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.
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