Relationship between Vancomycin Trough Concentrations and Nephrotoxicity: a Prospective Multicenter Trial

Abstract

Several single-center studies have suggested that higher doses of vancomycin, aimed at producing trough concentrations of >15 mg/liter, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to trough concentration in patients with documented methicillin-resistant Staphylococcus aureus (MRSA) infections at seven hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 h with at least one vancomycin trough concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin trough concentrations of >15 mg/ml and the occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, gender, race, dose, length of therapy, use of other nephrotoxins (including contrast media), intensive care unit (ICU) residence, episodes of hypotension, and comorbidities. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a >50% increase from the baseline for two consecutive measurements. MICs of vancomycin for the MRSA isolates were also determined. A total of 288 patients were studied between February 2008 and June 2010, with approximately one-half having initial trough concentrations of >15 mg/ml. Nephrotoxicity was observed for 42 patients (29.6%) with trough concentrations >15 mg/ml and for 13 (8.9%) with trough concentrations of <15 mg/ml. Multivariate analysis revealed vancomycin trough concentrations of >15 mg/ml and race (black) as risk factors for nephrotoxicity in this population. Vancomycin trough concentrations of >15 mg/ml appear to be associated with a 3-fold increased risk of nephrotoxicity.Staphylococcus aureus has become a major cause of serious infections in both community and institutional settings, with methicillin-resistant strains causing numerous invasive infections, especially those involving the bloodstream (2, 13, 34). Due to concerns with efficacy as they relate to adequacy of dosing and related plasma concentrations, it is currently commonplace to administer vancomycin in doses intended to achieve trough concentrations of 15 mg/liter or higher in the treatment of methicillin-resistant S. aureus (MRSA) infections. A consensus paper published in 2009 recommended that patients be dosed with this end in mind (30). Some practitioners have extrapolated these dosing recommendations with associated trough concentration goals to all vancomycin use. However, evidence of superior efficacy is lacking, and results of several single-center, mostly retrospective trials have suggested that this more aggressive dosing may be related to an increased incidence of vancomycin-related nephrotoxicity (12,14,18,20,27) and ototoxicity (9). The results and conclusions of these studies have been questioned, to varying degrees, due to design limitations, including the failure to account for other risk factors for renal compromise, and/or their single-center nature. Another relevant study, using Monte Carlo si...

Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 Milligrams per Liter

“…2). In addition, troughs of Ն15 mg/liter remained significantly associated with nephrotoxicity when articles (8,13,21,22,30,36,43) in which authors declared potential conflicts of interests with pharmaceutical companies were excluded (OR, 2.84; 95% CI, 1.65 to 4.87; P Ͻ 0.01).…”

“…The incidence of nephrotoxicity varied between studies from 5% to 43%. On average, nephrotoxicity occurred between 4.3 and 17 days after initiation of vancomycin therapy (13,21,22,30,32,36,38,39,43,51). The definition of nephrotoxicity was identical (increase in serum creatinine [S CR ] of 0.5 mg/dl, equivalent to 44.2 mol/liter or 50% from baseline on 2 consecutive measurements) in all but three studies ( Table 1).…”

Optimizing the Clinical Use of Vancomycin

“…A multicenter prospective clinical trial, including 288 adult patients (70), and a recent meta-analysis (71) have reaffirmed the high probability of nephrotoxicity with vancomycin trough levels of Ͼ15 mg/liter. This threshold is not uniform in all studies, and other authors have found that recommended dosages of vancomycin with target troughs of 15 to 20 mg/liter are not an independent risk factor for nephrotoxicity (72).…”

Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

“…In recent years, vancomycin dosing has escalated, driven by concerns of increasing treatment failure, thought to be the result of increasing vancomycin MICs (MIC creep) among S. aureus isolates (4)(5)(6). Consequently, this strategy may lead to increased rates of nephrotoxicity (7)(8)(9)(10). This risk appears to be highest for patients who are particularly vulnerable to acute kidney injury due to comorbidities such as preexisting renal disease, acute illness, hypoperfusion from sepsis, or concomitant nephrotoxic medication (10,11).…”