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Vancomycin dosing: Area Under the Curve versus Trough

17 Jan 2020 11:42 AM | Anonymous

Author: Miriam Chikodili Oguejiofor, Pharm.D

Learning Objectives:

  1. Understand the issues associated with trough-based vancomycin monitoring
  2. Identify scenarios where AUC-based vancomycin dosing approach may not be necessary
  3. Describe the benefits and limitations of the Bayesian and Equation-based approaches of AUC determination

Vancomycin is the antibiotic of choice for empiric and definitive treatment of methicillin resistant Staph aureus (MRSA) infection. Despite its introduction over half a century ago, controversies still exist regarding the optimum dosing regimens and pharmacokinetic/pharmacodynamic properties of vancomycin.1 Vancomycin drug monitoring continues to be a focus of pharmacists working both inpatient and at outpatient infusion centers due to its wide interpatient and intrapatient pharmacokinetic variability and vancomycin-induced nephrotoxicity (VIN). The therapeutic targets of vancomycin have evolved over time. The ratio of the 24-hour area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC) best characterizes the effectiveness of vancomycin as initially demonstrated by an experimental murine infection model.2

Moise-Broder and colleagues provided the first clinical evidence supporting AUC as a therapeutic target. They demonstrated improved time to pathogen eradication in patients with S. aureus pneumonia who achieved an AUC:MIC of at least 350 mg.hr/L.3 Subsequently, increasing data have been published supporting the AUC:MIC as the therapeutic target associated with improved outcomes. However, a trough targeted approach has been used for vancomycin monitoring due to a perceived difficulty associated with determining vancomycin AUC values in “real time” and a lack of clearly defined AUC:MIC targets.1,4

In 2009, the Infectious Disease Society of American, American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists published a consensus guideline on the therapeutic monitoring of vancomycin in adults. It was suggested that monitoring of pre-dose trough concentrations is “the most accurate and practical method for monitoring efficacy” and that the optimally timed sample should be obtained under steady state conditions in adults with normal renal function. The guideline abandoned the measurement of peak vancomycin concentrations with the rationale that there was no data correlating such peak concentration with either efficacy or vancomycin-associated toxicity. The guideline recommended that a ratio of the 24-hour area under the concentration-time curve (AUC0-24) to the MIC (AUC/MIC ratio) that is ≥ 400 times the MIC for the organism should be targeted for clinical effectiveness. The committee asserted that vancomycin trough concentration is a good surrogate for the AUC in adults with normal renal function (CrCl ≥ 100 ml/min). It was also recommended that vancomycin trough be maintained above 10 mcg/ml for all infections and a goal of 15 to 20 mcg/ml should be targeted for complicated infections such as bacteremia, osteomyelitis, endocarditis, meningitis and S. aureus (MRSA) pneumonia. This higher trough goal value of 15-20 mcg/ml would correlate with an AUC target of ≥ 400 mg.hr/L when the vancomycin MIC is ≤ 1 mg/L.1, 5-9

These recommendations have been integrated into clinical practice. However, the clinical benefits of maintaining higher vancomycin trough have not been well-defined.10 In addition, as vancomycin doses are increased in attainment of target trough goal for these complicated infections, so did reported instances of vancomycin-associated nephrotoxicity. Even trough values within the target range of 15-20 mcg/ml are associated with increased incidence of nephrotoxicity relative to troughs < 15 mcg/ml.10-13 The result of the study conducted by Hale et al showed that although patients with trough levels >10 mcg/ml were more likely to achieve the pharmacodynamic AUC24:MIC target than those with trough levels < 10 mcg/ml, there was no statistically significant increase in AUC24:MIC target attainment with trough levels > 15 mcg/ml. The study also showed that patients who developed VIN had a mean trough of 19.5 mcg/ml compared to 14.5 mcg/ml in patients who did not. Thus, targeting a higher trough goal increased the risk of toxicity but did not increase the proportion of patients achieving the pharmacodynamic target.14

Using a 5,000-patient Monte Carlo simulation, Neely and colleagues estimated that about 60% of patients could achieve therapeutic AUC values with trough concentration of < 15 mcg/ml assuming a vancomycin MIC value of ≤ 1 mcg/ml. They support a reassessment of target serum levels of vancomycin given the aggressive trough concentrations (>15 mcg/ml) may not be necessary to achieve the desired AUC targets.2,5

Presently, a distinct threshold for toxic AUC exposure is undefined; however, an AUC based vancomycin dosing approach may be preferred to a trough-based approach due to potential benefits of safety and effectiveness. It is important for institutions to consider scenarios where AUC-based dosing might not be necessary prior to its implementation. A controversial scenario is for the treatment of meningitis or CNS infections. While the guidelines (strong recommendation, low quality evidence) support target trough of 15-20 mcg/ml, recent studies have emerged demonstrating increased toxicity associated with higher troughs. Thus, institutions must weigh the risk and benefits of targeting troughs over AUC. Another scenario where institutions can possibly avoid AUC-based dosing is in patients receiving renal replacement therapy in whom the duration of dialysis session and timing inconsistency can lead to unpredictable vancomycin elimination rate. Also, in patients with acute kidney injury, it is difficult to predict a standard maintenance dose due to unpredictable vancomycin clearance. Hence trough-based dosing as well as dosing by level is a better approach in these patients. However, AUC-based strategy should be initiated once renal function stabilizes. Of note, patients with stable chronic kidney disease (CKD) who are not receiving renal replacement therapy should be appropriate candidates for AUC-based dosing. In patients receiving vancomycin for surgical prophylaxis, AUC-based dosing strategy might be unnecessary since the anticipated duration of vancomycin therapy is short and routine serum concentration monitoring will not affect patients’ outcomes. Furthermore, some institutions may choose to exclude skin and soft tissue infections (in the absence of hemodynamic instability and/or bacteremia) as clinical trials support the standard weight-based vancomycin dosing without a need for any monitoring for short-course therapy.2

Vancomycin AUC can be determined using a Bayesian approach or an equation-based methodology such as trapezoidal model or first order equation. The Bayesian method is based on Bayes’ Theorem - “a theorem of conditional probabilities that describes how evidence from previous experiences and the likelihood of separate events are related”. First it provides estimates of an individual patient’s pharmacokinetic (PK) parameters such as volume of distribution, clearance prior to vancomycin administration based on the way the drug behaved in prior patient population that received vancomycin (the Bayesian prior). Secondly, after a given drug regimen and obtaining a single level from a patient, a revision of the pharmacokinetic estimates is provided. This estimate known as the Bayesian conditional posterior can be used to estimate a patient’s specific AUC. There are several advantages of the Bayesian approach over the traditional first-order equation method: i) Vancomycin concentrations can be obtained at any time, even over different dosing intervals. ii) Sample collection is not limited to trough and samples do not necessarily have to be taken under steady-state conditions. iii) It is an adaptive program as samples collected within the first 24-48 hours and the information obtained are used to influence subsequent dosing. iv) It accounts for the pathophysiological changes that readily occur in patients especially in critically ill patients by including covariates such as creatinine clearance in the PK models. These covariates which represent the dynamic changes are used to identify dosing schemes and predict future dosing in a patient whose PK profile is evolving. However, further studies on the incorporation of these covariates are required. A primary limitation of the Bayesian approach is the cost of the software which varies in price depending on the program type and the subscription model. Also, the Bayesian approach relies on many assumptions which tend to overestimate the AUC.1,4

The equation-based approach involves obtaining two levels during the same dosing interval drawn at steady state: a distributional peak (1-2 hours post infusion) and a trough. The levels are used to calculate a patient’s PK parameters which are then incorporated into equations such as trapezoidal formula to calculate a patient’s AUC for a single dose. To determine the AUC 24, the single dose must be multiplied by the number of daily doses administered. The equation-based approach relies on fewer assumptions and provides a” real-world” snapshot of the patient-level information which can be rapidly translated for clinical use. In addition, it does not require the purchase of a special software. Limitation of the equation-based model include sampling must be done at steady state since it only provides a snapshot of the AUC for the sampling period and cannot account for potential changes in AUC due to continuing physiologic changes. There is a possibility that the AUC may be slightly underestimated since it is unable to account for the entirety of the administrative and distributive phases. A key issue to consider when applying the equation-based approach is the optimal sampling window for collection of peaks as samples if collected too early lead to flawed results. However, the equation-based approach is a viable option for smaller hospitals and other institutions with cost concerns. Generally, the equation-based approach has been validated to have similar accuracy and bias as the Bayesian approach.1,4

In this modern era where individualized therapies are recognized, a one-size-fits-all approach to drug dose delivery may no longer be appropriate. Implementation of the AUC:MIC based vancomycin dosing is aimed at optimizing patient outcomes and minimizing toxicity. However, it presents a new challenge to pharmacists who will work towards educating themselves and other healthcare professionals about this change. With the anticipated transition in vancomycin dosing to AUC, hospitals and healthcare institutions must consider the pros and cons and decide which approach best meets the needs of both their institutions and their patients.

References

  1. Stevens R, Balmes, F. Use AUC to optimize vancomycin dosing. Pharmacy Times. https://www.pharmacytimes.com/publications/health-system edition/2019/march2019/use-auc-to-optimize-vancomycin-dosing. (Accessed November 02, 2019).
  2. Heil E, Claeys K, Mynatt R et al. Making the change to area under the curve-based vancomycin dosing. American Journal of Health-Syst Pharm. 2018; 75: 1986-1995
  3. Moise-Broder P, Forest A, Birmingham M, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory track infections. Clinical Pharmacokinet. 2004; 43:925-940
  4. Pai M, Neely M, Rodvoid K, et al. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Advanced Drug Delivery Reviews. 2014; 77: 50-57
  5. Neely M, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrobial agents and Chemotherapy. 2014; 58:309-316
  6. Rybak M, Lomaestro B, Rotschafer J, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American J. Health Syst. Pharm. 2009; 66:82-98
  7. Suzuki Y, Kawasaki K, Sato Y, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant Staphylococcus aureus pneumoniae. Chemotherapy. 2012; 58:308-312
  8. Elbarbry F. Vancomycin dosing and monitoring: critical evaluation of the current practice. Euro Journal of Drug Metab Pharmacokinet. 2018; 43:259-268
  9. Neely M, Kato L, Youn G et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. American Society for Microbiology. 2018; 62: 204-217
  10. Chung J, Oh M, Cho E, et al. Optimal dose of vancomycin for treating methicillin-resistant Staphylococcus aureus pneumonia in critically ill patients. Anaesth. Intensive Care. 2011; 39: 1030-1037
  11. Hal v, Paterson D, Lodise T, et al. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. 2013; 57: 734-744
  12. Chevada R, Ghosh N, Sandaradura M, et al. Establishment of an AUC0-24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicob agents and Chemotherapy. 2017; 61:2535-16
  13. Jung Y, Song K, Cho J et al. Area under the concentration-time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteremia. Intl Journal of Antimicrobial agents. 2014; 43:179-183
  14. Hale M, Seabury R, Steele J et al. Are vancomycin trough concentrations of 15 to 20 mg/l associated with increased attainment of an AUC/MIC ≥ 400 in patients presumed with methicillin-resistant Staphylococcus aureus infection? Jour of Pharm Practice. 2017; 30: 329-335.

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