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How Will AUC Monitoring With First-Order PK Equations Work in Practice?

Stephanie Hughes, PharmD
March 18, 2020

Summary:

  • First-order PK equations are one strategy for estimating vancomycin AUC recommended in the 2020 vancomycin guidelines
  • AUC monitoring of vancomycin using first-order PK equations requires drawing both peak and trough levels
  • Optimal prediction accuracy requires levels to be drawn precisely in relation to administered doses and after vancomycin reaches steady-state
  • AUC can be calculated manually with reasonable accuracy in stable patients, but may not fully account for a patient’s complete clinical status
  • Changes in sampling procedures will require education for nursing and/or phlebotomy staff to ensure accurate monitoring

Clinical Background

New consensus guidelines to be published in March 2020 recommend that vancomycin area under the 24-hour time-concentration curve (AUC24, often denoted AUC) be monitored in place of traditional trough-only monitoring, with an optimal therapeutic target for Staphylococcus aureus infections (assuming minimum inhibitory concentration of 1 mg/L) defined as an AUC of 400-600 mg/L*h. Because vancomycin follows first-order kinetics, clinicians may apply first-order pharmacokinetic (PK) equations to calculate AUC from patients’ serum vancomycin concentrations. If the estimated AUC is outside the recommended target range, clinicians are tasked with adjusting the vancomycin regimens and/or appropriately communicating dosing recommendations to achieve the intended targets. 

In addition to sampling vancomycin troughs at or near steady-state, using first-order PK equations for AUC calculations also requires measuring a “peak” vancomycin serum level one to two hours after the end of infusion. This level should also be drawn at or near steady-state in order to optimize accuracy of predictions. 

To calculate AUC24 from peak and trough levels, equations as reviewed by Pai et al. (2014) can be solved by hand, with spreadsheets, or using online calculators. Care must be taken to ensure that the AUC over the administered dosing interval is multiplied by the appropriate factor to calculate AUC24 (e.g., if vancomycin is given every 8 hours, the AUC for that interval must be multiplied by 3 to get AUC24).

Using first-order PK equations may slightly over or underestimate AUC. This is due to extrapolations involved in estimating serum concentrations during the alpha-phase—specifically, using a mono-exponential fit to estimate concentration decline. However, this method is still considered to be accurate and is recommended as one option when switching to AUC-guided vancomycin dosing.

Perhaps most importantly, consider that AUC calculations performed by this method represent only a snapshot of what was happening when the levels were taken. Therefore, changes in renal function or adjustments to dosing regimens in a 24-hour period will not be accounted for. This limitation is a key reason that the new vancomycin guidelines prefer Bayesian-derived AUC monitoring over first-order PK equations.

Operational Implications 

Implementing 2-level AUC monitoring in clinical practice will generally require education and training of all relevant clinical staff, including pharmacy staff, providers and advanced practice clinicians, nursing staff, and laboratory personnel. Policy and procedure documents may also need to be drafted and approved by the appropriate institutional committees. Education should particularly emphasize that:

  • Two timed levels will intentionally be ordered following the same dose of vancomycin:
  • Peak levels should be ordered for and drawn one to two hours after infusion is complete
  • Trough levels should be drawn just prior to the next dose administration
  • While trough levels >20 mg/L may require action (including holding subsequent doses), peak levels >20 mg/L are expected and should not prompt any action

Because proper timing of the blood draw is critical for accurate AUC estimation, pharmacists interpreting the levels must be aware of incorrectly timed sample draws, inaccurate documentation, or adjustments to administration times. Nursing staff should also notify pharmacists if a dose was given late, or if a level was taken at a time other than the time ordered. In any of these cases, the pharmacist will have to decide if the levels can still be interpreted or if a new set of levels should be ordered during the next dosing interval. Accurate level timing can be further complicated by diagnostic procedures, surgeries, or patient room transfers.3 Only after the peak and trough levels are accepted as appropriate and usable can a pharmacist calculate the AUC of that dosing interval.  

In conclusion, using first-order PK equations is one approach to adhere to the upcoming vancomycin guideline recommendation to switch to AUC-based dosing from trough-based dosing. The most apparent change will be that two vancomycin serum concentration levels will need to be taken, and education on this change will be crucial for implementation success. 

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