Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections

Abstract

This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets.

Keywords::

• aminoglycoside
• antibiotic
• critical care
• glycopeptide
• infectious disease
• MRSA
• pharmacodynamic
• pharmacometrics
• Staphylococcus aureus

Financial & competing interests disclosure

C Stockmann is supported by the American Foundation for Pharmaceutical Education’s Clinical Pharmaceutical Sciences Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Despite more than 50 years of experience with vancomycin, uncertainty remains regarding the most appropriate dosing strategy for many disease states and unique patient populations.

• Vancomycin pharmacokinetics are well described using a two-compartment model. The majority of population pharmacokinetic analyses have reported that renal function exerts a strong influence on vancomycin clearance and that weight also influences both vancomycin clearance and volume of distribution.

• The relationship between vancomycin concentrations and bacterial killing is best described by the area under the concentration versus time curve (AUC) divided by MIC of the infecting pathogen (AUC/MIC).

• A vancomycin AUC/MIC ≥400 was associated with clinical success and rapid bacterial eradication among adult patients with methicillin-resistant Staphylococcus aureus-associated lower respiratory tract infections, which has formed the foundation for current vancomycin dosing guidelines.

• Population pharmacokinetic/pharmacodynamic modeling leverages historical data describing the variability in vancomycin pharmacokinetics and the range of bacterial MICs encountered in clinical practice to derive probability density functions for the likelihood of achieving specific pharmacokinetic/pharmacodynamic targets.

• Rapid changes in renal function, body composition and weight early in life complicate efforts to develop an optimal vancomycin dosing strategy for neonates and infants. Recently, a continuous infusion algorithm incorporating postnatal age, serum creatinine, birth weight and current weight was found to improve target concentration attainment in a prospective validation study.

• After 1 year of age, vancomycin clearance declines with increasing age and serum creatinine concentration. Dosing regimens that account for the influence of age, creatinine clearance and the susceptibility of the target organism (e.g., MIC) have been reported to improve pharmacokinetic/pharmacodynamic target attainment rates among children.

• Morbidly obese individuals feature similar vancomycin pharmacokinetics as compared with non-obese individuals; however, the total daily dose should be divided at least three-times per day to prevent potentially toxic peak concentrations.

• Due to high variability in non-renal clearance over time and differences between continuous renal replacement therapy modalities, individualized vancomycin dosing regimens are essential for patients with acute renal failure.

• Continuous infusion of vancomycin is increasingly being performed for critically ill adults due to its convenience and the potential to maintain therapeutic concentrations throughout the entirety of the dosing interval. For patients with altered pharmacokinetic profiles, continuous infusion of vancomycin may be warranted.

Notes