Continuous Infusion May Improve the Efficacy of Vancomycin in Treatment of Experimental Endocarditis Due to Heterogeneous Vancomycin-Intermediate Staphylococcus aureus

Abstract

We read with interest the paper of Entenza and coworkers suggesting failure of continuous vancomycin infusion against experimental endocarditis due to heterogeneous vancomycinintermediate Staphylococcus aureus (hVISA) and VISA (1). In that study, it was stated that continuous vancomycin infusion for 5 days was unsuccessful, as 20 mg/liter was barely active against hVISA PC1 (6 of 13 sterile vegetations) and 40 mg/liter failed against VISA PC3 (2 of 9 sterile vegetations). Generally speaking, we agree that in this experimental model vancomycin led to suboptimal treatment of VISA infection; however, we believe that some findings related to the role that continuous infusion may have in improving the outcome of vancomycin treatment of hVISA infections deserve attention. Indeed, in the hVISA PC1 model (vancomycin MIC, 2 mg/ liter), there was a misinterpretation of the results, since it appears from Fig. 1 in that paper that the number of sterile vegetations obtained by continuous infusion was higher than stated (7/13 and not 6/13). More importantly, compared with intermittent vancomycin administration (peak and trough levels of at least 50 and 10 mg/liter, respectively), continuous infusion with a constant serum drug concentration of 20 mg/ liter was significantly more effective in sterilizing hVISA PC1 vegetations (54% versus 18%, P 0.05). Although fewer than 100% of the vegetations were sterilized, it must be highlighted that continuous infusion was the only bactericidal regimen, since it led to a more-than-4-log reduction of the mean bacterial burden in the vegetations at day 5 compared to that in the controls (3.57 2.1 versus 7.64 0.4 log 10 CFU/g [P 0.001]), which is different from what occurred with intermittent infusion (6.82 3.1 log 10 versus 7.64 0.4 log10 CFU/g [no statistically significant difference]). These data suggest that continuous infusion of vancomycin may significantly improve the treatment outcome of experimental endocarditis due to hVISA. Indeed, the incomplete sterilization seen even after 5 days of continuous vancomycin infusion may be in line with the time-dependent activity of this glycopeptide, which may take a much longer time for complete healing to occur, especially if the bacteria are embedded in biofilm (2). However, it is worth noting that by ensuring that the concentration persistently exceeds a value of at least four to five times the MIC, this strategy may also reduce the selective pressure due to very low trough levels (3) and may avert the development of frank vancomycin resistance, even in cases of long-term treatment (4). Considering that a recent systematic review and meta-analysis of the clinical significance of hVISA isolates (5) showed that hVISA infections were associated with a glycopeptide failure rate 2.37-fold greater than that obtained with vancomycinsusceptible S. aureus infections, we do believe that these experimental data may support the idea that continuous infusion may be worthwhile with the intent to decrease the failure rate of vancomycin treatment of humans with hVISA infections.