Chloramphenicol

Chloramphenicol

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Chloramphenicol is a bacteriostatic antimicrobial
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...

 that became available in 1949. It is considered a prototypical broad-spectrum antibiotic
Broad-spectrum antibiotic
The term broad-spectrum antibiotic refers to an antibiotic that acts against a wide range of disease-causing bacteria. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of...

, alongside the tetracycline
Tetracycline antibiotics
Tetracyclines are a group of broad-spectrum antibiotics whose general usefulness has been reduced with the onset of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications....

s, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.

Chloramphenicol is effective against a wide variety of Gram-positive and Gram-negative bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, including most anaerobic organism
Anaerobic organism
An anaerobic organism or anaerobe is any organism that does not require oxygen for growth. It could possibly react negatively and may even die if oxygen is present...

s. Due to resistance and safety concerns, it is no longer a first-line agent for any indication in developed nations, although it is sometimes used topically for eye infections
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...

. Nevertheless, the global problem of advancing bacterial resistance to newer drugs has led to renewed interest in its use. In low-income countries, chloramphenicol is still widely used because it is inexpensive and readily available.

The most serious adverse effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 associated with chloramphenicol treatment is bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

 toxicity, which may occur in two distinct forms: bone marrow suppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...

, which is a direct toxic effect of the drug and is usually reversible, and aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...

, which is idiosyncratic
Idiosyncratic drug reaction
Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known...

 (rare, unpredictable, and unrelated to dose) and in general fatal.

Spectrum of activity


Because it functions by inhibiting bacterial protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 synthesis, chloramphenicol has a very broad spectrum of activity: it is active against Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacteria (including most strains of MRSA
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...

), Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 bacteria and anaerobes. It is not active against Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...

, Chlamydiae
Chlamydiae
Chlamydiae is a bacterial phylum and class whose members are obligate intracellular pathogens. Many Chlamydiae coexist in an asymptomatic state within specific hosts, and it is widely believed that these hosts provide a natural reservoir for these species....

, or Enterobacter
Enterobacter
Enterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised hosts and in those who are on mechanical ventilation...

species. It has some activity against Burkholderia pseudomallei
Burkholderia pseudomallei
Burkholderia pseudomallei is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It infects humans and animals and causes the disease melioidosis. It is also capable of infecting plants....

, but is no longer routinely used to treat infections caused by this organism (it has been superseded by ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...

 and meropenem
Meropenem
Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...

). In the West, chloramphenicol is mostly restricted to topical uses because of the worries about the risk of aplastic anaemia.

Therapeutic uses


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
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...

.

Because of its excellent BBB penetration (far superior to any of the cephalosporins), chloramphenicol remains the first choice treatment for staphylococcal
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...

 brain abscess
Brain abscess
Brain abscess is an abscess caused by inflammation and collection of infected material, coming from local or remote infectious sources, within the brain tissue...

es. 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
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

: Neisseria meningitidis
Neisseria meningitidis
Neisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...

, Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...

and Haemophilus influenzae
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...

. In the West, chloramphenicol remains the drug of choice in the treatment of meningitis in patients with severe penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

 or cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...

 allergy and GP
General practitioner
A general practitioner is a medical practitioner who treats acute and chronic illnesses and provides preventive care and health education for all ages and both sexes. They have particular skills in treating people with multiple health issues and comorbidities...

s 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
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

.

Chloramphenicol has been used in the U.S. in the initial empirical treatment
Empirical treatment
Empirical treatment is a medical treatment not derived from the scientific method, but derived from observation, survey or common use.In the medical profession, the term is also used when treatment is started before a diagnosis is confirmed The most common reason is that investigations are...

 of children with fever and a petechial rash, when the differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...

 includes both Neisseria meningitidis
Neisseria meningitidis
Neisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...

septicaemia as well as Rocky Mountain spotted fever
Rocky Mountain spotted fever
Rocky Mountain spotted fever is the most lethal and most frequently reported rickettsial illness in the United States. It has been diagnosed throughout the Americas. Some synonyms for Rocky Mountain spotted fever in other countries include “tick typhus,” “Tobia fever” , “São Paulo fever” or “febre...

, pending the results of diagnostic investigations.

Chloramphenicol is also effective against Enterococcus faecium
Enterococcus faecium
Enterococcus faecium is a Gram-positive, alpha hemolytic or nonhemolytic bacterium in the genus Enterococcus. It can be commensal in the human intestine, but it may also be pathogenic, causing diseases such as neonatal meningitis.Vancomycin-resistant E. faecium is often referred to as VRE.Some...

, which has led to its being considered for treatment of vancomycin-resistant enterococcus
Vancomycin-Resistant Enterococcus
Vancomycin-resistant Enterococcus, or vancomycin-resistant enterococci , are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin. To become VRE, vancomycin-sensitive enterococci typically obtain new DNA in the form of plasmids or transposons which encode...

.

Although unpublished, recent research suggests chloramphenicol could also be applied to frogs to prevent their widespread destruction from fungal infections. Chloramphenicol has recently been discovered to be a life-saving cure for chytridiomycosis
Chytridiomycosis
Chytridiomycosis is an infectious disease of amphibians, caused by the chytrid Batrachochytrium dendrobatidis, a non-hyphal zoosporic fungus. Chytridiomycosis has been linked to dramatic population declines or even extinctions of amphibian species in western North America, Central America, South...

 in amphibians. Chytridiomycosis is a fungal disease, blamed for the extinction of one-third of the 120 frog species lost since 1980.

Aplastic anemia


The most serious side effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 of chloramphenicol treatment is aplastic anaemia. This effect is rare and is generally fatal: there is no treatment and 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. It is not known whether monitoring the blood count
Blood Count
"Blood Count" is a 1967 jazz composition by Billy Strayhorn. It was originally meant for a three-piece work Strayhorn was writing for Duke Ellington and initially titled "Blue Cloud". However, Strayhorn was hospitalized in 1967 due to cancer and finished the composition while in the hospital. He...

s of patients can prevent the development of aplastic anaemia, but patients are recommended to have a blood count check twice weekly while on treatment. 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 1 in 224,716 prescriptions).

Thiamphenicol
Thiamphenicol
Thiamphenicol is an antibiotic. It is the methyl-sulfonyl analogue of chloramphenicol and has a similar spectrum of activity, but is 2.5 to 5 times as potent. Like chloramphenicol, it is insoluble in water, but highly soluble in lipids...

, 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, and is not approved for use in humans.

Bone marrow suppression


Chloramphenicol commomly causes bone marrow suppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...

 during treatment; this is a direct toxic effect of the drug on human mitochondria. This effect manifests first as a fall in hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 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.

Leukemia


There is an increased risk of childhood leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

, as demonstrated in a Chinese case-controlled study, and the risk increases with length of treatment.

Possible Related Adverse Effects

Chloramphenicol is particularly toxic to people sensitive to benzene-based preservatives, such as preservatives 210 and 211.
Chloramphenicol poisoning can cause sensitivity reactions to organic acids and salicylates.
It is also known to cause tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

 and balance problems through inner ear damage.
It also causes folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...

 depletion, resulting in adverse effects to the thyroid, pituitary and prostate through effects on PABA levels. There may also be links to chronic lymphocytic leukemia (CLL) through folic acid "depletion" and resultant high levels of folic acid in the mutant lymphocytes that characterize CLL. Chloramphenicol stops the body's production of vitamin D and pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...

. This results in major hormone depletion, including DHEA and testosterone, that can result in death and also lowers the body's resistance to viral infection.
Chloramphenicol can cause testes pain, possibly through hormone effects.
Chinese research showed chloramphenicol affects motor neurones. It also affects insulin Igf1 levels and glutamate levels. Both conditions are considered indicative of a type of motor neurone disease. The adverse genetic effects of chloramphenicol are considered heritable.

Gray baby syndrome


Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome
Gray baby syndrome
Gray baby syndrome is a rare but serious side effect that occurs in newborn infants following the intravenous administration of the antimicrobial chloramphenicol.-Pathophysiology:...

.
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
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

 and cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...

. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.

Pharmacokinetics


Chloramphenicol is extremely lipid soluble; it remains relatively unbound to protein
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...

 and is a small molecule. It has a large apparent volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...

 of 100 litres, and penetrates effectively into all tissues of the body, including the brain. The concentration achieved in brain and cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 (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.

Chloramphenicol increases the absorption of iron
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...

.

Use in special populations


Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate
Glucuronic acid
Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid...

 (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.

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 (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.

Chloramphenicol passes into breast milk
Breast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...

, so should therefore be avoided during breast feeding, if possible.

Dose monitoring


Plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 levels of chloramphenicol must be monitored in neonates and in 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.
Peak levels (one hour after the dose is given) should be 15–25 mg/l; trough levels (taken immediately before a dose) should be less than 15 mg/l.

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
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...

 and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

 in the liver. Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics and proton pump inhibitors if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...

s, macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...

 antibiotics, SSRI
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...

s, statins and PDE5 inhibitor
PDE5 inhibitor
A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis...

s.

Mechanism of action


Chloramphenicol is bacteriostatic
Bacteriostatic agent
A bacteriostatic agent or bacteriostat, abbreviated Bstatic, is a biological or chemical agent that stops bacteria from reproducing, while not necessarily harming them otherwise. Depending on their application, bacteriostatic antibiotics, disinfectants, antiseptics and preservatives can be...

 (that is, it stops bacterial growth). It is a protein synthesis inhibitor
Protein synthesis inhibitor
A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins....

 (more specifically inhibiting protein chain elongation), causing inhibition of peptidyl transferase
Peptidyl transferase
The Peptidyl transferase is an aminoacyltransferase as well as the primary enzymatic function of the ribosome, which forms peptide links between adjacent amino acids using tRNAs during the translation process of protein biosynthesis....

 activity of the bacterial ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

, binding to A2451 and A2452 residues in the 23S rRNA
23S ribosomal RNA
The 23S rRNA is a 2904 nt long component of the large prokaryotic subunit The ribosomal peptidyl transferase activity resides in this rRNA...

 of the 50S ribosomal subunit, preventing peptide bond formation. While chloramphenicol and the macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...

 class of antibiotics both interact with ribosomes, chloramphenicol is not a macrolide. It directly interferes with substrate binding; macrolides sterically block the progression of the growing peptide.

Resistance


There are three mechanisms of resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...

 to chloramphenicol: 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
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 codes for an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 called chloramphenicol acetyltransferase
Chloramphenicol acetyltransferase
Chloramphenicol acetyltransferase is a bacterial enzyme that detoxifies the antibiotic chloramphenicol and is responsible for chloramphenicol resistance in bacteria. This enzyme covalently attaches an acetyl group from acetyl-CoA to chloramphenicol, which prevents chloramphenicol from binding to...

, which inactivates chloramphenicol by covalently linking one or two acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 groups, derived from acetyl-S-coenzyme A, to the hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 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
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...

, C=chloramphenicol, Co=co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...

, T=tetracycline), which mediates multiple-drug resistance in typhoid (also called R factors).

Formulations


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
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

 (CPE). CPE is inactive, and is hydrolysed
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 to active chloramphenicol in the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

. There is no difference in bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 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. There is now no oral formulation of chloramphenicol available in the U.S.

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

Intravenous


The intravenous (IV) preparation of chloramphenicol is the succinate ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

, because pure chloramphenicol does not dissolve in water. This creates a problem: Chloramphenicol succinate ester is an inactive prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

 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. 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.

Oily


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
Malta
Malta , officially known as the Republic of Malta , is a Southern European country consisting of an archipelago situated in the centre of the Mediterranean, south of Sicily, east of Tunisia and north of Libya, with Gibraltar to the west and Alexandria to the east.Malta covers just over in...

 and then in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

 from December 2004.

Oily chloramphenicol is recommended by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 (WHO) as the first-line treatment of meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...

 in low-income countries, and appears on the WHO essential drugs list. It was first used to treat meningitis in 1975 and numerous studies since have demonstrated its efficacy. It is the cheapest treatment available for meningitis (US$5 per treatment course, compared to US$30 for ampicillin
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...

 and US$15 for five days of ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...

). 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.

Eye drops


In the West
Western world
The Western world, also known as the West and the Occident , is a term referring to the countries of Western Europe , the countries of the Americas, as well all countries of Northern and Central Europe, Australia and New Zealand...

, chloramphenicol is still widely used in topical preparations (ointments and eye drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...

s) for the treatment of bacterial conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...

. Isolated case reports of aplastic anaemia following use of chloramphenicol eyedrops exist, but the risk is estimated to be less than 1 in 224,716 prescriptions. In Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...

, this is the treatment used prophylactically in newborns.

Trade names


Chloramphenicol has a long history and therefore a multitude of trade names in many different countries:
  • Alficetyn
  • Amphicol
  • Biomicin
  • Chlornitromycin
  • Chloromycetin (U.S., intravenous preparation)
  • Chlorsig (U.S., Australia, eye drops)
  • Dispersadron C (Greece, eye drops)
  • Edrumycetin 250 mg (Bangladesh, capsule)
  • Fenicol
  • Kemicetine (UK, intravenous preparation)
  • Kloramfenikol (Denmark, eye drops)
  • Laevomycetin
  • UK as an eye treatment
    • Brochlor (Aventis Pharma
      Aventis Pharma
      Aventis Pharma Limited , headquartered in Mumbai, is a part of Sanofi-Aventis group. Sanofi-Aventis and its 100% subsidiary Hoechst AG, are the major shareholders of Aventis Pharma Limited...

       Ltd)
    • Chloromycetin Redidrops (Goldshield Pharmaceuticals Ltd)
    • Golden Eye (Typharm Ltd)
    • Optrex Infected Eyes
  • Oftan Chlora (eye ointment)
  • Optacloran (Bolivia, eye drops)
  • Phenicol
  • Posifenicol 1% (Germany, eye ointment)
  • Medicom
  • Nevimycin
  • Renicol (India,eye drops)
  • Silmycetin (Thailand, eye drops)
  • Synthomycine (Israel, eye ointment and skin ointment)
  • Tifomycine (France, oily chloramphenicol)
  • Unison (Thailand, skin ointment)
  • Vanmycetin (Hong Kong, eye drops)
  • Vernacetin
  • Veticol
  • Orchadexoline (Orchidia pharmaceutical ind., Egypt, eye drops)
  • Isoptophenicol (Egypt, eye drops)
  • Cedoctine (Egypt, intravenous preparation)
  • Chloramex (South Africa, eye ointment)
  • Cloranfenicol (Portugal)

History


Chloramphenicol was originally derived from the bacterium Streptomyces venezuelae
Streptomyces venezuelae
Streptomyces venezuelae is a species of soil-dwelling Gram-positive bacterium of the genus Streptomyces.S. venezuelae is filamentous...

, isolated by David Gottlieb
David Gottlieb
David Gottlieb , a professor of plant pathology at the University of Illinois at Urbana-Champaign , was a pioneer in the field of fungi physiology and antibiotics for plants....

, 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.

In popular culture


Author/editor Eric Flint
Eric Flint
Eric Flint is an American author, editor, and e-publisher. The majority of his main works are alternate history science fiction, but he also writes humorous fantasy adventures.- Career :...

 chose the drug in his 1632 series
1632 series
The 1632 series, also known as the 1632-verse or Ring of Fire series, is an alternate history book series and sub-series created, primarily co-written, and coordinated by Eric Flint and published by Baen Books...

 as one which could be produced by seventeenth century technology and prevent disease deaths during the alternate history's modified Thirty Years War.

External links