Clinical Microbiology and Infection

Data evaluating human papillomavirus (HPV) vaccine impact in Spain remain limited. We aimed to assess HPV and cytology findings among vaccinated and unvaccinated women as an early indicator of its effectiveness. During April 2024-January 2026, a total of 908 women participating in a population-based cervical cancer screening in three regions of Spain were recruited (58% vaccinated). Cervical samples and epidemiological and vaccination data were obtained. HPV was detected in 37% (337/908) and high-risk HPV in 24% (221/908). High-grade cytological lesions (1.2%, 11/907) were more frequent in unvaccinated women (2.4% vs 0.38%, p=0.011) and showed higher prevalence of HPV 16/18 (5.5% vs 0.76%; aOR: 4.9; 95% CI: 1.4-17) and HPV31 (3.4% vs 1.3%; aOR: 2.7; 95% CI: 1.0-6.9) compared with vaccinated women. HPV51 and HPV70 were more frequent among vaccinated women; however, both were associated with factors unrelated to vaccination. HPV51 was linked to a higher number of sexual partners (aOR: 2.6; 95% CI: 1.2-5.6), while HPV70 to smoking (aOR: 0.36; 95% CI: 0.13-0.99). Lower detection of HPV 16/18, HPV31 and high-grade lesions among vaccinated women supports vaccine effectiveness and cross-protection, highlighting the importance of continuous comprehensive surveillance of HPV genotype, including epidemiological and sexual behavioral factors.

BackgroundOutbreaks of fluconazole-resistant Candida parapsilosis have recently emerged worldwide. In Spain, this phenomenon has been reported since 2020, mainly involving isolates from different clones harbouring the Y132F mutation at Erg11. MethodsWe analysed the expansion of fluconazole resistant C. parapsilosis strains within the national antifungal resistance surveillance program. Genetic clustering and relationships were assessed using microsatellite typing and whole genome sequencing. FindingsWe identified the expansion of three distinct clones carrying the Y132F mutation. Additionally, there was an increase in strains harbouring the G458S mutation, most of which belonged to a clonal complex, although other less prevalent clones were also detected. G458S isolates showed higher resistance to azoles than Y132F strains, particularly to voriconazole and isavuconazole. This increased resistance was associated with mutations in the Tac1 transcriptional regulator and duplication of a chromosomal region containing Tac1 and Erg11. One G458S isolate without mutation at Tac1 exhibited lower MIC values. Furthermore, two isolates carried the K143R mutation, and a distinct group of resistant strains without detectable ERG11 mutations was also identified. Resistant cases were detected across 31 hospitals in 12 autonomous regions. InterpretationOur findings indicate a concerning nationwide expansion of antifungal-resistant C. parapsilosis in Spain, involving multiple resistance mechanisms and clonal lineages, with implications for antifungal treatment and infection control strategies.

Genomic prediction of antimicrobial susceptibility aims to identify resistance determinants and thereby to report those antibiotics for which therapeutic failure is to be expected. We investigated what this approach can achieve in Pseudomonas aeruginosa, a species in which resistance often arises through changes in gene expression. For this purpose, 5,749 consecutive clinical isolates from the routine laboratories of two tertiary care centers were sequenced, each with paired phenotypic susceptibility test results for ciprofloxacin, ceftazidime, meropenem, and tobramycin. Genomic variation could be interpreted only after three adaptations. Variants were called against the population-wide major allele rather than against PAO1. This removes markers that are artefacts of the reference. Loss of gene function was captured systematically, as many genetic determinants of resistance act through loss-of-function mechanisms. Furthermore, we introduced a specificity ratio - enabled by testing all four antibiotics on the same isolates - which separated markers associated with resistance mechanisms from those that merely tracked clonal lineage; without this distinction, expanding the catalogue reduced rather than improved predictive performance. In addition to classical resistance determinants, markers of susceptibility were taken into account, such as the functional loss of an efflux pump that exports the antibiotic out of the cell. While resistance could only be assigned with corresponding confidence for a few percent of isolates, the absence of ciprofloxacin and meropenem resistance could be reported for substantially more isolates, in a conservative deduplicated analysis even for 43% and 87%, respectively. The remaining isolates were left blank rather than forced into one of the two categories. The blank is not an absence of information: resistance rates within it lay between those of the two reported groups, and its isolates clustered around the clinical breakpoint. It is the genomic counterpart of a population the phenotype already recognizes and reports as susceptible, increased exposure or as an area of technical uncertainty. For meropenem, the residual risk of a susceptibility finding already meets the accepted threshold of 3%, while for ciprofloxacin it approaches this threshold. For tobramycin, validation in a larger cohort, possibly specifically enriched for resistant isolates, is required before our results can be considered reliable. For ceftazidime, by contrast, it appears that additional markers need to be identified, in particular those associated with increased AmpC expression. Taken together, the present data show that, for two of the four antibiotics investigated here, clinically relevant findings can already be generated today: the genome allows the identification of an isolate group with no indication of resistance, marks a smaller group as resistant, and assigns the remaining isolates to an intermediate range close to the clinical breakpoint.

Background: Ensitrelvir reduced symptomatic COVID-19 after household exposure in the SCORPIO-PEP trial, but its economic value as post-exposure prophylaxis is unknown. Objective: To estimate the cost-effectiveness of ensitrelvir post-exposure prophylaxis for high-risk household contacts in Japan. Methods: We developed a decision-analytic cost-utility model from the Japanese public healthcare payer perspective. Trial risks of symptomatic COVID-19 through day 10 were linked to Japanese evidence on hospitalization, mortality, costs, quality of life, and life expectancy. Because the trial observed no COVID-19-related hospitalization or death, downstream outcomes were modeled only through prevention of symptomatic disease. We performed deterministic, probabilistic, structural, subgroup, and threshold analyses. Results: Ensitrelvir increased costs by JPY 54,945 and gained 0.003267 QALYs per exposed contact, yielding an ICER of JPY 16.82 million/QALY. None of 10,000 simulations was cost-effective at JPY 5 million/QALY. Applying the overall-trial relative risk to the high-risk baseline yielded JPY 19.24 million/QALY. Restricting post-acute utility loss to 6 months, halving it, or excluding it yielded ICERs of JPY 23.62 million, JPY 26.76 million, and JPY 65.51 million/QALY, respectively. The drug acquisition-cost threshold was JPY 11,021 per course. Conclusions: At current Japanese costs, ensitrelvir post-exposure prophylaxis for high-risk household contacts was unlikely to be cost-effective at JPY 5 million/QALY. This conclusion remained unfavorable under conservative efficacy, post-acute utility, hospitalization-attribution, and mortality assumptions. Severe-outcome benefits remain model-based extrapolations rather than trial-observed effects.

Background: Blood culture-negative infective endocarditis (BCNIE) poses a significant diagnostic challenge. This study evaluated a multimodal diagnostic algorithm combining serological and molecular methods at the Argentine National Reference Laboratory. Methods: A prospective analysis was conducted on 53 consecutive patients with suspected BCNIE referred between January 2019 and December 2024. The diagnostic workflow included indirect immunofluorescence for Bartonella spp. and Coxiella burnetii, species-specific PCR for Bartonella spp. and Tropheryma whipplei, and broad-range 16S rRNA PCR with Sanger sequencing on available blood and valvular tissue specimens. Results: An etiological diagnosis was established in 17 of 53 patients (32.1%). Bartonella spp. was the predominant pathogen (47.1%; 8/17), followed by T. whipplei (35.3%; 6/17) and Streptococcus spp. (17.6%; 3/17). All Bartonella cases were initially detected via serology, with molecular confirmation achieved exclusively through valvular tissue analysis. Conclusions: Implementing a standardized multimodal diagnostic algorithm significantly enhances etiological yields in BCNIE. The findings emphasize the complementary value of frontline serology and targeted molecular testing, highlighting that simultaneous submission of serum, blood, and valvular tissue is essential for optimal diagnosis.

Aim: Brucellosis remains endemic throughout the Mediterranean basin, the Middle East and Central Asia. Genitourinary involvement is an uncommon but clinically consequential focal complication that closely mimics urological emergencies and may precipitate unnecessary surgery. Contemporary data describing its frequency, laboratory signature and treatment outcomes in endemic settings remain limited. Material-Methods: We retrospectively screened all adults ([≥]18 years) with confirmed brucellosis managed at a tertiary infectious diseases unit between January 2008 and December 2020. Genitourinary involvement was defined as epididymo-orchitis, orchitis, epididymitis and/or brucellar pyelonephritis. Clinical, laboratory, ultrasonographic, therapeutic and outcome variables were abstracted using a standardised form. Proportions are reported with Wilson score 95% confidence intervals (CI). Reporting followed the STROBE statement. Result: Genitourinary involvement was identified in 18 of 125 patients with brucellosis (14.4%; 95% CI 9.3-21.6); 16 (88.9%) were men and the mean age was 35.2 years (range 22-62). Scrotal disease dominated the male presentation: epididymo-orchitis in 10 of 16 men (62.5%; 95% CI 38.6-81.5), orchitis in 4 (25.0%) and epididymitis in 2 (12.5%). Both women presented with pyelonephritis, one of whom developed a tubo-ovarian abscess requiring drainage. Constitutional features were near-universal (fatigue 100%, night sweats 88.9%, fever 77.8%). Leukocyte counts remained within the reference interval in every patient (mean 5,680/mm3), whereas erythrocyte sedimentation rate (mean 32 mm/h) and C-reactive protein (mean 24.2 mg/L) were only mildly to moderately raised. The Coombs anti-Brucella test was positive in 18 of 18 patients (100%) and the standard agglutination test in 17 of 18 (94.4%), whereas blood culture yielded Brucella melitensis in only 1 of 18 (5.6%). Concomitant extragenitourinary focal disease was present in 8 patients. All patients received doxycycline plus rifampicin; none required modification of the regimen or orchiectomy, and no treatment failure occurred (0 of 18; 95% CI 0-17.6). Median follow-up was 12 weeks (range 6-52) and no relapse was documented within this interval. Conclusions: In endemic regions, genitourinary brucellosis should be suspected in any patient with acute scrotal or flank symptoms accompanied by constitutional complaints, even when the leukocyte count is normal and acute-phase reactants are only marginally elevated. Coombs anti-Brucella serology rather than blood culture is the diagnostic cornerstone, and prompt doxycycline-rifampicin therapy averts surgical intervention.

Objectives To evaluate the impact of COVID-19 vaccination on the prevention of long COVID (LC) in the Omicron era through an updated systematic review and meta-analysis. Methods We performed an update of our previously published systematic review and meta-analysis of vaccination and LC risk (searches between 1 January 2022 and 1 March 2024). Databases (Embase, MEDLINE, PubMed, Europe PMC, LILACS, Cochrane COVID-19 Study Register) were searched for studies published between 1 March 2024 and 13 July 2026. Observational studies assessing the impact of vaccination on the risk of LC four or more weeks after SARS-CoV-2 infection were included. Vaccines were restricted to those centrally authorised in the European Union. Random-effects meta-analyses, restricted to adults, were performed to calculate pooled odds ratios (OR) of LC in three comparisons: vaccinated (any dose) versus unvaccinated; booster vaccination versus unvaccinated; and booster vaccination versus primary course vaccination only. Results Nineteen new studies were identified, of which ten were included in the updated meta-analyses alongside eight studies from the original review. The pooled OR of LC in vaccinated adults (any dose) versus unvaccinated was 0.75 (95% confidence interval [CI] 0.67-0.84; 13 studies). ORs were also lower for booster vaccination versus unvaccinated (0.73; 95% CI 0.65-0.82; 6 studies), and booster vaccination versus primary course vaccination (0.63; 95% CI 0.53-0.75; 6 studies). Significant associations between vaccination and lower LC odds were observed in subgroup analyses of mRNA-only vaccination and LC outcomes three or more months after infection. Conclusions This updated review and meta-analysis reinforces our previous finding that vaccination may reduce the burden of LC in the Omicron era, with booster doses potentially providing additional protection. Although evidence in high-risk groups now prioritised for vaccination in most countries remains limited, these findings clearly demonstrate the benefits of vaccination and support current seasonal vaccination strategies.

Pregnant women with late latent or latent of unknown duration syphilis are recommended to receive three doses of benzathine penicillin G each 9 or fewer days apart; data on interval variations are limited. We found no significant difference in risk of congenital syphilis between 9-day and 6-8 day dosing intervals.

Purpose: To compare the efficacy and safety of intravenous cefazolin versus antistaphylococcal penicillins for the treatment of MSSA bacteremia in adults using evidence exclusively from randomized controlled trials. Methods: We searched 5 databases for RCTs comparing definitive intravenous cefazolin with ASPs (oxacillin, cloxacillin, flucloxacillin, nafcillin) in adults with MSSA bacteremia. Primary outcomes were 90-day all-cause mortality and acute kidney injury (AKI). Secondary outcomes included adverse event-related treatment discontinuation and persistent bacteremia (>72h). Dichotomous outcomes were synthesized as risk ratios (RRs) with 95% confidence intervals (CIs) using random-effects models with Paule-Mandel estimation and Hartung-Knapp-Sidik-Jonkman inference. Fixed-effect Mantel-Haenszel models were performed as sensitivity analyses. Results: Two RCTs randomized 1,656 participants (SNAP, n = 1,341; CloCeBa, n = 315), of whom 1,579 contributed to the 90-day mortality analysis. There was no statistically significant difference in 90-day mortality (RR 0.90, 95% CI 0.57-1.41; I2 = 0%). Both trials favoured cefazolin for acute kidney injury, but the random-effects estimate was highly imprecise (RR 0.26, 95% CI 0.00-939,970.59; I2 = 81.7%). Treatment discontinuation also favoured cefazolin directionally, although the random-effects estimate was imprecise (RR 0.24, 95% CI 0.00-24.41; I2 = 36.2%). Microbiological outcomes were synthesized narratively because definitions and assessment time points differed between trials. Conclusion: Randomized evidence supports cefazolin as a potential definitive treatment option when adequate source control, appropriate antimicrobial dosing, and clinical monitoring can be achieved. However, the limited number of trials and imprecision in pooled estimates warrant cautious interpretation.

Objectives: To evaluate the epidemiological evolution of unique pneumococcal serotypes covered by either PCV20 or PCV21, common serotypes by both vaccines and non-vaccine serotypes in adults. Methods: We characterized all national IPD clinical isolates from January 2009 to June 2026. Results: The highest burden of IPD was caused by serotypes shared between PCV20 and PCV21 with serotypes 3 and 8 the most prevalent in adults of all ages. During the pre-pandemic period, IPD caused by unique-PCV20 serotypes declined probably due to herd protection by paediatric vaccination with PCVs. In contrast, unique-PCV21 serotypes increased in incidence accounting for more cases than unique-PCV20 serotypes. However, after the COVID-19 pandemic, a different pattern was observed with unique-PCV20 serotypes increasing in incidence due a marked rise in IPD caused by serotypes 4 and 14 that has progressively reduced the gap in disease coverage. In adults aged 18-64 years, the fraction of disease that could be prevented with PCV20/PCV21 changed from 5% in favour of PCV21 (years 2022/2023) to 15% in favour of PCV20 (year 2026) whereas in adults [≥]65 years the vaccine contribution declined from 20% in favour of PCV21 (year 2022) to 8% in 2026. Conclusions: IPD trends in adults have changed after the COVID-19 pandemic, especially in recent years. Our study emphasizes the rapid re-emergence of infections caused by traditional PCV7 serotypes especially serotypes 4 and 14 and reinforce the idea that the use of broader PCVs must be accompanied by an increase in the uptake rates in adults of all ages.

Background: Child-friendly sample collection methods are needed to improve microbiological tuberculosis diagnosis in children. We assessed the feasibility, diagnostic yield, safety, tolerability, and acceptability of nasopharyngeal aspirates (NPA) and stool sample collection for XpertMTB/RIF Ultra (Ultra) testing in children <5 years with severe pneumonia in six high tuberculosis incidence countries. Methods: We conducted a cross-sectional mixed-methods study (10/2020-03/2021) nested within the TB-Speed Pneumonia trial (NCT03831906) in 15 tertiary hospitals. Uptake and diagnostic yield of NPA and stool, sampled by trained nurses, were computed. Nurses documented NPA feasibility and related adverse events. NPA tolerability was assessed through discomfort/distress/pain scales completed by nurses, parents/caregivers, and children >3 years. Individual interviews investigated nurses and parents/caregivers perceptions and experiences of both procedures. Results: Of 542 children enrolled, 541 (99.8%) and 423 (75.5%) had NPA and stool samples successfully collected, respectively; 8 (1.5%) had positive Ultra on any sample, 8 (1.5%) on NPA, and 3 (0.6%) on stool samples. Nurses reported that NPA was difficult to collect in 27 (5.0%) children. 130 (24%) children had bloodstained NPA samples and <5% experienced transient heart rate deceleration, digestive or respiratory distress during NPA. Median nurse-assessed tolerability scores were 1/10 [0,3] before and 5/10 [2,6] during NPA. Although most respondents perceived NPA as painful, all appreciated that NPA aimed to improve child health. Nurses reported that NPA and stool collection was quicker, less invasive than gastric aspiration. Parents/caregivers trusted nurses skills and valued the novelty of NPA. All respondents easily engaged in stool collection, but were frustrated to depend on children passing stool. Nurses underlined that continuous staff training and mentoring would sustain feasibility and self-efficacy in obtaining adequate samples. Conclusions: NPA and stool are viable specimen collection options for microbiological diagnosis of tuberculosis in young children <5 years with severe pneumonia in high tuberculosis incidence countries.

Objectives- Among clinical methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) strains, we sought to determine the prevalence of {beta}-lactam-{beta}-lactamase inhibitor (BLBLI) susceptibility, and its association with oxacillin susceptibility, genotypic factors, and patient characteristics. Methods- Clinical MRSA BSI strains were tested for susceptibility to penicillin-clavulanate by Etest (n=117, 36% of the dataset) and to oxacillin by disk diffusion assay (n=328, 100%). Penicillin-clavulanate susceptibility was defined as MIC [&le;]2mg/L and oxacillin disk susceptibility as an inhibition zone > 6mm. All strains were whole-genome sequenced, and alleles of mecA annotated. The sensitivity and specificity of the oxacillin disk to predict penicillin-clavulanate 'susceptibility' were assessed. Clinical and genomic associations with BLBLI 'susceptibility' were assessed by calculating odds-ratios (OR). Results -We found 73/117 (62%) and 205/328 (62%) strains to be 'susceptible' to penicillin-clavulanate and oxacillin disk, respectively. Oxacillin disk susceptibility and penicillin-clavulanate susceptibility were highly correlated (sensitivity 97.3% and specificity 95.5%). We therefore used oxacillin disk susceptibility as a proxy for penicillin-clavulanate susceptibility. Comparative genomics of the mecA gene uncovered 8 alleles. The oxacillin disk 'susceptible' phenotype was associated with specific mecA alleles, community-associated MRSA sequence-types (OR 72.8, 95%CI 35.4-162), community acquisition of infection (OR 2.09, 95% CI 1.03-4.27), lower Charlson Comorbidity Index (OR 0.90, 95% CI 0.82-0.98) and SOFA (sequential organ failure assessment) scores at presentation (OR 0.88, 95% CI 0.79-0.98). Conclusion - BLBLI 'susceptibility' is common among MRSA strains and is strongly associated with the strain genotype. Infections caused by BLBLI 'susceptible' strains are associated with specific patients' characteristics, namely younger age, fewer comorbidities, acquisition in the community and milder presentations.

Background: Treponema pallidum quantitative polymerase chain reaction (qPCR) positivity and cycle threshold (Ct) by rapid plasma reagin (RPR), disease stage, and other characteristics are poorly characterized in routine-care specimens, leaving it unclear when qPCR of such specimens is informative for diagnosis. Methods: This Japanese multicenter cross-sectional study explored qPCR positivity and Ct by these characteristics. Nonblood specimens collected during routine care underwent qPCR at a central laboratory for this study. Bayesian logistic and normal regressions modeled positivity and mean Ct of TP0574 and polA with stage-specific continuous automated RPR terms, patient characteristics, collection site, and facility random intercepts. Estimates were standardized over the analyzed specimens. Population-group predictions were instead averaged within each group. Results: Among 154 nonblood specimens from 145 patients (71.7% non-MSM men and women) at 14 facilities, 109 (70.8%) were qPCR positive. At RPR 1, adjusted positivity was 72.2% (95% credible interval, 60.9%--82.9%) in primary and 43.8% (16.7%--69.9%) in secondary syphilis. Positivity showed a modest downward trend with RPR in primary but increased in secondary syphilis, reflecting a stage-by-RPR interaction (secondary-to-primary ratio of odds ratios, 1.78; 1.25--2.65). Predicted positivity showed an upward trend with RPR values among MSM; adjusted positivity was relatively high for genital/urethral/urinary and anal/perianal/rectal specimens. Adjusted mean Ct increased with RPR in primary and followed an inverted-U pattern in secondary syphilis. Conclusions: In primary syphilis, nonblood qPCR positivity was high even at low RPR. When serologic findings remain inconclusive in this stage, qPCR is highly recommended for securing an early diagnosis.

Background Nontuberculous mycobacteria (NTM) are clinically important pathogens but often weakly positioned within health systems, with unclear institutional ownership, variable notification arrangements, and limited surveillance visibility. Methods We conducted a multilingual online survey among programme-facing national and subnational mycobacterial stakeholders from November to December 2025. Using an adaptive hierarchical recruitment strategy, we targeted 217 countries and jurisdictions. One response per programme was requested. We assessed institutionalisation, notification, agenda maturity, thematic discussion priorities, and barriers to action. We also derived relative policy momentum from three urgency domains (diagnostics, clinical management, and surveillance) using within-WHO region hierarchical clustering. Findings were used to develop a heuristic roadmap for staged NTM governance and system visibility. Results We received 193 programme-level responses, including from subnational jurisdictions, representing 171 of 217 targeted countries (78.8% jurisdictional coverage). NTM institutionalisation status was heterogeneous: 34% reported NTM integration within the NTP, while 37% expressed intents to institutionalise within the NTP in nearest future. Mandatory notification was reported by 21% of programme units, voluntary notification by 10%, and notification under consideration by 24%. NTM appeared to enter policy discussions along a gradient, with clinical management and diagnostics attracting earlier attention than surveillance, training needs, and financing. Globally, pulmonary NTM was discussed more frequently than extrapulmonary disease. Across WHO regions, policy momentum clustering separated programmes into higher and lower profiles, with surveillance consistently being the weakest domain. Financing and lack of epidemiological data were identified as the most actionable barriers. There was broad support for TB-NTM surveillance integration. Conclusions NTM governance is heterogeneous and frequently weakly anchored globally. The findings do not support a single universal institutional model; rather, existing mycobacterial platforms may provide pragmatic starting points for improving programme visibility, coordination, and reporting. The proposed heuristic roadmap outlines staged governance options according to burden, capacity, and institutional context.

Background: Individuals living with HIV have been under-represented in operational research and trials of all-oral regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) treatment. We report outcomes from a prospective observational cohort study of a nine-month regimen comprised of bedaquiline, linezolid, a fluoroquinolone, delamanid, and clofazimine, in Lesotho, a setting with a high prevalence of HIV infection. Methods: We analyzed patients who initiated the regimen between 2020 and 2023. Overall, and by HIV status, we characterized treatment safety by summarizing the frequency and timing of clinically relevant adverse events. We described treatment effectiveness at the end of treatment and sustained treatment success eighteen months after treatment initiation. Results: Two hundred and fifty-five patients who initiated the shortened all-oral regimen were included in the analysis, of whom 161 (63.1%) were living with HIV. Regardless of HIV status, the most frequent clinically relevant adverse event was peripheral neuropathy, followed by myelosuppression. The estimated unadjusted rates of sustained treatment success at 18 months post-treatment initiation were 86.4% (95% confidence interval (CI): 81.4%, 90.5%) overall, 85.0% (95% CI: 78.2%, 90.4%) among patients living with HIV, and 88.8% (95% CI: 80.3%, 94.5%) among people without HIV. Conclusions: The effectiveness of the nine-month all-oral regimen was excellent. Although adverse events were common, they were manageable and did not appear to substantially impact treatment success. Results were similar regardless of HIV status, supporting the use of this regimen in this population.

Importance: Pharmacological targeting of host mechanisms that limit sepsis-induced organ dysfunction represents a new therapeutic approach. Preclinical studies showed that low-dose epirubicin enhances tissue damage control and attenuates sepsis severity independently of pathogen burden, thereby promoting disease tolerance to infection. Yet epirubicin can cause myelotoxicity when used in cancer therapy. Objective: To investigate whether low-dose epirubicin can safely be administered to patients with sepsis and septic shock. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial conducted in five German University hospitals. Patients with sepsis, defined by Sepsis-3 criteria, were eligible within 48 hours after diagnosis. The first patient was enrolled on October 19, 2022, and the last follow-up was conducted on May 21, 2025. Interventions: Eligible patients were randomized in a 4:1 ratio to receive either placebo or low-dose epirubicin in addition to standard care. There were three consecutive phases. Patients in the epirubicin group received a single dose of epirubicin (either 3.75 mg/m2, 7.5 mg/m2 or 15 mg/m2, depending on study phase). Main Outcomes and Measures: The primary endpoint of the trial was the 14-day myelotoxicity. Secondary and explorative outcomes included 90-day mortality, the degree of organ dysfunction as assessed by SOFA score, PK/PD modelling and cytokine release. Results: Of 854 patients assessed for eligibility, 32 were randomized and 31 were included in the primary analysis population. Six participants received placebo, nine participants received 3.75 mg/m2, nine received 7.5 mg/m2 and eight individuals received 15 mg/m2 epirubicin, respectively. There was no myelotoxicity in any group. Mortality at 90 days and SOFA-scores were not significantly different between groups. Two of 39 SAEs in the epirubicin group were assessed by the investigators as possibly related to epirubicin, Conclusions and Relevance Among patients with sepsis and septic shock, low dose epirubicin was not associated with increased myelotoxicity.

Importance: Immune checkpoint inhibitors (ICIs) produce diverse immune toxicities, but whether checkpoint blockade also modifies associations between other drugs and adverse events is poorly understood. Objective: To define ICI-associated toxicity organization and determine whether drug-associated adverse events and onset vary with ICI exposure and checkpoint pathway. Design and Setting: Cross-sectional analysis of deduplicated FAERS reports from 2016 through 2025; analyses performed in 2026. Participants: Among 13,701,106 deduplicated reports, 2,365,269 were cancer associated and 256,940 contained an ICI. Median age among cancer reports with observed age was 66 years (IQR, 56-75 years); 1,031,999 (43.6%) were female and 1,003,154 (42.4%) were male. Exposures: ICI exposure in any reported drug role, individual primary-suspect drugs, and checkpoint-pathway exposure. Main Outcomes and Measures: Reporting odds ratios (ORs), cross-organ adverse-event communities, adjusted primary-suspect drug x ICI interaction ORs for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), interstitial nephritis, drug-induced liver injury (DILI), and vomiting (VOM), and accelerated failure-time model time ratios for documented onset. Results: Of 3001 eligible Preferred Terms in cancer-associated reports, 2091 differed at a false discovery rate (FDR) less than .05. Four cross-organ toxicity communities were identified. Of 138 eligible drug-phenotype pairs, 65 had FDR-significant interactions, including moxifloxacin-SJS/TEN amplification (interaction OR, 101.72; 95% CI, 39.11-264.55), enfortumab vedotin-SJS/TEN attenuation (interaction OR, 0.17; 95% CI, 0.13-0.23), and omeprazole-interstitial nephritis amplification (interaction OR, 10.35; 95% CI, 7.62-14.05). Among 60,324 reports contributing to temporal analyses, ICI exposure was associated with longer adjusted documented time to onset for 5 of 6 phenotypes (time ratios, 1.37-1.59) but not AGEP (time ratio, 0.99; 95% CI, 0.67-1.46). Temporal associations also differed across checkpoint pathways. Conclusions and Relevance: ICIs were associated with a structured cross-organ toxicity landscape, phenotype-specific modification of drug-associated adverse events, and distinct temporal patterns across checkpoint pathways. These findings support checkpoint blockade as a modifier of drug-associated toxicity and motivate longitudinal and mechanistic validation.

Incidence of ventilator-associated pneumonia (VAP) is increased in patients admitted for brain injury. Staphylococcus aureus appears to be a particularly common pathogen in these respiratory infections. Our aim was to confirm the extent of S. aureus involvement in VAP among patients with neurological injuries. We conducted a retrospective, multicenter study including patients with and without neurological injuries who developed VAP during their ICU stay. Among 15 702 patients admitted in the participant centers during the study period. 407 were finally included in the study. S. aureus was involved in 122 (61.6%) VAP in brain-injured patients and 63 (30.1%) of non-brain-injured patients. In brain-injured patients, multivariate analysis identified age (0.97 [0.95; 0.98]), antibioprophylaxis (0.31 [0.18; 0.53]; p < 0.0001), subarachnoid hemorrhage (2.18 [1.01; 4.68]; p=0.0461), lower Glasgow coma score (0.92 [0.87; 0.97]; p= 0.004) and SAPS II (0.98 [0.97; 1]; p=0.0174) as critical factors associated with the risk of S. aureus in VAP. In the non-brain-injured population, multivariate analysis identified antibioprophylaxis (0.38 [0.22; 0.65]; p=0.0006), age (0.96 [0.95; 0.98]; p<0.0001), SAPS II (0.98 [0.97; 1]; p=0.0265), thoracic surgery (0.21 [0.09; 0.48]; p=0.0002) and peripheral neurosurgery (1.95 [1.2; 3.19]; p=0.0076) as critical factors. A total of 172 patients (42.3%) died during their ICU stay and 90-days mortality was 194 (47.7%). No difference of mortality was noticed function of VAP-associated pathogen.

Rationale. Guidelines disagree on antibacterial treatment for adults with community-acquired pneumonia and a positive respiratory viral test, particularly hospitalized patients and outpatients with comorbidities. Objectives. To estimate associations between antibacterial treatment selected for community-acquired pneumonia and outcomes in adults with virus-positive, imaging-evaluated nonsevere pneumonia. Methods. We conducted a retrospective multicenter study using Epic Cosmos data from 2016-2025. Hospitalized patients treated empirically by 24 hours were compared by continuation during hours 24-48; outpatients were compared by prescription at emergency-department discharge. Analyses were stratified by guideline-defined comorbidity and used propensity-score overlap weighting with source-cluster bootstrap confidence intervals. Exploratory analyses assessed respiratory virus, antiviral treatment, antibacterial class, and outpatient timing. Measurements and Main Results. The cohort included 376,320 adults: 275,604 inpatients and 100,716 outpatients. Inpatients who continued treatment had higher 30-day adverse-event risk without guideline comorbidity (adjusted risk difference, 1.70 percentage points; 95% confidence interval, 0.80-2.39) and with guideline comorbidity (2.56; 1.88-3.14), and longer post-landmark stay (adjusted mean ratios, 1.14 and 1.08). Exploratory class-specific analyses showed the largest adverse-event and mortality associations with broad therapy targeting resistant staphylococci or Pseudomonas; macrolide-containing and other atypical coverage showed no consistent adverse signal. Outpatient prescribing was associated with lower risks, but care-transition and residual confounding remained. Conclusions. Continued inpatient therapy after the empiric period showed no evidence of benefit and was associated with worse observed outcomes. Outpatient associations favored prescribing but remained vulnerable to care-transition and residual confounding.

Background Introducing a reimbursement restriction on lidocaine plaster prescribing in Ireland may have had unintended effects on prescribing of other analgesics with misuse potential. This study evaluates the impact of this policy on use, treatment intensification and initiation of opioids, gabapentinoids, and other analgesics. Methods This cohort study included adults eligible for Ireland's public health cover (approximately 33% of the population), using primary care dispensing data. The policy was fully implemented in December 2017, requiring individual patient approval for coverage of lidocaine plasters. In interrupted time series analysis, we examined change in level and trend of prescribing of other analgesics. In cohort analysis we compared lidocaine users to users of any other analgesic pre-policy and assessed outcomes of treatment intensification and initiation of opioids, gabapentinoids, and other analgesics in the three months post-policy. Results Among 1.65 million individuals, up to 1.4% were dispensed lidocaine plasters monthly pre-policy. Population-level use of other analgesics remained largely unchanged (except for topical agents). Compared to other analgesic users, lidocaine plasters users were significantly more likely to experience treatment intensification (adjusted risk ratio 1.47, 95%CI 1.38-1.57) of opioids after the policy, and initiation of strong (2.07, 1.85-2.30) and weak opioids (1.38, 1.21-1.59), controlling for baseline differences. Similar results were identified for gabapentinoid treatment intensification (1.26, 1.16-1.38) and initiation (1.34, 1.11-1.61), as well as for other analgesics. Conclusions This policy aimed at reducing low-value care was associated with greater opioid and gabapentinoid consumption, exposing patients to greater risk of drug-related harm from analgesic use and misuse.