Breakthrough daptomycin-, linezolid-, vancomycin-resistant Enterococcus faecium bacteremia during protracted daptomycin therapy: A case report

Abstract

Infections with multidrug resistant (MDR) Enterococcus faecium (Efm) are a growing problem. Vancomycin resistance in enterococci has long challenged treatment, necessitating the use of linezolid or daptomycin. Subsequently, daptomycin-, linezolid-, vancomycin-resistant Efm (DLVRE) infections have emerged. Case reports and guidelines for treating DLVRE infections are limited. Here, we describe the clinical and laboratory management of an MDR Efm protracted intraabdominal (IA) infection and breakthrough DLVRE bacteremia. Serial Efm resistance was evaluated using whole genome sequencing (WGS), susceptibility testing, and synergy analysis. Prior to in vitro synergy testing, combination antimicrobial therapy with daptomycin (DAP) and ceftaroline (CPT) was employed to treat the patient's central line-associated DLVRE bloodstream infection. In vitro antimicrobial testing revealed no synergy between daptomycin and ceftaroline; however, the patient's bacteremia cleared following initiation of both in conjunction with catheter removal. Sequencing of the DLVRE isolates revealed multiple genomic mutations which explained both linezolid and daptomycin resistance phenotypes and confirmed the presence of a plasmid containing the vanA operon. Sequential WGS of two additional bacterial isolates from the same patient revealed protracted colonization with a single DLVRE clone and suggested the development of bacterial subpopulations. Pairing clinical isolate susceptibilities with WGS and synergy testing should be encouraged in clinical practice to better inform antimicrobial management in cases of multidrug resistance.

Keywords: CLABSI, central line-associated bloodstream infection; CPT, ceftaroline; Case report; DAP, daptomycin; DLVRE, daptomycin-, linezolid-, vancomycin-resistant Enterococcus faecium; DNSE, daptomycin-non-susceptible enterococci; Daptomycin-resistance; Efm, Enterococcus faecium; IA, intraabdominal; LLQ, left lower quadrant; LZD, linezolid; Linezolid-resistance; MDR, multidrug resistant; MIC, minimal inhibitory concentration; PBP5, penicillin binding protein 5; PICC, peripherally inserted central catheter; POD, post-operative day; ST, sequence type; Synergy antimicrobial resistance testing; Vancomycin-resistant Enterococcus faecium; WGS, whole genome sequencing; Whole genome sequencing; p1–5, plasmids 1–5.

Fig. 1

Timeline of antimicrobial treatment andE. faeciumisolate recovery. Post-operative day and Efm isolate recovery profiles (V, vancomycin; L, linezolid, D, daptomycin; bottom) are shown together with antibacterial and antifungal treatment regimens. Vancomycin-resistant enterococci (VRE) targeted antimicrobials are highlighted in orange and other antimicrobials are presented in light grey. Isolate post-operative day recovery dates are highlighted in blue. Inverted carrots signify that the antimicrobial agent in question was continued throughout the time period in question. Two vertical forward slashes denote time breaks.

Fig. 2

Alignment of plasmid 3 from Isolates 4 and 5 to the vancomycin resistance plasmid 3 of Isolate 3. Regions present in Isolate 4 and 5 draft genomes are indicated in purple and green respectively. Identified resistance genes are indicated in black.