BACKGROUND: Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. A major contributor in patients with unimpaired renal function may be Augmented Renal Clearance (ARC), wherein urinary creatinine clearance exceeds that predicted by serum creatinine concentration. We used pharmacokinetic data to evaluate the diagnostic accuracy of a recently proposed ARC score.
METHODS: Pharmacokinetic data from trauma/surgical intensive care unit patients receiving piperacillin/tazobactam were evaluated. We combined intermediate scores (4–6 points) into a single low score (≤6) group and compared pharmacokinetic parameters against the high (≥7) ARC score group. Diagnostic performance was evaluated using median clearance and volume of distribution, area under the antibiotic time-concentration curve (AUC), and achievement of free concentrations greater than a minimum inhibitory concentration (MIC) of 16 μg/mL for at least 50% of the dose interval (fT > MIC ≥ 50%). Alternative dosing strategies were explored in silico.
RESULTS: The ARC score was 100% sensitive and 71.4% specific for detecting increased clearance, increased volume of distribution, decreased AUC, and fT > MIC < 50% at an MIC of 16 μg/mL. The area under the receiver operating characteristic curve was 0.86 for each, reflecting a high degree of diagnostic accuracy for the ARC score. Serum creatinine less than 0.6 mg/dL had comparable specificity (71.4%) but was less sensitive (66.7%) and accurate (area under the receiver operating characteristic curve, 0.69) for detecting higher clearance rates. Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic drug levels with extended infusion dosing at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens.
CONCLUSION: Given its ability to predict antimicrobial clearance above population medians, which could compromise therapy, the ARC score should be considered as a means to identify patients at risk for subtherapeutic antibiotic levels. Adequately powered studies should prospectively confirm the utility of the ARC score and the role of antimicrobial therapeutic drug monitoring in such patients.
LEVEL OF EVIDENCE: Diagnostic tests, level III.
From the United States Army Institute of Surgical Research (K.S.A., K.L.N., K.K.C.); and Infectious Disease Service (K.S.A., C.K.M.), Department of Medicine, and Department of Surgery (J.W.C.), San Antonio Military Medical Center, Fort Sam Houston; and Department of Pharmacy Practice (J.M.C.), University of the Incarnate Word Feik School of Pharmacy, San Antonio, Texas; and Departments of Medicine (K.S.A., K.K.C., C.K.M.) and Surgery (J.W.C.), Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Submitted: November 20, 2013, Revised: December 21, 2014, Accepted: January 3, 2014, Published online: April 24, 2014.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, Department of the Air Force, or the Department of Defense.
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Address for reprints: MAJ Kevin S. Akers, MD, United States Army Institute of Surgical Research, 3698 Chambers Pass, JBSA Ft. Sam Houston, TX 78234-6315; email: firstname.lastname@example.org.