Chloramphenicol is a derivative of dichloroacetic acid, and was first isolated from Streptomyces venezuelae in 1947.
Though chloramphenicol is one of the “broad spectrum” antibiotics, its serious adverse effects restricts its use only for certain cases of meningitis, typhus, and typhoid fever, as well as Rocky Mountain spotted fever.
Chloramphenicol is rapidly absorbed orally, and peak plasma concentrations are achieved within 3 hours. It can also be administered parenterally (usually IV) for serious infections, in the form of a succinate preparation. Chloramphenicol is well distributed in tissues and body fluids (including CSF), and crosses the placental barrier readily. Reported values (Vd) range from 0.57 L/kg to 1.55 L/kg. The major route of elimination is by hepatic metabolism to the inactive glucuronide which is excreted in the urine by filtration and secretion. About 50% of chloramphenicol is bound to plasma proteins.
· Chloramphenicol inhibits the 50s ribosomal subunit and protein synthesis in rapidly proliferating cells. Inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis, all contribute to the development of metabolic acidosis produced by this drug in overdose.
· Bone marrow suppression results from ultrastructural microsomal changes induced by chloramphenicol, resulting in the decreased production of essential proteins and enzymes. Inhibition of DNA synthesis in marrow stem cells by the p-nitrosulfathiazole group of this antibiotic is said to be responsible for the potentially fatal induction of aplastic anaemia.
■■ Skin rashes, fever, and angioedema are uncommonly reported hypersensitivity reactions to chloramphenicol.
■■ Jarisch- Herxheimer reaction has been observed during therapy for syphilis, brucellosis, and typhoid fever.
■■ Serious adverse reactions to chloramphenicol (usually but not always dose-related) include anaemia, leukopenia, and thrombocytopenia. Aplastic anaemia is not dose-related, but is instead an idiosyncratic reaction. The risk while being low (approximately 1 in 30,000), is potentially fatal if it does materialise. Even if recovery occurs, there is a subsequent increased predisposition to acute leukaemia.
· Oral administration of large doses causes nausea, vomiting, unpleasant taste, and diarrhoea. Glossitis, stomatitis, or enterocolitis may occur.
· Blurring of vision, optic neuritis, and digital paraesthesias.
· Metabolic acidosis (an early sign, more common with chronic toxicity).
· Hypotension, hypothermia, sudden cardiovascular collapse.
· Chronic toxicity: Anaemia and leukopenia (reversibleafter discontinuation), metabolic acidosis, optic neuritis, and peripheral neuritis.
· Overdose in neonates can result in Grey baby syndrome,* characterised by vomiting, refusal to feed, tachypnoea, abdominal distension, cyanosis, and loose, greenish stools. Within 24 hours the baby becomes flaccid, hypothermic, and turns ashen-grey in colour. Mortality is around 40%. Autopsy has shown both left and right ventricular dilation. Serum concentrations associated with this syndrome usually exceed 50 mcg/ml. A reduced dose (25 mg/kg) should be used in this age group (premature infants and newborns), and serum levels should not exceed 10 mcg/ml. Two factors are responsible for this syndrome: a) deficiency of gluc-uronyl transferase in the neonate, and b) inadequate renal excretion of unconjugated drug. Grey baby syndrome has also been observed in toddlers 6 to 25 months of age.
· Idiosyncratic reaction: Aplastic anaemia, which does notappear to be dose-related (incidence 1:30,000 to 1:50,000), and may occur weeks or months after therapy has been discontinued; it has occurred after IV, oral, and ocular routes. It carries high mortality (>50% mortality).
· Hypersensitivity reactions are rare, but contact dermatitis, rashes, drug fever, angioedema, urticaria, and occasional cases of anaphylaxis have been reported.
· Carcinogenecity: A population based case-control inter-view study in Shanghai suggests an 11-fold increased risk of acute lymphocytic leukaemia (ALL) and acute non-lymphocytic leukaemia (ANLL) following the use of chloramphenicol.
Obtain plasma chloramphenicol levels (therapeutic levels vary from 10 to 25 mcg/ml), baseline CBC, and arterial blood gas (to monitor for metabolic acidosis). Monitoring of leukocyte and reticulocyte counts during therapy is advisable. Following large overdoses (doses exceeding 100 mg/kg/dose, or single doses of 10 gm or more), observation in a medical facility for a minimum of 12 hours after the event is necessary, since manifestations may begin only 5 to 12 hours following ingestion.
· Gastric lavage may be helpful for recent ingestions. Activated charcoal can be administered subsequently (1 gm/kg).
· For optic neuritis, with or without peripheral neuritis: administration of vitamins B6 and B12 has been recom-mended. Doses used by these authors were 500 mg orally twice a day of vitamin B6, and 0.5 mg orally once a day of vitamin B12.
· Chloramphenicol is not well dialyzed. With a half-life of 1.6 to 4 hours in the setting of normal hepatic and renal function, it is unlikely that dialysis would remove the drug sufficiently and rapidly to prevent toxicity. However, in patients with impaired renal function, clearance is moder-ately increased by haemodialysis.
· Charcoal haemoperfusion is said to be beneficial.
· Exchange transfusion has been used successfully in neonates.
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