Effect of Continuous and Sequential Therapy among Veterans Receiving Daptomycin or Linezolid for Vancomycin-Resistant Enterococcus faecium Bacteremia

ABSTRACT Vancomycin-resistant Enterococcus faecium bloodstream infections (VREF-BSI) cause significant mortality, highlighting the need to optimize their treatment. We compared the effectiveness and safety of daptomycin (DAP) and linezolid (LZD) as continuous or sequential therapy for VREF-BSI in a national, retrospective, propensity score (PS)-matched cohort study of hospitalized Veterans Affairs patients (2004 to 2014). We compared clinical outcomes and adverse events among patients treated with continuous LZD, continuous DAP, or sequential LZD followed by DAP (LZD-to-DAP). Secondarily, we analyzed the impact of infectious diseases (ID) consultation and source of VREF-BSI. A total of 2,630 patients were included in the effectiveness analysis (LZD [n = 1,348], DAP [n = 1,055], LZD-to-DAP [n = 227]). LZD was associated with increased 30-day mortality versus DAP (risk ratio [RR], 1.11; 95% confidence interval [CI], 1.01 to 1.22; P = 0.042). After PS matching, this relationship persisted (RR, 1.13; 95% CI, 1.02 to 1.26; P = 0.015). LZD-to-DAP switchers had lower mortality than those remaining on LZD (RR, 1.29; 95% CI, 1.03 to 1.63; P = 0.021), suggesting a benefit may still be derived with sequential therapy. LZD-treated patients experienced more adverse events, including a ≥50% reduction in platelets (RR, 1.07; 95% CI, 1.03 to 1.11; P = 0.001). DAP was associated with lower mortality than was LZD in patients with endocarditis (RR, 1.20; 95% CI, 1.02 to 1.41; P = 0.024); however, there was no statistically significant association between treatment group and mortality with regard to other sources of infection. Therefore, source of infection appears to be important in selection of patients most likely to benefit from DAP over LZD.

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Impact of an Antimicrobial Stewardship Intervention on Within- and Between-Patient Daptomycin Resistance Evolution in Vancomycin-Resistant Enterococcus faecium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01800-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 9

Author(s):

Clare L. Kinnear ◽

Twisha S. Patel ◽

Carol L. Young ◽

Vincent Marshall ◽

Duane W. Newton ◽

...

Keyword(s):

Antimicrobial Stewardship ◽

Enterococcus Faecium ◽

Treatment Options ◽

Bloodstream Infections ◽

Prescribing Patterns ◽

Interrupted Time Series Analysis ◽

Content Type ◽

Days Of Therapy ◽

Vancomycin Resistant ◽

The Impact

ABSTRACT Vancomycin-resistant Enterococcus (VRE) is a leading cause of hospital-acquired infection, with limited treatment options. Resistance to one of the few remaining drugs, daptomycin, is a growing clinical problem and has previously been described in this hospital. In response to increasing resistance, an antimicrobial stewardship intervention was implemented to reduce hospital-wide use of daptomycin. To assess the impact of the intervention, daptomycin prescribing patterns and clinically reported culture results from vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) from 2011 through 2017 were retrospectively extracted and the impact of the intervention was estimated using interrupted time series analysis (ITS). We corrected for a change in MIC determination methodology by retesting 262 isolates using Etest and broth microdilution. Hospital-wide and within-patient resistance patterns of corrected daptomycin MICs are reported. Our data show that daptomycin prescriptions decreased from an average of 287 days of therapy/month preintervention to 151 days of therapy/month postintervention. Concurrently, the proportion of patients experiencing an increase in daptomycin MIC during an infection declined from 14.6% (7/48 patients) in 2014 to 1.9% (1/54 patients) in 2017. Hospital-wide resistance to daptomycin also decreased in the postintervention period, but this was not maintained. This study shows that an antimicrobial stewardship-guided intervention reduced daptomycin use and improved individual level outcomes but had only transient impact on the hospital-level trend.

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Reduced Chlorhexidine and Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium after Serial Chlorhexidine Exposure

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01235-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 38

Author(s):

Pooja Bhardwaj ◽

Amrita Hans ◽

Kinnari Ruikar ◽

Ziqiang Guan ◽

Kelli L. Palmer

Keyword(s):

Enterococcus Faecium ◽

Bloodstream Infections ◽

Nucleotide Metabolism ◽

Long Term Effects ◽

Membrane Phospholipids ◽

Content Type ◽

Vancomycin Resistant ◽

Clinically Significant ◽

Hospital Acquired ◽

Critical Public Health

ABSTRACT Vancomycin-resistant Enterococcus faecium strains (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections. Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci. In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC). Subpopulations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis. Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (efrE), global nutritional stress response (relA), nucleotide metabolism (cmk), phosphate acquisition (phoU), and glycolipid biosynthesis (bgsB), among others. Moreover, significant alterations in membrane phospholipids were identified for some populations with reduced DAP susceptibility. Our results are clinically significant because they identify a link between serial subinhibitory CHX exposure and reduced DAP susceptibility. In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.

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Unexpected Cell Wall Alteration-Mediated Bactericidal Activity of the Antifungal Caspofungin against Vancomycin-Resistant Enterococcus faecium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01261-20 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Christophe Isnard ◽

Sara B. Hernandez ◽

François Guérin ◽

Fanny Joalland ◽

Didier Goux ◽

...

Keyword(s):

Cell Wall ◽

Enterococcus Faecium ◽

Opportunistic Pathogen ◽

Glycerol Metabolism ◽

Content Type ◽

Mechanistic Pathway ◽

Bacterial Cell Viability ◽

Vancomycin Resistant ◽

The Impact

ABSTRACT Enterococcus faecium has become a major opportunistic pathogen with the emergence of vancomycin-resistant enterococci (VRE). As part of the gut microbiota, they have to cope with numerous stresses, including effects of antibiotics and other xenobiotics, especially in patients hospitalized in intensive care units (ICUs) who receive many medications. The aim of this study was to investigate the impact of the most frequently prescribed xenobiotics for ICU patients on fitness, pathogenicity, and antimicrobial resistance of the vanB-positive E. faecium Aus0004 reference strain. Several phenotypic analyses were carried out, and we observed that caspofungin, an antifungal agent belonging to the family of echinocandins, had an important effect on E. faecium growth in vitro. We confirmed this effect by electron microscopy and peptidoglycan analysis and showed that, even at a subinhibitory concentration (1/4× MIC, 8 mg/liter), caspofungin had an impact on cell wall organization, especially with respect to the abundance of some muropeptide precursors. By transcriptome sequencing (RNA-seq), it was also shown that around 20% of the transcriptome was altered in the presence of caspofungin, with 321 and 259 significantly upregulated and downregulated genes, respectively. Since the fungal target of caspofungin (i.e., β-1,3-glucan synthase) was absent in bacteria, the mechanistic pathway of caspofungin activity was investigated. The repression of genes involved in the metabolism of pyruvate seemed to have a drastic impact on bacterial cell viability, while a decrease of glycerol metabolism could explain the conformational modifications of peptidoglycan. This is the first report of caspofungin antibacterial activity against E. faecium, highlighting the potential impact of nonantibiotic xenobiotics against bacterial pathogens.

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Impact of Different Antimicrobial Therapies on Clinical and Fiscal Outcomes of Patients with Bacteremia Due to Vancomycin-Resistant Enterococci

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02943-14 ◽

2014 ◽

Vol 58 (7) ◽

pp. 3968-3975 ◽

Cited By ~ 16

Author(s):

Kayoko Hayakawa ◽

Emily T. Martin ◽

Uma Mahesh Gudur ◽

Dror Marchaim ◽

Dalia Dalle ◽

...

Keyword(s):

Propensity Score ◽

Medical Center ◽

Bloodstream Infections ◽

Multivariate Models ◽

Median Dose ◽

Content Type ◽

Treatment Groups ◽

Vancomycin Resistant Enterococci ◽

Vancomycin Resistant ◽

The Impact

ABSTRACTVancomycin-resistant enterococci (VRE) are a growing health problem, and uncertainties exist regarding the optimal therapy for bloodstream infection due to VRE. We conducted systematic comparative evaluations of the impact of different antimicrobial therapies on the outcomes of patients with bloodstream infections due to VRE. A retrospective study from January 2008 to October 2010 was conducted at Detroit Medical Center. Unique patients with blood cultures due to VRE were included and reviewed. Three major therapeutic classes were analyzed: daptomycin, linezolid, and β-lactams. Three multivariate models were conducted for each outcome, matching for a propensity score predicting the likelihood of receipt of one of the therapeutic classes. A total of 225 cases of bacteremia due to VRE were included, including 86 (38.2%) cases of VREnterococcus faecalisand 139 (61.8%) of VREnterococcus faecium. Bacteremia due to VRE. faecaliswas more frequent among subjects treated with β-lactams than among those treated with daptomycin or linezolid. The median dose of daptomycin was 6 mg/kg of body weight (range, 6 to 12 mg/kg). After controlling for propensity score and bacteremia due to VRE. faecalis, differences in mortality were nonsignificant among the treatment groups. Therapy with daptomycin was associated with higher median variable direct cost per day than that for linezolid. This large study revealed the three therapeutic classes (daptomycin, linezolid, and β-lactams) are similarly efficacious in the treatment of bacteremia due to susceptible strains of VRE.

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Activity of Oritavancin Against Gram-positive Pathogens Causing Bloodstream Infections in the United States Over 10 Years: Focus on Drug-Resistant Enterococcal Subsets (2010-2019)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01667-21 ◽

2021 ◽

Author(s):

Cecilia G. Carvalhaes ◽

Helio S. Sader ◽

Jennifer M. Streit ◽

Mariana Castanheira ◽

Rodrigo E. Mendes

Keyword(s):

United States ◽

Staphylococcus Aureus ◽

Enterococcus Faecium ◽

Bloodstream Infections ◽

The United States ◽

Drug Resistant ◽

Gram Positive ◽

Methicillin Resistant ◽

Vancomycin Resistant ◽

Over Time

Oritavancin displayed potent and stable activity (MIC 90 range, 0.06-0.5 mg/L) over time (2010-2019) against Gram-positive pathogens causing bloodstream infections, including methicillin-resistant Staphylococcus aureus and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus . Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2-4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.

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Predictors of Mortality in Bloodstream Infections Caused by Pseudomonas aeruginosa and Impact of Antimicrobial Resistance and Bacterial Virulence

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01759-19 ◽

2019 ◽

Vol 64 (2) ◽

Cited By ~ 3

Author(s):

Raúl Recio ◽

Mikel Mancheño ◽

Esther Viedma ◽

Jennifer Villa ◽

María Ángeles Orellana ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Resistance ◽

Multivariate Logistic Regression Analysis ◽

Empirical Therapy ◽

Bloodstream Infections ◽

Multivariate Logistic Regression ◽

Related Factors ◽

Content Type ◽

Crude Mortality ◽

The Impact

ABSTRACT Whether multidrug resistance (MDR) is associated with mortality in patients with Pseudomonas aeruginosa bloodstream infections (BSI) remains controversial. Here, we explored the prognostic factors of P. aeruginosa BSI with emphasis on antimicrobial resistance and virulence. All P. aeruginosa BSI episodes in a 5-year period were retrospectively analyzed. The impact in early (5-day) and late (30-day) crude mortality of host, antibiotic treatment, and pathogen factors was assessed by multivariate logistic regression analysis. Of 243 episodes, 93 (38.3%) were caused by MDR-PA. Crude 5-day (20%) and 30-day (33%) mortality was more frequent in patients with MDR-PA (34.4% versus 11.3%, P < 0.001 and 52.7% versus 21.3%, P < 0.001, respectively). Early mortality was associated with neutropenia (adjusted odds ratio [aOR], 9.21; 95% confidence interval [CI], 3.40 to 24.9; P < 0.001), increased Pitt score (aOR, 2.42; 95% CI, 1.34 to 4.36; P = 0.003), respiratory source (aOR, 3.23; 95% CI,2.01 to 5.16; P < 0.001), inadequate empirical therapy (aOR, 4.57; 95% CI, 1.59 to 13.1; P = 0.005), shorter time to positivity of blood culture (aOR, 0.88; 95% CI, 0.80 to 0.97; P = 0.010), an exoU-positive genotype (aOR, 3.58; 95% CI, 1.31 to 9.79; P = 0.013), and the O11 serotype (aOR, 3.64; 95% CI, 1.20 to 11.1; P = 0.022). These risk factors were similarly identified for late mortality, along with an MDR phenotype (aOR, 2.18; 95% CI, 1.04 to 4.58; P = 0.040). Moreover, the O11 serotype (15.2%, 37/243) was common among MDR (78.4%, 29/37) and exoU-positive (89.2%, 33/37) strains. Besides relevant clinical variables and inadequate empirical therapy, pathogen-related factors such as an MDR phenotype, an exoU-positive genotype, and the O11 serotype adversely affect the outcome of P. aeruginosa BSI.

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Identification of a Novel Genomic Island Associated withvanD-Type Vancomycin Resistance in Six Dutch Vancomycin-ResistantEnterococcus faeciumIsolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01793-17 ◽

2018 ◽

Vol 62 (3) ◽

Cited By ~ 6

Author(s):

Janetta Top ◽

Jan C. Sinnige ◽

Ellen C. Brouwer ◽

Guido Werner ◽

Jukka Corander ◽

...

Keyword(s):

Genetic Variation ◽

Enterococcus Faecium ◽

Genomic Island ◽

Gene Clusters ◽

Genomic Comparison ◽

Variable Size ◽

Content Type ◽

Enterococcal Species ◽

Vancomycin Resistant ◽

Species Specific

ABSTRACTGenomic comparison of the first six DutchvanD-type vancomycin-resistantEnterococcus faecium(VRE) isolates with fourvanDgene clusters from other enterococcal species and anaerobic gut commensals revealed that thevanDgene cluster was located on a genomic island of variable size. Phylogenetic inferences revealed that the Dutch VRE isolates were genetically not closely related and that genetic variation of thevanD-containing genomic island was not species specific, suggesting that this island is transferred horizontally between enterococci and anaerobic gut commensals.

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Microbe-Metabolite Associations Linked to the Rebounding Murine Gut Microbiome Postcolonization with Vancomycin-Resistant Enterococcus faecium

mSystems ◽

10.1128/msystems.00452-20 ◽

2020 ◽

Vol 5 (4) ◽

Author(s):

Andre Mu ◽

Glen P. Carter ◽

Lucy Li ◽

Nicole S. Isles ◽

Alison F. Vrbanac ◽

...

Keyword(s):

Gut Microbiome ◽

Enterococcus Faecium ◽

Molecular Mechanisms ◽

Microbial Community Composition ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Content Type ◽

Functional Roles ◽

Specific Pathogen ◽

Vancomycin Resistant

ABSTRACT Vancomycin-resistant Enterococcus faecium (VREfm) is an emerging antibiotic-resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between Bacteroidetes and Tenericutes within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone and to subsequent VREfm challenge. Using neural networking approaches to find cooccurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with Bacteroides, indicative of a transition toward a preantibiotic naive microbiome. This study shows the impacts of antibiotics on the gut ecosystem and the progression of the microbiome in response to colonization with VREfm. Our results offer insights toward identifying potential nonantibiotic alternatives to eliminate VREfm through metabolic reengineering to preferentially select for Bacteroides. IMPORTANCE This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.

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Complications of Hemodialysis Catheter Bloodstream Infections: Impact of Infecting Organism

American Journal of Nephrology ◽

10.1159/000501357 ◽

2019 ◽

Vol 50 (2) ◽

pp. 126-132 ◽

Cited By ~ 2

Author(s):

Crystal A. Farrington ◽

Michael Allon

Keyword(s):

Intensive Care ◽

Bloodstream Infections ◽

Gram Negative ◽

Hemodialysis Catheter ◽

Atypical Symptoms ◽

Source Of Infection ◽

Metastatic Infection ◽

Single Organism ◽

Alternate Source ◽

The Impact

Background: Catheter-related bloodstream infections (CRBSI) are associated with a high burden of morbidity and mortality, but the impact of infecting organism on clinical outcomes has been poorly studied. Methods: This retrospective analysis of a prospective vascular access database from a large academic dialysis center investigated whether the organism type affected the clinical presentation or complications of CRBSI. Results: Among 339 patients with suspected CRBSI, an alternate source of infection was identified in 50 (15%). Of 289 patients with CRBSI, 249 grew a single organism and 40 were polymicrobial. Fever and/or rigors were presenting signs in ≥90% of patients with Staphylococcus aureus or Gram-negative CRBSI, but only 61% of Staphylococcus epidermidis infections (p < 0.001). Hospitalization occurred in 67% of patients with S. aureus CRBSI versus 34% of those with S. epidermidis and 40% of those with a Gram-negative bacteria (p < 0.001). Admission to the intensive care unit was required in 14, 9, and 2% (p = 0.06); metastatic infection occurred in 10, 4, and 4% (p = 0.42); and median length of stay among patients admitted to the hospital was 4, 4, and 5.5 days (p = 0.60), respectively. Death due to CRBSI occurred in only 1% of patients with CRBSI. Conclusion: CRBSI is confirmed in 85% of catheter-dependent hemodialysis patients in whom it is suspected. S. epidermidis CRBSI tends to present with atypical symptoms. S. aureus CRBSI is more likely to require hospitalization or intensive care admission. Metastatic infection is relatively uncommon, and death due to CRBSI is rare.

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Homologous Recombination within Large Chromosomal Regions Facilitates Acquisition of β-Lactam and Vancomycin Resistance in Enterococcus faecium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00488-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 5777-5786 ◽

Cited By ~ 20

Author(s):

Mónica García-Solache ◽

Francois Lebreton ◽

Robert E. McLaughlin ◽

James D. Whiteaker ◽

Michael S. Gilmore ◽

...

Keyword(s):

Enterococcus Faecium ◽

Genomic Dna ◽

Large Scale ◽

Vancomycin Resistance ◽

Whole Genome ◽

Whole Genome Analysis ◽

Single Nucleotide ◽

Content Type ◽

Donor Chromosome ◽

Vancomycin Resistant

ABSTRACTThe transfer of DNA betweenEnterococcus faeciumstrains has been characterized both by the movement of well-defined genetic elements and by the large-scale transfer of genomic DNA fragments. In this work, we report on the whole-genome analysis of transconjugants resulting from mating events between the vancomycin-resistantE. faeciumC68 strain and the vancomycin-susceptible D344RRF strain to discern the mechanism by which the transferred regions enter the recipient chromosome. Vancomycin-resistant transconjugants from five independent matings were analyzed by whole-genome sequencing. In all cases but one, the penicillin binding protein 5 (pbp5) gene and the Tn5382vancomycin resistance transposon were transferred together and replaced the correspondingpbp5region of D344RRF. In one instance, Tn5382inserted independently downstream of the D344RRFpbp5gene. Single nucleotide variant (SNV) analysis suggested that entry of donor DNA into the recipient chromosome occurred by recombination across regions of homology between donor and recipient chromosomes, rather than through insertion sequence-mediated transposition. The transfer of genomic DNA was also associated with the transfer of C68 plasmid pLRM23 and another putative plasmid. Our data are consistent with the initiation of transfer by cointegration of a transferable plasmid with the donor chromosome, with subsequent circularization of the plasmid-chromosome cointegrant in the donor prior to transfer. Entry into the recipient chromosome most commonly occurred across regions of homology between donor and recipient chromosomes.

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