Thomas P Lodise1, Susan L Rosenkranz2, Matthew Finnemeyer2, Scott Evans3, Matthew Sims4, Marcus J Zervos5, C Buddy Creech6, Pratish C Patel6, Michael Keefer7, Paul Riska8, Fernanda P Silveira9, Marc Scheetz10,11, Richard G Wunderink11, Martin Rodriguez12, John Schrank13, Susan C Bleasdale14, Sara Schultz15, Michelle Barron16, Ann Stapleton17, Dannah Wray18, Henry Chambers19, Vance G Fowler20,21, Thomas L Holland20,21. 1. Albany College of Pharmacy and Health Sciences, New York. 2. Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 3. Department of Epidemiology and Biostatistics, Biostatistics Center, George Washington University, Washington, District of Columbia. 4. William Beaumont Hospital, Royal Oak. 5. Henry Ford Health System, Detroit, Michigan. 6. Vanderbilt University Medical Center, Nashville, Tennessee. 7. University of Rochester Medical Center. 8. Montefiore Medical Center, Bronx, New York. 9. University of Pittsburgh, Pennsylvania. 10. Department of Pharmacy Practice, Chicago College of Pharmacy, and Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove. 11. Northwestern Memorial Hospital, Chicago, Illinois. 12. Department of Medicine, University of Alabama at Birmingham. 13. Greenville Hospital System University Medical Center, South Carolina. 14. University of Illinois Hospital and Health Sciences System, Chicago. 15. Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania. 16. University of Colorado Denver, Aurora. 17. University of Washington Medical Center, Seattle. 18. Medical University of South Carolina, Charleston. 19. San Francisco General Hospital, California. 20. Duke Clinical Research Institute. 21. Duke University Medical Center, Durham, North Carolina.
Abstract
BACKGROUND: Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. METHODS: This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. RESULTS: Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). CONCLUSIONS: Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range.
BACKGROUND: Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. METHODS: This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. RESULTS: Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). CONCLUSIONS: Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range.
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