In vitro Antimicrobial Activity of Fosfomycin, Rifampin, Vancomycin, Daptomycin Alone and in Combination Against Vancomycin-Resistant Enterococci

Abstract

Purpose

The emergence of vancomycin resistant Enterococci (VRE) is shortening the choices for clinical anti-infective therapy. The aim of this study was to investigate the mechanism of vancomycin resistance and evaluate the effect of fosfomycin (FM), rifampin (RIF), vancomycin (VAN), linezolid (LNZ), daptomycin (DAP) alone or in combination against VRE.

Methods

Eight VRE isolates were collected. A total of 18 antibiotics susceptibility tests were further done for VRE. Whole genome sequencing and bioinformatics analysis were performed. The effect of FM, RIF, VNA, LNZ, DAP alone or in combination was determined using anti-biofilm testing and the time-kill assay.

Results

All isolates were susceptible to LNZ and DPA. The high-level resistance determinant of VAN in these strains was due to VanA-type cassette. MLST revealed two different STs for vancomycin-resistant Enterococcus faecium (VREm) and four different STs for vancomycin-resistant E. faecalis (VREs). Virulence genes in VREs were more than VREm, especially for 4942 isolated from blood. Gene acm and uppS were only identified in VREm, while virulence genes related to cytolysin were only found in E. faecalis. Further in vitro studies indicated FM (83 mg/L) combined with DAP (20.6 mg/L) and DAP monotherapy (47.1 mg/L) had bactericidal effect against VRE isolates at 24h.

Conclusion

High-level resistance determinant of VAN in tested isolates was due to VanA-type cassette. FM combined with DAP is a potential therapeutic option for VRE infections.

Keywords:

• vancomycin
• daptomycin
• combination therapy
• biofilm

Data Sharing Statement

The BioProject for VRE has been deposited at GenBank under the accession PRJNA662846 and PRJNA662849.

Ethics Approval

In our study, we did not perform any experiments with animals or higher invertebrates, neither performed experiments on humans nor the use of human tissue samples. Our data have been originated from bacteria which were frozen for antimicrobial resistance monitoring, not linked to clinical information. Therefore, our research was exempt from ethics approval.

Consent for Publication

All authors have seen and approved the content and fulfil the journal’s requirements for authorship.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by Department of Health of Zhejiang province [2019RC003].