Chloramphenicol pharmacokinetics in African children with severe malaria

Area of Science:

• Pharmacology
• Pediatric Infectious Diseases
• Clinical Pharmacy

Background:

• Severe malaria (SM) in children often requires presumptive treatment for bacterial meningitis.
• Chloramphenicol (CAP) is used, but its optimal dosing for achieving therapeutic plasma concentrations in this context is unclear.

Purpose of the Study:

• To evaluate if the current intravenous chloramphenicol sodium succinate (CAPS) dosage regimen achieves steady-state plasma concentrations within the 10-25 mg/l therapeutic range in children with severe malaria and presumptive bacterial meningitis.
• To determine the pharmacokinetic parameters of CAPS in this pediatric population.

Main Methods:

• Fifteen children with SM received intravenous CAPS (25 mg/kg every 6 hours for 72 hours).
• Plasma and cerebrospinal fluid (CSF) CAP concentrations were measured over 72 hours using high-performance liquid chromatography.
• Pharmacokinetic analysis, including clearance and CSF/plasma ratios, was performed.

Main Results:

• Average steady-state plasma CAP concentrations were approximately 17 mg/l, with a mean fraction unbound of 0.49 and a CSF/plasma ratio of 0.65.
• Trough plasma concentrations during the first dosing interval were low, averaging around 6 mg/l.
• Simulations suggested a loading dose of 40 mg/kg CAPS followed by maintenance doses would achieve target trough concentrations.

Conclusions:

• The current CAPS dosage regimen for SM with presumptive meningitis in children may not rapidly achieve therapeutic plasma CAP concentrations.
• Including a 40 mg/kg loading dose of CAPS is recommended to ensure plasma CAP levels remain within the 10-25 mg/l therapeutic range throughout treatment.