Chloramphenicol Overview

Chloramphenicol

• Originally isolated from Streptomyces venezuelae
• First broad-spectrum antibacterial developed (1947)
• Now produced synthetically due to simple structure
• Effective broad-spectrum antibiotic
• Limited clinical use due to serious toxicity
• Primarily bacteriostatic
• Due to resistance and safety concerns, it's no longer a first-line treatment for infections in developed nations, except for topical use in bacterial conjunctivitis.

Mechanism of Action

• Inhibits protein synthesis
• Reversible and bacteriostatic action
• Interferes with protein synthesis initiation
• Causes misreading of genetic code.
• Irreversible action leads to bacteriocidal effect

Antimicrobial Spectrum

• Active against a broad range of organisms, including gram-positive and gram-negative bacteria
• Effective against Streptococcus, Staphylococcus, Enterococcus, Bacillus anthracis, Listeria monocytogenes (gram-positive)
• Effective against Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Escherichia coli, Proteus, Salmonella, Shigella, Stenotrophomonas maltophilia, Bacteroides spp(gram-negative)
• Excellent activity against anaerobes
• Bactericidal against H. influenzae, N. meningitidis, and *S. pneumoniae

Resistance Mechanisms

• Inactivation of the drug by microbial enzymes, like acetyl transferase.

Pharmacokinetics

• Well absorbed from the gut and achieves high concentrations in the central nervous system (CNS) even without inflammation
• Useful in treating meningitis
• 30% protein bound
• Metabolized by the liver to glucuronide
• Excreted in the urine

Adverse Effects

• Grey baby syndrome: A rare but potentially fatal toxic effect in neonates due to the liver's impaired ability to glucuronidation of the drug during the first few weeks of life, causing cyanosis, weakness, respiratory depression, hypotension, and shock.
• Reversible dose-dependent anemia: Due to high drug concentration in the plasma, inhibiting ferrochelatase, which is critical for iron incorporation into heme, leading to anemia.
• Aplastic anemia: A serious and generally fatal side effect appearing weeks or months after treatment, caused by bone marrow suppression as a direct toxic effect on human mitochondria. It manifests as a fall in hemoglobin levels and is fully reversible after the drug is stopped.
• Increased risk of childhood leukemia

Drug Interactions

• Inhibits microsomal enzymes that metabolize other drugs, such as warfarin and phenytoin.

Uses

• Typhus, Rocky Mountain spotted fever

• Restricted to serious systemic infections due to potential toxicity (e.g., bone marrow aplasia)

• Meningitis (when other treatments are unsuitable)

• Pyogenic meningitis

• Anaerobic infections

• Intraocular infections

• Enteric fever

• Whooping cough

• Urinary tract infections

• External ear infections

• Topical use in eye infections—penetrates ocular tissues and aqueous humor due to solubility.

Dose

• 50-100 mg/kg/day in divided doses.
• Adjustments needed for neonates and cirrhotic patients due to lower levels of glucuronosyl-transferase and impaired metabolism.

Solubility

• Contains a nitrobenzene moiety and a dichloroacetic acid derivative
• Is non-ionized and highly lipophilic, enabling passive diffusion into bacterial cells.
• Oxygen and nitrogen-containing functional groups enhance water solubility while non-ionizable hydrocarbon chains and ring systems enhance lipid solubility.