Chloramphenicol
Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes use as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, and typhoid fever. Its use by mouth or by injection is only recommended when safer antibiotics cannot be used. Monitoring both blood levels of the medication and blood cell levels every two days is recommended during treatment.
Common side effects include bone marrow suppression, nausea, and diarrhea. The bone marrow suppression may result in death. To reduce the risk of side effects treatment duration should be as short as possible. People with liver or kidney problems may need lower doses. In young infants, a condition known as gray baby syndrome may occur which results in a swollen stomach and low blood pressure. Its use near the end of pregnancy and during breastfeeding is typically not recommended. Chloramphenicol is a broad-spectrum antibiotic that typically stops bacterial growth by stopping the production of proteins.
Chloramphenicol was discovered after being isolated from Streptomyces venezuelae in 1947. Its chemical structure was identified and it was first synthesized in 1949. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
Medical uses
The original indication of chloramphenicol was in the treatment of typhoid, but the presence of multiple drug-resistant Salmonella typhi has meant it is seldom used for this indication except when the organism is known to be sensitive.In low-income countries, the WHO no longer recommends only chloramphenicol as first-line to treat meningitis, but recognises it may be used with caution if there are no available alternatives.
During the last decade chloramphenicol has been re-evaluated as an old agent with potential against systemic infections due to multidrug-resistant gram positive microorganisms. In vitro data have shown an activity against the majority of vancomycin resistant E. faecium strains.
In the context of preventing endophthalmitis, a complication of cataract surgery, a 2017 systematic review found moderate evidence that using chloramphenicol eye drops in addition to an antibiotic injection will likely lower the risk of endophthalmitis, compared to eye drops or antibiotic injections alone.
Spectrum
Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular infections such as conjunctivitis, blepharitis etc. caused by a number of bacteria including Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. It is not effective against Pseudomonas aeruginosa. The following susceptibility data represent the minimum inhibitory concentration for a few medically significant organisms.- Escherichia coli: 0.015 – 10,000 μg/mL
- Staphylococcus aureus: 0.06 – 128 μg/mL
- Streptococcus pneumoniae: 2 – 16 μg/mL
Resistance
Three mechanisms of resistance to chloramphenicol are known: reduced membrane permeability, mutation of the 50S ribosomal subunit, and elaboration of chloramphenicol acetyltransferase. It is easy to select for reduced membrane permeability to chloramphenicol in vitro by serial passage of bacteria, and this is the most common mechanism of low-level chloramphenicol resistance. High-level resistance is conferred by the cat-gene; this gene codes for an enzyme called chloramphenicol acetyltransferase, which inactivates chloramphenicol by covalently linking one or two acetyl groups, derived from acetyl-S-coenzyme A, to the hydroxyl groups on the chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the ribosome. Resistance-conferring mutations of the 50S ribosomal subunit are rare.Chloramphenicol resistance may be carried on a plasmid that also codes for resistance to other drugs. One example is the ACCoT plasmid, which mediates multiple drug resistance in typhoid.
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.
Some other resistance genes beyond cat are known, such as chloramphenicol hydrolase, and chloramphenicol phosphotransferase.
Adverse effects
Aplastic anemia
The most serious side effect of chloramphenicol treatment is aplastic anaemia. This effect is rare but sometimes fatal. The risk of AA is high enough that alternatives should be strongly considered. Treatments are available but expensive. No way exists to predict who may or may not suffer this side effect. The effect usually occurs weeks or months after treatment has been stopped, and a genetic predisposition may be involved. It is not known whether monitoring the blood counts of patients can prevent the development of aplastic anaemia, but patients are recommended to have a baseline blood count with a repeat blood count every few days while on treatment. Chloramphenicol should be discontinued if the complete blood count drops. The highest risk is with oral chloramphenicol and the lowest risk occurs with eye drops.Bone marrow suppression
Chloramphenicol may cause bone marrow suppression during treatment; this is a direct toxic effect of the drug on human mitochondria. This effect manifests first as a fall in hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been given. The anaemia is fully reversible once the drug is stopped and does not predict future development of aplastic anaemia. Studies in mice have suggested existing marrow damage may compound any marrow damage resulting from the toxic effects of chloramphenicol.Leukemia
Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase of immature white blood cells. The risk of childhood leukemia is increased, as demonstrated in a Chinese case–control study, and the risk increases with length of treatment.Gray baby syndrome
Intravenous chloramphenicol use has been associated with the so-called gray baby syndrome.This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes, so chloramphenicol remains unmetabolized in the body.
This causes several adverse effects, including hypotension and cyanosis. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels.
Hypersensitivity reactions
Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur. Herxheimer's reactions have occurred during therapy for typhoid fever.Neurotoxic reactions
Headache, mild depression, mental confusion, and delirium have been described in patients receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn. It is theorized that this is caused by chloramphenicol's effects on the metabolism of B-Vitamins, specifically B-12.Myelodysplastic Syndrome
Although rare, Chloramphenicol exposure is associated with some cases of MDS. There is a report of a positive response to immunosuppressive treatment.Pharmacokinetics
Chloramphenicol is extremely lipid-soluble; it remains relatively unbound to protein and is a small molecule. It has a large apparent volume of distribution and penetrates effectively into all tissues of the body, including the brain. Distribution is not uniform, with highest concentrations found in the liver and kidney, with lowest in the brain and cerebrospinal fluid. The concentration achieved in brain and cerebrospinal fluid is around 30 to 50% of the overall average body concentration, even when the meninges are not inflamed; this increases to as high as 89% when the meninges are inflamed.Chloramphenicol increases the absorption of iron.
Use in special populations
Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate. 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 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.
Dose monitoring
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 should be 10–20 μg/mL with toxicity ; trough levels should be 5–10 μg/mL.
Drug interactions
Administration of chloramphenicol concomitantly with bone marrow depressant drugs is contraindicated, although concerns over aplastic anaemia associated with ocular chloramphenicol have largely been discounted.Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and CYP3A4 in the liver. Inhibition of CYP2C19 causes decreased metabolism and therefore increased levels of, for example, antidepressants, antiepileptics, proton-pump inhibitors, and anticoagulants if they are given concomitantly. Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic antidepressants, macrolide antibiotics, SSRIs, statins, cardiac antiarrhythmics, antivirals, anticoagulants, and PDE5 inhibitors.