Clinical heterogeneity in Staphylococcus aureus bacteremia (SAB) complicates clinical management and research. We have previously identified five clinically distinct subphenotypes of SAB associated with differences in outcomes and response to adjunctive rifampicin. Here, we aimed to identify these subphenotypes in geographically diverse observational cohorts, including a higher prevalence of methicillin-resistant S. aureus (MRSA) bacteremia and the USA300 clone.MethodsWe studied three cohorts of adults with SAB from observational studies: a UK retrospective study (Edinburgh cohort 2, n=463); a Dutch prospective study (IDISA, n=490); and a USA prospective study (SABG-PCS, n=755). Subphenotypes were identified from routinely available clinical data using latent class analysis.ResultsPatients from the SABG-PCS cohort had greater multimorbidity and more MRSA bacteremia (40.2%, 303/755), including infection with the USA300 clone (14.7%, 111/755). Five distinct subphenotypes were identified in each cohort: (A) older age and cardio-metabolic multimorbidity; (B) nosocomial acquisition and intravenous catheter portal of entry; (C) community acquisition and metastatic infection; (D) chronic kidney disease; and (E) younger age, injection drug use, and metastatic infection. Bacterial genotypes varied substantially between the Edinburgh 2 and SABG-PCS cohorts but did not differ between subphenotypes within each cohort. 90-day mortality was highest in subphenotype A, and persistent bacteremia in subphenotypes C and E.ConclusionsWe have reproducibly identified five clinical subphenotypes of SAB in observational cohorts including diverse bacterial genetic lineages and a cohort with a high prevalence of MRSA and USA300 bacteremia. These robustly reproducible clinical subphenotypes provide a framework to rationalize the heterogeneity intrinsic to SAB.

AbstractObjectivesVascular graft or endograft infections (VGEI) pose a detrimental complication when using vascular grafts and are challenging to diagnose and treat. This study examined the progression of infection and the antimicrobial response in VGEI using [18F]Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), ex vivo bacterial quantification, and histology in a VGEI rat model.MethodsIn this experimental study, 97 male Sprague-Dawley rats had a polytetrafluorethylene graft surgically implanted in the carotid artery. The graft was either pre-inoculated with Staphylococcus aureus, Staphylococcus epidermidis, or saline. Up to 31 days after surgery, rats were FDG-PET-scanned. Subsequently, they were euthanised, and the implants were retrieved for analysis. A subgroup of infected rats received daptomycin and rifampicin from days 20 to 29.ResultsTracer uptake around the implant, measured by maximum standardised uptake value (SUVmax), declined over time in all groups. Between groups, SUVmax was highest in untreated S. aureus-infected rats. When comparing antibiotic-treated and uninfected rats by day 31, there was no difference in SUVmax, although the treated rats were still infected.Histology revealed widespread inflammation by day 10 in S. aureus-infected rats, which decreased by days 20 and 31 with encapsulation of the infection, alongside increased plasma interleukin-10.ConclusionsFDG-PET differentiated untreated S. aureus-infected rats from uninfected ones but failed to monitor infection progression, as SUVmax declined over time despite a constant bacterial load.FDG-PET could not distinguish between uninfected rats and those with suppressed infection, likely due to reduced inflammation and encapsulation of the infection.

Mortality associated with Pseudomonas aeruginosa bloodstream infection (PABSI) remains high despite advances in clinical care and therapeutics. In a recent study using a mouse model of PABSI, the gallbladder was identified as a reservoir for bacterial expansion. Furthermore, bile exposure has been linked to increased antimicrobial resistance. Therefore, we asked whether patients with retained gallbladders might experience more antimicrobial-resistant PABSIs, extended culture positivity, and worsened clinical outcomes.MethodsWe conducted a retrospective cohort study of adults hospitalized over a 5-year period with PABSI. PABSI cases were defined as patients with ≥1 positive P. aeruginosa bacterial culture from the blood. Patients were categorized as those retaining a gallbladder (no cholecystectomy) or not (cholecystectomy). Cholecystectomy was defined as a history of cholecystectomy ≥1 year prior to the index episode of PABSI. Inferential statistics were used to identify associations between remote cholecystectomy and antimicrobial resistance profile, length of blood culture positivity, and in-hospital and 90-day mortality.ResultsThe overall study population included 336 patients: 262 (78%) with a retained gallbladder and 74 (22%) without. Using the entire study population and a matched cohort, we observed no difference in length of culture positivity, 90-day mortality, or in-hospital mortality between groups based on the presence of a gallbladder. Overall, composite 90-day mortality was 30.1%, which was similar to a prior investigation of PABSI outcomes at our institution. While the presence of a gallbladder did not affect the outcome, patients with PABSI and liver disease had significantly higher 90-day mortality than those without liver disease. Furthermore, no robust differences were observed in the antimicrobial resistance profile of P. aeruginosa isolates from the group with or without a gallbladder.ConclusionsIn our study, neither PABSI antimicrobial resistance pattern nor clinical outcomes were affected by remote cholecystectomy. However, we do demonstrate that mortality for patients with PABSI in the modern era remains high despite advances in antipseudomonal therapeutics.

Febrile neutropenia can lead to life-threatening infections in patients with haematological malignancies or after hematopoietic cell transplantation. Infection management is challenged by rising antibiotic resistance and regional differences in bacterial epidemiology. The 10th European Conference on Infections in Leukaemia panel recommends a personalised approach guided by local resistance patterns and individual risk factors. For patients who are haemodynamically stable without colonisation or infection by resistant Gram-negative bacteria in low-resistance prevalence settings, empirical monotherapy sparing carbapenems or novel β-lactams with or without β-lactamase inhibitors (BLI) is recommended.

Safe and effective vaccines are urgently needed to prevent infections caused by Klebsiella pneumoniae (K. pneumoniae), one of the most common antibiotic-resistant pathogens. We aimed to assess the safety and immunogenicity of a tetravalent bioconjugate vaccine Kleb4V, containing O antigen-polysaccharides of the most predominant K. pneumoniae serotypes (O1v1, O2a, O2afg and O3b).MethodsIn this observer-blind, randomised, placebo-controlled, phase I/II trial [ClinicalTrials.gov (number NCT04959344)], 166 healthy adults (18-40y n=16, 55-70y n=150) were enrolled and randomised to receive two intramuscular injections of Kleb4V (16μg or 64μg of total O-antigen +/- adjuvant AS03) or placebo on days 1 and 57. While the primary outcome was safety, the secondary outcomes included vaccine antigen immunogenicity.ResultsKleb4V was well tolerated, with most solicited and unsolicited AEs of mild to moderate intensity. Kleb4V was immunogenic for all four vaccine-serotypes at both antigen doses. O1v1, O2a and O2afg specific IgG increased two weeks after the 1st vaccination and the immune response persisted at six months after the second vaccination. For three of the four vaccine-serotypes, the AS03-adjuvanted formulations showed a superior immune response. O3b responses were reduced compared to the other vaccine antigens.DiscussionKleb4V is the first K. pneumoniae conjugate vaccine candidate to reach clinical assessment. The Kleb4V bioconjugate was immunogenic, well tolerated and with an acceptable safety profile in the target population of adults aged 55-70 years for all 4 vaccine-serotypes.

Central line-associated blood stream infection (CLABSI) surveillance is mandated and publicly reported in United States hospitals but requires manual chart review. Generative artificial intelligence (AI) may facilitate CLABSI identification.MethodsWe performed a retrospective cohort study of CLABSI surveillance using standardized prompts, clinical data, and Centers for Disease Control and Prevention definitions. In 11 hospitals, 24 infection control (IC) nurses and physicians retrospectively reviewed 220 CLABSI/non CLABSI bacteremias. Three methods of review were compared to original facility expert review: 1) AI-assist review, 2) AI-alone review, and 3) repeat expert review. Disagreement between any method of review was adjudicated by a 2-expert physician referee panel.ResultsAI-assist review had a 93.2% (205/220, 95% CI: 89.0–96.1) overall accuracy (agreement with facility reporting or refereeing panel) vs. AI-alone review, 90.0% (198/220, 95% CI: 85.3–93.6) overall accuracy or repeat expert review, 88.2% (97/110, 95% CI: 80.1–93.6) overall accuracy. Inter-site variability was greater for repeat expert review than AI-assist. AI-assist review required a median of 14 minutes (interquartile range, IQR 6-25.5) vs. 25 minutes (IQR 11-43) for repeat expert (p = 0.0001). AI-assist review was reported as low effort in 52% of cases vs. 21% of repeat expert cases (p < 0.0001). AI-assist review was reported as somewhat or very objective in 72% of cases vs. 61% of repeat expert cases (p=0.092).ConclusionsCLABSI detection by AI methods was at least as accurate as traditional methods, better liked by experts, faster and less variable. AI-assisted review could improve healthcare-associated infection reporting.

Staphylococcus aureus colonization predisposes to skin and soft tissue infection (SSTI). Given the waning effectiveness of decolonization, we evaluated periodic personal decolonization and household environmental decontamination to reduce SSTIs among households affected by S. aureus.MethodsHouseholds of children with community-associated S. aureus SSTI participated in an open-label randomized trial. After baseline decolonization, households were randomized 1:1:1 to a 3-month decolonization intervention: 1) Periodic-Personal (twice weekly chlorhexidine bathing and monthly intranasal mupirocin application); 2) Environmental-Hygiene (weekly household surface disinfection and enhanced laundry measures); or 3) Integrated-Approach of both Periodic-Personal and Environmental-Hygiene. Over 9 months, participants and household surfaces were sampled at 5 study visits to detect S. aureus; SSTI incidence was recorded. The primary outcome was household-level cumulative SSTI at 3 months, comparing the Integrated-Approach to the combined Personal-Periodic and Environmental-Hygiene groups.ResultsBetween 2015-2021, 196 index patients and their household contacts (n=623) were enrolled. Cumulative SSTI incidence did not differ between groups during the 3-month intervention. In index patients and household contacts with SSTI in the year prior to enrollment, SSTI incidence was lower among the Integrated-Approach at 6- and 9-months compared to the combined Periodic-Personal and Environmental-Hygiene groups. In multivariable analyses, prior year SSTI was associated with subsequent SSTI; intervention group was not significant. All interventions reduced MRSA, but not MSSA, personal colonization over 9 months.ConclusionsWhile an Integrated-Approach of prolonged personal and environmental decolonization reduced SSTIs among participants with prior year SSTI, prior SSTI strongly predicted SSTI incidence longitudinally. Novel prevention strategies are needed.

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