Development of daptomycin resistance in a bone marrow transplant patient with                 vancomycin-resistant Enterococcus durans

Green, Myke R.; Anasetti, Claudio; Sandin, Ramón L.; Rolfe, Nancy E.; Greene, John N.

doi:10.1177/1078155206069165

Cited by 28 publications

(21 citation statements)

References 12 publications

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“…3 However, a major drawback of the use of daptomycin for the treatment of infection with vancomycin-resistant enterococci is the development of resistance during therapy. 4–6 Although little is known about the mechanism of in vivo resistance, a critical step in the action of daptomycin is its interaction with the bacterial cell membrane in a calcium-dependent manner. In this study, comparative genomic sequencing and genetic manipulations of a clinical pair of daptomycin-susceptible and daptomycin-resistant E. faecalis strains, which were recovered from the bloodstream of a patient with fatal bacteremia, identified mutations in two genes not previously associated with antibiotic resistance in enterococci.…”

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confidence: 99%

Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

et al. 2011

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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 enterococci. However, the emergence of resistance to daptomycin during therapy threatens its usefulness. METHODS We 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. RESULTS Isolate 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. CONCLUSIONS Mutations 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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Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

et al. 2011

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“…While DAP susceptibility among enterococci remains Ͼ99%, continued use of DAP will likely increase the frequency of resistance worldwide (12). Several studies have already reported the development of resistance in both S. aureus (6,(13)(14)(15)(16) and enterococci (2,(17)(18)(19). Recent evidence strongly suggests that DAP inserts into the plasma membrane in a calcium-dependent manner and subsequently disrupts the functional integrity of the cell membrane, altering cell division.…”

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Biochemical Characterization of Cardiolipin Synthase Mutations Associated with Daptomycin Resistance in Enterococci

Davlieva

Zhang

Arias

et al. 2013

Antimicrob Agents Chemother

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dDaptomycin (DAP) resistance in enterococci has been linked to mutations in genes that alter the cell envelope stress response (CESR) (liaFSR) and changes in enzymes that directly affect phospholipid homeostasis, and these changes may alter membrane composition, such as that of cardiolipin synthase (Cls). While Cls substitutions are observed in response to DAP therapy, the effect of these mutations on Cls activity remains obscure. We have expressed, purified, and characterized Cls enzymes from both Enterococcus faecium S447 (residues 52 to 482; Cls447a) and Enterococcus faecalis S613 (residues 53 to 483; Cls613a) as well as Cls variants harboring a single-amino-acid change derived from DAP-resistant isolates of E. faecium. E. faecium Cls447a and E. faecalis Cls613a are tightly associated with the membrane and copurify with their substrate, phosphatidylglycerol (PG), and product, cardiolipin (CL). The amount of PG that copurifies with Cls is in molar excess to protein, suggesting that the enzyme localizes to PG-rich membrane regions. Both Cls447a H215R and Cls447a R218Q showed an increase in V max (M CL/min/M protein) from 0.16 ؎ 0.01 to 0.26 ؎ 0.02 and 0.26 ؎ 0.04, respectively, indicating that mutations associated with adaptation to DAP increase Cls activity. Modeling of Cls447a to Streptomyces sp. phospholipase D indicates that the adaptive mutations Cls447a H215R and Cls447a R218Q are proximal to the phospholipase domain 1 (PLD1) active site and near the putative nucleophile H217. As mutations to Cls are part of a larger genomic adaptation process, increased Cls activity is likely to be highly epistatic with other changes to facilitate DAP resistance.

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“…Daptomycin MIC 50 and MIC 90 are 2 and 4 mg/liter for E. faecium, and 0.5 and 1 mg/liter for Enterococcus faecalis versus 0.25 and 0.5 mg/liter for staphylococci (6). Reports of daptomycin resistance are now becoming more common, emphasizing the need for improved daptomycin dosing paradigms to help preserve the utility of this drug against these difficult to treat pathogens (7)(8)(9)(10). Due to the substantial morbidity and mortality associated with enterococcal infections, it is critical to identify characteristics that correlate with treatment failure and therefore improve antimicrobial optimization and patient outcomes.…”

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Defining Daptomycin Resistance Prevention Exposures in Vancomycin-Resistant Enterococcus faecium and E. faecalis

Werth

Steed

Ireland

et al. 2014

Antimicrob Agents Chemother

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Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance ( Enterococcus spp. are among the leading causes of nosocomial infections (1). Vancomycin-resistant Enterococcus faecium has been recognized as an important multidrug-resistant pathogen for which new or improved therapies are urgently needed (2, 3). Daptomycin is a lipopeptide antibiotic with potent in vitro bactericidal activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE). Although daptomycin lacks an approved indication from the FDA, it is frequently utilized as an alternative agent for the management of VRE infections. However, the optimal pharmacokinetic/pharmacodynamic (PK/PD) targets for resistance prevention and therapeutic success with daptomycin have not been defined (4). In fact, the susceptibility breakpoint designating resistance in enterococci also remains questionable; however, for ease of presentation, we will use the term resistance to refer to nonsusceptible enterococci with daptomycin MICs of Ͼ4 mg/liter. Most experts agree that the daptomycin doses of 4 to 6 mg/kg of body weight/day used for staphylococcal infections are likely inadequate for VRE infections due to reduced susceptibility observed in enterococci (3-5). Daptomycin MIC 50 and MIC 90 are 2 and 4 mg/liter for E. faecium, and 0.5 and 1 mg/liter for Enterococcus faecalis versus 0.25 and 0.5 mg/liter for staphylococci (6). Reports of daptomycin resistance are now becoming more common, emphasizing the need for improved daptomycin dosing paradigms to help preserve the utility of this drug against these difficult to treat pathogens (7-10). Due to the substantial morbidity and mortality associated with enterococcal infections, it is critical to identify characteristics that correlate with treatment failure and therefore improve antimicrobial optimization and patient outcomes.In order to derive daptomycin exposure targets for resistance prevention, we evaluated simulated daptomycin regimens from 4 to 12 mg/kg/day in a 14-day PK/PD model of simulated endocardial vegetations (SEVs) against two daptomycin-susceptible clinical VRE strains (E. faecium S447 and E. faecalis S613). Resistant strains derived from these models were then subjected to a variety of phenotypic and genotypic analyses to evaluate characteristics associated with development of daptomycin resistance. MATERIALS AND METHODSBacterial strains. Two daptomycin-susceptible and vancomycin-resistant enterococcal strains, E. faecalis S613 and E. faecium S447 recovered from the bloodstream and urine, respectively, of patients before daptomycin therapy, were evaluated (11, 12). Both isolates developed daptomycin-resistant derivatives in vivo during daptomycin therapy (11, 12) and

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Development of daptomycin resistance in a bone marrow transplant patient with vancomycin-resistant Enterococcus durans

Cited by 28 publications

References 12 publications

Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

Genetic Basis for In Vivo Daptomycin Resistance in Enterococci

Biochemical Characterization of Cardiolipin Synthase Mutations Associated with Daptomycin Resistance in Enterococci

Defining Daptomycin Resistance Prevention Exposures in Vancomycin-Resistant Enterococcus faecium and E. faecalis

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