ID: PK/PD of vancomycin against MRSA

steady-state

• the point at which a drug’s rate of administration equals its rate of elimination, leading to a stable concentration in the body

  • this means the drug levels fluctuate within a consistent range between doses, preventing excessive accumulation or subtherapeutic levels

• typically takes about 4-5 half-lives to reach

• influencing factors include the dose, dosing interval, drug half-life, and patient-specific factors (eg. renal function for vancomycin)

pharmacodynamic indicators for vancomycin

• AUC/MIC is the best pharmacodynamic parameter used to assess the effectiveness of time-dependent and concentration-dependent antibiotics like vancomycin

  • this is because it ensures optimal bacterial killing while minimizing toxicity risks, such as nephrotoxicity

• T>MIC (time above MIC) and Cmax/MIC is other parameters, but AUC/MIC is the best

AUC/MIC

• this is the area under the concentration-time curve over 24 hours divided by the minimum inhibitory concentration

  • by optimizing this ratio, vancomycin therapy can be effective, safe, and personalized for each patient

target AUC/MIC

• should be at least ≥ 400

• a range of 400-600 is the best because this range prevents the risk of nephrotoxicity while maintaining drug efficacy

  • this was studied with vancomycin efficacy at treating S. aureus, which is now used in general to achieve clinical effectiveness with MRSA

dangerous AUC/MIC

• when the AUC/MIC is > 600, this increases the risk of kidney damage

  • a range of 600-800 is usually nephrotoxic and thus, should be avoided

  • the nephrotoxicity risk even increases by 2.5x when the AUC ≥ 1300

trough

• the lowest level of a drug (in this case vancomycin) in the blood that is obtained typically right before the next dose is administered

  • this helps to assess drug accumulation, to ensure drug efficacy and try to prevent drug toxicity

  • typically with vancomycin, it is obtained prior to the 3rd or 4th dose to make sure vancomycin has reached its steady-state, to give us a more accurate depiction of how much vancomycin is actually in the patient’s blood

• for vancomycin, this method of measuring drug effectiveness/toxicity was used before AUC-guided dosing became preferred

  • this historically ranged from 15-20 mg/L for serious infections like MRSA or bacteremia

disadvantages to trough-based monitoring

• invasive and time-consuming

  • it requires frequent blood draws, which are uncomfortable for the patient and impractical for routine monitoring

  • they are not as accurate as AUC/MIC estimations

  • they don’t accurately predict the AUC/MIC, leading to potential over-dosing or under-dosing

• they are unreliable and prone to bias

  • they are truly accurate if they are measured at steady-state conditions in hemodynamically stable patients who have been receiving set scheduled regimens (eg. 1g q12h)

  • in stable patients, vancomycin doses must be administered at the exact times specified and they must be collected immediately prior to the next scheduled dose to ensure the value reflects the “lowest” concentration point during the dose interval

    • failure to collect them under these conditions will lead to imprecise and potentially erroneous dose adjustments

• nephrotoxicity risk

  • studies have shown that this method of drug monitoring can lead to unecessarily high exposure and renal toxicity, especially when targeting a range of 15-20 mg/L

  • vancomycin troughs of 15-20 mg/L result in daily AUC values that are associated with increased rates of acute kidney injury

    • lowering the trough range is also not a practical solution because troughs often don’t correlate with the AUC (bullet 2)

acute kidney injury (AKI)

• this is a common adverse event associated with vancomycin dosing

  • vancomycin is commonly nephrotoxic: it accumulates in proximal renal tubular cells, which triggers cellular oxidative stress and apoptosis leading to renal tubular ischemia and acute tubulointerstitial damage

• its incidence associated with vancomycin administration in clinical studies varies between 5% to 43%, with most events occuring after 4-5 days of treatment

  • attributable risk percentage is estimated to be 59% → most patients who receive vancomycin have a significant risk of this adverse event

• the extent of kidney damage increases as a function of the daily AUC and treatment duration

  • this just means that vancomycin-associated kidney damage is exposure and dosage related

consequences of vancomycin-associated acute kidney injury (VA-AKI)

• for most patients, this is mild and resolved within one week after discontinuation of therapy

  • it is a reversible and curable disease

• however, there are three major considerations with this:

  1. serum creatinine (SCr) is a crude biomarker that only increases after a substantial amount of kidney injury and decline in kidney functional status has already occurred

     • basically, the patient would have to “lose” ½ of their GFR in order to detect kidney damage

  2. even mild cases have been linked to a variety of adverse outcomes including increased in-hospital mortality, length of stay, and healthcare resource utilization

  3. data suggests that it is often accompanied by remote organ dysfunction, which increases a patient’s susceptibility to a number of conditions (eg. CVD events, infections due to immunosuppression, etc) over time

recommendations for vancomycin dosing and therapeutic drug monitoring

1. in patients with suspected or definitive serious MRSA infections, an individualized target AUC/MIC ratio of 400-600 (assuming a vancomycin MIC of 1 mg/L) should be advocated to achieve clinical efficacy while improving patient safety

   • if the vancomycin MIC is > 1 mg/L, this is unsafe for the patient → use a different agent

   • if the vancomycin MIC is ≤ 1 mg/L, we just assume it is 1, because this is safe for the patient

2. given the importance of early, appropriate therapy, vancomycin targeted exposure should be achieved early during the course of therapy, preferably within the first 24-48 hours

3. when the MIC is > 1, the probability of achieving an AUC/MIC target of ≥ 400 is low with conventional dosing

   • higher doses may risk unnecessary toxicity, and the decision to change therapy should be based on clinical judgement

   • some MRSA populations may be resistant/not susceptible, rendering the MIC > 1

4. when the MIC is < 1, it is not recommended to decrease the dose to achieve the AUC/MIC target

5. trough-only monitoring, with a target of 15-20 mg/L, is no longer recommended, based on efficacy and nephrotoxicity data in patients with serious infections due to MRSA

shift from trough-only monitoring to AUC-guided dosing

• this decision was established to minimize vancomycin-associated acute kidney injury (VA-AKI) while maintaining similar effectiveness

  • however, there is insufficient evidence to provide recommendations on whether trough-only or AUC-guided vancomycin monitoring should be used among patients with non-invasive MRSA or other infections

bayesian approach to AUC estimation

• the essence of this model is to use past data to predict future events → how a drug would affect a group of people based on who it had affected in the past

  • groups similar people together in that way

• this software only requires four specific components:

  1. a structural mathematical model that best describes the pharmacokinetics of a given agent

     • patient’s weight, GFR, Vd of the drug…

  2. a density file, which contains the parameter estimates and their associated dispersion for the embedded structural PK model

     • this is based among the population → for example, if we gave a population of people vancomycin and compared it to people who had ADEs to vancomycin (such as AKI), we can predict the effect that vancomycin would have on these patients based on their characteristics

  3. a patient file that contains their drug dosing and collected PK data

     • dose, effects, collected PK/PD data, or other patient-specific information

  4. a patient “target” file that contains the target exposure profuile and initial estimates of future dosing regimens

• with this information, the dose optimization software calculates a parameter value file for that patient

  • the dose optimization software then calculates the optimal dosing regimen based on the specified exposure profile in the target file

advantages to bayesian approach to AUC estimation

• innovative treatment schemes such as front-loading doses with a transition to a lower maintainence dosing regimen can be designed to rapidly achieve target concentrations within the first 24-48 hours among critically ill patients

  • can answer questions like: does the patient need a loading dose? how much?

• concentration-time information does not need to be collected at “steady-state” (after the 3rd to 4th dose)

  • based on vancomycin’s half-life instead

• they are dynamic and continuously learning over time

  • the more information you give it, the better predictions it can make

• it has the ability to include covarieties, such as creatinine clearance, in the structural PK models (density file) that accounts for the pathophysiological changes that readily occur in critically ill patients

• it is preferred to obtain two PK samples to estimate the AUC

  • a trough concentration alone may ne sufficient to estimate the AUC in some patients using this software, but more data accross different patient populations are needed to confirm the viability of trough-only data

disadvantages to bayesian approach to AUC estimation

• there are current limitations to widespread use of the dose optimization software that would be needed for a large-scale hospital or systemwide implementation

  • cost

  • educational barriers

  • logistical barriers (eg. compatibility and integration with existing electronic medical record systems)

equation-based approach to AUC estimation

• post-distributional peak (1-2 hours post infusion) and trough concentrations can be used to determine the daily AUC value with reasonable precision and low bias with simple first-order PK formulas

• they are simple and free to use, and can be programmed into electronic medical systems or excel spreadsheets to automatically compute the AUC

• they require peak/trough or steady-state/trough

• AUC levels are obtained at the first dose or at steady-state, and precise timing is required

disadvantages of equation-based approach to AUC estimation

• it is highly preferable to have concentration time data over same dosing interval (peak and trough data)

  • peaks should always be about the same

• it can only provide a snapshot of the AUC for the sampling period

• it may result in unreliable AUC estimates when vancomycin is not near the steady-state conditions, or if the patient is not stabilized on a regimen for ≥ 24 hours

• AUC calculations will not be correct if a physiologic change such as renal dysfunction occurs during or after the sampling period