Comment on: Successful therapy of treatment-emergent, non-clonal daptomycin-non-susceptible Enterococcus faecium infections

Sir,

Daptomycin-non-susceptible Enterococcus (DNSE) infections are increasingly being described.¹ King et al.² conclude that until there is a better understanding of the mechanisms of altered daptomycin susceptibility, clinicians should be aware of its uncommon existence.

The genetic basis for in vivo daptomycin resistance in enterococci was recently reported, and mutations in proteins involved in the stress-sensing response of the cell envelope to antibiotics (such as LiaF) and in enzymes that are responsible for phospholipid metabolism in the cell membrane [such as glycerophosphoryl-diester-phosphodiesterase (GdpB) and cardiolipin synthase] are implicated in the development of daptomycin resistance.^3,4 Arias et al.³ suggest that the mutations that occur in the LiaF and GdpD proteins may have originated from recombination between adjacent repetitive nucleotide sequences. Acquired resistance among Enterococcus spp. is mediated by transferable transposons or plasmids encoding resistance cassettes.^1,5 Thus, a possible mechanism of resistance in DNSE cases could be the co-transfer of resistance.^1,5 Many of these elements of resistance appear to have been mobilized from more obscure types of bacteria.⁵

Enterococci and anaerobes are members of the gastrointestinal tract consortium in humans and most other organisms.⁶ The dominant members of the colonic flora, anaerobic bacteria, can serve as reservoirs of antibiotic resistance genes, many of which are carried by mobile genetic elements.⁶ The transport of genetic elements of resistance between enterococci and anaerobes has been described previously.⁷ Changes in cardiolipin have been implicated in the mechanism of development of daptomycin resistance in enterococci.^3,4 A smaller amount of cardiolipin, which plays an important role in the bioenergetics of the cell and changes in phospholipid biosynthesis and the remodelling of membrane phospholipids, has been described in anaerobic bacteria such as clostridia.⁸

Another mutated gene that was identified by Arias et al.³ in daptomycin-resistant enterococci encodes a putative LacI (lactose-operon-repressor)-family transcriptional repressor that is probably involved in carbohydrate metabolism. Mutations that regulate lac operon expression have been described in anaerobes, including lactobacilli and facultative anaerobic bacteria.⁹

In addition, the anaerobic microflora provides an important host defence by inhibiting the growth of potentially pathogenic microorganisms.¹⁰ Thus, the use of antianaerobic antibiotics in hospitalized patients may increase the risk for the acquisition and overgrowth of a variety of nosocomial and antibiotic-resistant bacteria, including vancomycin-resistant enterococci (VRE).¹⁰ In a recent multivariate analysis of risk factors for the isolation of daptomycin-non-susceptible versus daptomycin-susceptible VRE, the use of metronidazole in the past 3 months was a significant risk factor for the development of daptomycin resistance.¹¹ In a recent case–control study at our institution, patients with de novo (no prior exposure to daptomycin) DNSE infection were significantly less likely to have received antianaerobic antibiotics in the prior 3 months compared with patients who developed DNSE infection after exposure to daptomycin (T. Kelesidis, A. Chow, R. Humphries, D. Uslan and D. Pegues, unpublished data).

Lastly, various anaerobes can have daptomycin non-susceptibility.¹² However, it remains unknown whether there is gene transfer of daptomycin resistance factors between Enterococcus spp. and anaerobes. The above evidence may suggest a possible role of the interplay between anaerobes and enterococci in the dissemination of daptomycin resistance. Although King et al.² do not report whether their patients were receiving antianaerobic antibiotics, this information may be important when evaluating cases of DNSE infections. Further studies are needed to confirm this hypothesis.

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