Bacteriophage and antibiotic combination therapy for recurrentEnterococcus faeciumbacteremia

Enterococcus faeciumis a member of the human gastrointestinal (GI) tract microbiota but can also cause invasive infections, especially in immunocompromised hosts. Enterococci display intrinsic resistance to many antibiotics, and most clinicalE. faeciumisolates have acquired vancomycin resistance, leaving clinicians with a limited repertoire of effective antibiotics. As such, vancomycin-resistantE. faecium(VREfm) has become an increasingly difficult to treat nosocomial pathogen that is often associated with treatment failure and recurrent infections. We followed a patient with recurrentE. faeciumbloodstream infections (BSIs) of increasing severity that ultimately became unresponsive to antibiotic combination therapy over the course of 7 years. Whole genome sequencing (WGS) showed that the patient was colonized with closely relatedE. faeciumstrains for at least two years, and that invasive isolates likely emerged from a largeE. faeciumpopulation in the patient’s GI tract. The addition of bacteriophage (phage) therapy to the patient’s antimicrobial regimen was associated with several months of clinical improvement and reduced intestinal burden of VRE andE. faecium. Eventual recurrence ofE. faeciumBSI was not associated with the development of antibiotic or phage resistance in post-treatment isolates. However, an anti-phage neutralizing antibody response occurred simultaneously with an increased relative abundance of VRE in the GI tract, both of which may have contributed to clinical failure. Taken together, these findings highlight the potential utility and limitations of phage therapy to treat antibiotic-resistant enterococcal infections.ImportancePhage therapy is an emerging therapeutic approach for treating bacterial infections that do not respond to traditional antibiotics. The addition of phage therapy to systemic antibiotics to treat a patient with recurrentE. faeciuminfections that were non-responsive to antibiotics alone resulted in fewer hospitalizations and improved the patient’s quality of life. Combination phage and antibiotic therapy reducedE. faeciumand VRE abundance in the patient’s stool. Eventually an anti-phage antibody response emerged that was able to neutralize phage activity, which may have limited clinical efficacy. This study demonstrates the potential of phages as an additional option in the antimicrobial toolbox for treating invasive enterococcal infections and highlights the need for further investigation to ensure phage therapy can be deployed for maximum clinical benefit.