Chloramphenicol

Spectrum

Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections such as conjunctivitis, blepharitis etc. caused by a number of bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. It is not effective against Pseudomonas aeruginosa. The following susceptibility data represent the minimum inhibitory concentration for a few medically significant organisms.^[13]

• Escherichia coli: 0.015 – 10,000 μg/mL
• Staphylococcus aureus: 0.06 – 128 μg/mL
• Streptococcus pneumoniae: 2 – 16 μg/mL

Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains of E coli, for example, show spontaneous emergence of chloramphenicol resistance.^[14][15]

Resistance

Three mechanisms of resistance to chloramphenicol are known: reduced membrane permeability, mutation of the 50S ribosomal subunit, and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability to chloramphenicol in vitro by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High-level resistance is conferred by the cat-gene;^[16] this gene codes for an enzyme called chloramphenicol acetyltransferase, which inactivates chloramphenicol by covalently linking one or two acetyl groups, derived from acetyl-S-coenzyme A, to the hydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.^{[medical citation needed]}

Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the ACCoT plasmid (A=ampicillin, C=chloramphenicol, Co=co-trimoxazole, T=tetracycline), which mediates multiple drug resistance in typhoid (also called R factors).^{[medical citation needed]}

As of 2014 some Enterococcus faecium and Pseudomonas aeruginosa strains are resistant to chloramphenicol. Some Veillonella spp. and Staphylococcus capitis strains have also developed resistance to chloramphenicol to varying degrees.^[17]

Some other resistance genes beyond cat are known, such as chloramphenicol hydrolase,^[18] and chloramphenicol phosphotransferase.^[19]

Aplastic anemia

The most serious side effect of chloramphenicol treatment is aplastic 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 the blood counts of patients can prevent the development of aplastic anaemia, but patients are recommended to have a baseline blood count with a repeat blood count every few days while on treatment.^[20] Chloramphenicol should be discontinued if the complete blood count drops. The highest risk is with oral chloramphenicol (affecting 1 in 24,000–40,000)^[21] and the lowest risk occurs with eye drops (affecting less than one in 224,716 prescriptions).^[22]

Thiamphenicol, a related compound with a similar spectrum of activity, is available in Italy and China for human use, and has never been associated with aplastic anaemia. Thiamphenicol is available in the U.S. and Europe as a veterinary antibiotic, but is not approved for use in humans.^{[citation needed]}

Bone marrow suppression

Chloramphenicol may cause bone marrow suppression during treatment; this is a direct toxic effect of the drug on human mitochondria.^[23] This effect manifests first as a fall in hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been given. The anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia. Studies in mice have suggested existing marrow damage may compound any marrow damage resulting from the toxic effects of chloramphenicol.^[24]

Leukemia

Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhood leukemia is increased, as demonstrated in a Chinese case–control study,^[25] and the risk increases with length of treatment.

Gray baby syndrome

Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.^[26] 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.^[27] This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.^[28][29][30]

Hypersensitivity reactions

Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer's reactions have occurred during therapy for typhoid fever.^[31]

Neurotoxic reactions

Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn.^[31] It is theorized that this is caused by chloramphenicol's effects on the metabolism of B-Vitamins, specifically B-12.^[32]

Use in special populations

Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (which is inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. No standard dose reduction exists for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations.

The majority of the chloramphenicol dose is excreted by the kidneys as the inactive metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is excreted by the kidneys unchanged. Plasma levels should be monitored in patients with renal impairment, but this is not mandatory. Chloramphenicol succinate ester (an intravenous prodrug form) is readily excreted unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason why levels of chloramphenicol in the blood are much lower when given intravenously than orally.^[34] Chloramphenicol passes into breast milk, so should therefore be avoided during breast feeding, if possible.^[35]

Dose monitoring

Plasma levels of chloramphenicol must be monitored in neonates and patients with abnormal liver function. Plasma levels should be monitored in all children under the age of four, the elderly, and patients with kidney failure. Because efficacy and toxicity of chloramphenicol are associated with a maximum serum concentration, peak levels (one hour after the intravenous dose is given) should be 10–20 μg/mL with toxicity > 40 μg/mL; trough levels (taken immediately before a dose) should be 5–10 μg/mL.^[36][37]

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.^[38]

Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver.^[39] Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics, proton-pump inhibitors, and anticoagulants if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic antidepressants, macrolide antibiotics, SSRIs, statins, cardiac antiarrhythmics, antivirals, anticoagulants, and PDE5 inhibitors.^[31][40]

Drug antagonistic

Chloramphenicol is antagonistic with most cephalosporins and using both together should be avoided in the treatment of infections.^[41]

Drug synergism

Chloramphenicol has been demonstrated a synergistic effect when combined with fosfomycin against clinical isolates of Enterococcus faecium.^[42]

Names

Chloramphenicol is available as a generic worldwide under many brandnames^[52] and also under various generic names in eastern Europe and Russia, including chlornitromycin, levomycetin, and chloromycetin; the racemate is known as synthomycetin.^[53]

Formulations

Chloramphenicol is available as a capsule or as a liquid. In some countries, it is sold as chloramphenicol palmitate ester (CPE). CPE is inactive, and is hydrolysed to active chloramphenicol in the small intestine. No difference in bioavailability is noted between chloramphenicol and CPE.^{[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.^[54]

In molecular biology, chloramphenicol is prepared in ethanol.^{[citation needed]}