New Regimen for Continuous Infusion of Vancomycin in Critically Ill Patients

Abstract

Vancomycin remains a primary treatment for infections caused by Gram-positive bacteria resistant to ␤-lactam antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and ampicillin-resistant enterococci (1). Despite extensive clinical use of vancomycin over recent years, the optimal dosing strategy for rapid achievement of therapeutic concentrations still remains a challenge for physicians. This is of particular interest for patients with septic shock, who require adequate antibiotic therapy, especially in terms of drug concentrations, from the early phase of treatment (2, 3). To rapidly achieve optimal vancomycin concentrations in such patients, a loading dose followed by a continuous drug infusion (CI) has been proposed (4).Although CI of vancomycin is increasingly used, especially in the intensive care unit (ICU), there is still a controversy as to whether this mode of administration provides better results than standard intermittent drug administration (II). Several studies have shown no differences in clinical efficacy or mortality between the two therapeutic strategies in infections with Gram-positive bacteria (4-6). However, Wysocki et al. (5) demonstrated that CI allowed faster achievement of target concentrations, presented less variability in drug concentrations, and resulted in reduced costs of therapy. Furthermore, a recent meta-analysis showed that CI was associated with a significantly lower risk of drug-related nephrotoxicity than II, despite the use of similar daily doses (6).Nevertheless, because of significant changes in vancomycin pharmacokinetics (PK) during critical illness, such as increased volume of distribution (V) and augmented clearance, the standard CI regimen (e.g., a loading dose of 15 mg/kg of body weight, followed by 30 mg/kg over 24 h for patients with normal renal function) (5) has been associated with inadequate drug concentrations in a high proportion of septic patients in the first 2 days of therapy (7). As such, Roberts et al. (8), using a population PK analysis, suggested that a vancomycin loading dose of 35 mg/kg, followed by daily doses adjusted to creatinine clearance (CrCL, ranging from 7 to 45 mg/kg/day), would rapidly achieve adequate drug concentrations in critically ill patients. Nevertheless, this approach has not been prospectively validated yet.Another important issue concerning vancomycin is that clinical efficacy is best predicted when the ratio between the area under the curve of drug concentrations over 24 h (AUC 0 -24 ) and the MIC for the pathogen isolated (AUC 0 -24 /MIC) exceeds 400 (9-12). To ensure optimal AUC 0 -24 /MIC ratios, several studies have proposed target serum drug concentrations between 15 and 30 mg/liter during CI of vancomycin (5, 13-15). Nevertheless, no study has evaluated the correlation between vancomycin concentrations and the achievement of an AUC 0 -24 /MIC ratio of Ն400 in critically ill patients, in particular during the first day of therapy.The aim of thi...

Vancomycin is commonly under‐dosed in critically ill children and neonates

“…These findings are also consistent with data for other drugs that are renally cleared, such as gentamicin, where increased doses are required in the intensive care setting secondary to an illness‐induced hyperdynamic state and consequent increased volume of distribution . Continuous infusions of vancomycin have been proposed as a solution to the poor attainment of therapeutic vancomycin concentrations with intermittent dosing . Overall, our data suggest that a more aggressive approach to vancomycin dosing in critically ill children and neonates is necessary.…”

“…36 Continuous infusions of vancomycin have been proposed as a solution to the poor attainment of therapeutic vancomycin concentrations with intermittent dosing. [37][38][39][40] Overall, our data suggest that a more aggressive approach to vancomycin dosing in critically ill children and neonates is necessary. Doses at the higher end of daily recommendations were required in older children, with 75% of children attaining therapeutic concentrations with doses >50 mg/kg/day.…”

Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

“…However, initiation of a vancomycin CI calls for a loading dose that quickly reaches blood levels of 20-30 mg/L [11,15] to cover isolates with vancomycin MICs of 1-2 mg/L. Thus, loading doses of 15-20 mg/kg are often recommended [11,12] but may frequently lead to subtherapeutic concentrations [15][16][17][18] . A simulation study using a one-compartment model applied to critically ill patients showed that a loading dose of 35 mg/kg could be necessary [15] , but also resulted in a large proportion of patients with supratherapeutic vancomycin concentrations [16] .…”

Using a Vancomycin PBPK Model in Special Populations to Elucidate Case‐Based Clinical PK Observations

“…Vancomycin is administered to critically ill patients with multiple underlying diseases, such as heart failure, chronic renal disease, and cirrhosis of the liver. It is also administered postoperatively for wound infection treatment 7, 8. Thus, multiple pathology and resultant changes to normal physiology may be the reason for the unexplained PK variability among patients.…”

“…It is also administered postoperatively for wound infection treatment. 7,8 Thus, multiple pathology and resultant changes to normal physiology may be the reason for the unexplained PK variability among patients.…”