Chapter 20

### INTRODUCTION

Vancomycin is a glycopeptide antibiotic, approved by the FDA in 1958, which is slowly bactericidal against most gram-positive organisms. It is active against Staphylococci (including penicillin- and oxacillin-resistant strains), Streptococci, Enterococci, and other gram-positive organisms. It exerts its bactericidal effect by complexing with the D-alanyl-D-alanine portion of the peptide precursor units on the outer surface of the cell membrane and interferes with cell wall synthesis.

During the first few decades of clinical use, vancomycin demonstrated consistent activity against gram-positive bacteria and became the drug of choice to treat most methicillin-resistant Staphylococcus aureus (MRSA) infections. However, due to the emergence and increased prevalence of vancomycin-resistant Enterococci (VRE), vancomycin intermediate (VISA) and resistant S. aureus (VRSA), and heterogenous VISA (hVISA), our confidence in vancomycin as a reliable bactericidal agent has decreased, motivating a renewed interest in appropriate utilization and optimal dosing of vancomycin.1, 2, and 3

### DOSING

Due to limited pharmacokinetic studies done when vancomycin was first approved in the late 1950s, it appears that the original intravenous dosing of 1,000 mg every 12 hours or 500 mg every 6 hours was derived arbitrarily. Also, the serum therapeutic ranges accepted for vancomycin of 5–10 mg/L were originally established as guidelines for dosage adjustments in patients with renal failure and was not validated by clinical outcomes. Because vancomycin was thought to be a time-dependent killer and sensitive vancomycin MICs (minimum inhibitory concentration) were ≤4 mg/L, these values were considered acceptable.2,3

It is more recently recommended that weight-based dosing be used to dose vancomycin, especially in more moderate/severe infections, and that dosing intervals be adjusted according to renal function.1 Depending on severity of infection, doses for patients with normal renal function range from 10–15 mg/kg administered intravenously every 8–12 hours. In clinical practice, doses are derived using weight-based dosing via dosing nomograms or by pharmacokinetic calculations. For the purpose of this chapter, we will be discussing vancomycin pharmacokinetic calculations for the adult patient.

### PHARMACOKINETICS/PHARMACODYNAMICS

Vancomycin is poorly absorbed from the gastrointestinal tract so it is only given intravenously when treating systemic infections (exception: treatment of Clostridium difficile–associated colitis with oral vancomycin). Vancomycin serum concentration-time profile has been described using one-, two-, and three-compartment pharmacokinetic models. The half-life of the first distributive phase is approximately 0.4 hours where as the half-life of the second distributive phase is about 1.6 hours. Plasma protein binding varies and ranges from 30–55 percent.1,3,4 The volume of distribution is variable and depends on many things such as fluid status, disease state, and age; range is from 0.4–1.0 L/kg.5, 6, 7, and 8 The elimination half-life is approximately 6 hours, and can be prolonged up to 7 days in patients with renal failure. Approximately 70–90 percent of the drug is excreted unchanged in the kidney ...

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