Optimizing the Clinical Use of Vancomycin

Abstract

The increasing number of infections produced by beta-lactam-resistant Gram-positive bacteria and the morbidity secondary to these infections make it necessary to optimize the use of vancomycin. In 2009, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists published specific guidelines about vancomycin dosage and monitoring. However, these guidelines have not been updated in the past 6 years. This review analyzes the new available information about vancomycin published in recent years regarding pharmacokinetics and pharmacodynamics, serum concentration monitoring, and optimal vancomycin dosing in special situations (obese people, burn patients, renal replacement therapy, among others). Vancomycin efficacy is linked to a correct dosage which should aim to reach an area under the curve (AUC)/MIC ratio of ≥400; serum trough levels of 15 to 20 mg/liter are considered a surrogate marker of an AUC/MIC ratio of ≥400 for a MIC of ≤1 mg/liter. For Staphylococcus aureus strains presenting with a MIC >1 mg/liter, an alternative agent should be considered. Vancomycin doses must be adjusted according to body weight and the plasma trough levels of the drug. Nephrotoxicity has been associated with target vancomycin trough levels above 15 mg/liter. Continuous infusion is an option, especially for patients at high risk of renal impairment or unstable vancomycin clearance. In such cases, vancomycin plasma steady-state level and creatinine monitoring are strongly indicated.

FIG 1

Recommendations of a vancomycin loading dose (LD), to achieve early therapeutic levels, have been established after several studies evaluating trough serum vancomycin concentrations after an LD. In critically ill patients (CIP), trough vancomycin levels (mean ± SD) after a fixed LD of 2 g (≈30 mg/kg, n = 21 patients) was higher than in patients without an LD (n = 31) (P = 0.01) in an intervention observational study (31) (evidence level IIB [83]). In patients presenting to an emergency department (EDP), trough levels (mean ± SD) after an LD of 30 mg/kg (n = 50) were higher than without an LD (n = 49) (P < 0.001) in a randomized clinical trial (30) (evidence level IA [83]). Finally, in patients on hemodialysis (HD) (n = 15), trough serum levels (mean ± SD) after an LD of 20 mg/kg (32) were similar to those found in the above-mentioned two studies carried out in patients with normal renal function (evidence level IIC [83]).

FIG 2

Continuous (CoI) versus intermittent (InI) vancomycin infusion impact on mortality and nephrotoxicity has been evaluated through a systematic review and meta-analysis of vancomycin for the treatment of Gram-positive infections (34). The global mortality was not different between patients on CoI versus those on InI (RR, 1.03; 95% CI, 0.7 to 1.6; P = 0.9). On the contrary, nephrotoxicity was higher in patients receiving vancomycin InI than in those with CoI (P = 0.02).

FIG 3

The suggested steady-state concentrations to be reached in vancomycin continuous infusion (CoI) should be between 20 and 30 mg/liter (evidence level IIB [83]), to avoid nephrotoxicity. Spapen et al. (43), in a retrospective cohort study carried out in critically ill patients, found high acute kidney injury frequency in patients with vancomycin levels of >30 mg/liter (P < 0.01). Norton et al. (42), in a retrospective outpatient cohort, found high nephrotoxicity in patients with vancomycin levels of ≥32 mg/liter (P < 0.01). The diverse types of patients and the nonhomogeneous criteria to determine nephrotoxicity may explain the difference in the proportions of nephrotoxicity between the two studies.

FIG 4

The dosing vancomycin in patients undergoing intermittent hemodialysis, to achieve vancomycin trough concentrations between 15 and 20 mg/liter, must include a loading dosage of ≈20 mg/kg (evidence level IIB [83]), as suggested by a study carried out to develop a vancomycin dose calculator (Vandecasteele et al. [32]) and by several observational studies (Lin et al. [57], Rymarz et al. [58], and Jeremiah et al. [59]) (data expressed as mean ± SD). Thereafter, using pharmacokinetics data from 41 patients (32), the estimated doses for different intervals to the next hemodialysis may be 15, 25, and 35 mg/kg for 1-day, 2-day, and 3-day elapse times, respectively.

FIG 5

Burn patients have higher vancomycin clearance and lower serum trough levels than control patients, as found by Dolton et al. (64). In this context, vancomycin continuous infusion (CoI) may improve the achievement of the target serum trough levels (mean ± SD, solid bars) without increasing nephrotoxicity (gridded bars) (65), compared with patients receiving vancomycin intermittent infusion (InI) (evidence level IIC [83]).