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The innate immune system eliminates bloodstream pathogens such as Escherichia coli in part through complement protein deposition and subsequent bacterial death (i.e., "serum killing"). Some E. coli strains have developed mechanisms to resist serum killing, though the extent of variation in serum killing among bloodstream infection (BSI) isolates and the clinical impact of this variation is not well understood. To address this issue, we developed a novel assay that uses flow cytometry to perform high throughput serum bactericidal assays (SBAs) with E. coli BSI isolates (n = 183) to define the proportion of surviving bacteria after exposure to serum. We further determined whether E. coli resistance to serum killing is associated with clinical outcomes (e.g., in-hospital attributable mortality, in-hospital total mortality, septic shock) and bacterial genotype in the corresponding patients with E. coli BSI. Our novel flow cytometry-based SBA performed similarly to a traditional SBA, though with significantly decreased hands-on bench work. Among E. coli BSI isolates, the mean proportion that survived exposure to 25% serum was 0.68 (Standard deviation 0.02, range 0.57-0.93). We did not identify associations between E. coli resistance to serum killing and clinical outcomes in our adjusted models. Together, this study describes a novel flow cytometry-based approach to the bacterial SBA that allowed for high-throughput testing of E. coli BSI isolates and identified high variability in resistance to serum killing among a large set of BSI isolates., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Poteete et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P = .04). Persistent GN-BSI may be a marker of complicated infection., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio, Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending; support for meetings and/or travel from Contrafect. J. T. T. reports being a Scientific Advisor for Resonantia Diagnostics, Inc, and grants or contracts from NIH and CDC. C. A. A. received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics, Harris County Public Health, NIH; support for meetings and/or travel from Infectious Diseases Society of America, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, Merieux Foundation, Sociedad Argentina d Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, Brazilian Society for Infectious Diseases; participation on the World Health Organization, Antibacterial Pipeline Advisory Group, NIH Grant Review Study Sections, Editor-in-Chief of Antimicrobial Agents and Chemotherapy. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Clinical data characterizing invasive Escherichia coli disease (IED) are limited. We assessed the clinical presentation of IED and antimicrobial resistance (AMR) patterns of causative E. coli isolates in older adults., Methods: EXPECT-2 (NCT04117113) was a prospective, observational, multinational, hospital-based study conducted in patients with IED aged ≥ 60 years. IED was determined by the microbiological confirmation of E. coli from blood; or by the microbiological confirmation of E. coli from urine or an otherwise sterile body site in the presence of requisite criteria of systemic inflammatory response syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick SOFA (qSOFA). The primary outcomes were the clinical presentation of IED and AMR rates of E. coli isolates to clinically relevant antibiotics. Complications and in-hospital mortality were assessed through 28 days following IED diagnosis., Results: Of 240 enrolled patients, 80.4% had bacteremic and 19.6% had non-bacteremic IED. One-half of infections (50.4%) were community-acquired. The most common source of infection was the urinary tract (62.9%). Of 240 patients, 65.8% fulfilled ≥ 2 SIRS criteria, and 60.4% had a total SOFA score of ≥ 2. Investigator-diagnosed sepsis and septic shock were reported in 72.1% and 10.0% of patients, respectively. The most common complication was kidney dysfunction (12.9%). The overall in-hospital mortality was 4.6%. Of 299 E. coli isolates tested, the resistance rates were: 30.4% for trimethoprim-sulfamethoxazole, 24.1% for ciprofloxacin, 22.1% for levofloxacin, 16.4% for ceftriaxone, 5.7% for cefepime, and 4.3% for ceftazidime., Conclusions: The clinical profile of identified IED cases was characterized by high rates of sepsis. IED was associated with high rates of AMR to clinically relevant antibiotics. The identification of IED can be optimized by using a combination of clinical criteria (SIRS, SOFA, or qSOFA) and culture results., (© 2024. The Author(s).)

Background: Clinical outcomes in bacterial bloodstream infections (BSIs) are influenced by bacterial species, host immunity, and antibiotic therapy. The mechanisms by which such factors influence outcomes are poorly understood. We aimed to identify bacterial- and antibiotic-specific host transcriptional signatures in patients with bacterial BSI., Methods: RNA sequencing was performed on blood samples from patients with BSI due to gram-negative (GN) versus gram-positive (GP) pathogens: Escherichia coli (n = 30) or Klebsiella pneumoniae (n = 28) versus methicillin-susceptible Staphylococcus aureus (MSSA) (n = 24) or methicillin-resistant S. aureus (MRSA) (n = 58). Patients were matched by age, sex, and race., Results: No significant host transcriptome differences were detected in patients with E. coli versus K. pneumoniae BSI, so these were considered together as GN BSI. Relative to S. aureus BSI, patients with GN BSI had increased activation of the classic complement system. However, the most significant signal was a reduction in host transcriptional signatures involving mitochondrial energy transduction and oxidative burst in MRSA versus MSSA. This attenuated host transcriptional signature remained after controlling for antibiotic therapy., Conclusions: Given the importance of immune cellular energetics and reactive oxygen species in eliminating hematogenous or intracellular MRSA, these findings may offer insights into its persistence relative to other bacterial BSIs., Competing Interests: Potential conflicts of interest. J. T. T. reports being a scientific advisor for Resonantia Diagnostics. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Company, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, GSK, and Roche; grants from the National Institutes of Health, AstraZeneca/MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as associate editor of Clinical Infectious Diseases; and a sepsis diagnostics patent pending. M. R. Y. reports honoraria for academic educational services from Alexion/Astrazeneca, Horizon/Amgen, and Genentech-Roche. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Staphylococcus aureus is the leading cause of death due to bacterial bloodstream infection. Female sex has been identified as a risk factor for mortality in S aureus bacteremia (SAB) in some studies, but not in others., Objective: To determine whether female sex is associated with increased mortality risk in SAB., Data Sources: MEDLINE, Embase, and Web of Science were searched from inception to April 26, 2023., Study Selection: Included studies met the following criteria: (1) randomized or observational studies evaluating adults with SAB, (2) included 200 or more patients, (3) reported mortality at or before 90 days following SAB, and (4) reported mortality stratified by sex. Studies on specific subpopulations (eg, dialysis, intensive care units, cancer patients) and studies that included patients with bacteremia by various microorganisms that did not report SAB-specific data were excluded., Data Extraction and Synthesis: Data extraction and quality assessment were performed by 1 reviewer and verified by a second reviewer. Risk of bias and quality were assessed with the Newcastle-Ottawa Quality Assessment Scale. Mortality data were combined as odds ratios (ORs)., Main Outcome and Measures: Mortality at or before 90-day following SAB, stratified by sex., Results: From 5339 studies retrieved, 89 were included (132 582 patients; 50 258 female [37.9%], 82 324 male [62.1%]). Unadjusted mortality data were available from 81 studies (109 828 patients) and showed increased mortality in female patients compared with male patients (pooled OR, 1.12; 95% CI, 1.06-1.18). Adjusted mortality data accounting for additional patient characteristics and treatment variables were available from 32 studies (95 469 patients) and revealed a similarly increased mortality risk in female relative to male patients (pooled adjusted OR, 1.18; 95% CI, 1.11-1.27). No evidence of publication bias was encountered., Conclusions and Relevance: In this systematic review and meta-analysis, female patients with SAB had higher mortality risk than males in both unadjusted and adjusted analyses. Further research is needed to study the potential underlying mechanisms.

Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Despite appropriate antibiotic treatment, relapse of GNB-BSI with the same bacterial strain is common and associated with poor clinical outcomes and high healthcare costs. The role of persister cells, which are sub-populations of bacteria that survive for prolonged periods in the presence of bactericidal antibiotics, in relapse of GNB-BSI is unclear. Using a cohort of patients with relapsed GNB-BSI, we aimed to determine how the pathogen evolves within the patient between the initial and subsequent episodes of GNB-BSI and how these changes impact persistence. Using Escherichia coli clinical bloodstream isolate pairs (initial and relapse isolates) from patients with relapsed GNB-BSI, we found that 4/11 (36%) of the relapse isolates displayed a significant increase in persisters cells relative to the initial bloodstream infection isolate. In the relapsed E. coli strain with the greatest increase in persisters (100-fold relative to initial isolate), we determined that the increase was due to a loss-of-function mutation in the ptsI gene encoding Enzyme I of the phosphoenolpyruvate phosphotransferase system. The ptsI mutant was equally virulent in a murine bacteremia infection model but exhibited 10-fold increased survival to antibiotic treatment. This work addresses the controversy regarding the clinical relevance of persister formation by providing compelling data that not only do high-persister mutations arise during bloodstream infection in humans but also that these mutants display increased survival to antibiotic challenge in vivo., Competing Interests: Competing interests statement:V.G.F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; Royalties from UpToDate, stock options from Valanbio and ArcBio, Honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. CA.A. reports honoraria from UptoDate and salary support from the American Society for Microbiology as Editor in Chief of Antimicrobial Agents and Chemotherapy.

The UDP-3- O -( R -3-hydroxyacyl)- N -acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.

Escherichia coli sequence type 131 (ST131) is a globally dominant multidrug-resistant clone, although its clinical impact on patients with bloodstream infection (BSI) is incompletely understood. This study aims to further define the risk factors, clinical outcomes, and bacterial genetics associated with ST131 BSI. A prospectively enrolled cohort study of adult inpatients with E. coli BSI was conducted from 2002 to 2015. Whole-genome sequencing was performed with the E. coli isolates. Of the 227 patients with E. coli BSI in this study, 88 (39%) were infected with ST131. Patients with E. coli ST131 BSI and those with non-ST131 BSI did not differ with respect to in-hospital mortality (17/82 [20%] versus 26/145 [18%]; P = 0.73). However, in patients with BSI from a urinary tract source, ST131 was associated with a numerically higher in-hospital mortality than patients with non-ST131 BSI (8/42 [19%] versus 4/63 [6%]; P = 0.06) and increased mortality in an adjusted analysis (odds ratio of 5.85; 95% confidence interval of 1.44 to 29.49; P = 0.02). Genomic analyses showed that ST131 isolates primarily had an H4:O25 serotype, had a higher number of prophages, and were associated with 11 flexible genomic islands as well as virulence genes involved in adhesion ( papA , kpsM , yfcV , and iha ), iron acquisition ( iucC and iutA ), and toxin production ( usp and sat ). In patients with E. coli BSI from a urinary tract source, ST131 was associated with increased mortality in an adjusted analysis and contained a distinct repertoire of genes influencing pathogenesis. These genes could contribute to the higher mortality observed in patients with ST131 BSI., Competing Interests: The authors declare no conflict of interest.

Background: The causes and clinical characteristics of recurrent gram-negative bacterial bloodstream infections (GNB-BSI) are poorly understood., Methods: We used a cohort of patients with GNB-BSI to identify clinical characteristics, microbiology, and risk factors associated with recurrent GNB-BSI. Bacterial genotyping (pulsed-field gel electrophoresis [PFGE] and whole-genome sequencing [WGS]) was used to determine whether episodes were due to relapse or reinfection. Multivariable logistic regression was used to identify risk factors for recurrence., Results: Of the 1423 patients with GNB-BSI in this study, 60 (4%) had recurrent GNB-BSI. Non-White race (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.38-4.01; P = .002), admission to a surgical service (OR, 2.18; 95% CI, 1.26-3.75; P = .005), and indwelling cardiac device (OR, 2.73; 95% CI, 1.21-5.58; P = .009) were associated with increased risk for recurrent GNB-BSI. Among the 48 patients with recurrent GNB-BSI whose paired bloodstream isolates underwent genotyping, 63% were due to relapse (30 of 48) and 38% were due to reinfection (18 of 48) based on WGS. Compared with WGS, PFGE correctly differentiated relapse and reinfection in 98% (47 of 48) of cases. Median time to relapse and reinfection was similar (113 days; interquartile range [IQR], 35-222 vs 174 days; IQR, 69-599; P = .13). Presence of a cardiac device was associated with relapse (relapse: 7 of 27, 26%; nonrelapse: 65 of 988, 7%; P = .002)., Conclusions: In this study, recurrent GNB-BSI was most commonly due to relapse. PFGE accurately differentiated relapse from reinfection when compared with WGS. Cardiac device was a risk factor for relapse., Competing Interests: Potential conflicts of interest. V. G. F. reports personal fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, Armata, Valnbio, Akagera, Aridis, Roche, Pfizer, and C3J; grants from NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, Janssen, Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; royalties from UpToDate; a patent pending in sepsis diagnostics; support from Contrafect to present phase 2 data at 2019 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); serving as associate editor, Clinical Infectious Diseases; and stock or stock options to self from ArcBio and Valanbio. J. T. T. is a scientific advisor for Resonantia, Inc. C. A. A. reports grant support from Merck Pharmaceuticals, Entasis Pharmaceuticals and MeMed Diagnostics, and Harris County Public Health; payments made to the institution during the conduct of this study from NIH/NIAID ARLG UM1AI104681, NIH/NIAID T32 AI141349, NIH/NIAID U19 AI144297, NIH/NIAID R01 AI150685, and NIH/NIAID R21 AI151536; royalties or licenses from UpToDate paid to self; reimbursements to attend IDWeek as speaker and part of the organizing committee from the Infectious Diseases Society of America, to attend ASMMicrobe as speaker from American Society for Microbiology, to attend the Society for Healthcare Epidemiology of America (SHEA) Conference as speaker from Society of Hospital Epidemiology of America, to attend ECCMID as speaker from the European Society for Clinical Microbiology and Infectious Diseases, to attend the Interdisciplinary Course on Antibiotics and Resistance (ICARE) course as faculty from Merieux Foundation, and to attend annual meeting as speaker from Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, and Brazilian Society for Infectious Diseases; participation on the World Health Organization’s Antibacterial Pipeline Advisory Group (received no financial compensation, no travel, meetings have all been virtual); payment made to self from NIH Grant Review Study Section; a voluntary position, no compensation, payment for travel and accommodation for board meetings as member of the Infectious Diseases Society of America Board of the Directors; and payment made to self as editor in chief, Antimicrobial Agents and Chemotherapy. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Outcomes from Gram-negative bacteremia (GNB) in solid organ transplant (SOT) recipients are poorly understood., Methods: This is a single center prospective cohort study comparing the clinical characteristics and outcomes of SOT recipients with GNB to immunocompetent non-SOT patients with GNB between 1/1/2002 through 12/31/2018. Outcomes of interest included incidence of septic shock, respiratory failure, and time to death. A multivariable logistic regression model was used to determine factors associated with incidence of septic shock and respiratory failure. Time to death was evaluated using Cox proportional hazard models., Results: A total of 297 SOT and 1245 immunocompetent non-SOT patients were included. Incidence of septic shock did not significantly differ between the groups (SOT 25.3% vs. non-SOT 24.6%, p = .8225). Overall survival did not significantly differ by transplant status (30-day survival: SOT 76%, 95% confidence interval [CI] 70, 92, non-SOT 74%, 95% CI 71, 77: log rank: p = .76). SOT recipients taking three immunosuppressive medications had significantly lower odds of developing septic shock or respiratory failure requiring intubation and mechanical ventilation than those taking ≤1 agent (shock: adjusted odds ratio [aOR] 0.29, 95% CI 0.09, 0.90, p = .0316; respiratory failure: aOR 0.14, 95% CI: 0.04, 0.49, p = .0020)., Conclusions: SOT recipients with GNB do not experience higher rates of septic shock, respiratory failure, or mortality than immnon-SOT recipients with GNB. Among SOT recipients, a greater number of immunosuppressive medications may be associated with improved outcomes during GNB. Future studies are needed to understand the potential relationship between levels of immunosuppression and clinical outcome in SOT recipients with GNB., (© 2022 Wiley Periodicals LLC.)

Importance: Obtaining follow-up blood cultures (FUBCs) in patients with Staphylococcus aureus bloodstream infection (BSI) is standard practice, although its utility in patients with gram-negative bacterial BSI (GN-BSI) is unclear., Objective: To examine whether obtaining FUBCs is associated with decreased mortality (key question [KQ] 1) and whether positive vs negative FUBCs are associated with increased mortality (KQ2)., Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and gray literature were searched from inception to March 11, 2022., Study Selection: Two investigators used predefined eligibility criteria to independently screen titles, abstracts, and relevant full texts. Randomized clinical trials or observational studies that matched or statistically adjusted for differences in, at minimum, level of acute illness between patients in the intervention (eg, FUBCs obtained) and control (eg, FUBCs not obtained) groups were included in primary analyses. Articles published in languages other than English were excluded., Data Extraction and Synthesis: Data abstraction and quality assessments were performed by one investigator and verified by a second investigator. Risk of bias was assessed with the Newcastle-Ottawa Scale. Effect sizes were pooled using random-effects models. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline., Main Outcomes and Measures: Mortality before hospital discharge or up to 30 days from the index blood culture., Results: From 3495 studies, 15 were included (all nonrandomized). In the 5 studies (n = 4378 patients) that met criteria for the KQ1 primary analysis, obtaining FUBCs was associated with decreased mortality (hazard ratio, 0.56; 95% CI, 0.45-0.71). For KQ2, 2 studies met criteria for the primary analysis (ie, matched or statistically adjusted for differences in patients with positive vs negative FUBCs), so an exploratory meta-analysis of all 9 studies that investigated KQ2 (n = 3243 patients) was performed. Positive FUBCs were associated with increased mortality relative to negative blood cultures (odds ratio, 2.27; 95% CI, 1.54-3.34). Limitations of the literature included a lack of randomized studies and few patient subgroup analyses., Conclusions and Relevance: In this systematic review and meta-analysis, obtaining FUBCs in patients with GN-BSI was associated with decreased mortality. The benefit of FUBCs may stem from identification of patients with positive FUBCs, which was a poor prognostic marker.

Rationale & Objective: Staphylococcus aureus (Saureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period., Study Design: Prospective cohort study., Setting & Participants: 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015., Exposure: Clinical characteristics and bacterial genotype., Outcome: All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications., Analytical Approach: Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression., Results: Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent Saureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (-1.32% [95% CI, -2.05 to-0.56%] per year) or arteriovenous graft (-1.08% [95% CI, -1.54 to-0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41])., Limitations: Single-center, inpatient cohort., Conclusions: The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Trials supporting shorter durations of antibiotic therapy for Gram-negative bloodstream infections (GN-BSI) have recently been published. However, adoption of these findings into practice is unclear given limited eligibility criteria and relatively large non-inferiority margins of these studies. To better understand contemporary management of GN-BSI, we conducted an international survey of infectious diseases (ID) specialists., Methods: We developed and disseminated an online survey to assess practice patterns involving treatment duration of GN-BSI, including providers from 28 countries. χ 2 tests, t -tests and multivariable linear regression with generalized estimating equations were used to identify factors associated with treatment duration., Results: In total, 277 ID specialists completed the survey (64% physicians, 31% pharmacists). The median reported duration of antibiotics was 7 days (IQR, 7-10 days) for all GN-BSI sources. Thirty percent of providers typically recommend durations that differ by ≥7 days depending on the source of GN-BSI, and 71% treat ≥10 days for at least one source. In an adjusted model, factors associated with increased duration included intra-abdominal (+1.01 days, 95% CI 0.57-1.45 days; P  < 0.0001), vascular catheter (+0.74 days; 0.33-1.15 days; P  = 0.0004), and respiratory (+0.76 days; 0.38-1.14 days; P  < 0.0001) sources of GN-BSI relative to urinary sources. Providers that transition patients to oral therapy report shorter durations than those who treat with full IV therapy (-0.60 days; -1.12 to -0.09 days; P  = 0.02)., Conclusions: There is extensive heterogeneity in duration of therapy for treating GN-BSI, particularly with respect to source of GN-BSI. Investigations into appropriate treatment durations for different GN-BSI sources are needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide range of acute and chronic infections and is frequently associated with healthcare-associated infections. Because of its ability to rapidly acquire resistance to antibiotics, P. aeruginosa infections are difficult to treat. Alternative strategies, such as a vaccine, are needed to prevent infections. We collected a total of 413 P. aeruginosa isolates from the blood and cerebrospinal fluid of patients from 10 countries located on 4 continents during 2005-2017 and characterized these isolates to inform vaccine development efforts. We determined the diversity and distribution of O antigen and flagellin types and antibiotic susceptibility of the invasive P. aeruginosa. We used an antibody-based agglutination assay and PCR for O antigen typing and PCR for flagellin typing. We determined antibiotic susceptibility using the Kirby-Bauer disk diffusion method., Results: Of the 413 isolates, 314 (95%) were typed by an antibody-based agglutination assay or PCR (n = 99). Among the 20 serotypes of P. aeruginosa, the most common serotypes were O1, O2, O3, O4, O5, O6, O8, O9, O10 and O11; a vaccine that targets these 10 serotypes would confer protection against more than 80% of invasive P. aeruginosa infections. The most common flagellin type among 386 isolates was FlaB (41%). Resistance to aztreonam (56%) was most common, followed by levofloxacin (42%). We also found that 22% of strains were non-susceptible to meropenem and piperacillin-tazobactam. Ninety-nine (27%) of our collected isolates were resistant to multiple antibiotics. Isolates with FlaA2 flagellin were more commonly multidrug resistant (p = 0.04)., Conclusions: Vaccines targeting common O antigens and two flagellin antigens, FlaB and FlaA2, would offer an excellent strategy to prevent P. aeruginosa invasive infections., (© 2022. The Author(s).)

There are important gaps in the literature regarding the role and timing of oral therapy for Gram-negative bloodstream infections (GN-BSIs). To better understand contemporary management practices involving oral step-down in GN-BSI, we conducted an international survey of infectious diseases (ID) specialists. We developed and disseminated an online survey to ID specialists to assess practice patterns involving oral step-down in GN-BSIs, including providers from six continents and 28 countries. χ 2 tests and generalised estimating equations were used to identify factors associated with oral step-down. In total, 277 ID specialists completed the survey (64% physicians, 31% pharmacists). Relative to a line source, oral step-down was more common in abdominal [OR = 1.96 (95% CI 1.48-2.61); P < 0.001], pneumonia [2.24 (1.67-2.99); P < 0.001], skin [7.26 (4.71-11.20); P < 0.001] and urinary [9.15 (5.73-14.60); P < 0.001] sources of GN-BSI. US providers were more likely to practice oral step-down than non-US providers (OR = 4.35, 95% CI 2.57-7.36; P < 0.001). Moreover, 40% of providers practice oral step-down for some, but not all, sources of GN-BSI. Among all providers, 23-53% (depending on GN-BSI source) recommend extended (≥5 days) intravenous (IV) therapy before oral step-down or ongoing IV therapy. Most respondents (76% of all providers; 80% of ID physicians) expressed interest in enrolling patients in a trial of full IV versus early oral step-down for GN-BSI. There is extensive heterogeneity in oral step-down practices for GN-BSI. The optimal role of oral step-down in managing GN-BSIs warrants further investigation., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)