1643. Pharmacodynamics (PD) of Daptomycin (DAP) in Combination Therapy for Enterococcal Bloodstream Infection (BSI)
Session: Oral Abstract Session: Novel Therapies for Superbugs
Friday, October 5, 2018: 3:00 PM
Room: S 158
Background: DAP is frequently employed in combination with a second antibiotic for enterococcal BSI. We previously observed that a free drug area under the curve to MIC ratio (fAUC/MIC) >27.43 was predictive of survival when DAP was administered as monotherapy. The extent to which combination therapy affects DAP PD remains unexplored.

Methods: This study pooled data from 7 published trials assessing outcomes in DAP treated enterococcal BSI. fAUC/MIC was calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding, and baseline DAP MIC for each patient that received ≥72 hours of DAP as part of a combination antibiotic regimen. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis and confirmed by multivariable logistic regression. To control for comorbidities, the threshold was examined in the low-acuity patients only (APACHE-II score <21, Charlson co-morbidity index <5, or Pitt bacteremia score <4). Monte Carlo simulation was performed to determine the probability of target attainment (PTA) over a range of MICs.

Results: In total, 240 adults were included and 137 (57.1%) were alive at 30 days. A majority of patients (62.8%) were immunosuppressed. Combination therapy with DAP plus a β-lactam was observed in 187 (77.9%) patients and with a β-lactam and 1 other active agent in 34 (14.2%) patients. Low-acuity patients (n=135) were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% versus 20.0%, p=0.015). This difference remained significant when controlling for BSI source and immunosuppression (p=0.017). The PTA for a 6 mg/kg/day dose was 95.2% at MIC=2 mg/L and 43.0% at MIC=4 mg/L; PTA for a 12 mg/kg/day dose was 95.2% at 4 mg/L.

Conclusion: Compared with our previous observations for DAP monotherapy against enterococcal BSI, a lower DAP PD exposure was required when administered with at least one additional antibiotic. For combination therapy with DAP, a fAUC/MIC >12.3 was associated with 30-day survival. As part of an active combination therapy regimen, DAP 6 mg/kg/day was appropriate for treatment of BSI caused by enterococci with MICs ≤2 mg/L, while 12 mg/kg/day was optimal for isolates with MICs of 4 mg/L.

Lindsay Avery, PharmD1, Joseph L. Kuti, PharmD1, Maja Weisser, MD2, Adrian Egli, MD3,4, Michael J. Rybak, PharmD, MPH, PhD5, Evan J. Zasowski, PharmD, MPH, BCPS5,6, Cesar Arias, MD, PhD, FIDSA7, German Contreras, MD7, Pearlie Chong, MD, MSCR8, Samuel L. Aitken, PharmD9, Adam J. DiPippo, PharmD9, Jann-Tay Wang, MD, PhD10, Nicholas S. Britt, PharmD, MS11,12 and David P. Nicolau, PharmD, FCCP, FIDSA13,14, (1)Ctr. for Anti-Infect. Res. & Dev., Hartford Hospital, Hartford, CT, (2)Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland, (3)Department of Clinical Microbiology, University Hospital Basel, Basel, Switzerland, (4)Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland, (5)Anti-Infective Research Laboratory, College of Pharmacy, School of Medicine, Division of Infectious Diseases, Wayne State University, Detroit, MI, (6)Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, (7)Division of Infectious Diseases, University of Texas McGovern Medical School at Houston, Houston, TX, (8)Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX, (9)Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, (10)Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, (11)Research Department, Dwight D. Eisenhower Veterans Affairs Medical Center, Leavenworth, KS, (12)Department of Pharmacy Practice, University of Kansas School of Pharmacy, Kansas City, KS, (13)Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, (14)Division of Infectious Diseases, Hartford Hospital, Hartford, CT

Disclosures:

L. Avery, None

J. L. Kuti, Merck & Co., Inc.: Consultant and Grant Investigator , Consulting fee and Research support . Pfizer, Inc.: Consultant , Consulting fee . Theravance Biopharma: Grant Investigator , Research support . Shionogi, Inc.: Grant Investigator , Research support . Allergan: Scientific Advisor and Speaker's Bureau , Research support .

M. Weisser, None

A. Egli, None

M. J. Rybak, None

E. J. Zasowski, None

C. Arias, Merck & Co., Inc.: Grant Investigator , Research support . MeMed: Grant Investigator , Research support . Allergan: Grant Investigator , Research support .

G. Contreras, None

P. Chong, None

S. L. Aitken, None

A. J. DiPippo, None

J. T. Wang, None

N. S. Britt, Merck & Co., Inc.: Grant Investigator , Research support . Gilead Sciences, Inc.: Grant Investigator , Research support .

D. P. Nicolau, None

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