In this episode, I’ll discuss the dosing of beta-lactam antibiotics in the setting of augmented renal clearance.
Augmented renal clearance (ARC) of medications has been reported in 30% to 85% of patients in the intensive care unit, depending on patient-specific factors.
A 2015 review article found that there is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes.
An ARC score, which is a weighted scoring system, may be used to predict whether a patient is at risk of ARC.
Patients get 6 points if they are 50 years or younger, 3 points if they are admitted for trauma, and 1 point if their SOFA score is 4 or less upon ICU admission.
An ARC score >7 is associated with 100% sensitivity and 71.4% specificity for detecting ARC. This correlates with a 75% positive predictive value and a 100% negative predictive value.
It has been proposed that an 8 hour urine collection for creatinine clearance calculation be obtained in critically ill patients with a serum creatinine less than 1.3 mg/dL and either an ARC score >7 or traumatic brain injury/subarachnoid hemorrhage. If the measured creatinine clearance is >130ml/min, higher doses of antibiotics should be considered to account for the augmented renal clearance.
For antibiotics with therapeutic drug monitoring, the effects of ARC are readily identifiable via drug levels, and adjustments can be made accordingly.
However, beta-lactam antibiotics do not have therapeutic drug monitoring options in most hospitals.
Beta-lactam antibiotics are primarily renally eliminated, and ARC would be expected to dramatically affect antibiotic exposure.
Beta-lactams exhibit a time-dependent pharmacodynamic profile. Maximal bactericidal activity occurs when the concentrations are 4–5 times the MIC. In addition, the time spent above the MIC should be about 50% of the dosing interval for most beta-lactams.
For this reason, prolonged or continuous infusions of beta-lactams will enhance the fraction of the dosing interval that is above the MIC in patients with ARC.
The doses of beta-lactams that have been studied for use in patients with ARC are as follows:
– Piperacillin-tazobactam 4.5 g over 4 hours every 6 hours
– Meropenem 2 g over 3 hours every 8 hours
– Cefepime 2 g over 3 hours every 6 hours
In the case of piperacillin-tazobactam and cefepime, these doses will have an 85% chance to attain the desired pharmacological target for MICs of 16.
In the case of meropenem, it is unclear whether MICs above 2 will attain the desired pharmacologic target. For this reason, I conservatively use a MIC of 2 as the cut off of feasibility for meropenem in patients with ARC.
It should be noted that a creatinine clearance of 130 mL/min is what most studies of beta-lactams in ARC have used. In patients with significantly higher creatinine clearances, alternative dosing strategies such as continuous infusions of cefepime or piperacillin-tazobactam should be considered.
If the MICs are found to be lower than 16 for piperacillin-tazobactam or cefepime, and 2 for meropenem, the intensity of antibiotic dosing may be scaled back.
Patients with dose adjustments made based on the presence of ARC should be monitored both for drug toxicity and for resolution of ARC.
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