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• Ciprofloxacin treatment has a deep impact on the gastrointestinal microbiome, irrespective of treatment duration. • The effect after longer treatment (>7 days) is not completely reversed within one month. • The oropharyngeal community is less affected by treatment and changes are reversed within one month. • gyr and par gene mutations encoding fluoroquinolone resistance temporarily increase, then return to baseline levels. • Longer treatment duration enriches for genes encoding resistance to other antibiotic classes. Urinary tract infections (UTIs) are one of the main reasons for antibiotic prescriptions in primary care. Recent studies demonstrate similar clinical outcomes with short vs. long antibiotics courses. The aim of this study was to investigate the differential collateral effect of ciprofloxacin treatment duration on the gastrointestinal and oropharyngeal microbiome in patients presenting with uncomplicated UTI to primary care practices in Switzerland, Belgium and Poland. Stool and oropharyngeal samples were obtained from 36 treated patients and 14 controls at the beginning of antibiotic therapy, end of therapy and one month after the end of therapy. Samples underwent shotgun metagenomics. At the end of therapy, patients treated with both short (≤7 days) and long (>7 days) ciprofloxacin courses showed similar changes in the gastrointestinal microbiome compared to non-treated controls. After one month, most changes in patients receiving short courses were reversed; however, long courses led to increased abundance of the genera Roseburia, Faecalicatena and Escherichia. Changes in the oropharynx were minor and reversed to baseline levels within one month. Ciprofloxacin resistance encoding mutations in gyrA/B and parC/E reads were observed in both short and long treatment groups but decreased to baseline levels after one month. An increased abundance of resistance genes was observed in the gastrointestinal microbiome after longer treatment, and correlated to increased prevalence of aminoglycoside, β-lactam, sulphonamide, and tetracycline resistance genes. Collateral effects on the gastrointestinal community, including an increased prevalence of antimicrobial resistance genes, persists for up to at least one month following longer ciprofloxacin therapy. These data support the use of shorter antimicrobial treatment duration. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Pseudomonas aeruginosa (PA) is a common causative pathogen of pneumonia acquired in the ICU. The aim of this study was to determine the incidence of PA ICU pneumonia (PAIP) and to quantify its independent association with PA colonisation at different body sites., Methods: Adult patients on mechanical ventilation at ICU admission were prospectively enrolled across 30 European ICUs. PA colonisation in the perianal area and in the lower respiratory tract were assessed within 72 hours after ICU admission and twice weekly until ICU discharge. PAIP development was evaluated daily. Competing risk models with colonisation as a time-varying exposure and ICU death and discharge as competing events were fitted and adjusted for confounders to investigate the association between PA carriage and PAIP., Results: 1971 subjects were enrolled. The colonisation prevalence with P. aeruginosa in the first 72 hours of ICU admission was 10.4% (179 perianal, 51 respiratory), while the acquisition incidence during the ICU stay was 7.0% (158 perianal, 47 respiratory). Of the 43 (1.8%) patients who developed PAIP, 11 (25.6%) were PA colonised on admission and 9 (20.9%) acquired colonisation prior to PAIP onset. Both perianal (adjusted sub distribution hazard ratio [aSHR] 4.4, 95%CI 1.7-11.6) and respiratory colonisation (aSHR 4.6, 95%CI 1.9-11.1) were independently associated with PAIP development., Conclusions: PAIP incidence was higher in PA colonised vs non-colonised patients. Both colonisation of the rectum and of the respiratory tract were associated with development of PAIP. The increased risk of P. aeruginosa colonisation for subsequent infection provides an opportunity for targeted preventive interventions., Competing Interests: Potential conflicts of interest CHvW reports research funds from LimmaTech, DaVolterra, and bioMerieux, and consultancy fees from MSD and Sanofi-Pasteur. AD and MTE are employees of AstraZeneca and hold stock in the company. MB reports grants or contracts from Merck, GSK, Atea Pharma, Sanofi and Novartis, consulting fees from GSK, Merck and Shionogi and Participation on a Data Safety Monitoring Board or Advisory Board from Sanofi. FS reported being an employee at Gilead Sciences and owner of Gilead Sciences stock, and an employee of AstraZeneca and owner of AstraZeneca stock at the time of study conduct. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Klebsiella pneumoniae is an opportunistic pathogen known for two main pathotypes: classical K. pneumoniae (cKp), often multidrug-resistant and common in hospitals, and hypervirulent K. pneumoniae (hvKp), associated with severe community-acquired infections. The recent emergence of strains combining hypervirulence and resistance is alarming. This study investigates the distribution of sequence types (STs), resistance, and virulence factors in K. pneumoniae strains causing bloodstream and urinary tract infections in Croatia. In 2022, 200 consecutive K. pneumoniae isolates were collected from blood and urine samples across several Croatian hospitals. Whole genome sequencing was performed on 194 isolates. Within the analyzed K. pneumoniae population, the distribution of sequence types was determined with multi-locus sequence typing (MLST) and capsule loci, resistance, and virulence determinants were assessed with the bioinformatics tool Kleborate. The analysis identified 77 different STs, with ST101 (24.6%) being the most prevalent, predominantly linked to the K17 capsular type (CT), invasive device usage, high antimicrobial resistance, and low virulence scores. The highest virulence scores were recorded in ST86 isolates, which were predominantly linked to the K2 CT and included some strains with medium resistance scores. String tests were positive in 19 strains, but only four of those harbored hypermucoviscous genetic determinants. The most prevalent ST101 clone in Croatia demonstrated a diverging association between resistance and virulence. An alarming co-existence of resistance and virulence was recorded in the ST86 strains.

Background and Aims: Mucosal healing is considered as a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the mucosal barrier function that give rise to structurally diverse isoforms. Unraveling disease-associated mucin isoforms that could act as an indication for barrier function would greatly enhance IBD management., Methods: We present the intestinal mucin RNA isoform landscape in IBD and control patients using a targeted mucin isoform sequencing approach on a discovery cohort (n = 106). Random Forest modeling (n = 1683 samples) with external validation (n = 130 samples) identified unique mucin RNA isoform panels that accurately stratified IBD patients in multiple subpopulations based on inflammation, IBD subtype (Crohn's disease (CD), ulcerative colitis (UC)), and anatomical location of the intestinal tract (i.e. ileum, proximal colon, distal colon, rectum)., Results: Particularly, the mucin RNA isoform panels obtained from the inflamed UC and CD distal colon showed high performance in distinguishing inflamed biopsies from their control counterparts (AUC of 93.3% and 91.1% in the training, 95.0% and 96.0% in the test, and 89.5% and 78.3% in the external validation datasets, respectively). Furthermore, the differentially expressed MUC4 (PB.1238.363), MUC5AC (PB.2811.15), MUC16 (ENST00000397910.8) and MUC1 (ENST00000462317.5, ENST00000620103.4) RNA isoforms frequently occurred throughout the different panels highlighting their role in IBD pathogenesis., Conclusion: We unveiled region-specific mucin RNA isoform panels capturing the heterogeneity of the IBD patient population and showing great potential to indicate barrier function in IBD patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objectives: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years., Methods: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days., Results: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%)., Conclusions: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age., Competing Interests: Declarations of competing interest JS has received research grants by the German Federal Ministry of Education and Research (BMBF), Noscendo and Basilea Pharmaceuticals; has received speaker honoraria by AbbVie, Hikma, Pfizer and Gilead; has been a consultant to Gilead, Produkt&Markt GmbH, Alvea Vax and Micron Research and has received travel grants by German Society for Infectious Diseases (DGI) and Meta-Alexander Foundation, all outside the submitted work. MA has received research grants from Pfizer and Gilead. Contributed to educational activities organized/supported by Pfizer, Roche, Gilead, GSK, Moderna and Sanofi. All honoraria from these activities are paid to the Institution. JSG has received speaker honoraria from Gilead and Pfizer, outside of the submitted work. MZ has received honoraria for lecturing courses by Pfizer Malaysia; is now an employee with AiCuris AG. RS has received lecture honoraria from Pfizer and Hikma, outside of the submitted work. JFI has received research grants by the Instituto de Salud Carlos III, Ministry of Science. Spain has received grants or research contracts from Laboratorios Faes, Normon, Pfizer, Italfarmaco, GSK, Prestige; has been a consultant or has received speaker honoraria from Faes, Normon, Cinfa, Mundipharma, Abbott, Novartis, and collaborations from AbbVie. PWGM has received honoraria and/or grant funding from Gilead, Janssen, MSD, ViiV Healthcare, GSK, and AstraZeneca, outside of the submitted work. SMK has received grants from Pfizer, MSD, Huvepharma, AiCuris, Astra Zeneca, Mylan, Janssen pharma. PK reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., Datamed GmbH, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, HELIOS Kliniken GmbH, Lahn-Dill-Kliniken GmbH, medupdate GmbH, MedMedia GmbH, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC, streamedup! GmbH and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, Shionogi; payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group. Kristin G-I Mohn has received honoraria for lectures from Takeda, IQVIA and BioNTech, has received a Research Grant from Norwegian Regional Health authorities, West, grant nr F12626 and is a Member of an advisory board on committee for National vaccination programs, Norwegian Public Health Institute. The remaining authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

People living with HIV (PLWH) despite having an appreciable depletion of CD4 + T-cells show a good severe acute respiratory syndrome coronavirus 2 vaccination response. The underlying mechanism(s) are currently not understood. We studied serological and polyfunctional T-cell responses in PLWH receiving anti-retroviral therapy stratified on CD4 + counts as PLWH-high (CD4 ≥ 500 cells/mm 3 ) and PLWH-low (<500 cells/mm 3 ). Responses were assessed longitudinally before the first vaccination (T0), 1-month after the first dose (T1), 3-months (T2), and 6-months (T3) after the second dose. Expectedly, both PLWH-high and -low groups developed similar serological responses after T2, which were also non-significantly different from age and vaccination-matched HIV-negative controls at T3. The immunoglobulin G titers were also protective showing a good correlation with angiotensin-converting enzyme 2-neutralizations (R = 0.628, p = 0.005). While surface and intracellular activation analysis showed no significant difference at T3 between PLWH and controls in activated CD4 + CD154 + and CD4 + memory T-cells, spike-specific CD4 + polyfunctional cytokine expression analysis showed that PLWH preferentially express interleukin (IL)-2 (p < 0.001) and controls, interferon-γ (p = 0.017). CD4 + T-cell counts negatively correlated with IL-2-expressing CD4 + T-cells including CD4 + memory T-cells (Spearman ρ: -0.85 and -0.80, respectively; p < 0.001). Our results suggest that the durable serological and CD4 + T-cell responses developing in vaccinated PLWH are associated with IL-2-mediated CD4 + T-cell activation that likely compensates for CD4 + T-cell depletion in PLWH., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: The independent effects of extranasal-only carriage, carriage at multiple bodily sites, or the bacterial load of colonizing Staphylococcus aureus (SA) on the risk of developing SA surgical site infections and postoperative bloodstream infections (SA SSI/BSIs) are unclear. We aimed to quantify these effects in this large prospective cohort study., Methods: Surgical patients aged 18 years or older were screened for SA carriage in the nose, throat, or perineum within 30 days before surgery. SA carriers and noncarriers were enrolled in a prospective cohort study in a 2:1 ratio. Weighted multivariable Cox proportional hazard models were used to assess the independent associations between different measures of SA carriage and occurrence of SA SSI/BSI within 90 days after surgery., Results: We enrolled 5004 patients in the study cohort; 3369 (67.3%) were SA carriers. 100 SA SSI/BSI events occurred during follow-up, and 86 (86%) of these events occurred in SA carriers. The number of colonized bodily sites (adjusted hazard ratio [aHR], 3.5-8.5) and an increasing SA bacterial load in the nose (aHR, 1.8-3.4) were associated with increased SA SSI/BSI risk. However, extranasal-only carriage was not independently associated with SA SSI/BSI (aHR, 1.5; 95% CI, 0.9-2.5)., Conclusions: Nasal SA carriage was associated with an increased risk of SA SSI/BSI and accounted for the majority of SA infections. Higher bacterial load, as well as SA colonization at multiple bodily sites, further increased this risk., Competing Interests: Potential conflicts of interest. Van Werkhoven reported receiving research grants/in-kind contribution from DaVolterra, BioMerieux, and Limmatech and consultancy fees from Merck/MSD and Sanofi-Pasteur. Ruzin reported being an employee of AstraZeneca and owner of AstraZeneca stock at the time of study conduct. Sifakis reported being an employee at Gilead Sciences and owner of Gilead Sciences stock and an employee of AstraZeneca and owner of AstraZeneca stock at the time of study conduct. All other authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria., (© 2024. The Author(s).)

Background: Streptococcus pneumoniae is a global cause of community-acquired pneumonia (CAP) and invasive disease in children. The CAP-IT trial (grant No. 13/88/11; https://www.capitstudy.org.uk/ ) collected nasopharyngeal swabs from children discharged from hospitals with clinically diagnosed CAP, and found no differences in pneumococci susceptibility between higher and lower antibiotic doses and shorter and longer durations of oral amoxicillin treatment. Here, we studied in-depth the genomic epidemiology of pneumococcal (vaccine) serotypes and their antibiotic resistance profiles., Methods: Three-hundred and ninety pneumococci cultured from 1132 nasopharyngeal swabs from 718 children were whole-genome sequenced (Illumina) and tested for susceptibility to penicillin and amoxicillin. Genome heterogeneity analysis was performed using long-read sequenced isolates (PacBio, n = 10) and publicly available sequences., Results: Among 390 unique pneumococcal isolates, serotypes 15B/C, 11 A, 15 A and 23B1 were most prevalent (n = 145, 37.2%). PCV13 serotypes 3, 19A, and 19F were also identified (n = 25, 6.4%). STs associated with 19A and 19F demonstrated high genome variability, in contrast to serotype 3 (n = 13, 3.3%) that remained highly stable over a 20-year period. Non-susceptibility to penicillin (n = 61, 15.6%) and amoxicillin (n = 10, 2.6%) was low among the pneumococci analysed here and was independent of treatment dosage and duration. However, all 23B1 isolates (n = 27, 6.9%) were penicillin non-susceptible. This serotype was also identified in ST177, which is historically associated with the PCV13 serotype 19F and penicillin susceptibility, indicating a potential capsule-switch event., Conclusions: Our data suggest that amoxicillin use does not drive pneumococcal serotype prevalence among children in the UK, and prompts consideration of PCVs with additional serotype coverage that are likely to further decrease CAP in this target population. Genotype 23B1 represents the convergence of a non-vaccine genotype with penicillin non-susceptibility and might provide a persistence strategy for ST types historically associated with vaccine serotypes. This highlights the need for continued genomic surveillance., (© 2024. The Author(s).)

Scope: Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen considered one of the paradigms of antimicrobial resistance, is among the main causes of hospital-acquired and chronic infections associated with significant morbidity and mortality. This growing threat results from the extraordinary capacity of P. aeruginosa to develop antimicrobial resistance through chromosomal mutations, the increasing prevalence of transferable resistance determinants (such as the carbapenemases and the extended-spectrum β-lactamases), and the global expansion of epidemic lineages. The general objective of this initiative is to provide a comprehensive update of P. aeruginosa resistance mechanisms, especially for the extensively drug-resistant (XDR)/difficult-to-treat resistance (DTR) international high-risk epidemic lineages, and how the recently approved β-lactams and β-lactam/β-lactamase inhibitor combinations may affect resistance mechanisms and the definition of susceptibility profiles., Methods: To address this challenge, the European Study Group for Antimicrobial Resistance Surveillance (ESGARS) from the European Society of Clinical Microbiology and Infectious Diseases launched the 'Improving Surveillance of Antibiotic-Resistant Pseudomonas aeruginosa in Europe (ISARPAE)' initiative in 2022, supported by the Joint programming initiative on antimicrobial resistance network call and included a panel of over 40 researchers from 18 European Countries. Thus, a ESGARS-ISARPAE position paper was designed and the final version agreed after four rounds of revision and discussion by all panel members., Questions Addressed in the Position Paper: To provide an update on (a) the emerging resistance mechanisms to classical and novel anti-pseudomonal agents, with a particular focus on β-lactams, (b) the susceptibility profiles associated with the most relevant β-lactam resistance mechanisms, (c) the impact of the novel agents and resistance mechanisms on the definitions of resistance profiles, and (d) the globally expanding XDR/DTR high-risk lineages and their association with transferable resistance mechanisms., Implication: The evidence presented herein can be used for coordinated epidemiological surveillance and decision making at the European and global level., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Heteroresistance (HR) to colistin is especially concerning in settings where multi-drug-resistant (MDR) K. pneumoniae are prevalent and empiric use of colistin might lead to treatment failures. This study aimed to assess the frequency of occurrence of colistin HR (CHR) among (MDR) K. pneumoniae ( n = 676) isolated from patients hospitalized in 13 intensive care units (ICUs) in six European countries in a clinical trial assessing the impact of decolonization strategies. All isolates were whole-genome-sequenced and studied for in vitro colistin susceptibility. The majority were colistin-susceptible (CS) ( n = 597, MIC ≤ 2 µg/mL), and 79 were fully colistin-resistant (CR) (MIC > 2 µg/mL). A total of 288 CS isolates were randomly selected for population analysis profiling (PAP) to assess CHR prevalence. CHR was detected in 108/288 CS K. pneumoniae . No significant association was found between the occurrence of CHR and country, MIC-value, K-antigen type, and O-antigen type. Overall, 92% (617/671) of the K. pneumoniae were MDR with high prevalence among CS (91%, 539/592) and CR (98.7%, 78/79) isolates. In contrast, the proportion of carbapenemase-producing K. pneumoniae (CP-Kpn) was higher among CR (72.2%, 57/79) than CS isolates (29.3%, 174/594). The proportions of MDR and CP-Kpn were similar among CHR (MDR: 85%, 91/107; CP-Kpn: 29.9%, 32/107) and selected CS isolates (MDR: 84.7%, 244/288; CP-Kpn: 28.1%, 80/285). WGS analysis of PAP isolates showed diverse insertion elements in mgrB or even among technical replicates underscoring the stochasticity of the CHR phenotype. CHR isolates showed high sequence type (ST) diversity (Simpson's diversity index, SDI: 0.97, in 52 of the 85 STs tested). CR (SDI: 0.85) isolates were highly associated with specific STs (ST101, ST147, ST258/ST512, p ≤ 0.003). The widespread nature of CHR among MDR K. pneumoniae in our study urge the development of rapid HR detection methods to inform on the need for combination regimens.