Clinical pharmacokinetics of vancomycin

Abstract

Vancomycin utilisation has increased dramatically in the last 10 years due to the increasing clinical significance of infections with methicillin-resistant staphylococci. Recent studies have focused on characterising the disposition of vancomycin in patients and assessing the relationship between serum concentrations and therapeutic as well as adverse effects. Although vancomycin is not appreciably absorbed from the intact gastrointestinal tract, several recent case reports have documented the attainment of therapeutic and potentially toxic vancomycin serum concentrations following oral administration to patients with pseudomembranous colitis. The disposition of parenterally administered vancomycin has been best characterised by a triexponential model. The half-life of the initial phase (t1/2 pi) is approximately 7 minutes, that of the second phase (t1/2 alpha) is approximately 0.5 to 1 hour, while the terminal elimination half-life (t1/2 beta) ranges from 3 to 9 hours in subjects with normal renal function. The volume of the central compartment (Vc) in adults is approximately 0.15 L/kg while the steady-state volume of distribution (Vdss) ranges from 0.39 to 0.97 L/kg. More than 80% of a vancomycin dose is excreted unchanged in the urine within 24 hours after administration, and the concentration of vancomycin in liver tissue and bile has been reported to be at or below detection limits. Vancomycin renal clearance approximates 0.5 to 0.8 of simultaneously determined creatinine or 125I-iothalamate clearances, suggesting that the primary route of renal excretion is glomerular filtration. Recently, non-renal factors such as hepatic conjugation have been proposed as an important route of vancomycin elimination. However, these data are difficult to reconcile with other studies showing minimal non-renal clearance of vancomycin in subjects with end-stage renal disease. As yet, the disposition of vancomycin in patients with hepatic disease has not been adequately defined. Only limited data are available regarding the concentrations of vancomycin in biological fluids other than plasma. The penetration of vancomycin into cerebrospinal fluid (CSF) in patients with and without meningitis has been quite variable. Although early studies suggested that adequate CSF concentrations may not be achieved in subjects with uninflamed meninges, more recent investigations have reported contradictory results. Therapeutic concentrations of vancomycin, i.e. greater than 2.5 mg/L, have, however, been reported in ascitic, pericardial, pleural and synovial fluids. Tissue concentrations of vancomycin have exceeded simultaneous serum concentrations in heart, kidney, liver and lung sp