Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint

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.

Keywords: Enterococcus; bacteremia; daptomycin; pharmacodynamics.

Figure 1.

CART-derived pharmacodynamic thresholds in (A) all patients and (B) the low-acuity cohort for the 30-day survival outcome. Survival thresholds were identified in low-acuity patients to control for unknown confounding variables, which may contribute to overall mortality risk. Low acuity was defined as the absence of any of the following conditions: APACHE-II score ≥21, Charlson comorbidity index ≥5, and Pitt bacteremia score ≥4. Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CART, classification and regression tree analysis; fAUC/MIC, area under the free drug concentration-time curve to minimum inhibitory concentration ratio.

Figure 2.

CART-derived pharmacodynamic thresholds in (A) all patients and (B) the low-acuity cohort for the microbiological response outcome. Low acuity was defined as the absence of any of the following conditions: APACHE-II score ≥21, Charlson comorbidity index ≥5, and Pitt bacteremia score ≥4. Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CART, classification and regression tree analysis; fAUC/MIC, area under the free drug concentration-time curve to minimum inhibitory concentration ratio. ^aDifference assessed by Fisher’s exact test.

Figure 3.

Monte Carlo simulation results for (A) males and (B) females. The probability of target attainment (PTA) was higher in simulations for female patients (Supplementary Table 2); however, both PTAs were either above or below 90% at each dose simulated, except for 10 mg/kg/day (males: 80.4%, females: 92.9%). Abbreviations: DAP, daptomycin; fAUC/MIC, area under the free drug concentration-time curve to minimum inhibitory concentration ratio; MIC, minimum inhibitory concentration.