Is More Always Better? Rethinking Monotherapy for <i>Enterococcus faecalis</i> Infective Endocarditis

To the Editor—We read with great interest the article by Danneels et al [1] reporting on 1 of the largest observational cohorts of patients with Enterococcus faecalis infective endocarditis (EFIE). Mortality and relapse rates were compared across different treatment regimens and amoxicillin-ceftriaxone and amoxicillin-gentamicin appeared to be comparable. However, the amoxicillin monotherapy group (n = 9) had numerically higher mortality (3/9; adjusted hazard ratio = 1.94; 95% confidence interval [CI] = .56–6.74) and relapse (3/9; adjusted sub-hazard ratio = 2.38; 95% CI = .57–10.05) than amoxicillin-gentamicin. Based on these results, the authors suggested that amoxicillin monotherapy should not be used for EFIE. We wish to highlight some counterarguments to this position. First and foremost, the results were underpowered to draw conclusions. Second, there was likely confounding by indication. Adjunctive therapy is recommended as the standard of care for EFIE by the European Society of Cardiology guidelines [2, 3]. Given that this study was observational, the reason for which the amoxicillin group received monotherapy may have been related to factors inherently tied to a poorer outcome, such as prognosis or renal function. Along these lines, the models for mortality and relapse did not adjust for other important confounders such as paravalvular complications and embolic phenomena [4, 5]. Third, the analyses did not consider treatment as a time-dependent variable, which introduces immortal time bias. Adjunctive therapy is recommended for the treatment of EFIE and not E faecalis bacteremia without infective endocarditis (IE) [2]. Thus, adjunctive therapy may only be administered following a diagnosis of IE, whereas monotherapy is often administered at the outset for a positive culture with E faecalis. The difference in “time zero” between adjunctive and monotherapy groups renders the adjunctive group “immortal” to the outcome of death during the time between a positive culture for E faecalis to the administration of adjunctive therapy, whereas the monotherapy group can experience death throughout this time frame [6]. Finally, there was the potential for misclassification bias. The classification criteria in this study were not strictly defined a priori. For example, 3 patients classified as amoxicillin monotherapy received amoxicillin for only 13.3% of antibiotic days. These patients accounted for 2 of the 3 deaths, including a death after 1 day of amoxicillin monotherapy preceded by 25 days of daptomycin and levofloxacin. Given these limitations, we posit that a randomized controlled trial of monotherapy versus adjunctive therapy for EFIE is both ethical and needed, especially considering that both adjunctive ceftriaxone and gentamicin are associated with higher toxicity, cost, as well as the potential for increased colonization with resistant organisms [7–9].

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