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Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians.

ABSTRACT: Daptomycin is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant Enterococcus (VRE) that is approved by the Food and Drug Administration (FDA). Data on the potential emergence of daptomycin nonsusceptibility among enterococci remain limited. We systematically reviewed the published literature for reports of isolates of enterococci that were daptomycin nonsusceptible and assessed the clinical significance and outcome of therapy. Based on susceptibility breakpoints approved by the Clinical Laboratory Standards Institute (CLSI), daptomycin has in vitro activity against >90% of enterococcal isolates. Less than 2% of enterococcal isolates were daptomycin nonsusceptible, with minimum inhibitory concentrations (MICs) >4 μg/mL. The prevalence of nonsusceptibility of VRE isolates to daptomycin may be overestimated due to the spread of clonally related isolates in health care settings. Clinicians should be aware of the possibility of the emergence of daptomycin nonsusceptibility and should closely monitor daptomycin MICs of enterococci isolated during treatment.

SUBMITTER: Kelesidis T

PROVIDER: S-EPMC8483151 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians.

Kelesidis Theodoros T Humphries Romney R Uslan Daniel Z DZ Pegues David A DA

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20110101 2

Daptomycin is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant Enterococcus (VRE) that is approved by the Food and Drug Administration (FDA). Data on the potential emergence of daptomycin nonsusceptibility among enterococci remain limited. We systematically reviewed the published literature for reports of isolates of enterococci that were daptomycin nonsusceptible and assessed the clinical significance and outcome of therapy. Based on susceptibility breakpoint ...[more]

PMID: 21288849

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Project description:BackgroundDaptomycin is a lipopeptide with bactericidal activity that acts on the cell membrane of enterococci and is often used off-label to treat patients infected with vancomycin-resistant enterococci. However, the emergence of resistance to daptomycin during therapy threatens its usefulness.MethodsWe performed whole-genome sequencing and characterization of the cell envelope of a clinical pair of vancomycin-resistant Enterococcus faecalis isolates from the blood of a patient with fatal bacteremia; one isolate (S613) was from blood drawn before treatment and the other isolate (R712) was from blood drawn after treatment with daptomycin. The minimal inhibitory concentrations (MICs) of these two isolates were 1 and 12 μg per milliliter, respectively. Gene replacements were made to exchange the alleles found in isolate S613 with those in isolate R712.ResultsIsolate R712 had in-frame deletions in three genes. Two genes encoded putative enzymes involved in phospholipid metabolism, GdpD (which denotes glycerophosphoryl diester phosphodiesterase) and Cls (which denotes cardiolipin synthetase), and one gene encoded a putative membrane protein, LiaF (which denotes lipid II cycle-interfering antibiotics protein but whose exact function is not known). LiaF is predicted to be a member of a three-component regulatory system (LiaFSR) involved in the stress-sensing response of the cell envelope to antibiotics. Replacement of the liaF allele of isolate S613 with the liaF allele from isolate R712 quadrupled the MIC of daptomycin, whereas replacement of the gdpD allele had no effect on MIC. Replacement of both the liaF and gdpD alleles of isolate S613 with the liaF and gdpD alleles of isolate R712 raised the daptomycin MIC for isolate S613 to 12 μg per milliliter. As compared with isolate S613, isolate R712--the daptomycin-resistant isolate--had changes in the structure of the cell envelope and alterations in membrane permeability and membrane potential.ConclusionsMutations in genes encoding LiaF and a GdpD-family protein were necessary and sufficient for the development of resistance to daptomycin during the treatment of vancomycin-resistant enterococci. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health.).

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Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians.

Publications

Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians.

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