Enterococcal Infections: Getting More Difficult to Treat

By Stan Deresinski, MD, FACP, FIDSA

Synopsis: Increasing resistance among enterococci dictates the need for careful antibiotic choices, even in the absence of high-quality clinical data.

Source: Turner AM, Kinsella P, Miller WR, et al. Therapeutic approach to difficult-to-treat multidrug-resistant enterococcal infections. Antimicrob Agents Chemother. 2025;69(10):e0106024.

A group of experts from Australia and the United States addressed the problem of antibiotic therapy selection in the face of the increasing incidence of infections caused by antibiotic-resistant Enterococcus faecalis and Enterococcus faecium. Their recommendations are based on a literature review of in vitro data and clinical reports. However, the latter are very limited in number and in quality of evidence.

The experts specifically focus on “difficult-to-treat” (DTR) enterococcal infections for which they have a broad understanding, taking into account the microbiological characteristics of the infection strain together with the patient characteristics and the treatment challenge posed by the pattern of antimicrobial resistance.

The experts recommend that when daptomycin is used, a dose of ≥ 11 mg/kg be administered to reduce the risk of the emergence of resistance (but with the increased risk of causing myositis). They advocate for the use of daptomycin in combination with ampicillin, ceftaroline, or ertapenem in DTR cases. Its use with fosfomycin also is discussed.

The investigators argue against the use of linezolid because they assess there is insufficient evidence of efficacy in these infections. There is even less clinical data with tedizolid. They also are skeptical of its value when used in combination with a second agent.

Eravacycline and omadacycline each have potent in vitro activity, but the authors point out the low concentrations achieved in the bloodstream may be problematic in cases of bacteremia.

Limited clinical data suggest that oritavancin may be a reasonable choice.

The authors discuss the emergence of ampicillin resistance as a result of changes in the organism’s PBP4 and provide recommendations for treatment of invasive infections caused by such isolates, as well as E. faecalis, that are penicillin-resistant but have retained in vitro susceptibility to ampicillin. In the latter case, they recommend ampicillin plus either daptomycin or gentamicin, vancomycin plus gentamicin, or linezolid alone. For E. faecium isolates resistant to both vancomycin and ampicillin, they recommend daptomycin plus ampicillin with consideration of a third active agent, such tigecycline or eravacycline. Other choices include linezolid alone or with another active agent, or oritavancin plus another active agent such as ampicillin.

Finally, the authors discuss the role of phage therapy, acknowledging the very limited relevant clinical data.

Commentary

The notion of DTR infections largely has revolved around gram-negative bacteria, but Turner and colleagues have applied it to Enterococcus, which often has become increasingly resistant to common antibiotics. While several somewhat newer antibiotics remain active, high-level clinical data supporting their efficacy has been minimal to absent. This is true especially regarding the use of these and older agents in combination.

Although this report cannot be considered a guideline, it does provide existing information that allows clinicians to make therapeutic decisions, albeit with the caveat that the decisions may necessarily be based on limited data.

Stan Deresinski, MD, FACP, FIDSA, is Clinical Professor of Medicine, Stanford University.