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Background The selection pressure exercised by antibiotic drugs is an important consideration for the wise stewardship of antimicrobial treatment programs. Treatment decisions are currently based on crude assumptions, and there is an urgent need to develop a more quantitative knowledge base that can enable predictions of the impact of individual antibiotics on the human gut microbiome and resistome. Results Using shotgun metagenomics, we quantified changes in the gut microbiome in two cohorts of hematological patients receiving prophylactic antibiotics; one cohort was treated with ciprofloxacin in a hospital in Tübingen and the other with cotrimoxazole in a hospital in Cologne. Analyzing this rich longitudinal dataset, we found that gut microbiome diversity was reduced in both treatment cohorts to a similar extent, while effects on the gut resistome differed. We observed a sharp increase in the relative abundance of sulfonamide antibiotic resistance genes (ARGs) by 148.1% per cumulative defined daily dose of cotrimoxazole in the Cologne cohort, but not in the Tübingen cohort treated with ciprofloxacin. Through multivariate modeling, we found that factors such as individual baseline microbiome, resistome, and plasmid diversity; liver/kidney function; and concurrent medication, especially virostatic agents, influence resistome alterations. Strikingly, we observed different effects on the plasmidome in the two treatment groups. There was a substantial increase in the abundance of ARG-carrying plasmids in the cohort treated with cotrimoxazole, but not in the cohort treated with ciprofloxacin, indicating that cotrimoxazole might contribute more efficiently to the spread of resistance. Conclusions Our study represents a step forward in developing the capability to predict the effect of individual antimicrobials on the human microbiome and resistome. Our results indicate that to achieve this, integration of the individual baseline microbiome, resistome, and mobilome status as well as additional individual patient factors will be required. Such personalized predictions may in the future increase patient safety and reduce the spread of resistance. Trial registration ClinicalTrials.gov, NCT02058888 . Registered February 10 2014

The understanding of longitudinal changes in the urinary microbiota of healthy women and its relation to intestinal microbiota is limited. From a cohort of 15 premenopausal women without known urogenital disease or current symptoms, we collected catheter urine (CU), vaginal and periurethral swabs, and fecal samples on four visits over six months. Additionally, ten participants provided CU and midstream urine (MU) to assess comparability. Urine was subjected to expanded culture. 16S rRNA gene sequencing was performed on all urine, fecal, and selected vaginal and periurethral samples. Sequence reads were processed (DADA2 pipeline) and analyzed using QIIME 2 and R. Relative abundances of urinary microbiota were variable over 6-18 months. The degree of intraindividual variability of urinary microbiota was higher than that found in fecal samples. Still, nearly half of the observed beta diversity of all urine samples could be attributed to differences between volunteers (R2 = 0.48, p = 0.001). After stratification by volunteer, time since last sexual intercourse was shown to be a factor significantly contributing to beta diversity (R2 = 0.14, p = 0.001). We observed a close relatedness of urogenital microbial habitats and a clear distinction from intestinal microbiota in the overall betadiversity analysis. Microbiota compositions derived from MU differed only slightly from CU compositions. Within this analysis of low-biomass samples, we identified contaminating sequences potentially stemming from sequencing reagents. Results from our longitudinal cohort study confirmed the presence of a rather variable individual urinary microbiota in premenopausal women. These findings from catheter urine complement previous observations on temporal dynamics in voided urine. The higher intraindividual variability of urinary microbiota as compared to fecal microbiota will be a challenge for future studies investigating associations with urogenital diseases and aiming at identifying pathogenic microbiota signatures.

Bacteriophage therapy holds promise in addressing the antibiotic-resistance crisis, globally and in Germany. Here, we provide an overview of the current situation (2023) of applied phage therapy and supporting research in Germany. The authors, an interdisciplinary group working on patient-focused bacteriophage research, addressed phage production, phage banks, susceptibility testing, clinical application, ongoing translational research, the regulatory situation, and the network structure in Germany. They identified critical shortcomings including the lack of clinical trials, a paucity of appropriate regulation and a shortage of phages for clinical use. Phage therapy is currently being applied to a limited number of patients as individual treatment trials. There is presently only one site in Germany for large-scale good-manufacturing-practice (GMP) phage production, and one clinic carrying out permission-free production of medicinal products. Several phage banks exist, but due to varying institutional policies, exchange among them is limited. The number of phage research projects has remarkably increased in recent years, some of which are part of structured networks. There is a demand for the expansion of production capacities with defined quality standards, a structured registry of all treated patients and clear therapeutic guidelines. Furthermore, the medical field is still poorly informed about phage therapy. The current status of non-approval, however, may also be regarded as advantageous, as insufficiently restricted use of phage therapy without adequate scientific evidence for effectiveness and safety must be prevented. In close coordination with the regulatory authorities, it seems sensible to first allow some centers to treat patients following the Belgian model. There is an urgent need for targeted networking and funding, particularly of translational research, to help advance the clinical application of phages.

The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter–related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.

Background Recurrent or refractory Clostridioides difficile infection (CDI) often affects older and immunocompromised patients, posing clinical and economic challenges. While fidaxomicin has shown lower recurrence rates than vancomycin in the general population, evidence in this population remains limited. Methods This retrospective, multicentre case-control study compared patients aged > 65 years or immunocompromised patients receiving fidaxomicin (case group) with those treated with vancomycin (control group) for recurrent or refractory CDI. A microcosting approach was used to assess direct treatment costs. Results A total of 344 patients were included (172 per group). Compared to the control group, the fidaxomicin group presented a significantly higher rate of symptom reduction on day 10 ( n  = 163, 95% vs. n  = 147, 86%; p  = 0.004) and lower CDI recurrence rates ( n  = 36, 21% vs. n  = 63, 37%; p  = 0.001). While the mean CDI treatment costs per patient were significantly higher in the fidaxomicin group ( p  < 0.001), the hospitalisation and overall treatment costs were comparable (€19,898, 95% CI €16,151-€23,645 vs. €20,469, 95% CI €16,837-€24,101, p  = 0.811; €17,798, 95% CI €14,620-€20,975 vs. €17,300, 95% CI €14,199-€20,400, p  = 0.840). Key cost drivers were hospitalisation, intensive care unit treatment, and severe initial CDI. Conclusions Despite higher drug acquisition costs of fidaxomicin, overall treatment costs were comparable between the two groups with better clinical outcomes in patients treated with fidaxomicin. Clinical trial number Not applicable.

In recent years, an increase in invasive VRE infections has been reported worldwide, including Germany. The most common gene encoding resistance to glycopeptides is VanA, but predominant VanB clones are emerging. Although neither the incidence rates nor the exact routes of nosocomial transmission of VRE are well established, screening and strict infection control measures, e.g. single room contact isolation, use of personal protective clothing by hospital staff and intensified surface disinfection for colonized individuals, are implemented in many hospitals. At the same time, the impact of VRE infection on mortality remains unclear, with current evidence being weak and contradictory. In this short review, we aim to give an overview on the current basis of evidence on the clinical effectiveness of infection control measures intended to prevent transmission of VRE and to put these findings into a larger perspective that takes further factors, e.g. VRE-associated mortality and impact on patient care, into account.

Moulds are ubiquitous components of outdoor and indoor air and local conditions, temperature, humidity and season can influence their concentration in the air. The impact of these factors on mould exposure in hospitals and the resulting risk of infection for low to moderately immunocompromised patients is unclear. In the present retrospective analysis for the years 2018 to 2022, the monthly determined mould contamination of the outdoor and indoor air at the University Hospital Frankfurt am Main is compared with the average air temperature and the relative humidity. Mould infections (Aspergillus spp., Mucorales) of low to moderately immunosuppressed patients of a haematological-oncological normal ward were determined clinically according to the criteria of the European Organisation for Research and Treatment of Cancer (EORTC, Brussels, Belgium) and of the National Reference Centre for Surveillance of Nosocomial Infections (NRC-NI, Berlin, Germany). The data revealed that in the summer months (May–October), increased mould contamination was detectable in the outdoor and indoor air compared to the winter months (November–April). The mould levels in the patient rooms followed the detection rates of the outdoor air. Two nosocomial Aspergillus infections, one nosocomial Mucorales (Rhizopus spp.) infection (according to both NRC-NI and EORTC criteria) and five Aspergillus spp. infections (according to EORTC criteria) occurred in 4299 treated patients (resulting in 41,500 patient days). In our study, the incidence density rate of contracting a nosocomial mould infection (n = 3) was approximately 0.07 per 1000 patient days and appears to be negligible.

Background Establishing a strong correlation between active SARS-CoV-2 infection and COVID-19 severity could enhance early risk assessment, predict disease outcomes, and identify patients needing urgent treatment. Methods In this prospective SARS-CoV-2 transmission cohort study, we introduce the potential of a symptoms severity score (S3) based on patient self-reported symptoms and further evaluate its utility for predicting SARS-CoV-2 infection status and viral load. The S3 construct, derived from a participant survey using pre-defined scales (Cronbach’s alpha=0.7), was categorized as asymptomatic, mild to moderate, or severe. This analysis comprised nine household contacts, contributing 1,410 qualitative and 89 quantitative visit‑test observations. Results S3 showed a high correlation with total symptoms (Pearson r  = 0.963, p  < 0.0001). The categorized version (S3C) also correlated strongly with the number of symptoms (Spearman’s r  = 0.988, p  < 0.0001). A generalized estimating equation (GEE) model revealed that participants with severe symptoms had 6.5 times higher odds of having an active SARS-CoV-2 infection than those with no symptoms (Odds Ratio = 6.5, 95% CI: 3.5 to 12.4, p  < 0.0001). Similar significant results were found for severe vs. mild to moderate symptoms (OR = 2.3, CI: 1.3 to 4.1, p  = 0.0025) and mild to moderate vs. asymptomatic (OR = 2.8, 95% CI: 1.4 to 5.4, p  = 0.0030). Conclusions Our findings demonstrate that self-reported symptom severity and number of symptoms are robust predictors of SARS-CoV-2 infection and viral load, providing potential utility in clinical risk stratification. However, limitations, including a small sample size for viral load analyses and reliance on self-reported data, should be considered.

Background Composition of the intestinal microbiota has been correlated to therapeutic efficacy of immune checkpoint inhibitors (ICI) in various cancer entities including melanoma. Prediction of the outcome of such therapy, however, is still unavailable. This prospective, non-interventional study was conducted in order to achieve an integrated assessment of the connection between a specific intestinal microbiota profile and antitumor immune response to immune checkpoint inhibitor therapy (anti-PD-1 and/or anti-CTLA-4) in melanoma patients. Methods We assessed blood and stool samples of 29 cutaneous melanoma patients who received immune checkpoint inhibitor therapy. For functional and phenotypical immune analysis, 12-color flow cytometry and FluoroSpot assays were conducted. Gut microbiome was analyzed with shotgun metagenomics sequencing. To combine clinical, microbiome and immune variables, we applied the Random Forest algorithm. Results A total of 29 patients was analyzed in this study, among whom 51.7% ( n  = 15) reached a durable clinical benefit. The Immune receptor TIGIT is significantly upregulated in T cells ( p  = 0.0139) and CD56 high NK cells ( p  = 0.0037) of responders. Several bacterial taxa were associated with response (e.g. Ruminococcus torques ) or failure (e.g. Barnesiella intestinihominis ) to immune therapy. A combination of two microbiome features ( Barnesiella intestinihominis and the Enterobacteriaceae family) and one immune feature (TIGIT + CD56 high NK cells) was able to predict response to ICI already at baseline (AUC = 0.85; 95% CI: 0.841–0.853). Conclusions Our results reconfirm a link between intestinal microbiota and response to ICI therapy in melanoma patients and furthermore point to TIGIT as a promising target for future immunotherapies.