Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

  title={Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium},
  author={George Sakoulas and Warren E. Rose and Poochit Nonejuie and Joshua Olson and Joe Pogliano and Romney M. Humphries and Victor Nizet},
  journal={Antimicrobial Agents and Chemotherapy},
  pages={1494 - 1500}
ABSTRACT Daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium (VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and… 

A combination of ceftaroline and daptomycin has synergistic and bactericidal activity in vitro against daptomycin nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA)

Daptomycin and ceftaroline combinations may be promising against persistent MRSA bacteremia in patients with methicillin-resistant Staphylococcus aureus who have failed conventional therapy.

Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin-susceptible and -resistant VRE.

Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE, and further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftoiprole as opposed to ispicillin.

In Vitro Activity of Daptomycin in Combination with β-Lactams, Gentamicin, Rifampin, and Tigecycline against Daptomycin-Nonsusceptible Enterococci

Ampicillin plus daptomycin yielded the most consistent synergy but did so only for isolates with mutations to the liaFSR system, adding support to the growing body of evidence indicating that therapy combining daptomecin and ampicillin may be helpful in eradicating refractory VRE infections.

Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with β-Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions

Combinations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and reduced potential for resistance, allowing de-escalation of the DAP dose and pave the way for testing these approaches in humans.

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge.

β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium.

The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE and demonstrate that combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with d aptomycin alone.

Whole-Genome Analyses of Enterococcus faecium Isolates with Diverse Daptomycin MICs

The presence of changes in 43 predicted proteins previously associated with DAP resistance in enterococci and staphylococci using the genomes of 19 E. faecium using DAP MICs above the susceptibility breakpoint suggests that genotypic information may be crucial to predict response to DAP plus β-lactam combinations.

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

Compared to DAP alone, combination regimens provide better killing and prevent resistance, and clinical research involving DAP combinations is warranted.



Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians.

Clinicians should be aware of the possibility of the emergence of daptomycin nonsusceptibility and should closely monitor d aptomycin MICs of enterococci isolated during treatment, and the prevalence of nonsUSceptibility of VRE isolates to daptoniccin may be overestimated.

Ampicillin Enhances Daptomycin- and Cationic Host Defense Peptide-Mediated Killing of Ampicillin- and Vancomycin-Resistant Enterococcus faecium

It is concluded that ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-daptomycin and a diverse range of other cationsic peptides in vitro.

Genetic basis for in vivo daptomycin resistance in enterococci.

BACKGROUND Daptomycin 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

Vancomycin-resistant enterococcal bacteraemia and daptomycin: are higher doses necessary?

The frequency of daptomycin MICs of 3-4 mg/L reported in this study is higher than those reported in the literature, and the study was not powered to detect a difference in TMC.

Correlation between Mutations in liaFSR of Enterococcus faecium and MIC of Daptomycin: Revisiting Daptomycin Breakpoints

A strong association between DAP MICs within the upper susceptibility range and mutations in the liaFSR system is provided and the current DAP breakpoint for E. faecium may need to be reevaluated.

Daptomycin Resistance in Enterococci Is Associated with Distinct Alterations of Cell Membrane Phospholipid Content

Resistance to DAP in E. faecium was associated with distinct structural alterations of the cell envelope and cell wall thickening, as well as a decreased ability of DAP to depolarize and permeabilize the CM.

Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding.

  • A. DhandA. Bayer G. Sakoulas
  • Biology, Medicine
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
  • 2011
In vitro studies showed enhanced daptomycin bactericidal activity, increased membrane daptomecin binding, and decrease in positive surface charge induced by ASBLs against d aptomycin nonsusceptible MRSA.

Daptomycin Activity against Staphylococcus aureus following Vancomycin Exposure in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations

It is suggested that reduced daptomycin susceptibility can be a strain-specific and unstable event and further evaluation of the susceptibility relationship between d aptomycin and vancomycin is necessary to understand the factors involved and their clinical significance.

Treatment of High-Level Gentamicin-Resistant Enterococcus faecalis Endocarditis with Daptomycin plus Ceftaroline

ABSTRACT A recurrent case of left-sided endocarditis caused by high-level aminoglycoside-resistant Enterococcus faecalis was successfully treated with ceftaroline and daptomycin. This combination

Genotypic and Phenotypic Evaluation of the Evolution of High-Level Daptomycin Nonsusceptibility in Vancomycin-Resistant Enterococcus faecium

Whole-genome sequencing and cell membrane studies of three clonal Enterococcus faecium strains with daptomycin MICs revealed nonsynonymous single nucleotide variants in eight open reading frames, including those predicted to encode a phosphoenolpyruvate-dependent, mannose-specific phosphotransferase system, cardiolipin synthetase, and EzrA.