SLR - May 2019 - Melissa M. Journot

In Vitro Activity of Oritavancin Alone or in Combination Against Vancomycin-Susceptible and –Resistant Enterococci

Reference: T. Wu, K. Meyer, A.T. Harrington, L.H. Danzizger and E. Wenzler. In Vitro Activity of Oritavancin Alone or in Combination Against Vancomycin-Susceptible and –Resistant Enterococci. Journal of Antimicrobial Chemotherapy. 2019 January 2.
 

Scientific Literature Review

Reviewed By: Melissa M. Journot, DPM

Residency Program: Truman Medical Center Lakewood, Kansas City, MO

Podiatric Relevance: Treatment for susceptible and resistant enterococci can be difficult, and it is recommended to perform combination therapy. This study uses oritavancin alone and in combination to achieve optimal treatment in serious infections and reduction in bacteria. This study looked at how oritavancin performs when it is combined with ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin versus alone against enterococci strains.
 

Methods: Five different enterococcal strains, three of the strains were resistant VanA-type enterococcus faecium (VRE S38141, H19570, W21579), vancomycin resistant VanA-type Enterococcus faecium (ATCC 7002210) and vancomycin-susceptible VanA-negative Enterococcus faecalis (ATCC 29212). Analytical grade ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin were purchased commercially, and oritavancin was provided by the Medicine Company. MICs determined in triplicate via broth microdilution; detection of high-level aminoglycoside resistance was performed via broth microdilution and disc diffusion according to CLSI guidelines. Time kill experiments with individual drugs added to the suspension so final concentration was 0.25, 0.5, 1, 2 and 4x the MIC. Time kill curves plotting average (±SD)log10cfu/mL versus time to compare 24-hour killing effects of single agents alone and in combination. Bacteriostatic defined as ≥0 to <3log10cfu/mL and bactericidal >3log10cfu/mL reduction in bacterial density. Synergy ≥2log10 reduction in cfu/mL between the combination and the most active single drug alone at 0.25x MIC.

Results:

  • All five isolates were susceptible to linezolid and daptomycin.
  • All VRE strains displayed high-level resistance to gentamicin.
  • E. faecalis was intermediate to rifampicin, and all VRE isolates were resistant.
  • Time kill study results:
    • Ceftriaxone had no bactericidal activity.
    • Daptomycin was bactericidal in 5/5 strains.
    • Gentamicin alone was bactericidal against 2/4 VRE and Vancomycin sensitive e. faecium.
    • Linezolid bacteriostatic in 5/5 strains.
    • Rifampicin bactericidal VRE W21579, not bactericidal against others.
    • Oritavancin bactericidal against 3/4 VRE strains.
    • Oritavancin was synergistic with gentamicin against VRE H19570.
    • Oritavancin and daptomycin antagonistic against 2/4 VRE strains.
Conclusions: Oritavancin was bactericidal in 2/5 of the enterococcal strains, and daptomycin was shown to be the most active agent alone, bactericidal in 5/5 of the enterococcus. Oritavancin was synergistic with gentamicin and improved activity, but those strains did not have high aminoglycoside resistance. This study adds to the previously done work, which shows a lack of synergistic activity with oritavancin when it is in combination. This study added lipopeptides and oxazolidinones for further assessment in possible synergistic activity. This study could have gone further and done more strains and more antibiotics for a potential to find a more suitable antibiotic with which oritavancin is synergistic. Overall, this study showed that oritavancin should not be used in combination therapy when treating VRE. From this study specifically, oritavancin is a viable single option, but it may not potentially be available if combination therapy is required due to its antagonistic effects with other antibiotics. I believe additional studies are warranted to confirm this study's findings and to further assess if oritavancin can be synergistic with other antibiotics.

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