilization and strand breakage.
Predisposition to aplasia may be explained by genetically determined differences in metabolism of the agent. Risk of fatal aplastic anemia has been estimated to increase 13-fold on average treatment with 4 g of chloramphenicol. Corresponding increases are 10-fold in patients treated with mepacrine (quinacrine) and 4-fold in patients treated with oxyphenbutazone.
Infants given large doses may develop exceedingly high plasma levels of the drug because of their immature conjugation and excretion mechanisms. A life-threatening disorder called the ‘gray baby’ syndrome, characterized by vomiting, refusal to suck and abdominal distention followed by circulatory collapse, may appear when the plasma concentration exceeds 20 mg/L. If concentrations reach 200 mg/L, the disorder can develop in older children or even adults.
Optic neuritis has been described in children with cystic fibrosis receiving prolonged treatment for pulmonary infection. Most improve when the drug is discontinued, but central visual acuity can be permanently impaired. There is some experimental evidence that ear drops containing 5% chloramphenicol sodium succinate can damage hearing. One study identified an increased risk of acute leukemia following childhood administration of chloramphenicol, particularly for durations exceeding 10 days.
- Safety ProfileConfirmed human carcinogen producing leukemia, aplastic anemia, and other bone marrow changes. Experimental tumorigenic data. Poison by intravenous and subcutaneous routes. Moderately toxic by ingestion and intraperitoneal routes. Human systemic effects by an unknown route: changes in plasma or blood volume, unspecified liver effects, and hemorrhaging. Experimental teratogenic and reproductive effects. Human mutation data reported. An antibiotic. When heated to decomposition it emits very toxic fumes of NOx and Cl-. See also other chloramphenicol entries.
- Potential ExposureAn antibiotic derived from streptomyces venezuelae. A potential danger to those involved in the manufacture, formulation, and application of this antibiotic and antifungal agent
- Veterinary Drugs and TreatmentsChloramphenicol is used for a variety of infections in small animals and horses, particularly those caused by anaerobic bacteria. The FDA has prohibited the use of chloramphenicol in animals used for food production because of the human public health implications.
- CarcinogenicityChloramphenicol is reasonably anticipated to be a human carcinogen, based on limited evidence of carcinogenicity from studies in humans.
- Metabolic pathwaySix metabolites of chloramphenicol are identified, among which the sulfate conjugate is characterized in goat urine.
- ShippingUN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required.
- Purification MethodsPurify chloramphenicol by recrystallisation from H2O (solubility is 2.5mg/mL at 25o) or ethylene dichloride as needles or long plates, and by sublimation at high vacuum. It has A 1cm 298 at max 278nm, and it is slightly soluble in H2O (0.25%) and propylene glycol (1.50%) at 25o but is freely soluble in MeOH, EtOH, BuOH, EtOAc and Me2CO. [Relstock et al. J Am Chem Soc 71 2458 1949, Confroulis et al. J Am Chem Soc 71 2463 1949, Long & Troutman J Am Chem Soc 71 2469, 2473 1949, Ehrhart et al. Chem Ber 90 2088 1957, Beilstein 13 IV 2742.]
- IncompatibilitiesCompounds of the carboxyl group react with all bases, both inorganic and organic (i.e., amines), releasing substantial heat, water, and a salt that may be harmful. Incompatible with arsenic compounds (releases hydrogen cyanide gas), diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, sulfides (releasing heat, toxic, and possibly flammable gases), thiosulfates, and dithionites (releasing hydrogen sulfate and oxides of sulfur).
- Waste DisposalIt is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Chloramphenicol Preparation Products And Raw materials
- Preparation Productsp-Nitrobenzoic acidDIETHOXYMETHANEChloramphenicol palmitate
- Raw materialsEtanolMethanolSulfuric acid TolueneNitric acidBromineAcetic anhydrideAluminium chlorideFormaldehydeIsopropanolAcetyl chlorideBenzaldehydeChlorobenzeneHexamethylenetetramineStyreneAluminium4-NitroacetophenoneCinnamyl alcoholDichloroacetic acid methyl ester4-Nitrobenzaldehyde(1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol
- Methylparaben p-Nitrobenzoic acid 3-Diethylaminophenol Methyl bromide N,N-Dimethylacetamide Acetamide Ethylparaben Ethyl cyanoacetate Ethyl acetate CHLOROPHOSPHONAZO III Methyl Kresoxim-methyl ISOXADIFEN-ETHYL Nitrobenzene Methyl acrylate Trinexapac-ethyl 1-Hydroxyethylidene-1,1-diphosphonic acid Ethyl acrylate
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