Influence of daptomycin dose and fosfomycin susceptibility on outcome of vancomycin-resistant Enterococcus faecium bloodstream infections treated with daptomycin and fosfomycin combination

Abstract

Abstract Objectives Synergistic combinations of daptomycin and β-lactam antibiotics are currently recommended for treatment of VRE bloodstream infection (BSI). The efficacy of these combinations is jeopardized by VRE inherently resistant to β-lactam antibiotics. The combination of daptomycin and fosfomycin is recommended as an alternative therapy for VRE BSI; however, clinical data to support use of this combination are lacking. Patients and methods We conducted a prospective observational multicentre study of patients treated with a combination of daptomycin and fosfomycin for VRE BSI during 2016–20. The primary outcome was 28 day mortality. Multivariable logistic regression was performed for outcome analysis. Results The study included 106 patients from 1112 VRE BSI episodes. The overall 28 day mortality was 40.6%. The median (IQR) daptomycin dose was 10.18 mg/kg (9.43–10.70). The fosfomycin dose was 16 g/day (8–22.5). Ninety-six isolates were available for MIC testing. The fosfomycin MIC was 32 mg/L in 6 (6.3%), 64 mg/L in 68 (70.8%) and ≥128 mg/L in 22 (22.9%) isolates. Independent of Charlson comorbidity index and Pitt bacteraemia score, fosfomycin MIC ≥128 mg/L [adjusted OR (aOR) = 3.05; 95% CI = 1.01–9.19; P = 0.047] and daptomycin dose (aOR = 0.64; 95% CI = 0.43–0.97; P = 0.04) predicted mortality. Conclusions Higher daptomycin dose and susceptibility to fosfomycin were independently associated with lower mortality in patients with VRE BSI. Our results suggest that higher doses of daptomycin are indicated for VRE BSI, whether or not it is used in combination with fosfomycin. The combination was less effective for patients with fosfomycin-resistant isolates.