Lindsay M Avery1, Joseph L Kuti1, Maja Weisser2, Adrian Egli3,4, Michael J Rybak5, Evan J Zasowski5,6, Cesar A Arias7,8,9, German A Contreras7, Pearlie P Chong10, Samuel L Aitken11, Adam J DiPippo11, Jann-Tay Wang12, Nicholas S Britt13,14, David P Nicolau1,15. 1. Center for Anti-infective Research and Development, Hartford Hospital, Connecticut. 2. Division of Infectious Diseases and Hospital Epidemiology. 3. Division of Clinical Microbiology, University Hospital Basel. 4. Applied Microbiology Research, University of Basel, Switzerland. 5. Anti-infective Research Laboratory, College of Pharmacy, School of Medicine, Division of Infectious Diseases, Wayne State University, Detroit, Michigan. 6. Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy. 7. Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, University of Texas Health Science Center, McGovern Medical School at Houston. 8. Center for Infectious Diseases, University of Texas Health Science Center, School of Public Health, Houston. 9. Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Colombia. 10. Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas. 11. Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston. 12. Department of Internal Medicine, National Taiwan University Hospital, Taipei. 13. Research Department, Dwight D. Eisenhower Veterans Affairs Medical Center, Leavenworth. 14. Department of Pharmacy Practice, University of Kansas School of Pharmacy. 15. Division of Infectious Diseases, Hartford Hospital, Connecticut.
Abstract
BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.
BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.
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