Chloramphenicol is commonly administered to infants and children. A wide interpatient variation in the apparent volume of distribution and elimination makes standard dosage recommendations an initial estimate: monitoring of serum concentration is mandatory, and empirical dose adjustment. Repeated assessment of serum chloramphenicol concentration causes discomfort, exposes the child to nosocomial infection and incurs costs. We seek to define the mechanism of the interpatient difference in chloramphenicol pharmacokinetics after intravenous administration. To achieve this goal, we will define the relationship of the kinetics of the two esters of chloramphenicol succinate, and the contribution of the known elimination pathway of chloramphenicol to total body clearance. One factor necessitating repeated measurement of serum chloramphenicol concentration is an increasing plasma clearance during a therapeutic course. We will test the hypothesis that early in disease interleukin 1, produced in response to infection with H. influenzae, inhibits metabolic clearance of chloramphenicol (hepatic P-450 activity). As the infection is eradicated, interleukin 1 levels decrease and P-450 activity is """"""""depressed."""""""" Data accumulated from this work defining how these differences occur will allow the development or rational chloramphenicol dosing guidelines in ill infants and children.
