An evaluation of the combination of daptomycin and rifampin against vancomycin-resistant Enterococci isolated from the bloodstream of neutropenic patients

Purpose: Therapeutic options for vancomycin-resistant Enterococci (VRE) endovascular infections are limited.  This fact, along with the high morbidity and mortality resulting from these infections are cause for grave concern.  Our objective was to evaluate the activity of daptomycin in combination with rifampin against VRE using in vitro time-kill experiments.

Methods: VRE isolates (n=8) from the bloodstream of neutropenic patients from the University of Rochester Medical Center treated with the combination of daptomycin and rifampin were utilized.  Minimal inhibitory concentrations (MIC) were determined according to Clinical and Laboratory Standards Institute guidelines.  Time-kill experiments were performed at a starting inoculum of approximately 10⁸ colony-forming units (CFU)/mL over 48 hours using two VRE isolates.  A 5x4 concentration array of daptomycin alone (0,1,4,16,64mg/L) and in combination with rifampin (0,0.5,2,8mg/L) was evaluated.  Serial samples were withdrawn and bacterial counts were determined at 0,1,2,4,8,24,26,28,32, and 48 hours.

Results: All isolates were susceptible to daptomycin (MIC 0.5-2mg/L).  Daptomycin, at concentrations less than or equal to 4mg/L, alone and in combination exhibited limited activity with less than 1 log reduction in CFU/mL at 48 hours.  Conversely, rapid bactericidal activity was exhibited at 16 and 64mg/L with log reductions in CFU/mL at 24/48 hours of 3.80/3.97 and 4.73/5.58 respectively.  The addition of rifampin 0.5 and 2mg/L to high concentrations of daptomycin (64mg/L) provided an additional 2.36 and 2.46 log reduction in bacterial count at 48 hours, respectively.  Interestingly, there was a trend toward decreased activity of daptomycin 16 and 64mg/L when combined with high concentrations of rifampin (8mg/L) with log reductions in CFU/mL at 24/48 hours of 2.67/3.00 and 5.20/6.18 respectively. 

Conclusions: The combination of daptomycin and rifampin achieved bactericidal activity against a high bacterial density of VRE.  These results are promising and support further exploration of this combination as a potential therapeutic option for VRE endovascular infections.