View abstract Objective:An automated CLuster AleRt system (CLAR) is employed at our hospital to detect clusters of relevant microorganisms. Alerts are subsequently assessed by infection prevention and control (IPC) experts to determine their epidemiological relevance. This study compares expert assessment of CLAR alerts with genotyping results.Design:Retrospective observational studyMethods:We analyzed all CLAR alerts and genotyping reports generated during routine IPC activities between 08/2019 and 12/2024. CLAR alerts were classified relevant/not relevant based on epidemiological assessment by IPC physicians. Selected isolates were genotyped when transmission was suspected. Where multiple alerts and genotyping reports were available for an epidemiological cluster, only the first alert with genotyped isolates and the first corresponding genotyping report were considered, in order to emulate conditions at the onset of potential outbreaks. Genotyping was performed either by whole-genome sequencing (cgMLST) or repetitive-sequence-based polymerase chain reaction (rep-PCR). We calculated the proportion of CLAR alerts with ≥1 genotypically clustering isolate and performed a multivariable regression analysis to identify parameters associated with a higher likelihood of concordance.Results:We identified 116 relevant CLAR alerts corresponding to first genotyping reports (n = 77 cgMLST, n = 39 rep-PCR) of epidemiological clusters. Overall, these alerts contained 253 genotyped isolates. Genotypic clustering of ≥1 CLAR alert isolate was confirmed for 87 CLAR alerts (75.0%). A higher proportion of concordance with genotyping was seen for relevant alerts in neonatology (93.8%) and with carbapenem-resistant Enterobacterales (94.4%), also confirmed by multivariable analysis.Conclusions:Expert-assessed epidemiological relevance of CLAR alerts showed promising concordance with genomic findings and may inform future machine learning-based predictions.

View abstract Background:Extensively drug-resistant Acinetobacter baumannii (XDR-AB) is a significant cause of healthcare-associated infections, particularly in neonatal intensive care units. This study aimed to determine the prevalence of XDR-AB colonization and the odds of subsequent invasive infection. The secondary objectives were to identify risk factors and in-hospital outcomes.Methods:A retrospective study was conducted among 485 neonates admitted to Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa, from June 1, 2020 to December 31, 2022, using laboratory data and medical records.Results:Among 485 neonates, 116 babies (23.9%) were colonized with XDR-AB, with a median colonization age of 4 days. A total of 32 neonates developed invasive infections. Invasive XDR-AB disease was significantly more common among colonized neonates (29 neonates (25%)) compared to 3 (0.81%) non-colonized neonates. In-hospital mortality was significantly higher in colonized neonates (12 (10.34%)) compared to non-colonized neonates (5 cases (1.36%)). Other in-hospital outcomes were not significantly associated with colonization status. Independent colonization risk factors were all affected by confounding.Conclusions:This study highlights the high prevalence of early colonization and subsequent invasive disease with its associated mortality in neonates. Screening of neonates for early colonization helps in empiric antibiotic choices for those found to be colonized.

Antimicrobial stewardship (AMS) and infection prevention and control (IPC) are complementary strategies to improve patient safety and address antimicrobial resistance (AMR). In low- and middle-income countries (LMICs), they are often implemented separately, limiting potential impact.ObjectiveTo evaluate the feasibility of an aligned AMS-IPC improvement approach and describe changes in implementation in Vietnamese hospitals.MethodsWe conducted a quality improvement initiative in 4 hospitals within the national AMR surveillance network in Viet Nam (March–September 2025). We used US-CDC's tools to guide implementation, including the Global Antibiotic Stewardship Evaluation Tool (G-ASET) and the Infection Control Assessment and Response (ICAR) tool. Baseline assessments were followed by feedback, multidisciplinary action planning, and targeted capacity building. Follow-up occurred 2–5 months later. Changes were analyzed descriptively using quantitative scores and qualitative synthesis and reported following the SQUIRE 2.0 guidelines.ResultsAll hospitals had established IPC programs at baseline, while AMS maturity varied. G-ASET scores increased across all sites, with larger absolute gains in hospitals starting from lower baselines. Improvements were seen in leadership and governance, education and training, stewardship actions, and monitoring and reporting. Selected IPC activities aligned with AMS priorities also improved, particularly transmission-based precautions, environmental cleaning, and cross-team coordination. Infrastructure-dependent areas, such as water safety, showed limited short-term progress.ConclusionsThis aligned AMS-IPC quality improvement strategy was feasible and associated with improvements in implementation capacity and program maturity over short follow-up. Further studies with longer follow-up, comparator designs, and outcome-level measures are needed to evaluate effectiveness, sustainability, and generalizability.

Invasive group B Streptococcus (GBS) infection in nonpregnant adults is increasing, particularly among older adults and those with underlying comorbidities. However, multicenter data on prognostic factors for adult GBS bacteremia in Japan remain limited.MethodsWe conducted a multicenter retrospective observational cohort study of adults with GBS bacteremia at 7 hospitals in western Japan between 2015 and 2024. Variables analyzed included clinical characteristics, infection sites, microbiological characteristics, and antimicrobial susceptibility profiles. Univariable and multivariable logistic regression analyses were performed to identify factors associated with 30-day mortality.ResultsA total of 442 patients were included. Median age [interquartile range] was 75 [64-84] years, and 83.0% had at least 1 comorbidity. The overall 30-day all-cause mortality for GBS bacteremia was 9.3% (41/442), which rose to 39.3% (11/28) among patients with streptococcal toxic shock syndrome (STSS). In multivariable analysis, STSS was the strongest predictor of death (adjusted odds ratio [aOR], 9.16; 95% confidence interval [CI], 3.28–25.58), followed by immunosuppressive therapy (aOR, 4.62; 95% CI, 1.66–12.86), cirrhosis (aOR, 3.40; 95% CI, 1.23–9.40), respiratory infection (aOR, 3.30; 95% CI, 1.08–10.06), advanced renal dysfunction (aOR, 2.66; 95% CI, 1.09–6.52), and polymicrobial bacteremia (aOR, 2.40; 95% CI, 1.03–5.57), whereas skin and soft tissue infection was associated with lower mortality (aOR, 0.07; 95% CI, 0.01–0.53).ConclusionsAdult GBS bacteremia carries a high burden of short-term mortality, with a wide variety of clinical presentations, necessitating prompt diagnostic and therapeutic intervention.

AbstractPatients requiring long-term vascular access are at risk of experiencing recurrent or relapsing infections. Decisions to remove and replace these devices when infected depend on their clinical status, the pathogen involved, options for alternative access sites, the risk of mechanical complications or loss of access with attempted catheter replacement, and interruptions of care plans. This State-of-the-Art Review focuses on a team approach to the management of such complex patients. Management involves empiric and then directed systemic antimicrobial therapy, antimicrobial lock therapy, decisions regarding the use of antibiotic-impregnated catheters, and intentional preservation of central venous access for future device insertion. Meticulous documentation, a team approach to care including shared decision-making with the patient and family, optimization of available prophylactic medications and devices, and individualized adherence to evidence-based best practices and professional standards fill important gaps in care delivery and will improve the prevention and management of these infections in this vulnerable patient population.

Infections caused by multidrug-resistant organisms (MDROs) are a growing concern in patients with advanced chronic liver disease and acute-on-chronic liver failure, worsening clinical outcomes. Although prior antibiotic exposure is associated with resistance, prospectively defined, clinically actionable exposure thresholds in this population are lacking. We aimed to quantify cumulative-exposure thresholds for de novo MDRO acquisition and assess the prognostic impact of MDRO emergence on survival.MethodsWe prospectively enrolled 256 consecutive adults with advanced chronic liver disease at the University Hospital Frankfurt (2020–2023). Antibiotic exposure was quantified using defined daily doses (DDD) and antibiotic use density (AUD); MDRO colonisation and infection were captured by systematic microbiological surveillance. Time-to-death was analysed in a competing-risk framework with liver transplantation as competing event.ResultsAmong 246 patients without MDRO at the first admission swab, de novo acquisition of vancomycin-resistant enterococci (VRE) or Gram-negative MDR was strongly associated with cumulative antibiotic exposure (p<0.001). The 20% probability threshold for VRE was reached at 9.6 cumulative DDDs of any antibiotic, with substantially lower thresholds for β-lactam/β-lactamase inhibitor combinations, carbapenems, and glycopeptides. De novo MDRO detection during follow-up, but not at baseline, was independently associated with increased 180-day mortality (HR 2.15, 95% CI 1.27–3.64; p=0.004).ConclusionsIn advanced cirrhosis, MDRO emergence is associated with cumulative antibiotic exposure beyond distinct, class-specific thresholds and carries excess mortality. These prospective findings identify cumulative antibiotic burden as a modifiable risk factor and support an exposure-aware approach to antimicrobial stewardship in this population.

Chronic Pseudomonas aeruginosa airway colonization in bronchiectasis (BE) is associated with frequent exacerbations. Bispecific antibody AZD0292, targeting P. aeruginosa Psl and PcrV, was engineered from gremubamab with a Fc N3Y substitution to extend half-life and is being developed to reduce exacerbations in BE with chronic P. aeruginosa colonization.MethodsPreclinical studies assessed opsonophagocytic killing and anti-cytotoxicity assays, repeat-dose toxicology with ex vivo pharmacodynamic analyses in cynomolgus monkeys, and pharmacokinetics in human FcRn transgenic mice. In Phase I, healthy adults were randomized to receive a single dose of AZD0292 (n =24) or placebo (n = 8) in 4 cohorts (100-2,000 mg) and followed for 61 days or 161 days in cohort 4. Endpoints included safety, pharmacokinetics, immunogenicity, and exploratory cytokine/complement assessments.ResultsAZD0292 demonstrated comparable functional activity to gremubamab, an approximately 55% lower clearance in transgenic mice, and retained anti-P. aeruginosa activity in cynomolgus monkey serum after repeated dosing. In Phase I, AZD0292 was generally well tolerated. Mild/moderate infusion-related reactions occurred only at higher doses and were managed with routine clinical measures. Transient cytokine increases were observed after dosing, with no meaningful complement activation. Pharmacokinetics were approximately dose-dependent but slightly less than dose-proportional across 100-2,000 mg. Geometric mean half-life ranged from 24 to 47 days, though estimates are provisional given small cohort sizes and limited follow-up. No treatment-emergent anti-drug antibodies were detected.ConclusionsThese results support further clinical development of AZD0292 for reduction of exacerbations in BE with chronic P. aeruginosa colonization, with pharmacokinetics requiring confirmation in the target patient population.

Yellow fever virus is transmitted by mosquitoes among humans and non-human primates (NHPs) in South America. The 2024–2025 yellow fever (YF) outbreak was notable for its spread into new areas, including the department of Tolima in Colombia's Andean region. We investigated the eco-epidemiology of human and NHP YF cases to understand the patterns and factors associated with the Tolima outbreak.MethodWe collected spatiotemporal, sociodemographic, and mortality data on human YF cases in Tolima, as well as the locations of deceased NHPs with YF. We then conducted exploratory, descriptive, and spatial statistical analyses to identify risk factors and hotspots for YF. We then used inferential spatiotemporal modeling to compare ecological and sociodemographic factors.ResultsFrom September 2024 to October 2025, 116 human and 53 non-human primate YF cases were detected in Tolima. Among the human cases, 77% were male (89/116), and the median age was 47 (interquartile range 34–63). Of these cases, 45 (39%) died, and older age was associated with increased odds of death (adjusted odds ratio, 1.43 per 10 years; 95% confidence interval, 1.18–1.78). There was significant clustering among human and NHP cases. Higher rainfall and poverty/deprivation were associated with increased YF incidence at the neighborhood level, and rainfall during the outbreak was above average due to La Niña.ConclusionsThese findings demonstrate significant mortality from YF, which reemerged in Tolima after nearly a century. Rural populations with greater ecological risk and poverty/deprivation could benefit from targeted vaccination strategies for YF.

Improved diagnostics are needed for tuberculosis (TB) among adolescents. Tongue swab (TS) molecular testing is a promising strategy for TB testing. We evaluated diagnostic accuracy and acceptability of Xpert MTB/RIF Ultra (“Xpert”) using TSs for TB detection in adolescents.MethodsWe conducted a cross-sectional diagnostic accuracy study in southern Vietnam. Adolescents aged 10–19 years who were recommended to undergo investigation for TB were eligible. Participants provided TS and sputum samples and were surveyed regarding sampling experiences. TS samples were tested on Xpert, with sputum tested on Xpert and liquid culture. We utilized a composite reference standard of a positive sputum Xpert or culture result to define disease status. Sensitivity, specificity, and diagnostic yield were calculated for TS Xpert.ResultsFrom July to December 2025, we enrolled 225 adolescents. Most participants (157/225 [70%]) were close contacts of a person recently diagnosed with TB and many (129/225 [57%]) did not exhibit symptoms of presumptive TB. All adolescents could provide a TS, while 116 (52%) could produce mucopurulent sputum. Tuberculosis prevalence was relatively low (12/225 [5.3%]). TS Xpert sensitivity and specificity were 58.3% (90% confidence interval [CI], 35.6%–78.0%) and 99.5% (90% CI, 97.9%–99.9%), respectively. TS diagnostic yield among all diagnosed was 58.3% (7/12). TS sampling was highly acceptable to adolescents; the quickness and simplicity of collecting TSs were considered favorably.ConclusionsTS Xpert sensitivity and diagnostic yield were relatively low among adolescents recommended for TB investigation. All participants were able to provide a TS. Specificity was excellent. TS's high acceptability indicates it remains a promising sample for diagnostic algorithms.

Naturally acquired antibodies to Chlamydia trachomatis (CT) are associated with reduced cervical bacterial burden but not with protection from endometrial or subsequent CT infection. We investigated whether antibody-mediated opsonophagocytosis, a functional measure of humoral immunity, was associated with protection against these clinical outcomes.MethodsSerum samples from 139 women enrolled in the longitudinal T cell Response Against Chlamydia (TRAC) cohort and 11 healthy seronegative controls were evaluated for Fc receptor-mediated opsonophagocytosis of CellTrace Violet-labeled CT elementary bodies using THP-1 monocytes. Associations with anti-chlamydial antibody titers, cervical bacterial burden, endometrial infection, and incident CT infection during 12 months of follow-up were assessed.ResultsOpsonophagocytic activity correlated strongly with anti-chlamydial antibody titers and was significantly higher in seropositive women than in seronegative controls. Although a weak inverse correlation with cervical bacterial burden was observed, neither the proportion of phagocytic cells nor the extent of bacterial uptake was associated with reduced endometrial infection. Similarly, neither measure differed between women who experienced incident CT infection during follow-up and those who remained infection-free.ConclusionsNaturally acquired anti-chlamydial antibodies promoted Fc receptor-mediated uptake of CT; however, antibody-mediated opsonophagocytic activity was not associated with protection from endometrial or subsequent CT infection. These findings suggest that naturally acquired antibody-mediated opsonophagocytic activity is unlikely to serve as a correlate of protection against CT infection.

AbstractGut dysbiosis is associated with chronic immune activation in people with HIV (PWH), but is not well-characterized in elite controllers (ECs) or PWH receiving aspirin or statins. We analyzed gut microbiota among 22 virally-suppressed PWH and 12 ECs before and 9-months after randomization to aspirin or atorvastatin. There were no differences in microbiota between PWH and EC at baseline. There was a significant change in beta diversity after aspirin administration, but no difference in microbiota after atorvastatin. These findings suggest that ECs have gut microbiota resembling virally-suppressed PWH, and aspirin but not atorvastatin may impact gut microbiota diversity in PWH.

Diphtheria, commonly resulting in severe respiratory or cutaneous disease, is caused by toxigenic strains of Corynebacterium diphtheriae; nontoxigenic strains can also cause disease. In the United States, only toxigenic disease is reportable, and the Centers for Disease Control and Prevention perform the only Elek testing to confirm diphtheria toxin production. We examine the epidemiology, toxigenicity, and trends of C diphtheriae isolates reported during 2016–2023 in the United States.MethodsC diphtheriae isolates submitted to the Centers for Disease Control and Prevention were cultured and tested by polymerase chain reaction and Elek. Laboratory and epidemiological data were linked; we conducted descriptive statistics by toxigenicity status.ResultsA total of 1155 C diphtheriae isolates were submitted during 2016–2023; 96.1% (n = 1110) were nontoxigenic, 3.0% (n = 35) were nontoxigenic tox-bearing, and 0.9% (n = 10) were toxigenic. From 2016 to 2023, the annual number of reported isolates increased over 10-fold. Median patient age was 43 years (range: <1–98), and 68.6% (n = 793) were male. Isolates were primarily obtained from cutaneous sites (69.8%, n = 806). Risk factors for nontoxigenic and nontoxigenic tox-bearing infections included housing instability and history of intravenous drug use. Nine of the 10 toxigenic isolates were from patients with recent international travel to a diphtheria-endemic country, and none were from patients with respiratory symptoms.ConclusionsThere has been an increase in C diphtheriae isolates identified in the United States. However, toxigenic cases remained infrequent and risk factors appear to differ between patients with toxigenic compared with non-toxin-producing infections. Risk factor awareness may help to guide public health intervention prior to confirmation of toxigenicity.

View abstract Objective:To evaluate the association between department-level implementation of broad multiplex respiratory pathogen panels and antibacterial prescribing.Design:Retrospective repeated cross-sectional staggered-adoption study with cohort-stacked difference-in-differences models.Setting:US emergency and urgent-care departments contributing deidentified electronic health record data to Epic Cosmos, 2016–2025.Participants:Adults with acute respiratory illness without a concurrent clear nonrespiratory bacterial indication.Methods:Incident implementation was the first sustained increase in strict panel use from below 2% to at least 10%, with complete 8-quarter preimplementation and postimplementation windows. Adopters were compared with contemporaneous nonadopters and not-yet-adopters. The primary outcome was a same-day systemic oral or enteral antibacterial order after emergency department discharge.Results:Among 55,059,432 eligible encounters, 32 adopting departments in 9 cohorts were compared with 1,075 departments, yielding 114,832 department-quarter observations. Implementation was associated with a 23.53-percentage-point increase in panel use (95% CI, 20.32 to 26.74) and a 1.21-percentage-point reduction in same-day antibacterial prescribing (95% CI, −2.37 to −0.05; P = .041), a 5.7% relative decrease. However, alternative 5, 15, and 20% thresholds were not statistically significant, unrestricted analyses were null, and several preimplementation diagnostics rejected flat trends.Conclusions:Sustained panel implementation was associated with a small reduction in antibiotic prescribing. Threshold sensitivity and mixed preimplementation diagnostics limit causal interpretation and support integrating testing into broader diagnostic-stewardship workflows.

View abstract Objective:Multidrug-resistant (MDR) bacteria poses a significant threat to patient care, especially in vulnerable populations. This study evaluates antimicrobial resistance (AMR) trends at a tertiary cancer center in Jordan, analyzing data from 2007 to 2022.Design and settings:This retrospective study analyzed 51,697 first bacterial isolates from 108,432 cultures at King Hussein Cancer Center (2007–2022). Data were stratified into three periods and processed using the AMR package for R. Binomial logistic regression models were employed to forecast resistance trends to 2030.Results:The comprehensive analysis of 51,697 first bacterial isolates revealed that 61% were Gram-negative bacteria (GNB) and 39% were Gram-positive bacteria (GPB), with Escherichia coli, coagulase-negative staphylococci (CoNS), and Klebsiella pneumonia predominating. MDR was identified in 36.5% of isolates, with GNB accounting for 84.4%, while extensively drug-resistant (XDR) was confined to Acinetobacter baumannii-calcoaceticus and Pseudomonas aeruginosa. Conversely, nonfermenting GNB showed declining resistance trajectories for piperacillin/tazobactam and amikacin. Among Gram-positives, methicillin-resistant Staphylococcus aureus (MRSA) surged from 37% to 57%. Vancomycin-resistant enterococci (VRE) increased reaching 13%. Blood cultures were predominantly GPB (65%), while respiratory and urine samples were primary sources of resistant GNB. Hematologic malignancy patients exhibited the highest extensively drug-resistant (XDR) rates (5.6%–7.9%) and VRE burden (32% in leukemia). Predictive models forecast escalations by 2030: MRSA 72.7%, VRE in Enterococcus faecium 70%, and cefepime resistance in Enterobacterales 61.9%.Conclusion:Our AMR patterns are alarming and vary significantly by specimen site and cancer diagnosis, underscoring the urgent need for enhanced stewardship, infection control, and diagnosis-specific empirical protocols.

In the United States, testing for latent tuberculosis (TB) infection is recommended for persons from higher-TB-prevalence countries, but guidelines do not address repeat testing for persons with international travel.MethodsUsing 2010–2022 data from a Californian federally qualified health center serving an Asian American population, we measured the incidence of TB test conversion (negative to positive result) and proportion of test converters receiving treatment among routinely tested patients (ie, patients with no history of TB infection, at least one prior negative result, and annual or biennial TB testing). We performed a nested case–control study to measure the association between TB test conversion and travel outside the United States.ResultsOf 5668 patients receiving routine TB testing at annual/biennial frequencies, conversions occurred in 117 patients with TB skin tests (2.9%) and 52 patients with interferon-gamma release assays (3.2%); the overall test conversion incidence rate was 2.1/100 person-years. Latent TB infection treatment was initiated in 57% of test converters. Two patients were diagnosed with TB disease after test conversion, representing a 2-year TB incidence rate of 0.35/100 person-years. Patients with documented international travel had a 1.95-fold increased odds of TB test conversion (95% confidence interval 1.07–3.57) compared to patients without documented travel, with most travel occurring in medium or high-TB-prevalence countries.ConclusionsWithin a 13-year study period, among a routinely tested population at higher risk of TB infection due to race and nativity, risk of TB test conversion was low. However, recent travel to higher-TB-prevalence settings nearly doubled the odds of TB test conversion.

Diagnostic performance of tongue swab Mycobacterium tuberculosis polymerase chain reaction (PCR) has been evaluated for triage of symptomatic tuberculosis (TB). It is unknown whether performance differs for detection of asymptomatic TB in community-based screening.MethodsTongue swabs were collected from adult household contacts of persons with TB (HHC cohort), and symptomatic adults presenting with presumptive TB (clinic cohort), at six South African sites. Drug-susceptible pulmonary TB was defined by positive sputum Xpert Ultra (excluding trace) or liquid culture, which were performed in all participants. Tongue swabs from participants with and without TB, matched by propensity score, were tested by high-volume quantitative PCR (qPCR) and, in the clinic cohort, also by sequence-specific magnetic capture (SSMaC) with qPCR.ResultsThe clinic cohort included 217 participants with TB (100% symptomatic) and 437 participants without TB. The HHC cohort included 44 participants with TB (84.1% asymptomatic) and 136 participants without TB. In the clinic cohort, sensitivity of SSMaC with qPCR was 73.2% (specificity 94.6%), but not significantly higher than high-volume qPCR (63.8%; P = .14) (specificity 94.4%). Sensitivity of high-volume qPCR in the clinic cohort (63.8%) was significantly higher than the HHC cohort (34.1%; P = .0007) (specificity 91.9%). Among HHC, high-volume qPCR sensitivity was 35.1% for asymptomatic TB, 52.2% for TB with abnormal chest radiograph, and 100% for TB with high sputum Xpert Ultra grade.ConclusionsSensitivity of tongue swab high-volume qPCR in community-based, household screening for asymptomatic TB was low, approximately half that of facility-based triage for symptomatic TB, but increased with radiographic severity and sputum bacillary load.

View abstract Objective:To assess the surveillance characteristics of respiratory syndromic surveillance criteria and their usefulness for monitoring infection trends in long-term care (LTC) facilities.Design:Retrospective observational study.Setting:Two wards caring for children and adults with severe motor and intellectual disabilities in an LTC facility with 110 beds.Patients:Inpatients who underwent respiratory pathogen testing during febrile episodes between November 2022 and December 2025 were included. Episodes were defined as testing events associated with febrile periods and surveillance characteristics were assessed among tested episodes.Interventions:Surveillance criteria, derived from the patient-based component of the CARES strategy, were defined as fever ≥38.0°C lasting for ≥2 consecutive days accompanied by at least one respiratory symptom. Associations between surveillance-positive episodes and microbiologically confirmed respiratory infections were examined, and temporal trends were assessed. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios were calculated as descriptive surveillance characteristics.Results:Overall, 1,467 episodes from 124 patients were analyzed, including 375 microbiologically confirmed episodes. Surveillance criteria identified 140 (9.5%) episodes, of which 87 (62.1%) were microbiologically confirmed, with 23.2% sensitivity (95% confidence interval, 19.0–27.8) and 95.1% specificity (95% confidence interval, 93.7–96.3). Surveillance-positive episodes demonstrated temporal patterns consistent with confirmed infections.Conclusions:Respiratory syndromic surveillance criteria demonstrated high specificity and captured temporal changes in microbiologically confirmed respiratory infections in LTC wards. Although not designed to identify every infection, simple signals, such as ≥2 surveillance-positive episodes per week, may facilitate monitoring respiratory infection activity and support timely infection prevention and control responses.

Clostridioides difficile infection (CDI) imposes a burden that extends well beyond the gastrointestinal tract, yet existing outcome measures only partially capture the patient experience. We used frontier large language models (LLMs) on patient and caregiver narratives at scale to describe how burden shifts with disease course.MethodsWe analyzed 189 testimonials from the Peggy Lillis Foundation corpus, sorted into four cohorts with recurrence (r) and fulminant (f) severity as axes (rfCDI, fCDI, rCDI, non-rfCDI). Two independent LLMs coded eight thematic domains, four fulminant flags, thirteen emerging semantic fields, the dominant dimension, and narrative arcs. Two physicians independently coded a subset for inter-rater reliability (PABAK, Gwet's AC1).ResultsTreatment trajectory was the dominant theme in recurrent disease, whereas death and near-death dominated non-recurrent fulminant narratives. Psychological burden was near-universal in fulminant disease (98.0% in rfCDI, 97.2% in fCDI). Caregiver and bereavement content concentrated in fCDI (66.7%). Diagnostic failure was frequent across recurrent cohorts (47.6 - 56.1%). Mentions of bacteriotherapy (fecal microbiota transplantation) concentrated in recurrent cohorts (60.2% rfCDI versus 5.6% fCDI). Financial, mental-health, and caregiver burdens were prominent and remain largely unaddressed by guidelines. Human-human reliability was substantial (PABAK 0.79 for semantic fields, 0.76 for domains); arc coding was least reliable.ConclusionsPatient narratives reveal a course-dependent, multidimensional burden in CDI. Concrete gaps exist between what patients prioritize, what guidelines recommend, and what therapy access provides. Frontier-LLM coding, validated against clinicians, offers a reproducible route to translate these priorities into research, care, and policy.

View abstract Introduction:Wastewater-based epidemiology (WBE) offers pooled biological samples of defined populations, complementing clinical surveillance for infectious diseases. Hospitals are hotspots for antimicrobial resistance (AMR). We performed a scoping review assessing hospital wastewater for AMR monitoring.Methods:We searched Medline, Embase, Biosis, Web of Science, and biorxiv.org from inception to May 5, 2026, for studies using hospital wastewater to monitor AMR. The primary outcome was AMR detection and concordance with traditional surveillance. Concordance was reported by resistance class, and reported as strain- or gene-level, as discordant, or as not assessed. Secondary outcomes included sampling methods, and laboratory techniques.Results:Of 4,695 screened studies, 36 from 22 countries met inclusion criteria (high-income 53%, upper-middle-income 42%, and lower-middle-income 5%). Traditional surveillance used mostly routine diagnostics (58%); only 39% of studies aligned temporally with wastewater sampling. Extended-Spectrum Beta-Lactamase-producing organisms showed strain-level concordance in 2/6 studies, and gene-level concordance in 4/6; carbapenem resistance showed strain-level concordance in 2/9 and gene-level concordance in 4/9. Concordance was present for vancomycin-resistant enterococci (2/3), while inconsistent for Methicillin-resistant Staphylococcus aureus (0/2) and Candida auris (1/2). One study quantified correlation statistically, finding strong association (Spearman’s rho = .88). Wastewater sampling methods included grab sampling (39%), composite sampling (36%), and was unreported (25%). Most studies combined culture-based (89%) and molecular methods (PCR 75%, WGS 42%, metagenomics 17%), mostly targeting Gram-negatives (83%).Conclusion:Hospital WBE showed variable concordance with traditional surveillance, but methodological heterogeneity and limited temporal alignment constrain comparisons. Standardized frameworks and patient-level studies, particularly from low- and middle-income countries, are needed.

Treatment of tuberculosis infection (TBI) is a key pillar of the World Health Organization End TB Strategy. Two short-course rifamycin-based regimens—3 months of weekly isoniazid plus rifapentine (3HP) and 4 months of daily rifampicin (4RIF)—are widely recommended; however, they have not previously been directly compared in a randomized controlled trial. We compared treatment completion between 3HP and 4RIF among individuals with TBI.MethodsWe conducted a multicenter, open-label, parallel-group randomized controlled trial across 7 tuberculosis clinics in Sydney, Australia, between July 2019 and June 2024. Participants of any age with TBI were randomized 1:1, stratified by site, to receive either weekly 3HP or daily 4RIF. All doses were self-administered. Participants in the 3HP group received weekly Short Message Service (SMS) adherence reminders; both groups received standard clinic follow-up. The primary outcome was treatment completion, defined as ingestion of ≥90% of prescribed doses. Analyses were conducted on an intention-to-treat basis.ResultsA total of 210 participants were enrolled (106 assigned to 3HP and 104 to 4RIF). Treatment completion was significantly higher in the 3HP group (84.9%) than in the 4RIF group (65.4%; relative risk, 1.30 [95% confidence interval, 1.22–1.38]; P < .001). Adverse events of any grade occurred in 24.5% of participants receiving 3HP and 20.2% receiving 4RIF. No treatment-related deaths were reported.ConclusionsWeekly 3HP supported by SMS reminders achieved significantly higher treatment completion than daily 4RIF, with similar safety. These findings support broader implementation of 3HP to optimize adherence and outcomes in TBI treatment programs.Clinical Trials RegistrationAustralian New Zealand Clinical Trials Registry (ACTRN12618001672246).

Bedaquiline improves culture conversion in drug-resistant tuberculosis (DR-TB) treatment, but its main safety concern is QTc prolongation, particularly when combined with other anti-TB drugs. This study assessed the incidence and predictors of QTc prolongation among DR-TB patients receiving Bedaquiline under programmatic conditions in Uganda.MethodsWe conducted a retrospective cohort study using medical records from 14 DR-TB treatment sites across Uganda (January 2017–December 2022). Data on demographics, clinical characteristics, Bedaquiline-based regimens, treatment duration, and QTc intervals were collected. Incidence rates with 95% confidence interval (CI) were calculated for QTc prolongation, while modified Poisson regression was used to identify predictors of QTc prolongation.ResultsData were abstracted from 532 patients, 70.9% of whom were male. The mean (SD) age was 41.4 (±15.9) years, and 34.6% were co-infected with HIV. The baseline mean (SD) QTc was 426.8 (±28.4) ms, with a median follow-up of 10.3 months (IQR: 7.2–13.5). The overall incidence of QTc prolongation was 12.0 cases per 1,000 person-months (95% CI: 10.8–16.8). Lower BMI (IRR: 0.924 95% CI: 0.860, 0.993, p-value:0.031) increases risk of QTc prolongation. Treatment success was similar among patients with and without QTc prolongation: 73.9% (51/69) vs. 68.3% (316/463), p = 0.873.ConclusionsAn average of 12 new cases of QTc prolongation were observed for every 1,000-person months of accumulated observation time. The recommended monthly ECG monitoring should be emphasized among patients with low baseline BMI. QTc prolongation was not linked to poor treatment outcomes.

The Healthcare Effectiveness Data and Information Set’s antibiotic utilization for respiratory conditions (AXR) is a new, broad antibiotic prescribing metric. Higher AXR values indicate higher respiratory encounter prescribing rates. Relationships between clinician-level AXR and prescribing/diagnostic practices are unclear.MethodsThis was a retrospective observational study of respiratory urgent care (UC) encounters across 32 UC centers in our health system, conducted from 1 July 2022 to 30 June 2025. Correlations between clinician-level AXR and prespecified outcomes (tier 3 prescribing, antibiotics for pharyngitis despite negative group A Streptococcus antigen testing, sinusitis/acute otitis media (AOM) treatment/diagnosis rates, narrow-spectrum antibiotic prescriptions excluding encounters with penicillin allergy, and <7-day treatment duration for sinusitis/AOM in patients ≥2 years) were assessed using quartile-based logistic regression and weighted Spearman correlations.ResultsAmong 528 444 respiratory encounters, 37.1% (195 891) were associated with an antibiotic prescription; 303 clinicians were included. Clinicians in the highest AXR quartile (AXR quartile 4 [Q4]) were more likely to be in Q4 than in quartile 1 for the following: tier 3 prescribing (odds ratio, 15.38 [95% confidence interval, 5.58–42.39]), pharyngitis prescribing despite negative group A Streptococcus testing (11.16 [4.04–30.79]), and the treatment (8.95 [3.23–24.80]) or diagnosis (33.92 [11.14–103.27]) of sinusitis/AOM. AXR-Q4 clinicians were less likely to be in Q4 for narrow-spectrum antibiotic prescriptions excluding encounters with penicillin allergy (odds ratio, 0.36 [95% confidence interval, .17–.77]) and prescriptions of <7 days for sinusitis/AOM for patients ≥2 years old (0.25 [.11–.55]).ConclusionsIn our UC network, high clinician-AXR was correlated with antibiotic prescription/diagnostic measures. AXR can serve as an efficient screening metric but should be paired with prescription/diagnosis-specific measures and prescription characteristics to guide outpatient stewardship efforts.

The diagnosis of talaromycosis, a life-threatening invasive fungal disease endemic in Southeast Asia, still relies on protracted culture methods. We report the development and clinical evaluation of a novel lateral flow assay (LFA) for the rapid diagnosis of talaromycosis.MethodsThe LFA used 2 novel monoclonal antibodies targeting the Talaromyces marneffei-specific protein Mp1p. In a retrospective, case-cohort study, we evaluated the diagnostic performance of the Mp1p LFA against the reference standard of culture-proven talaromycosis from any clinical specimens, and compared to our validated Mp1p enzyme immunoassay (EIA) in paired plasma and urine samples from 239 talaromycosis and 160 non-talaromycosis participants randomly selected from cohorts of hospitalized adults with advanced human immunodeficiency virus (HIV) disease from 5 centers across Vietnam.ResultsThe Mp1p LFA demonstrated an analytical limit-of-detection of 400 pg/mL, comparable to the EIA. No cross-reactivity with 16 common human fungal pathogens was observed. Clinical sensitivity was higher in urine compared to plasma (95.4% vs 88.7%, P < .01), and clinical specificity was >95% in both specimen types. Clinical performance was similar to the EIA: sensitivity 95.4% versus 97.1%, P = .87 and specificity 95.6% versus 97.5%, P =1.0. Both the LFA and EIA were substantially more sensitive than conventional blood culture collected at the same time (95.4% vs 97.1% vs 77.8%, P < .01).ConclusionsThe Mp1p LFA has excellent diagnostic performance, comparable to the EIA, is superior to blood culture, and has the potential to rapidly rule in and rule out talaromycosis at the point-of-care within 15 minutes without need for laboratory infrastructure.

Timely antibiotics are key determinants of sepsis survival and are presumed to be especially critical in immunocompromised patients. However, evidence supporting this assumption is limited.MethodsWe identified all adults treated for suspected sepsis in the emergency departments of 9 US hospitals, 2015–2024. We identified immunocompromised patients using diagnosis codes, supplemented with clinical data to define a severely immunocompromised subgroup. We used multivariable logistic regression to assess associations between time to antibiotics (primary analysis: 1–3 vs 0–1 hour; secondary analysis: 3–6 vs 0–3 hours) and in-hospital mortality, stratified by immune status and sepsis severity.ResultsAmong 39 842 hospitalizations with suspected sepsis, 20 721 occurred in non-immunocompromised patients and 19 121 in immunocompromised (2283 severe). Overall, antibiotic administration at 1–3 versus 0–1 hour was associated with increased mortality in non-immunocompromised (OR 1.33, 95% CI 1.12–1.59) but not immunocompromised patients (OR 1.08, 95% CI 0.94–1.25). Increased risk was limited to septic shock, where delayed antibiotics were associated with higher mortality in both non-immunocompromised (OR 1.41, 95% CI 1.12–1.76) and immunocompromised patients (OR 1.21, 95% CI 1.002–1.47). In contrast, no association was observed in sepsis without shock regardless of immune status, including for antibiotic administrations at 3–6 versus 0–3 hours. Effect estimates were similar for mild–moderate and severe immunocompromise.ConclusionsShort delays in antibiotic administration were associated with increased mortality in septic shock but not in sepsis without shock, with no evidence of greater vulnerability among immunocompromised patients. These findings suggest antibiotic urgency should be guided primarily by clinical severity rather than immune competence.

To the  Editor—Recent failures of toxin-directed Clostridioides difficile vaccines raise an important question: are current trial endpoints measuring the disease these vaccines are designed to prevent? In the phase 3 CLOVER trial of PF-06425090, published in Clinical Infectious Diseases, vaccinated participants had fewer primary-endpoint cases than placebo recipients, but the primary efficacy endpoint was not met [1]. A useful framework for interpreting this result may already exist in the IDSA/SHEA diagnostic literature [2, 3]. Those guidelines emphasize that nucleic acid amplification testing (NAAT) detects toxigenic organisms but does not by itself distinguish colonization from active toxin-mediated disease.

The study aim was to evaluate the effectiveness of anti–methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins in combination with daptomycin (anti-MRSA Ceph + DAP) compared to other antimicrobial regimens (OARs) as initial treatment of MRSA bloodstream infection (BSI).MethodsThis retrospective observational study enrolled patients with MRSA-BSI from 1 January 2020 to 31 December 2024 at 4 large Italian hospitals. The primary endpoint was 90-day all-cause mortality. Cox regression was used for primary endpoint analysis; results were confirmed with inverse probability of treatment weighting (IPTW). Treatment efficacy was also assessed using the desirability of outcome ranking (DOOR) approach, assigning 1 additional point beyond recovery for 1 of the following negative outcomes: (i) persistent MRSA infection, (ii) persistent bacteremia (≥5 days), (iii) drug resistance, (iv) any adverse event, and (v) 90-day relapse. A score of 7 was assigned for death at any time point.ResultsOverall, 465 patients were enrolled: Median age was 76 (IQR, 61–83) years, 59% male, with a Charlson Comorbidity Index score of 7 (IQR, 4–8). Of them, 50 (11%) and 116 (25%) patients had endocarditis and metastatic infection, respectively. Importantly, 90-day mortality occurred in 181 (39%) patients, while 260 (56%) experienced at least 1 negative outcome included in DOOR analysis. Overall, patients in the anti-MRSA Ceph + DAP arm had a 59.9% (95% CI, 52.4%–67.4%) probability of having a better outcome than those in the OAR arm. Particularly, anti-MRSA Ceph + DAP was associated with reduced mortality (aHR, 0.54 [95% CI, .34–.85]), confirmed after adjustment with IPTW analysis.ConclusionsAnti-MRSA Ceph + DAP could represent a valid initial therapy for MRSA-BSI, especially in patients with high risk of worse outcomes.

AbstractObjectivesA subset of clinical Pseudomonas aeruginosa isolates from the INVICTUS I study was selected to compare antimicrobial susceptibility performance for disc diffusion and broth microdilution of ceftolozane/tazobactam and five comparator antipseudomonal agents.MethodsOverall, 159 non–cystic fibrosis isolates were chosen from INVICTUS I that had the smallest zone diameters from disc testing to ceftolozane/tazobactam, including isolates that were close to the breakpoints. The isolates were tested across 14 centres in the UK. Susceptibility results were interpreted using EUCAST 2026 criteria.ResultsDiscrepancy analysis showed combined error rates (very major and major errors) highest for ceftolozane/tazobactam, ceftazidime and piperacillin/tazobactam (15.7%, 14.5% and 12.6%, respectively); when adjusted to remove isolates close to the breakpoint for ceftolozane/tazobactam and piperacillin/tazobactam there were still remarkably high error rates (10.6% and 7.2%, respectively). Essential agreement and bias analysis were not performed as MICs were being compared with zone diameters.DiscussionOur findings highlight substantial challenges in performing and interpreting susceptibility testing for these two important antipseudomonal β-lactam/β-lactamase inhibitors, which are commonly employed as either first-line empirical therapy (piperacillin/tazobactam) or for serious and MDR infection (ceftolozane/tazobactam). A review of disc testing for these agents may be warranted, and diagnostic laboratories may wish to review the technical limitations and put in place mitigating measures.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome diagnosed using composite clinical and laboratory criteria. Several features used to classify HLH overlap with manifestations of severe malaria, raising uncertainty about the specificity and prognostic significance of HLH classification in this context. We examined the frequency of HLH and its association with mortality in children with severe malaria.MethodsWe analyzed two cohorts of Ugandan children hospitalized with Plasmodium falciparum severe malaria (cohort #1, n = 461; cohort #2, n = 594). HLH was classified using the HLH-2004 criteria and the HScore. To address differences in laboratory availability, concordance analyses were performed using criteria assessed in both cohorts. Associations with in-hospital mortality were examined using logistic regression.ResultsFeatures included in HLH diagnostic criteria were common in both cohorts. Hyperferritinemia (≥500 ng/mL) was present in >75% of children, whereas hypofibrinogenemia was uncommon (<2%). Using complete criteria, the frequency of HLH classification varied between cohorts (HLH-2004: 3.5% vs 13.0%; HScore >169: 0% vs 17.8%), but was similar in concordance analyses. Classification by HLH-2004 criteria was not associated with mortality in either cohort. In cohort #2, higher HScores were associated with increased unadjusted mortality (OR 3.04, 95%CI 1.57–5.86), although this association was attenuated after adjustment for markers of organ dysfunction (aOR 1.87, 95%CI .90–3.89).ConclusionsChildren with severe malaria frequently meet clinical and laboratory criteria used to classify HLH. However, HLH classification using current diagnostic frameworks was not independently associated with mortality, suggesting substantial overlap between HLH criteria and manifestations of severe malaria.

HIV-associated lipohypertrophy is characterized by excess central and visceral adiposity and is associated with increased cardiometabolic risk among people with HIV (PWH). In a previously reported randomized trial, semaglutide significantly reduced body weight, regional adiposity, and insulin resistance over 32 weeks of active treatment. However, the durability of these benefits after treatment discontinuation is unknown.MethodsWe conducted a randomized, placebo-controlled trial in PWH with HIV-associated lipohypertrophy. Participants were randomized to semaglutide or placebo for 32 weeks, followed by discontinuation of study drug and observational follow-up through week 56. The current analysis investigated effects of semaglutide at week 56, as compared to baseline and week 32. Outcomes included adipose tissue quantity by body compartment. Analyses were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete.ResultsOf 108 participants initially randomized, 92 completed the 32-week intervention and 80 participants (39 semaglutide, 41 placebo) completed the post-treatment phase. Participants previously assigned to semaglutide experienced increases in body weight, BMI, waist circumference, total body fat, and visceral adipose tissue between weeks 32 and 56, accompanied by worsening glycemic indices and insulin resistance. Despite this rebound, net reductions in body weight, BMI, and waist circumference were retained at week 56 compared with baseline. Placebo-treated participants demonstrated relative stability across outcomes.ConclusionsDiscontinuation of semaglutide in PWH with lipohypertrophy resulted in partial loss of improvements in weight, adiposity, and metabolic parameters. These findings support that sustained pharmacologic exposure is likely needed to achieve long-term benefit.

Influenza A viruses pose a persistent pandemic threat. We report safety, reactogenicity, and immunogenicity findings for mRNA-1018 pandemic influenza vaccine candidates from a phase 1/2 study in healthy adults.MethodsIn part A, participants were randomized to receive 1 of 4 mRNA-1018 candidates at 1 of 3 dose levels across 2 influenza A groups: (1) H5N8/H5-only or (2) H7N9/H7-only. Part B participants were randomized to receive H5-only-CG. The primary objectives were to evaluate the safety and reactogenicity. The secondary objectives included evaluation of humoral immunogenicity through day 205 by hemagglutination inhibition (HAI), neuraminidase inhibition, and microneutralization assays.ResultsParts A and B comprised 1195 and 304 dosed participants, respectively. Overall, solicited local adverse reactions (ARs) within 7 days of vaccination occurred in 76.8% of participants across vaccine candidates and dose levels, most commonly injection-site pain. Solicited systemic ARs were reported in 62.8% of participants, most frequently fatigue and headache. Postvaccination immune responses, assessed absolutely, by HAI titers and dynamically, by seroconversion rates, tended to increase with vaccine dose. H5-based candidates induced stronger strain-specific HAI.ConclusionsVaccine candidates were sufficiently well tolerated and immunogenic. Further development of mRNA pandemic influenza vaccines is warranted.Clinical Trials Registration. NCT05972174

View abstract Objective:To describe and cautiously compare two cross-sectional snapshots of healthcare-associated infections (HAIs) and antimicrobial use (AU) at the same Greek tertiary hospital in 2012 and 2022.Design:Secondary analysis of two cross-sectional point-prevalence surveys using European Centre for Disease Prevention and Control protocol versions 4.3 and 6.1.Setting:A public tertiary-care university referral hospital in northwestern Greece.Patients:Eligible inpatients present in participating wards before 08:00; 276 patients were included in 2012 and 391 in 2022.Methods:Patient-level HAI prevalence was the primary comparison, and AU prevalence was secondary. Infection site, microbiological, susceptibility, antimicrobial indication, and prophylaxis findings were analyzed descriptively because only aggregate outputs were available.Results:HAI prevalence was 23/276 (8.3%) in 2012 and 48/391 (12.3%) in 2022 (prevalence ratio [PR], 1.47; 95% confidence interval [CI], 0.92–2.36; P = .126). AU prevalence was 147/276 (53.3%) and 206/391 (52.7%), respectively (PR, 0.99; 95% CI, 0.86–1.14; P = .937). Pneumonia was the most frequently recorded infection-site category in both surveys. Surgical prophylaxis exceeded 1 day in 51/58 (87.9%) courses in 2012 and 47/48 (97.9%) in 2022. Protocol-year carbapenem non-susceptibility markers were frequent among small numbers of tested isolates.Conclusions:Both snapshots showed substantial HAI and AU burdens. The observed HAI difference cannot be separated from changes in patient mix, season, the COVID-19 pandemic, surveillance practices, and protocol definitions. Prolonged surgical prophylaxis was highly prevalent at both survey dates and represents a clear stewardship target.

View abstract Objective:To describe and cautiously compare two cross-sectional snapshots of healthcare-associated infections (HAIs) and antimicrobial use (AU) at the same Greek tertiary hospital in 2012 and 2022.Design:Secondary analysis of two cross-sectional point-prevalence surveys using European Centre for Disease Prevention and Control protocol versions 4.3 and 6.1.Setting:A public tertiary-care university referral hospital in northwestern Greece.Patients:Eligible inpatients present in participating wards before 08:00; 276 patients were included in 2012 and 391 in 2022.Methods:Patient-level HAI prevalence was the primary comparison, and AU prevalence was secondary. Infection site, microbiological, susceptibility, antimicrobial indication, and prophylaxis findings were analyzed descriptively because only aggregate outputs were available.Results:HAI prevalence was 23/276 (8.3%) in 2012 and 48/391 (12.3%) in 2022 (prevalence ratio [PR], 1.47; 95% confidence interval [CI], 0.92–2.36; P = .126). AU prevalence was 147/276 (53.3%) and 206/391 (52.7%), respectively (PR, 0.99; 95% CI, 0.86–1.14; P = .937). Pneumonia was the most frequently recorded infection-site category in both surveys. Surgical prophylaxis exceeded 1 day in 51/58 (87.9%) courses in 2012 and 47/48 (97.9%) in 2022. Protocol-year carbapenem non-susceptibility markers were frequent among small numbers of tested isolates.Conclusions:Both snapshots showed substantial HAI and AU burdens. The observed HAI difference cannot be separated from changes in patient mix, season, the COVID-19 pandemic, surveillance practices, and protocol definitions. Prolonged surgical prophylaxis was highly prevalent at both survey dates and represents a clear stewardship target.

Immune protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies by prior infection and vaccination history. This study evaluated whether 2 coronavirus disease (COVID-19) vaccine doses after prior infection provide additional protection compared with a single dose.MethodsA national matched retrospective cohort study was conducted in Qatar from December 1, 2020-March 3, 2025. Incidence of SARS-CoV-2 reinfection and severe COVID-19 at reinfection was compared between 61 854 previously infected individuals who completed primary-series vaccination (2-dose cohort) and 61 854 matched individuals who received a single dose (single-dose cohort).ResultsAfter 360 days of follow-up, cumulative incidence of reinfection was 5.0% (95% CI, 3.8%–6.7%) in the 2-dose cohort and 7.7% (95% CI, 6.1%–9.6%) in the single-dose cohort. No reinfections progressed to severe, critical, or fatal COVID-19 in either cohort. Relative vaccine effectiveness (rVE) of 2 doses vs 1 dose was 38.9% (95% CI, 20.4%–53.2%). The rVE was 26.9% (95% CI, −12.7%–53.4%) within <24 days, 51.8% (95% CI, 19.2%–71.2%) during Days 24–179, and 36.8% (95% CI, 0.9%–59.7%) at ≥180 days of follow-up. Subgroup analyses by time between prior infection and vaccination, prior infection variant, and vaccine type yielded broadly similar rVE estimates, while analyses stratified by age and clinical vulnerability suggested higher point estimates among older and clinically vulnerable individuals.ConclusionsAmong individuals with prior infection, completion of primary-series vaccination provided modest additional protection against reinfection compared with a single dose. These findings support risk-based dose-optimization strategies in settings with constrained vaccine supply.

Rapid diagnostics such as the BIOFIRE® FILMARRAY® Pneumonia (PN) Panel may enhance antibiotic optimization, yet real-world evidence remains limited, and few studies have assessed how differences in institutional antimicrobial stewardship (ASP) capacity influence clinical outcomes.MethodsWe conducted a national, multicenter retrospective study of ICU patients with pneumonia admitted to Veterans Health Administration hospitals. Hospitals that implemented the PN Panel for ≥6 months served as intervention sites, while matched facilities without implementation served as controls. Outcomes were assessed using a difference-in-differences framework with inverse probability weighting to account for baseline imbalances and secular trends, including those related to the COVID-19 pandemic. Co-primary outcomes, assessed following index culture collection, were early antimicrobial de-escalation (24–48 hours) and early appropriate therapy (0–24 hours); secondary outcomes were 30-day and ICU mortality.ResultsThe study included 11 746 patients, including 4523 from hospitals that implemented the BIOFIRE® PN Panel and 7223 from matched control hospitals. Overall, PN implementation was associated with early antimicrobial de-escalation (adjusted RR [aRR], 1.14; 95% CI, 1.04–1.26). Among culture-positive patients, PN Panel implementation was significantly associated with early antimicrobial de-escalation (aRR, 1.23; 95% CI, 1.02–1.50) and early appropriate therapy (aRR, 1.11; 95% CI, 1.04–1.18). Overall ICU and 30-day mortality did not differ, though ICU mortality among culture-positive patients was relatively lower following PN Panel implementation (aRR, .70; 95% CI, 0.50–0.97). Improvements in antimicrobial optimization were most evident in hospitals with greater ASP capacity.ConclusionsBIOFIRE® PN Panel implementation improved antibiotic optimization in critically ill pneumonia patients, with the greatest gains seen in hospitals with comprehensive ASP programs.

Immune protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies by prior infection and vaccination history. This study evaluated whether 2 coronavirus disease (COVID-19) vaccine doses after prior infection provide additional protection compared with a single dose.MethodsA national matched retrospective cohort study was conducted in Qatar from December 1, 2020-March 3, 2025. Incidence of SARS-CoV-2 reinfection and severe COVID-19 at reinfection was compared between 61 854 previously infected individuals who completed primary-series vaccination (2-dose cohort) and 61 854 matched individuals who received a single dose (single-dose cohort).ResultsAfter 360 days of follow-up, cumulative incidence of reinfection was 5.0% (95% CI, 3.8%–6.7%) in the 2-dose cohort and 7.7% (95% CI, 6.1%–9.6%) in the single-dose cohort. No reinfections progressed to severe, critical, or fatal COVID-19 in either cohort. Relative vaccine effectiveness (rVE) of 2 doses vs 1 dose was 38.9% (95% CI, 20.4%–53.2%). The rVE was 26.9% (95% CI, −12.7%–53.4%) within <24 days, 51.8% (95% CI, 19.2%–71.2%) during Days 24–179, and 36.8% (95% CI, 0.9%–59.7%) at ≥180 days of follow-up. Subgroup analyses by time between prior infection and vaccination, prior infection variant, and vaccine type yielded broadly similar rVE estimates, while analyses stratified by age and clinical vulnerability suggested higher point estimates among older and clinically vulnerable individuals.ConclusionsAmong individuals with prior infection, completion of primary-series vaccination provided modest additional protection against reinfection compared with a single dose. These findings support risk-based dose-optimization strategies in settings with constrained vaccine supply.

Invasive meningococcal disease (IMD) is traditionally associated with younger populations, but its impact on older adults is rising. We aimed to describe the clinical characteristics and outcomes of critically ill older patients with IMD and identify risk factors for in-hospital mortality.MethodsWe conducted an ancillary analysis of the French nationwide multicenter RETRO-MENINGO cohort (2016–2024). All adults admitted to 102 ICUs with microbiologically confirmed IMD were included and stratified by age (≥65 vs <65 years). The primary outcome was all-cause in-hospital mortality. Multivariable logistic regression identified factors independently associated with death.ResultsAmong 654 patients, 114 (17%) were aged ≥65 years, of whom only 0.9% were reported as vaccinated. Compared to younger adults, older patients presented more frequently with hemodynamic failure and less often with classic purpura or meningeal symptoms. Serogroup W predominated in the older group, while serogroup B was more common in younger patients. Older adults required more organ support and had significantly higher in-hospital mortality (28.1%, n = 32/114 vs 9.6%, n = 52/540 P < .001). After adjustment, age ≥ 65 years remained independently associated with in-hospital mortality (aOR 2.99; 95% CI 1.57–5.72; P < .001), while administration of a third-generation cephalosporin before ICU admission was protective (aOR 0.45; 95% CI, .24–.84; P = .01).ConclusionsCritically ill older adults with IMD exhibit atypical clinical features, a high prevalence of serogroup W, and nearly triple the in-hospital mortality of younger patients. These findings emphasize the need for high clinical suspicion, rapid antibiotic therapy, and potential expansion of vaccination strategies to include older populations.

Influenza predisposes individuals to bacterial co-infections, which can result in disseminated infection and bacteremia. We describe the epidemiology and outcomes of blood culture co-detections among those hospitalized with influenza over 2 influenza seasons.MethodsWe sampled individuals of all ages from FluSurv-NET, a US population–based surveillance network of persons hospitalized with laboratory-confirmed influenza, during the 2022–2023 and 2023–2024 seasons. Surveillance staff collected information on bacterial blood cultures within 3 days before or 3 days following admission. We described patient characteristics and in-hospital outcomes, stratified by culture positivity, number of positive cultures, and type of co-detection, using unweighted counts and weighted percentages to account for the complex survey design.ResultsOverall, 14 316 patients were included, with a median (interquartile range) age of 57 (14–74) years, 53.6% female, 52.0% non-Hispanic White, and 25.6% with ≥4 categories of underlying medical conditions. Of these, 50.8% had ≥1 blood cultures obtained and 5.2% overall had ≥1 bacterial co-detections. Intensive care unit admission occurred for 9.6%, 19.2%, 31.2%, and 47.9% among patients with no blood cultures, negative cultures, 1 co-detection, and >1 co-detection documented, respectively; in-hospital mortality occurred in 1.5%, 3.3%, 9.4%, and 14.5%, respectively. Among patients with positive cultures, 22.1% had Staphylococcus aureus and 7.5% had Streptococcus pneumoniae co-detections; both were associated with severe illness (with 22.4% in-hospital mortality each).DiscussionBacterial co-detections in persons hospitalized with influenza were associated with poor in-hospital outcomes. Efforts to prevent severe influenza and bacterial co-infections, including through vaccination, may reduce substantial morbidity and mortality from influenza.

Respiratory syncytial virus (RSV) illness and pneumococcal disease present high disease burden and health risks to older adults. Vaccination against these 2 illnesses is a key strategy to reduce this burden, and co-administration of the 2 vaccines could enhance vaccine uptake. This study evaluated the immunogenicity, safety, and reactogenicity of co-administration of adjuvanted RSV prefusion F protein vaccine (adjuvanted RSVPreF3) with 20-valent pneumococcal conjugate vaccine (PCV20) in adults aged ≥60 years.MethodsThis phase III, open-label, randomized, non-inferiority trial was conducted across 38 centers in Belgium, Poland, Spain, and the United States. Participants (N = 1112) were randomized 1:1 to receive adjuvanted RSVPreF3 vaccine and PCV20 vaccine either concomitantly (Co-Ad group) or 1 month apart (Control group). The primary objectives were to assess immunogenicity as measured by RSV-A and RSV-B neutralizing titers and opsonophagocytic titers for the PCV20 serotypes. Safety and reactogenicity were assessed as secondary objectives.ResultsAll primary immunogenicity objectives were met. The upper limit of the 95% confidence interval of the geometric mean titer ratios for RSV-A, RSV-B, and all 20 PCV20 serotypes was within the pre-defined non-inferiority margins. Safety profiles were similar across both groups, with most adverse events being mild to moderate in severity and of short duration. Serious adverse events and potential immune-mediated diseases were rare and unrelated to vaccination.ConclusionsCo-administration of adjuvanted RSVPreF3 vaccine and PCV20 vaccine in older adults is immunologically non-inferior to their sequential administration, with an acceptable safety profile. These findings support co-administration as a strategy to enhance vaccine uptake.Clinical Trials RegistrationNCT05879107.

Household contact tracing (HHCT) is a widely recommended intervention for tuberculosis (TB) but is poorly implemented. Multidimensional poverty, encompassing deprivations in health, education, and living standards, may hinder implementation success.MethodsUsing a cluster-randomized trial in South Africa, we examined the relationship between household multidimensional poverty as a composite deprivation score and HHCT reach as (1) initiation (at least one household contact screened); (2) continuous proportion of eligible household contacts screened; and (3) completion (all eligible household contacts screened once initiated). We performed multilevel mixed-effects modeling with modified Poisson and ordered beta regression.ResultsDespite near-universal comfort with HHCT (97%) among 3392 households, only 43% initiated HHCT and 19% completed screening. Greater multidimensional poverty was significantly associated with lower HHCT initiation in urban households (adjusted prevalence ratio [aPR]: 0.903, 95% confidence interval [CI]: 0.831, 0.984, per 10% higher deprivation; P = .021), but not in rural households (aPR: 1.06, 95% CI: 0.99, 1.13; P = .083). Across all households, we observed a modest but statistically significant association between greater poverty and lower predicted proportion of household contacts screened (adjusted average marginal effect [aAME]: −1.22% [−2.20%, −0.236%], per 10% higher deprivation; P = .015). Among households that initiated HHCT, multidimensional poverty was not significantly associated with screening completion (aPR: 0.945, 95% CI: 0.865, 1.03; P = .207).ConclusionsStated comfort with HHCT may not directly translate into implementation success. Multidimensional poverty was a significant structural barrier for HHCT initiation in an urban, South African township. Once initiated, getting all household contacts screened may require targeting additional operational and health system barriers.

While human papillomavirus (HPV)-specific T cell responses are believed to contribute to regression of HPV-associated cervical neoplasia, their role has not been fully elucidated. We investigated HPV16 E7-specific T cell responses in the cervix and peripheral blood and their association with pathological outcomes in cervical intraepithelial neoplasia grade 2 (CIN2).MethodsHPV16 E7-specific T cell responses in cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were quantified using overlapping peptide (OLP) pools of E7 in 38 subjects with HPV16-positive CIN2 with defined pathological outcomes. Breadth and HLA restriction of these responses were assessed using single OLPs on in vitro-expanded PBMCs.ResultsHPV16 E7-specific T cell responses were detected in over 30% of CxL samples but rarely detected in PBMCs unless expanded in vitro. Higher magnitudes of E7-stimulated responses in CxLs, along with elevated non-specific background responses, were associated with pathological regression of CIN2 lesions. The E7-specific T cell responses in expanded PBMCs varied in breadth among subjects and were mediated by both CD4+ and CD8+ T cells with diverse HLA restrictions. Importantly, response breadth was significantly greater in subjects with lesion regression.ConclusionsHPV-specific T cell responses are preferentially localized at the site of infection and maintained at low frequencies in peripheral blood. The magnitude of local E7-stimulated response in CxLs and the breadth of E7-specific responses in expanded PBMCs were associated with pathological regression of CIN2. These associations support a potential role for E7-specific T cell responses in the regression of HPV-related cervical neoplasia.

A novel Pfkelch13 mutation clinically associated with partial resistance to artemisinin is spreading in Zambia. Additional clinical evaluations are urgently needed in the region.

Paracoccidioidomycosis (PCM) is a neglected systemic mycosis in which accurate staging is critical but challenging with conventional methods. This study evaluated 18F-FDG PET/CT compared with standard evaluation for PCM staging and assessed its impact on disease severity classification.MethodsThirty-four patients with confirmed PCM (treatment-naïve or with suspected treatment failure) underwent conventional staging and whole-body 18F-FDG PET/CT. Disease severity was classified as mild, moderate, or severe. PET/CT images were analyzed qualitatively and quantitatively (SUVmax, TMLV, TLG).ResultsPET/CT detected more than twice as many lesions as conventional evaluation (150 vs 62; mean 4.4 ± 1.6 vs 1.8 ± 0.9 affected organ systems per patient), with statistically significant superiority for lymph node, pulmonary, and adrenal involvement (McNemar's test, P < .05). PET/CT reclassified 97% of patients as multifocal versus 59% by conventional staging and produced a significant unidirectional shift toward higher severity—the proportion classified as severe increased from 70.6% to 91.2% (P = .016). Patients with suspected treatment failure showed significantly lower TMLV and TLG than treatment-naïve patients (P < .05). Quantitative PET parameters correlated with serological titers and inflammatory markers (P < .05), and PET/CT detected four times as many sites as gallium-67 scintigraphy.Conclusions18F-FDG PET/CT systematically reveals greater disease burden than conventional evaluation in PCM, reclassifying most patients toward higher severity with direct implications for treatment duration and follow-up. Where available, it should be considered an important complementary modality for initial disease assessment.

Live attenuated influenza vaccine (LAIV) induces mucosal immunity through limited viral replication in the upper respiratory tract, but postvaccination viral shedding dynamics and their clinical correlates remain incompletely characterized.MethodsWe evaluated 283 healthy adults (108 in 2023–2024, 175 during the 2024–2025 influenza seasons) following intranasal LAIV administration. Nasal swabs were collected on post-LAIV days 1, 2–4, and 5–7 to quantify influenza A and B RNA by RT-PCR. Viral detection, shedding duration and burden, clearance kinetics, and probability of detection were compared across seasons, vaccine strain compositions (quadrivalent vs trivalent), and host factors. Respiratory symptoms were assessed.ResultsEarly viral shedding was frequent: influenza A or B RNA was detected in 86.9% of participants on day 1, with codetection in 52.7%. Probability of detection declined from 92% on day 1% to 9% on day 7. Influenza B had longer shedding duration (median, 2.0 vs 1.0 days; P < .001) and higher shedding burden (4.2 vs 4.0 log10 RNA copies/mL; P < .001). Three clearance profiles—rapid (clearance ≤4 days), moderate (5–7 days), and slow (≥7 days)—were identified. Profiles were consistent across seasons but influenza B was disproportionately represented in slower-clearance groups (P < .001). Total viral burden (P < .01) and shedding duration (P = .01) were associated with total symptom burden.ConclusionsLAIV replication begins within 24 h and declines over the first week, with persistent shedding uncommon after day 7. Influenza B replicates more extensively and persists longer than influenza A. Symptom burden correlates with shedding duration and viral burden.

A 74-year-old man with end-stage renal disease (ESRD) on dialysis and cardiac sarcoidosis on chronic prednisone 20 mg daily presents to hospital with 2–3 weeks of fevers, confusion, and weakness. He is found to have a large left upper lobe cavitary mass with scattered pulmonary consolidations (Figure 1). During further work-up for possible malignancy, he is found as well to have multiple hypermetabolic subpleural and omental implants and diffuse soft tissue and musculoskeletal deposits involving the abdominal wall and lower extremities noted on a positron emitted tomography—computed tomography scan (PET-CT) (Figure 2). The cavitary chest lesion is also hypermetabolic on nuclear imaging. A magnetic resonance image (MRI) of the brain and spine show multiple rim-enhancing lesions as large as 1.6 × 1.1 cm with foci of suspected ventriculitis as well as an intra-medullary rim-enhancing lesion suspicious for abscess at the level of T5 (Figure 3).

To the  Editor—We read with interest the debate between experts representing the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) regarding community-acquired pneumonia (CAP) guidelines [1, 2]. As members of WikiGuidelines, a nonprofit organization that seeks to transform the process by which clinical guidelines are constructed, we believe both perspectives overlook a more fundamental concern.

AbstractIntroductionCryptococcosis increasingly affects non-HIV, non-transplant (NHNT) adults, but factors associated with extrapulmonary dissemination remain incompletely defined. We evaluated associations between comorbidities, immunosuppressive therapy, and cryptococcal disease phenotype.MethodNHNT adults with cryptococcosis in Merative MarketScan were classified as having pulmonary or extrapulmonary disease. Extrapulmonary disease was further classified as central nervous system (CNS) or non-CNS disseminated disease. Comorbidities and immunosuppressant, systemic glucocorticoid, and antineoplastic exposures during the 6 months before diagnosis were evaluated. Multivariable logistic regression identified factors associated with extrapulmonary disease, with secondary phenotype-specific analyses.ResultsAmong 722 NHNT adults, 52% had extrapulmonary cryptococcosis, including 82% with CNS involvement. Extrapulmonary disease was associated with longer hospitalization, greater ICU utilization, and lower community discharge (all P < .001). Renal disorders (aOR 1.51, 95% CI 1.05–2.18) and immunosuppressant exposure (aOR 2.75, 95% CI 1.61–4.86) were associated with extrapulmonary disease. Immunosuppressant exposure was also associated with both CNS and non-CNS disseminated disease. Among glucocorticoid-exposed patients, longer exposure was associated with extrapulmonary disease (aOR 1.05 per week, 95% CI 1.02–1.08), primarily CNS disease, whereas higher average daily dose was associated with non-CNS disseminated disease only within shorter exposure windows.ConclusionsExtrapulmonary cryptococcosis was common among NHNT adults and was associated with substantially greater morbidity than pulmonary disease. Immunosuppressant exposure was consistently associated with both CNS and non-CNS disseminated disease, whereas associations with glucocorticoid duration and average daily dose varied by phenotype and timing. These findings support guideline-recommended systematic evaluation for dissemination and suggest that pre-diagnostic immunosuppressive therapy history may inform assessment of extrapulmonary disease risk.

Safe and effective therapies are needed for hospitalized patients with complicated Staphylococcus aureus infections, including approaches capable of eradicating intracellular bacterial reservoirs that contribute to treatment failure. This study evaluated the safety, tolerability, and pharmacokinetics of DSTA4637S, an antibody–antibiotic conjugate combining an anti-S. aureus antibody with a rifamycin-class antibiotic, in patients with complicated S. aureus bacteremia.MethodsIn this phase 1b, randomized, double-blind, placebo-controlled study, 25 patients with methicillin-sensitive (MSSA, 68%) or -resistant (MRSA, 32%) complicated S. aureus bacteremia received weekly intravenous doses of DSTA4637S at 15, 45, or 100 mg/kg in combination with at least 4 weeks of standard-of-care antistaphylococcal antibiotics.ResultsMost patients (92%) experienced ≥1 treatment-emergent adverse event (TEAE), of which 44% were considered treatment-related. Grade ≥3 TEAEs and serious adverse events occurred in 72% and 56% of patients, respectively. The most common grade ≥3 TEAEs were infusion-related reactions (IRRs), pneumonia, anemia, and respiratory failure. Four patients (21%) receiving DSTA4637S discontinued study treatment due to treatment-related IRRs. Systemic exposure of DSTA4637S in patients increased approximately dose-proportionally from 15 to 100 mg/kg but was 30%–60% lower than previously observed in healthy volunteers.ConclusionsThe safety profile of DSTA4637S, characterized by unpredictable IRRs, and its pharmacokinetic behavior in patients differed substantially from those observed in healthy volunteers, highlighting the critical importance of conducting early phase studies in the target patient population.

To the  Editor—Gilmore et al [1] provide a rigorous synthesis of indirect influenza vaccine effectiveness (IVE) from randomized trials, reporting a pooled cluster-randomized trial (cluster-RCT) estimate of 17.6% (95% CI: 3.9%, 29.4%) with moderate heterogeneity (I2 = 42.9%). In their discussion, the authors identify potential contributors to the heterogeneity in IVE estimates, including community coverage and between-trial variation in direct vaccine effectiveness (DVE) (itself reflecting factors such as vaccine-strain mismatch). Here, we report an exploratory meta-regression of the 10 trial-season estimates from cluster-RCTs from that review, showing that much of the between-trial variation in IVE is explained by variation in DVE.

Patients with bloodstream infections (BSIs) with antimicrobial resistant bacteria often receive ineffective empirical therapy (IET). The implications are still uncertain.MethodsWe performed a retrospective, multicenter, study of patients with BSIs caused by extended-spectrum β-lactamase (ESBL)-producing gram-negative bacteria in southern Sweden from 2013 to 2022. Patients were categorized based on time to effective therapy: ≤24 hours (EET) and >24 hours (IET). Therapy was considered effective if the agent was active in susceptibility testing and administered intravenously at an appropriate dose. The primary outcome was 30-day mortality. Secondary outcomes were ICU admission and hospital length of stay.ResultsA total of 289/644 (44.9%) patients received IET within the first 24 hours after the index blood culture collection. No significant impact of IET on 30-day mortality was found in univariable (Hazard ratio 0.66; P = .15) or multivariable Cox regression analysis (Hazard ratio 0.64; P = .13). Patients receiving EET were more likely to receive intensive care (Odds ratio 0.38; P = .008), but the association was nonsignificant after adjusting for severity of illness and comorbidities. IET was not associated with a longer hospital stay in Fine–Gray competing risks regression analysis (univariable: sHR 1.15; P = .082; multivariable: sHR 1.11; P = .20).ConclusionsIET was not associated with 30-day mortality, in patients with BSIs with ESBL-producing Enterobacterales. If confirmed in prospective studies, our findings could support antimicrobial stewardship efforts by reducing unnecessary empirical carbapenem use without compromising short-term clinical outcomes, particularly in low-prevalence settings.

AbstractArboviral diseases represent an escalating global health threat, yet therapeutic development has been markedly slower than for other viral illnesses. Key barriers include the unpredictability and variability of arbovirus transmission, which complicate site selection, limit recruitment, and increase delays and the risk of inconclusive trials. Additional challenges include maintaining trial-ready sites, recruitment within the narrow therapeutic window, ensuring rapid diagnostics, and including high-risk groups. To address these barriers, we propose several innovative strategies based on a Clinical Experts meeting convened by the Dengue Alliance. These include pre-activated trial networks for rapid initiation during outbreaks; early-warning surveillance to guide geographic activation using real-time transmission signals; decentralized trial models to expand recruitment beyond major research centers; platform trial designs that allow treatment arms to be added or discontinued adaptively; and participant inclusion based on clinical syndrome supported by rapid diagnostics. Their successful adoption requires regulatory harmonization, ethical oversight, and emphasis on equity.