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Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS)
(Oxford University Press (OUP), 2025-07-08)
Shelby R Simar
;
Truc T Tran
;
Kirsten B Rydell
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Rachel L Atterstrom
;
Pranoti V Sahasrabhojane
Background: Patients with recalcitrant enterococcal bloodstream infections are at greater risk of adverse outcomes. We identified patients in the 2016-2022 Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS) cohort experiencing recalcitrant bloodstream infections for further clinical and genomic characterization. Methods: Bacteremia episodes were considered "persistent" if there was a lack of clearance on day four while receiving >= 48 hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, "recalcitrant" bacteremia). A matched comparison group of non-recalcitrant bacteremia patients was chosen in a 2:1 control:case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline. Findings: A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the ICU upon admission relative to controls. E. faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between E. faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation. Discussion: Enterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index vs. persistent isolates revealed that E. faecium may be genetically pre-adapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. This data lays groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.
2Scopus© Citations 3
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Membrane Lipids Augment Cell Envelope Stress Signaling via the MadRS System to Defend Against Antimicrobial Peptides and Antibiotics in Enterococcus faecalis
(2024)
William R Miller
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April Nguyen
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Kavindra V Singh
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Samie Rizvi
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Ayesha Khan
<jats:title>Abstract</jats:title> <jats:p>Enterococci have evolved resistance mechanisms to protect their cell envelopes against bacteriocins and host cationic antimicrobial peptides (CAMPs) produced in the gastrointestinal environment. Activation of the membrane stress response has also been tied to resistance to the lipopeptide antibiotic daptomycin. However, the actual effectors mediating resistance have not been elucidated. Here, we show that the MadRS (formerly YxdJK) membrane antimicrobial peptide defense system controls a network of genes, including a previously uncharacterized 3-gene operon (madEFG) that protects the Enterococcus faecalis cell envelope from antimicrobial peptides. Constitutive activation of the system confers protection against CAMPs and daptomycin in the absence of a functional LiaFSR system and leads to persistence of cardiac microlesions in vivo. Moreover, changes in the lipid cell membrane environment alter CAMP susceptibility and expression of the MadRS system. Thus, we provide a framework supporting a multilayered envelope defense mechanism for resistance and survival coupled to virulence.</jats:p>
Scopus© Citations 2 3
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Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review
(2023)
Sarah B Doernberg
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Cesar A Arias
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Deena R Altman
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Ahmed Babiker
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Helen W Boucher
<jats:title>Abstract</jats:title><jats:p>The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.</jats:p>
8Scopus© Citations 7
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Clinical Outcomes and Bacterial Characteristics of Carbapenem-resistant Acinetobacter Baumannii Among Patients From Different Global Regions
(2023)
Minggui Wang
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Lizhao Ge
;
Liang Chen
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Lauren Komarow
;
Blake Hanson
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality.</jats:p> <jats:p>Clinical Trials Registration. NCT03646227.</jats:p> </jats:sec>
Scopus© Citations 94 3
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Antibiotic Consumption During the Coronavirus Disease 2019 Pandemic and Emergence of Carbapenemase-Producing Klebsiella pneumoniae Lineages Among Inpatients in a Chilean Hospital: A Time-Series Study and Phylogenomic Analysis
(2023)
Kasim Allel
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Anne Peters
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José Conejeros
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José R W Martínez
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Maria Spencer-Sandino
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>The impact of coronavirus disease 2019 (COVID-19) on antimicrobial use (AU) and resistance has not been well evaluated in South America. These data are critical to inform national policies and clinical care.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>At a tertiary hospital in Santiago, Chile, between 2018 and 2022, subdivided into pre- (3/2018–2/2020) and post–COVID-19 onset (3/2020–2/2022), we evaluated intravenous AU and frequency of carbapenem-resistant Enterobacterales (CRE). We grouped monthly AU (defined daily doses [DDD]/1000 patient-days) into broad-spectrum β-lactams, carbapenems, and colistin and used interrupted time-series analysis to compare AU during pre- and post-pandemic onset. We studied the frequency of carbapenemase-producing (CP) CRE and performed whole-genome sequencing analyses of all carbapenem-resistant (CR) Klebsiella pneumoniae (CRKpn) isolates collected during the study period.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Compared with pre-pandemic, AU (DDD/1000 patient-days) significantly increased after the pandemic onset, from 78.1 to 142.5 (P &lt; .001), 50.9 to 110.1 (P &lt; .001), and 4.1 to 13.3 (P &lt; .001) for broad-spectrum β-lactams, carbapenems, and colistin, respectively. The frequency of CP-CRE increased from 12.8% pre–COVID-19 to 51.9% after pandemic onset (P &lt; .001). The most frequent CRE species in both periods was CRKpn (79.5% and 76.5%, respectively). The expansion of CP-CRE harboring blaNDM was particularly noticeable, increasing from 40% (n = 4/10) before to 73.6% (n = 39/53) after pandemic onset (P &lt; .001). Our phylogenomic analyses revealed the emergence of two distinct genomic lineages of CP-CRKpn: ST45, harboring blaNDM, and ST1161, which carried blaKPC.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>AU and the frequency of CP-CRE increased after COVID-19 onset. The increase in CP-CRKpn was driven by the emergence of novel genomic lineages. Our observations highlight the need to strengthen infection prevention and control and antimicrobial stewardship efforts.</jats:p> </jats:sec>
30Scopus© Citations 36
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Selective digestive decontamination with oral colistin plus gentamicin for persistent bacteraemia caused by non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae in a neutropenic patient
(2021)
Maria Spencer-Sandino
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Roberto Riquelme-Neira
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William C Shropshire
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An Q Dinh
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Gerardo González-Rocha
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Carbapenem-resistant Klebsiella pneumoniae (CRKp) have become an increasing public health problem worldwide. While most CRKp around the world harbour a carbapenemase enzyme, the clinical relevance of non-carbapenemase-producing CRKp (non-CP-CRKp) is increasingly recognized. Selective digestive decontamination (SDD) has been proven successful as a decolonization strategy for patients colonized with Gram-negatives in the ICU. However, it is not regularly used to treat invasive infections.</jats:p> </jats:sec> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>To report the use of SDD as a useful strategy for managing recalcitrant CRKp bloodstream infections.</jats:p> </jats:sec> <jats:sec> <jats:title>Patients and methods</jats:title> <jats:p>We present a neutropenic patient with a recalcitrant bloodstream infection with non-CP-CRKp treated with SDD. Besides, genomic analyses of five isolates of non-CP-CRKp was performed.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>After 11 days of SDD treatment with oral colistin and gentamicin, bacteraemia was successfully eradicated. Genomic analysis indicates a fully carbapenem-resistant phenotype evolved in vivo and suggests that the mechanism of carbapenem resistance in our strains relates to gene amplification of narrow-spectrum β-lactamases.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our report highlights that SDD might be a useful strategy to manage CRKp bloodstream infections, when intestinal translocation is the likely source of the bacteraemia. In addition, the development of a resistant phenotype during therapy is worrisome as therapies directed against these organisms are likely to favour the amplification process.</jats:p> </jats:sec>
Scopus© Citations 3 1
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Clinical characteristics, microbiology and outcomes of a cohort of patients treated with ceftolozane/tazobactam in acute care inpatient facilities, Houston, Texas, USA
(2022)
Truc T Tran
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Nicolo L Cabrera
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Anne J Gonzales-Luna
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Travis J Carlson
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Faris Alnezary
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16–0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa.</jats:p> </jats:sec>
Scopus© Citations 3 2
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Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study
(2023)
Jinnethe Reyes
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Lauren Komarow
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Liang Chen
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Lizhao Ge
;
Blake M Hanson
Scopus© Citations 165 3
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Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study
(2022)
Minggui Wang
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Michelle Earley
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Liang Chen
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Blake M Hanson
;
Yunsong Yu
Scopus© Citations 226 7
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Multiomics characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates with heterogeneous intermediate resistance to vancomycin (hVISA) in Latin America
(2022)
Betsy E Castro
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Rafael Rios
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Lina P Carvajal
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Mónica L Vargas
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Mónica P Cala
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and hydrophilic interaction in six CC5-MRSA.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Genomic relatedness of MRSA associated to hVISA phenotype was not detected. The change Try38 → His in Atl (autolysin) was identified in 92% of the hVISA. We identified SNPs and k-mers associated to hVISA in 11 coding regions with predicted functions in virulence, transport systems, carbohydrate metabolism and tRNA synthesis. Further, capABCDE, sdrD, esaA, esaD, essA and ssaA genes were overexpressed in hVISA, while lacABCDEFG genes were downregulated. Additionally, valine, threonine, leucine tyrosine, FAD and NADH were more abundant in VSSA, while arginine, glycine and betaine were more abundant in hVISA. Finally, we observed altered metabolic pathways in hVISA, including purine and pyrimidine pathway, CoA biosynthesis, amino acid metabolism and aminoacyl tRNA biosynthesis.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our results show that the mechanism of hVISA involves major changes in regulatory systems, expression of virulence factors and reduction in glycolysis via TCA cycle. This work contributes to the understanding of the development of this complex resistance mechanism in regional strains.</jats:p> </jats:sec>
1Scopus© Citations 8 3

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