Chloramphenicol

Chloramphenicol is a broad-spectrum bacteriostatic antibiotic with excellent tissue and CSF penetration. Its use is limited by marrow toxicity and the risk of aplastic anaemia, but it remains important where alternatives are scarce: epidemic meningococcal meningitis, typhoid in some settings, rickettsial infection and eye infection. It is inexpensive and widely stocked in East Africa.

Mechanism. Binding to the 50S ribosomal subunit blocks peptidyl transferase, preventing peptide bond formation. Bacteriostatic against most organisms, though bactericidal against H. influenzae, S. pneumoniae and N. meningitidis.

Pharmacokinetics. Oral bioavailability about 80 to 90 percent. The IV form is the succinate ester prodrug, of which about 70 percent is converted to active drug (the rest is excreted unchanged in urine), so IV levels are less predictable. CSF concentrations reach 30 to 50 percent of serum levels. Hepatic glucuronidation; half-life 1.5 to 4 hours in adults, up to 24 hours in neonates and in severe hepatic impairment.

Spectrum. S. pneumoniae, N. meningitidis, H. influenzae, Salmonella Typhi (resistance common), Rickettsia, Chlamydia, Brucella, anaerobes including Bacteroides, many VRE. Resistance by acetyltransferase (cat) genes.

Chloramphenicol is the sole member; formulations include oral, IV, intramuscular oily suspension, and topical eye drops and ointment. Thiamphenicol and florfenicol (veterinary) are related drugs without aplastic anaemia risk in thiamphenicol.

Adult regimens (normal renal and hepatic function).

• Usual systemic dose: 12.5 to 25 mg/kg IV or orally every 6 hours (maximum 4 g daily); 50 mg/kg daily for typhoid, for 14 days (resistance is common).
• Epidemic meningococcal meningitis in resource-limited settings: oily chloramphenicol 100 mg/kg IM as a single dose (maximum 3 g), repeated at 24 hours if no improvement.
• Bacterial meningitis when beta-lactams cannot be used, brain abscess, severe rickettsial infection in pregnancy or doxycycline intolerance.
• Eye infection: 0.5 percent drops or 1 percent ointment every 2 to 6 hours.
• Children (over 1 month): 12.5 to 25 mg/kg every 6 hours; neonates are given a lower dose with level monitoring.

Selection. Alternative first-line agent when a third generation cephalosporin is unavailable or contraindicated. Not used for minor infection.

Contraindications. Neonates (without level monitoring); late pregnancy and breastfeeding; previous aplastic anaemia or marrow suppression with chloramphenicol; porphyria.

Serious effects.

• Dose-related reversible marrow suppression (anaemia, leucopenia, thrombocytopenia), usually with serum levels over 25 mg/L or prolonged courses.
• Idiosyncratic aplastic anaemia, rare (about 1 in 25,000 to 40,000 courses), not dose-related, irreversible, may occur weeks to months after therapy and has been reported rarely after topical use.
• Grey baby syndrome in neonates (vomiting, abdominal distension, hypothermia, grey cyanosis, circulatory collapse).
• Optic and peripheral neuritis with long courses; haemolysis in G6PD deficiency.

Interactions. Inhibits CYP2C9, CYP2C19 and CYP3A4, raising levels of phenytoin, warfarin, sulphonylureas, tacrolimus, ciclosporin and phenobarbital. Rifampicin and phenobarbital lower chloramphenicol levels. Additive marrow toxicity with other myelosuppressive drugs.

Monitoring. Full blood count at baseline and twice weekly; stop if the neutrophil count falls under 1.5 x 10^9/L or platelets under 100 x 10^9/L. Serum levels where available: peak 10 to 25 mg/L, trough 5 to 15 mg/L (higher peaks accepted in meningitis), and always in neonates and hepatic impairment.

Special groups. Pregnancy: avoided near term (grey baby risk to the newborn). Breastfeeding: avoided. Hepatic impairment: reduce dose and monitor levels. Renal impairment: succinate ester accumulates, with no major dose change. Older adults: marrow toxicity risk. Region: chloramphenicol remains an accepted field treatment in meningitis belt outbreaks and in some typhoid settings.