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 (t_½π) is approximately 7 minutes, that of the second phase (t_½α) is approximately 0.5 to 1 hour, while the terminal elimination half-life (t_½β) 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 (Vd_ss) 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 specimens. The disposition of vancomycin in paediatric and geriatric patients appears to be primarily related to the degree of renal function. However, there is some evidence of altered tissue binding and/or tissue distribution in geriatric patients. Since significant interpatient variability has been reported, further investigation will be required to substantiate dosing recommendations for these patient populations. Vancomycin clearance is decreased and the elimination half-life progressively prolonged in association with declining glomerular filtration rate, but the volume of distribution at steady-state is not significantly correlated with declining renal function. Although marked variability in vancomycin clearance within a defined range of renal function has been observed, highly significant relationships between vancomycin clearance and creatinine clearance have been reported and may be utilised for the adjustment of dosage in this patient population. Haemodialysis provides no significant contribution to total body clearance of vancomycin, while haemoperfusion has produced prompt and sharp declines in vancomycin serum concentrations. Peritoneal dialysis clearances of vancomycin are markedly lower than those observed during haemodialysis or haemoperfusion. However, due to the longer course of this mode of dialysis, contribution to total body clearance may be significant for some patients. Although early reports suggested that vancomycin therapy was frequently associated with adverse events, several recent reports have indicated that vancomycin is extremely safe. Nephrotoxicity has been observed in approximately 5% of patients and is associated with trough serum vancomycin concentrations of 30 mg/L or greater. The combination of an aminoglycoside and vancomycin may significantly increase the risk of nephrotoxicity. A causal relationship between attainment of peak vancomycin serum concentrations of 25 to 50 mg/L and/or trough concentrations of 13 to 32 mg/L and ototoxicity has been reported. Ototoxicity may be reversed, if not prevented, by close monitoring of vancomycin serum concentrations. The remaining adverse reactions which have been reported do not appear to be related to vancomycin dosage or serum concentrations. The prospective design of vancomycin dosage regimens would appear to be warranted in adults with impaired renal function, elderly patients, morbidly obese patients, and paediatric patients. Although the pharmacokinetic profile of vancomycin is best described by a 2- or 3-compartment model, the collection of a sufficient number of serum concentrations to perform these characterisations in individual patients is not practical or cost-justified in routine clinical practice. Therefore an approach similar to that used for the aminoglycoside antibiotics would appear to be most practical.