Chloramphenicol : Therapeutic uses, Dosage & Side Effects
Chloramphenicol is an broad spectrum antibiotic. It has a nitrobenzene substitution, which is probably responsible for the antibacterial activity and its intensely bitter taste.
Dose : 250-500 mg 6 hourly (max total dose 28 g), children 25–50 mg/kg/day
Route : Oral, IV, IM, Topical (Eye/Ear)
Onset of action : ?
Plasma Half-life : 3-5 hours
Duration of action : ?
Bioavailability : 75–90%
Plasma protein binding : 50-60%
Metabolism : Hepatic
Pregnancy risk category : C
Chemical formula : C11H12Cl2N2O5
IUPAC name : 2,2-dichloro-N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide
Trade name : Chloromycetin, Enteromycetin, Pentamycetin, Paraxin, Kemicetine, Phenimycin, Vanmycetin, Lykacetin, Chlornitromycin, Levomycetin, Synthomycetin
Antibacterial spectrum : Chloramphenicol is primarily bacteriostatic, but depending on the dose and organism, it may be bactericidal.
Like tetracyclines, Chloramphenicol is a broad-spectrum antibiotic active against most of microorganisms such as gram-positive and negative bacteria, rickettsiae, mycoplasma, chlamydiae, spirochetes, and anaerobes.
Like tetracyclines, it is ineffective against Mycobacteria, Pseudomonas, many Proteus, viruses and fungi.
Remarkable differances between Tetracyclines & Chloramphenicol are as following :
- Chloramphenicol was highly active against Salmonella including S. typhi, but resistant strains are now rampant.
- Chloramphenicol is more active than tetracyclines against H. influenzae (though many have now developed resistance), B. pertussis, Klebsiella, N. meningitidis and anaerobes including Bact. fragilis.
- Chloramphenicol is less active against gram-positive cocci, spirochetes, certain Enterobacteriaceae and Chlamydia. Entamoeba and Plasmodia are not inhibited.
Therapeutic uses : Chloramphenicol use is restricted to life-threatening infections for which no alternatives exist.
Indications of chloramphenicol are :
- Enteric fever : Most of S. typhi strain had emerged resistance and spread globally; As a result, it became clinically unreliable.
- Pyogenic meningitis : Chloramphenicol in a dose of 50-75 mg/kg/ day may be used as a second line drug for H. influenzae and meningococcal meningitis, especially in young children and cephalosporin allergic patients, because it has excellent penetration into CSF and clinical efficacy has been demonstrated. Third generation cephalosporins (± vancomycin) are presently the first line drugs for empirical therapy of bacterial meningitis.
- Anaerobic infections caused by Bact. fragilis and others (wound infections, pelvic and brain abscesses, etc.) respond well to chloramphenicol. However, clindamycin or metronidazole are preferred for these. Chloramphenicol may be used in addition or as an alternative in patients not tolerating these drugs. A penicillin/ cephalosporin is generally combined since most of these are mixed infections.
- Intraocular infections : Chloramphenicol given systemically attains high concentration in ocular fluid. It is the preferred drug for endophthalmitis caused by sensitive organisms.
- Used as second choice drug to tetracyclines for brucellosis and rickettsial infections, especially in young children and pregnant women in whom tetracyclines are contraindicated.
- Used as second choice drug to erythromycin for whooping cough.
- Urinary tract infections : It should be used only when kidney substance is involved and the organism is found to be sensitive only to this drug. More safer drugs are now available.
- Topically, it can be used in conjunctivitis, external ear infections-chloramphenicol 0.5-5.0% is highly effective. Topical use on skin or other areas is not recommended because of risk of sensitization.
Because of serious (though rare) bone marrow toxicity :
- Regular blood counts (especially reticulocyte count) may detect dose-related bone marrow toxicity but not the idiosyncratic type.
- Combined formulation of chloramphenicol with any drug meant for internal use is banned in India.
Mechanism of action : Chloramphenicol binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction by interferring with transfer of the elongating peptide chain to the newly attached aminoacyl-tRNA at the ribosome-mRNA complex. It may hinder the access of aminoacyl-tRNA to the acceptor site for amino acid incorporation.Probably by acting as a peptide analogue, it prevents formation of peptide bonds.
Due to some similarity of mammalian mitochondrial ribosomes to those of bacteria, at high doses, it can inhibit mammalian mitochondrial protein synthesis as well. Bone marrow cells are especially susceptible producing bone marrow toxicity.
Resistance : Most bacteria are capable of developing resistance to chloramphenicol, which generally emerges in a graded manner, as with tetracyclines.
Microorganisms can develop resistance to drug through following mechanisms :
- By the presence of enzymes that inactivate drug : Resistance among gram negative bacteria e.g. S. typhi (transfer of R factor by conjugation) is generally due to acquisition of R plasmid encoded for an acetyl transferase which inactivates drug. Acetyl-chloramphenicol does not bind to the bacterial ribosome. In many cases, this plasmid has also carried resistance to ampicillin and tetracycline. Multidrug-resistant S. typhi have arisen.
- Decreased ability to penetrate the organism : Chloramphenicol appears to enter bacterial cell both by passive as well as facilitated diffusion.
- Ribosomal binding site alterations.
Partial cross resistance between chloramphenicol and erythromycin/clindamycin has been noted, because all these antibiotics bind to 50S ribosome at adjacent sites. Some cross resistance with tetracyclines also occurs, though the latter binds to 30S ribosome.
Side effects : Chloramphenicol can cause following side effects :
- Bone marrow depression : Of all drugs, chloramphenicol is the most important cause of aplastic anaemia, hemolytic anemia (seen in patients with glucose-6-phosphate dehydrogenase deficiency), agranulocytosis, thrombocytopenia or pancytopenia. It may be non-dose related idiosyncratic reaction or dose and duration of therapy related myelosuppression. Aplastic anemia is independent of dose and may occur after therapy has ceased.
- Gray baby syndrome : It occurred when high doses (-100 mg/kg) were given prophylactically to neonates, especially premature. Neonates have a low capacity to glucuronidate (or metabolize) the drug, and they have underdeveloped renal function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes & blocks electron transport in the liver, myocardium and skeletal muscle, resulting in poor feeding, depressed breathing, hypothermia, abdomen distention, ashen grey cyanosis (hence the term “gray baby”), cardiovascular collapse, and death. Adults who have received very high doses of the drug can also exhibit this toxicity.
- Irritative effects : Nausea, vomiting, diarrhoea, pain on injection.
- Superinfections : Like tetracyclines, it can also cause superinfection but less common.
- Hypersensitivity reactions : Rashes, fever, atrophic glossitis, angioedema are infrequent.
Precautions
- It should be avoided in neonates, and even if given, dose should be – 25 mg/kg/day.
- Avoid repeated courses.
- Daily dose not to exceed 2-3 g; duration of therapy to be < 2 weeks, total dose in a course < 28 g.
- Use of this antibiotic may result in an overgrowth of nonsusceptible organisms, including fungi. If infections caused by nonsusceptible organisms appear during therapy, appropriate measures should be taken.
Drug Interactions : Chloramphenicol may interact with following drugs :
- Warfarin, phenytoin, tolbutamide, chlorpropamide, cyclophosphamide : Blockage of the metabolism thereby elevating concentrations and potentiating effects of these drugs. because chloramphenicol inhibits some of the hepatic mixed-function oxidases.
- Phenobarbitone, phenytoin, rifampin : Enhance chloramphenicol metabolism & reduce its concentration thus, failure of therapy may occur.
- ß-lactams / aminoglycosides : Decrease in cidal action because chloramphenicol is bacteriostatic.
Contraindications
- It should be avoided in breastfeeding mothers.
- Contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to it.
- It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, influenza, infections of the throat; or as a prophylactic agent to prevent bacterial infections.
- Concurrent therapy with bone marrow depressant drugs should be avoided.
- Chloramphenicol is antagonistic with most cephalosporins and using both together should be avoided in the treatment of infections.
For detailed query or in case of uncertainty, Always consult your doctor or pharmacist.
