CHAPTER 22 VANCOMYCIN Jeremiah J. Duby, Monica A. Donnelley, Chelsea L. Tasaka, and Brett H. Heintz

Vancomycin is a tricyclic glycopeptide antibiotic that is active against many Gram-positive organisms. It is used principally for the treatment of severe and/or resistant staphylococcal and enterococcal infections and may also be used for moderate infections in patients who may be allergic to first-line antibiotics (e.g., penicillins). Vancomycin is bactericidal and acts by binding to the C-terminal D-alanyl- D-alanine residue of the pentapeptide cell wall building block, thereby inhibiting cell wall synthesis. Renal excretion is the primary route of elimination, and kidney injury is the principle toxicity associated with vancomycin use. Vancomycin represents parallel paradoxes in infectious disease and pharmacokinetics. First, it remains a first-line antibiotic for limb- and life-threatening infections due to multidrug resistant pathogens despite decades of use.1 However, avoidance of selective antibiotic pressure is increasingly contradicted by reports of declining susceptibility through minimum inhibitory concentration (MIC) creep.2 Second, vancomycin is the subject of more than 30 yr of intensive pharmacokinetic research and therapeutic drug monitoring; however, objectives for clinical management continue to evolve. The challenge is for practice changes to match the evolving threats of resistance and the slow pace of new antibiotic discovery. Clinicians must adapt to use of new dosing methods, targets, and tools (e.g., Bayesian estimation) as the potential risks and benefits of losing this critical antibiotic for patient care have never been greater.

USUAL DOSAGE RANGE IN ABSENCE OF CLEARANCE- ALTERING FACTORS

Initiation of therapy The foremost responsibility for initiation of therapy is determining why vancomycin is necessary. Antibiotic stewardship practices are essential to preserving the utility of the agent. The probability of multidrug resistant, Gram-positive infection must be investigated with a strong bias for discontinuation upon exclusion of a clear indication for therapy or resolution of infection. Consideration of patient- specific factors, source(s) of infection, pathogen, MIC, and potential kidney injury also play crucial roles in whether vancomycin is used, and how. Finally, individualized dosing is essential to maximize treatment success and mitigate the risks of toxicity.3

Dosing weight Actual body weight (ABW) appears to represent the anthropometric measure with the closest correlation to steady state volume of distribution (V) and to total body clearance of vancomycin.4 Weight-based dosing based on ABW is especially important for markedly obese patients as standard empiric dosing (e.g., 1 g intravenous [IV] every 12 hr) is likely to result in concentrations below the accepted therapeutic range.5 Additional detail is provided in following sections.

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Loading dose The primary advantage of a vancomycin loading dose is earlier attainment of target concentrations.6 Loading doses of 25–30 mg/kg (ABW) may be used for patients with normal renal function; however, lower doses (e.g., 20 mg/kg) may be appropriate for patients with stage 4 or 5 chronic kidney disease (CKD) (see Table 22-1).1 A clinical advantage to loading doses is indirectly inferred from a retrospective study of vancomycin pharmacodynamics. A more than 50% reduction in 30-day mortality rate and composite treatment failure was observed in patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections that achieved an area under the concentration-time curve over 24 hr relative to minimum 7 inhibitory concentration (AUC24/MIC) > 521 mg × hr/L within the first 24 hr of therapy (the AUC/MIC ratio is the pharmacodynamic parameter that indexes total drug exposure or the AUC over 24 hr to the MIC of the pathogen). The potential benefit of loading doses is therefore especially important for patients with critical illness.8 Delay to therapeutic concentrations may occur for patients with a larger V (e.g., obesity, renal failure) or impaired elimination if an insufficient loading dose (or no loading dose) is given. Patients with poor renal function may experience a lag in achieving therapeutic concentrations without an adequate loading dose, particularly if maintenance dose size is adjusted downward due to poor renal function. The time to achieve steady state concentrations is three times greater for a patient with half-life of 24 hr than for a patient with a half-life of 8 hr. There is no clinical evidence of a meaningful advantage to a loading dose with intermittent dosing in children with normal renal function, which is likely explained by the relatively high elimination rate and consequent short time to steady state.9 The focus for this population lies in providing a sufficient maintenance dose.

TABLE 22-1. SUGGESTED LOADING DOSES FOR ADULT PATIENTS

a,b Renal Function (mL/min) Suggested Load (mg/kg) Cpeak (mg/L) CrCl > 30 25–30 31–43 CrCl ≤ 30 20 25–29 a Estimated V = 0.7–0.8 L/kg. bRange of peaks that would occur if the loading dose (or dose range in CrCl > 30) were matched with the range of V.

Maintenance dose Elimination is dynamic because it is largely dependent on renal filtration, which is highly variable. Therefore, renal function represents the primary, clearance-altering factor for vancomycin dosing. The vancomycin package insert recommends 1 g every 12 hr for “patients with normal renal function.”10 Conventionally, normal renal function refers to creatinine clearance (CrCl) >60 mL/min as the standard for which renal dose adjustment is considered unnecessary. However, this assumption neglects a wide range of patients (i.e., CrCl of 90–250 mL/min), and may result in subtherapeutic dosing for young and hyperdynamic populations. Because renal elimination is the primary clearance-altering factor for dosing, determining maintenance dose is principally about estimating renal function. Unfortunately, the most common biomarker used to estimate renal filtration, serum creatinine (SCr), is commonly confounded by patient- specific factors such as age, chronic disease, nutrition, ethnicity, and body habitus. Further, SCr is a lagging indicator of function and can lead to over- and underestimates of CrCl during the dynamic phases of acute kidney injury.

DOSAGE FORM AVAILABILITY11 Vancomycin is available in oral and IV forms (see Table 22-2). Oral therapy is reserved for the treatment of pseudomembranous colitis. As systemic absorption is minimal, concentration monitoring is not warranted for most patients.