Reply to White and Siegrist, “Multi-drug-resistant enterococcal infections: duration of combination therapy and OPAT challenges”

W e thank White and Siegrist for their interest in our manuscript that reviews the challenges of difficult-to-treat enterococcal infections (1).The authors wanted to highlight important issues on the duration of combination therapy and challenges with outpatient parenteral therapy (OPAT).The first point that White & Siegrist raised relates to the duration of combina tion therapy.We essentially agree with the authors that data are even more limited to make recommendations on the duration of combination therapy in bloodstream infections caused by multidrug-resistant Enterococcus faecium, particularly in the type of patient population often afflicted by vancomycin-resistant enterococcal (VRE) infections (immunocompromised individuals who often have undergone cancer chemotherapy for hematological malignancies, bone marrow transplant, or recipients of liver transplant).Thus, we focused on providing some guidance on high-risk patients (Figure 1 in Turner et al.) (2) for initial therapy, and we purposely avoided making strong statements on the duration of combination therapy.An individualized approach should be taken for each clinical scenario to determine if source control is achieved (a major issue in intra-abdominal infections after liver transplant), the presence of infective endocarditis or suspected endovascular infection (more frequently identified with E. faecalis than E. faecium), among others.With the above issues in mind, we feel it may be reasonable to de-escalate to monotherapy once the bacteremia is cleared, source control is achieved, and endovascu lar foci have been ruled out.Interestingly, previous pharmacokinetic/pharmacodynamic models suggest that the activity of daptomycin (DAP) against E. faecium strains with MICs below the susceptible dose-dependent range is not only concentration-dependent but also appears to be inoculum-dependent (3).Indeed, in simulated endocardial vegetation models, DAP monotherapy appeared to be effective at high doses at lower inoculum (ca. 10 7 CFU/g), supporting the de-escalation strategy once the bacterial load falls below a critical threshold.These data are consistent with the notion that an individualized approach is warranted, and the duration of therapy may vary according to the clinical scenario.Of note, we avoided using the term "complicated" bacteremia since definitions for this scenario are heterogeneous and difficult to standardize.Instead, we opted for a more patient-centric approach where the risk of poor outcomes is determined by individual patient characteristics.We also want to point out that the combination of DAP plus ampicillin might be useful for strains that have MICs above the current CLSI proposed breakpoints (>4 µg/mL) due to the robust see-saw effect that has been documented in vitro and in vivo (4).In this scenario, a more cautious approach should be taken since it is likely that DAP exposures would be grossly suboptimal even at higher doses (10-12 mg/kg), and combination therapy may be required for the entire duration of the treatment course.Again, robust clinical data to support these assumptions are lacking.