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Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells., (© 2024. The Author(s).)

Objectives: From September 2022 an increase in Corynebacterium diphtheriae (C. diphtheriae) infections was reported in Europe. Our study focuses on 31 adolescent and young adult refugees with cutaneous C. diphtheriae infections detected in Germany. We examined treatment regimens and outcomes to provide targeted insights into the management of this infection., Methods: We distributed a standardized survey, focused on children and adolescents presenting to paediatric clinics through the German Paediatric Infectious Diseases Society (DGPI) and additional professional contacts in Germany. Data were extracted from routine medical documentation and reported anonymously., Results: A total of 31 individuals with cutaneous C. diphtheriae infection were reported by 9 centres. Two of these showed diphtheria toxin (DT) related systemic symptoms and four exhibited systemic inflammation requiring complex management. The remaining 25 cases, with exclusively cutaneous manifestations, were afebrile. Treatment with topical antiseptics and systemic antibiotics, mainly aminopenicillin/beta-lactamase inhibitors (BLI) (35%) or clindamycin (25%), achieved eradication in all but two cases treated with aminopenicillin/BLI. Treatment duration varied between 5 and 17 days., Conclusions: In refugees presenting with chronic skin wounds, C. diphtheriae should be included into the differential diagnosis. Fever seems to be a valuable marker to differentiate severe cases with potentially DT-mediated sequelae from exclusively cutaneous diphtheria (CD). For afebrile CD, topical antiseptics and oral antibiotic therapy with clindamycin for 7 days, followed by clinical surveillance appears to be a safe treatment regimen. Patients with CD who present with fever or pharyngitis should be thoroughly investigated including blood and pharyngeal swab cultures., (© 2024. The Author(s).)

Background: Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Infections with multidrug-resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation., Aim: The aim of the study was to assess the influence of non-antibiotic medication contributing to MDRO colonisation., Methods: Three hundred twenty-four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi-centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes., Results: A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%-confidence interval (CI) 1.82-4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%-CI 2.96-30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%-CI 1.22-23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911-6.823, p = 0.075) and associated with risk of MDRO infection during follow-up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001)., Conclusions: Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non-antibiotic co-medications had negligible influence. Future prospective trials are needed to confirm these results., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

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.

Objective: Outpatient parenteral antimicrobial therapy (OPAT) is a well-established and cost-effective method for improving the efficient use of healthcare resources. However, only a few centres in Germany perform it. Here we analysed OPAT for the treatment of patients with cranial infections in our neurosurgical department., Methods: This retrospective study analysed patients with cranial infections and the need for intravenous (i.v.) antimicrobial treatment between 2018 and 2021.All diagnosed intracranial infections were defined into two infection categories such as long-term antimicrobial treatment and short-term antimicrobial treatment. All included patients were discharged with a peripherally inserted central catheter (PICC) line. Prior to discharge, all patients received training in the safe administration of their medications via the PICC line. The duration of OPAT and the rate of readmission after OPAT were analysed., Results: We identified a total of 45 patients treated with OPAT for cranial infections. Intradural involvement was present in 40 cases (88.9%). The average length of hospital stay for this cohort after surgical treatment was 45 ± 15 days. 5 patients were treated for soft tissue/skin infection. Surgery was not required in this cohort. The mean hospital stay for this cohort was 8 ± 6 days. Gram-positive organisms were isolated in most cases (53.3%). The most common pathogens were Staphylococcus aureus followed by other Staphylococcus species . For all included patients, OPAT was performed after discharge for an average of 43.1 ± 14 days. There were five cases of readmission due to treatment failure. No serious adverse events or complications of OPAT were observed., Conclusion: OPAT enables better patient-centred healthcare close to home. The length of hospital stay can be reduced and adverse events due to prolonged hospitalisation can be avoided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kilinc, Setzer, Behmanesh, Jussen, Gessler, Bayerl, Kempf, Kessel, Czabanka and Prinz.)

Malignancies can cause severe stenosis of the biliary tract and therefore predispose a patient to bacterial cholangitis. Upon endoscopic drainage, antibiotic therapy (AT) is performed according to individual clinical judgement, as the optimal duration of AT is unclear to date, especially in the case of multidrug-resistant organisms (MDROs). In a case-based retrospective study, patients with malignant biliary strictures and acute cholangitis were included upon endoscopic retrograde cholangiography (ERC). The outcome of cases treated with short AT (≤6 days) was compared to that of long AT (≥7 days). Recurrent cholangitis (RC) before scheduled stent exchange was the primary end point. In total, 124 patients were included, with 183 cases of proven cholangitis in total. The overall median duration of AT was 7 days (range 1-20), with 74 cases (40%) receiving short AT and 109 (60%) receiving long AT. Short AT was not an independent risk factor for RC (HR = 0.66, p > 0.2), while colonization with MDROs was associated with a higher risk of RC (HR = 2.21, p = 0.005). Placement of a metal stent was associated with minor risk of RC (HR = 0.4, p = 0.038). In conclusion, short AT is possible in selected patients with non-severe cholangitis and malignant biliary strictures. Scheduled screening for MDROs is recommended and placement of a metal stent should be performed if possible.

Acinetobacter baumannii is an antibiotic-resistant, Gram-negative pathogen that causes a multitude of nosocomial infections. However, pathogenicity mechanisms and the host cell response during infection remain unclear. In this study, we determined virulence traits of A. baumannii clinical isolates belonging to the most widely disseminated international clonal lineage, international cluster 2 (IC2), in vitro and in vivo . Complexome profiling of primary human endothelial cells with A. baumannii revealed that mitochondria, and in particular complexes of the electron transport chain, are important host cell targets. Infection with highly virulent A. baumannii remodelled assembly of mitochondrial protein complexes and led to metabolic adaptation. These were characterized by reduced mitochondrial respiration and glycolysis in contrast to those observed in infection with low-pathogenicity A. baumannii. Perturbation of oxidative phosphorylation, destabilization of mitochondrial ribosomes, and interference with mitochondrial metabolic pathways were identified as important pathogenicity mechanisms. Understanding the interaction of human host cells with the current global A. baumannii clone is the basis to identify novel therapeutic targets. IMPORTANCE Virulence traits of Acinetobacter baumannii isolates of the worldwide most prevalent international clonal lineage, IC2, remain largely unknown. In our study, multidrug-resistant IC2 clinical isolates differed substantially in their virulence potential despite their close genetic relatedness. Our data suggest that, at least for some isolates, mitochondria are important target organelles during infection of primary human endothelial cells. Complexes of the respiratory chain were extensively remodelled after infection with a highly virulent A. baumannii strain, leading to metabolic adaptation characterized by severely reduced respiration and glycolysis. Perturbations of both mitochondrial morphology and mitoribosomes were identified as important pathogenicity mechanisms. Our data might help to further decipher the molecular mechanisms of A. baumannii and host mitochondrial interaction during infection., Competing Interests: The authors declare no conflict of interest.

Background and Study Aim: The incidence of wound infections after percutaneous endoscopic gastrostomy (PEG) varies widely in recent studies. The present study systematically investigates the underlying risk factors for the development of wound infections in a large cohort of patients over a long-term follow-up period., Patients and Methods: A retrospective cohort study of patients undergoing PEG insertion using either the pull or push technique was conducted and patients followed up for 3 years. Tube-related wound infections were identified, and pathogens regularly cultured from wound swabs. Adjusted analysis was performed via univariate and multivariate logistic regression analysis., Results: 616 patients were included in this study. A total of 25% percent of patients developed wound infections upon PEG tube insertion and 6.5% showed recurrent infections. Nicotine abuse ( p = 0.01), previous ischemic stroke ( p = 0.01) and head and neck cancer ( p < 0.001) showed an increased risk for wound infection after PEG placement. Moreover, radio-chemotherapy was associated with the occurrence of wound infections ( p < 0.001). Infection rates were similar between pull and push cohorts. The most common bacterial pathogen detected was Enterobacterales (19.2%). Staphylococcus aureus , Pseudomonas aeruginosa and enterococci were frequently detected in recurrent infection (14.2%, 11.4% and 9.6%, respectively). Antibiotic prophylaxis showed no effect on infection rates., Conclusions: Wound infections after PEG placement are common and occasionally occur as recurrent infections. There is potential for improvement in everyday clinical practice, particularly regarding antibiotic prophylaxis in accordance with guidelines.

Background & Aims: Colonization with multidrug-resistant organisms (MDRO) has been shown to impair survival in patients with various malignancies. Despite the increasing spread of MDRO, its impact on patients with cholangiocarcinoma (CCA) is unclear. Aim of this study was to analyse the impact of MDRO-colonization on overall prognosis in CCA patients., Methods: All patients with surgically resected CCA diagnosed between August 2005 and November 2021 at the University Hospital Frankfurt were screened for MDRO. CCA patients with a positive MDRO screening before or within the first 90 days after diagnosis of CCA were defined as colonized. Patients with a negative MDRO screening were defined as non-colonized., Results: Hundred and sixty nine patients were included. 32% (n = 54) were screened MDRO positive, while 68% (115) were non-colonized. Median overall survival (OS) for colonized patients was 17.1 months (95% CI = 9-25.2 months) compared to 50 months (95% CI = 37.1-62.8) for MDRO-negative patients (p ≤ .001). Non-cancer-related mortality (p ≤ .001) and infectious-related death (p ≤ .001) was significantly higher in the MDRO-colonized group. In multivariate analysis, MDRO colonization (HR = 2.1, 95% CI = 1.4-3.3, p = .001), ECOG 1 (HR = 2.5, 95% CI = 1.6-4, p ≤ .001) and N1 status (HR = 1.7, 95% CI = 1.1-2.6, p = .017) were independent risk factors for OS., Conclusion: MDRO-colonization contributes to poor survival in patients with surgically resected CCA. MDRO surveillance is necessary to optimize clinical management of infections and to potentially reduce mortality in this critical population., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

BackgroundSince the beginning of the war in Ukraine in February 2022, Ukrainians have been seeking shelter in other European countries.AimWe aimed to investigate the prevalence and the molecular epidemiology of multidrug-resistant Gram-negative (MDRGN) bacteria and meticillin-resistant Staphylococcus aureus (MRSA) in Ukrainian patients at admittance to the University Hospital Frankfurt, Germany.MethodsWe performed screening and observational analysis of all patients from March until June 2022. Genomes of MDRGN isolates were analysed for antimicrobial resistance, virulence genes and phylogenetic relatedness.ResultsWe included 103 patients (median age: 39 ± 23.7 years), 57 of whom were female (55.3%; 95% confidence interval (CI): 45.2-5.1). Patients were most frequently admitted to the Department of Paediatrics (29/103; 28.2%; 95% CI: 19.7-37.9). We found 34 MDRGN isolates in 17 of 103 patients (16.5%; 95% CI: 9.9-25.1). Ten patients carried 21 carbapenem-resistant (CR) bacteria, five of them more than one CR isolate. Four of six patients with war-related injuries carried eight CR isolates. In six of 10 patients, CR isolates caused infections. Genomic characterisation revealed that the CR isolates harboured at least one carbapenemase gene, bla being the most frequent (n = 10). Core genome and plasmid analysis revealed no epidemiological connection between most of these isolates. Hypervirulence marker genes were found in five of six NDM-1 CR isolates. No MRSA was found.ConclusionHospitals should consider infection control strategies to cover the elevated prevalence of MDRGN bacteria in Ukrainian patients with war-related injuries and/or hospital pre-treatment and to prevent the spread of hypervirulent CR isolates.Klebsiella pneumoniae CR isolates. No MRSA was found.ConclusionHospitals should consider infection control strategies to cover the elevated prevalence of MDRGN bacteria in Ukrainian patients with war-related injuries and/or hospital pre-treatment and to prevent the spread of hypervirulent CR isolates.

Colistin (polymyxin E) is increasingly used as a last-resort antibiotic for the treatment of severe infections with multidrug-resistant Gram-negative bacteria. In contrast to human medicine, colistin is also used in veterinary medicine for metaphylaxis. Our objective was to decipher common colistin resistance mechanisms in Klebsiella pneumoniae isolates from animals. In total, 276 veterinary K. pneumoniae isolates, derived from companion animals or livestock, and 12 isolates from human patients were included for comparison. Six out of 276 veterinary isolates were colistin resistant (2.2%). Human isolates belonging to high-risk clonal lineages (e.g., ST15, ST101, ST258), displayed multidrug-resistant phenotypes and harboured many resistance genes compared to the veterinary isolates. However, the common colistin resistance mechanism in both human and animal K. pneumoniae isolates were diverse alterations of MgrB, a critical regulator of lipid A modification. Additionally, deleterious variations of lipopolysaccharide (LPS)-associated proteins (e.g., PmrB P95L, PmrE P89L, LpxB A152T) were identified. Phylogenetic analysis and mutation patterns in genes encoding LPS-associated proteins indicated that colistin resistance mechanisms developed independently in human and animal isolates. Since only very few antibiotics remain to treat infections with MDR bacteria, it is important to further analyse resistance mechanisms and the dissemination within different isolates and sources.

Multidrug-resistant (MDR) Pseudomonas aeruginosa increasingly causes health care-associated infections. In this study, we determined the activity of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against 223 MDR P. aeruginosa clinical isolates recovered from 2013 to 2017 at the University Hospital Frankfurt by using MIC test strips. Furthermore, we evaluated the presence of genes encoding major β-lactamases, such as VIM, IMP, NDM, GIM, SPM, and KPC; the extended spectrum β-lactamase (ESBL)-carbapenemase GES; and the virulence-associated traits ExoS and ExoU, as in particular ExoU is thought to be associated with poor clinical outcome. For MDR P. aeruginosa isolates, the MIC 50 /MIC 90 values of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol were 8/>256 mg/L, 16/>256 mg/L, and 0.25/1 mg/L, respectively. Cefiderocol showed the highest susceptibility rate (97.3%) followed by ceftazidime-avibactam (48.4%) and ceftolozane-tazobactam (46.6%). In 81 (36.3%) isolates, carbapenemase gene bla VIM was detected (with a positive association of bla GES ). More than half of the isolates belong to the so-called international P. aeruginosa "high-risk" clones, with sequence type 235 (ST235) (24.7%) being the most prevalent. This study underlines that ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol are important options for the treatment of infections due to MDR P. aeruginosa, with cefiderocol currently being the most active available antipseudomonal β-lactam agent. According to our clinical experience, the outcome of cefiderocol therapy (8 patients) was favorable especially in cases of MDR P. aeruginosa-associated complicated urinary tract infections. exoU After testing ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against a collection of 233 multidrug-resistant (MDR) Pseudomonas aeruginosa, we showed that cefiderocol is the most active antipseudomonal β-lactam agent (susceptibility rates were 46.6%, 48.4%, and 97.4%, respectively). The most prevalent one was sequence type 235 (ST235) (24.7%), followed by ST244, ST175, and ST233, with all belonging to the top 10 P. aeruginosa high-risk clones with worldwide distribution. Our data indicate that during surveillance studies special attention should be paid to the MDR and highly virulent VIM- and ExoU-producing variant of ST235. Furthermore, in the case of infections caused by carbapenemase-producing MDR P. aeruginosa, cefiderocol is the preferred treatment option, while outcomes of complicated urinary tract infections and hospital-acquired pneumonia with cefiderocol were favorable.bla VIM ). More than half of the isolates belong to the so-called international P. aeruginosa "high-risk" clones, with sequence type 235 (ST235) (24.7%) being the most prevalent. This study underlines that ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol are important options for the treatment of infections due to MDR P. aeruginosa, with cefiderocol currently being the most active available antipseudomonal β-lactam agent. According to our clinical experience, the outcome of cefiderocol therapy (8 patients) was favorable especially in cases of MDR P. aeruginosa-associated complicated urinary tract infections. IMPORTANCE After testing ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against a collection of 233 multidrug-resistant (MDR) Pseudomonas aeruginosa, we showed that cefiderocol is the most active antipseudomonal β-lactam agent (susceptibility rates were 46.6%, 48.4%, and 97.4%, respectively). The most prevalent one was sequence type 235 (ST235) (24.7%), followed by ST244, ST175, and ST233, with all belonging to the top 10 P. aeruginosa high-risk clones with worldwide distribution. Our data indicate that during surveillance studies special attention should be paid to the MDR and highly virulent VIM- and ExoU-producing variant of ST235. Furthermore, in the case of infections caused by carbapenemase-producing MDR P. aeruginosa, cefiderocol is the preferred treatment option, while outcomes of complicated urinary tract infections and hospital-acquired pneumonia with cefiderocol were favorable.

Objectives: Stenosis of the biliary anastomosis predisposes liver graft recipients to bacterial cholangitis. Antibiotic therapy (AT) is performed according to individual clinical judgment, but duration of AT remains unclear., Methods: All liver graft recipients with acute cholangitis according to the Tokyo criteria grade 1 and 2 after endoscopic retrograde cholangiography (ERC) were included. Outcome of patients treated with short AT (<7 days) was compared to long AT (>6 days). Recurrent cholangitis (RC) within 28 days was the primary end point., Results: In total, 30 patients were included with a median of 313 (range 34-9849) days after liver transplantation until first proven cholangitis. Among 62 cases in total, 51/62 (82%) were graded as Tokyo-1 and 11/62 (18%) as Tokyo-2. Overall median duration of AT was 6 days (1-14) with 36 cases (58%) receiving short AT and 26 (42%) receiving long AT. RC was observed in 10 (16%) cases, without significant difference in occurrence of RC in short versus long AT cases. CRP and bilirubin were significantly higher in patients with long AT, while low serum albumin and low platelets were associated with risk of RC., Conclusion: A shorter antibiotic course than 7 days shows good results in selected, ERC-treated patients for post-transplantation biliary strictures., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Introduction: MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients., Materials and Methods: All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients., Results: 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis., Conclusion: MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents., (© 2021. The Author(s).)

Background & Aims: It remains unclear whether rectal colonization with multidrug-resistant organisms (MDROs) is prevalent and predisposes to infections by the same pathogens in patients with cirrhosis., Methods: Two series of critically ill patients were evaluated. In the Barcelona cohort, 486 consecutive patients were prospectively evaluated, 129 with and 357 without cirrhosis (2015-2016). Rectal swabs were performed at admission and weekly thereafter (until intensive care unit [ICU] discharge) to detect MDRO colonization. Risk factors for colonization and infection by MDROs were evaluated. A retrospective cohort from Frankfurt (421 patients with cirrhosis; 2010-2018) was investigated to evaluate MDRO rectal colonization in another epidemiological scenario., Results: In the Barcelona cohort, 159 patients were colonized by MDROs (32.7%), 102 (64.2%) at admission and 57 (35.8%) during follow-up. Patients with cirrhosis showed higher rates of rectal colonization at admission than those without cirrhosis (28.7% vs. 18.2%, p = 0.01) but similar colonization rates during ICU stay. Extended-spectrum beta-lactamase-Enterobacterales were the most frequent MDROs isolated in both groups. Colonization by MDROs independently increased the risk of infection by MDROs at admission and during follow-up. Risk of new infection by the colonizing strain was also significantly increased in patients with (hazard ratio [HR] 7.41) and without (HR 5.65) cirrhosis. Rectal colonization by MDROs was also highly prevalent in Frankfurt (n = 198; 47%; 131 at admission [66.2%] and 67 [33.8%] during follow-up), with vancomycin-resistant enterococci being the most frequent colonizing organism. Rectal colonization by MDROs was also associated with an increased risk of infection by MDROs in this cohort. Infections occurring in MDR carriers were mainly caused by the colonizing strain., Conclusion: Rectal colonization by MDROs is extremely frequent in critically ill patients with cirrhosis. Colonization increases the risk of infection by the colonizing resistant strain., Lay Summary: Rectal colonization by multidrug-resistant organisms (MDROs) is a prevalent problem in patients with cirrhosis requiring critical care. The pattern of colonizing bacteria is heterogeneous with relevant differences between centers. Colonization by MDROs is associated with increased risk of infection by the colonizing bacteria in the short term. This finding suggests that colonization data could be used to guide empirical antibiotic therapy and de-escalation policies in patients with cirrhosis., Competing Interests: Conflicts of interest Javier Fernandez has received grant and research support from Grifols, speaker honorarium from MSD and educational grant from Pfizer. Jonel Trebicka has received speaking and/or consulting fees from Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Phalloplasty is a crucial part of female-to-male genital gender-affirming surgery, however, up to date, there is still no standardized phalloplasty technique., Aim: To evaluate the outcome of a single-center series of phalloplasties using the free radial forearm flap variations by Chang and Hwang vs by Gottlieb and Levine on a similar number of transgender patients., Methods: Between 2018 and 2020, 45 female to male transgender patients underwent phalloplasty using a neuro-microvascular free radial forearm flap in our department. Twenty patients underwent phalloplasty by the use of the Chang and Hwang design, whereas 25 patients were subjects to a phalloplasty according to Gottlieb and Levine technique. Patients' demographics, procedural characteristics, postoperative complications, and outcome of both groups were retrospectively evaluated and compared with each other., Results: Patients' demographics were similar in both groups. We did not observe relevant differences concerning postoperative complications comparing the two groups, except for the statistically significant lower rate of partial flap necrosis in the Gottlieb and Levine group. No statistically significant risk factors for an increase in complication rate could be identified. Urethral fistulas were the leading cause of revision., Clinical Implication: Optimizing a phalloplasty surgical technique and contributing to establish the gold standard in phalloplasty., Strengths & Limitation: This retrospective study presents the first comparison between the free radial forearm flap phalloplasty by Chang and Hwang and by Gottlieb and Levine performed at the same department on a similar number of transgender patients published so far., Conclusion: The Chang and Hwang design is associated with a lower rate of urologic complications (fistulas, stenosis) while the Gottlieb and Levine design has a statistically significant lower incidence of partial flap necrosis. Future prospective trials are needed to establish the gold standard in phalloplasty. Spennato S, Ederer IA., Borisov K et al. Radial Forearm Free Flap Phalloplasty in Female-to-Male Transsexuals - A Comparison Between Gottlieb and Levine's and Chang and Hwang's Technique. J Sex Med 2022;19:661-668., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

The paramedian forehead flap is considered the gold standard for nasal reconstruction following oncologic surgery. During the 21-day delay in two-stage surgery protocols, many patients report considerably reduced quality of life because of the pedicle. This prospective case series study examined the usefulness of near-infrared (NIR) fluorescence with indocyanine green (ICG) for flap perfusion assessment and identified variables associated with time to flap perfusion. Ten patients (mean age 75.3 ± 11.6 years) with diagnosis of basal cell carcinoma (n = 9) or squamous cell carcinoma (n = 1) underwent intravenous indocyanine injection and NIR fluorescence imaging for assessment of flap vascularisation 2 to 3 weeks after stage 1 surgery. NIR fluorescence imaging showed 90% to 100% perfusion areas in all patients after 14 to 21 days. Early pedicle division occurred in two patients on postoperative days 14 and 16. One minor complication (wound healing disorder) was seen following flap takedown after 14 days. There were no associations between time to flap perfusion and defect size or flap area. NIR fluorescence imaging with ICG dye is a useful method for non-invasive perfusion assessment when used in conjunction with clinical assessment criteria. However, a decision for early pedicle division may raise risk of complications in specific patient groups and must therefore be made with great care., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes. Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts. Results: Carbapenem-resistant (CR) Klebsiella pneumoniae ( n =9) and CR Pseudomonas aeruginosa ( n =7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN. Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schultze, Ferstl, Villinger, Hogardt, Bechstein, Göttig, Wichelhaus, Zeuzem, Trebicka, Waidmann, Welker and Kempf.)

Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset., Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask., Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0 dB HL, p < 0.001) and speech recognition scores in quiet (100.0 ± 0.0% vs. 2.5 ± 4.2%, p < 0.001; OLSA: 20.8 ± 1.8 dB vs. 61.0 ± 3.3 dB SPL, p < 0.001) when compared to hearing without PAPR. Hearing with PAPR was significantly improved when the subjects were equipped with an in-ear headset (p < 0.001). Sound attenuation by FFP3 respirators and surgical face masks had no clinically relevant impact on speech perception., Conclusions: The PAPR system evaluated here can be considered for high-risk procedures in SARS-CoV-2-positive patients, provided that hearing and communication of the surgical team are optimized by the additional use of a headset., (© 2021. The Author(s).)

Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW)., Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed., Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9)., Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently "routine cases", is highly recommended., (© 2021. The Author(s).)

Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.

OXA-48-like carbapenemases are among the most frequent carbapenemases in Gram-negative Enterobacterales worldwide with the highest prevalence in the Middle East, North Africa and Europe. Here, we investigated the so far uncharacterized carbapenemase OXA-484 from a clinical E. coli isolate belonging to the high-risk clone ST410 regarding antibiotic resistance pattern, horizontal gene transfer (HGT) and genetic support. OXA-484 differs by the amino acid substitution 214G compared to the most closely related variants OXA-181 (214R) and OXA-232 (214S). The bla OXA . Intraspecies and intergenus HGT of pOXA-484 to different recipients occurred at low frequencies of 1.4 × 10 - 484 . OXA-484 increased MICs of temocillin and carbapenems similar to OXA-232 and OXA-244, but lower compared with OXA-48 and OXA-181. Hence, OXA-484 combines properties of OXA-181-like plasmid support and transferability as well as β-lactamase activity of OXA-232.bla OXA - 181 . Intraspecies and intergenus HGT of pOXA-484 to different recipients occurred at low frequencies of 1.4 × 10 -7 to 2.1 × 10 -6 . OXA-484 increased MICs of temocillin and carbapenems similar to OXA-232 and OXA-244, but lower compared with OXA-48 and OXA-181. Hence, OXA-484 combines properties of OXA-181-like plasmid support and transferability as well as β-lactamase activity of OXA-232., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sommer, Gerbracht, Krause, Wild, Tietgen, Riedel-Christ, Sattler, Hamprecht, Kempf and Göttig.)

Objectives: This study analysed the novel carbapenem-hydrolysing class D β-lactamase OXA-822 identified in the clinical Acinetobacter calcoaceticus isolate AC&#95;2117., Methods: WGS was employed for identification of β-lactamases. Micro-broth dilution was used for evaluation of antibiotic susceptibility of AC&#95;2117 and transformants containing blaOXA-822. After heterologous purification of OXA-822, OXA-359 and OXA-213, enzyme kinetics were determined using spectrometry. The effect of OXA-822 upon meropenem treatment was analysed in the Galleria mellonella in vivo infection model., Results: OXA-822 is a member of the intrinsic OXA-213-like family found in A. calcoaceticus and Acinetobacter pittii. Amino acid sequence similarity to the nearest related OXA-359 was 97%. Production of OXA-822, OXA-359 and OXA-213 in Acinetobacter baumannii ATCC® 19606T resulted in elevated MICs for carbapenems (up to 16-fold). Penicillinase activity of the purified OXA-822 revealed high KM values, in the millimolar range, combined with high turnover numbers. OXA-822 showed the highest affinity to carbapenems, but affinity to imipenem was ∼10-fold lower compared with other carbapenems. Molecular modelling revealed that imipenem does not interact with a negatively charged side chain of OXA-822, as doripenem does, leading to the lower affinity. Presence of OXA-822 decreased survival of infected Galleria mellonella larvae after treatment with meropenem. Only 52.7% ± 7.7% of the larvae survived after 24 h compared with 90.9% ± 3.7% survival in the control group., Conclusions: The novel OXA-822 from a clinical A. calcoaceticus isolate displayed penicillinase and carbapenemase activity in vitro, elevated MICs in different species and decreased carbapenem susceptibility in A. baumannii in vivo., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Vancomycin-resistant E. faecium (VRE) is a common cause of healthcare-associated infections. The emergence of VRE with tigecycline resistance (TVRE) is increasing but its impact on patient outcome is still not well defined. This study aimed to assess risk factors for the acquisition of TVRE and of patient outcomes associated with TVRE carriage/infection., Methods: At the University Hospital Frankfurt, we conducted a matched pair TVRE-VRE analysis to identify risk factors for TVRE carriage. Bed-to-bed contacts and potential transmission routes were reconstructed. TVRE were whole-genome sequenced to confirm suspected transmission events and to identify tigecycline resistance mechanisms., Results: 76 TVRE cases were identified between 02/2014-04/2017 and compared to VRE colonized or infected controls. TVRE carriage was associated with exposure to tigecycline, an increased rate of bloodstream infections (BSI) with VRE or Candida spp., and higher mortality. Whole-genome sequencing-based analysis of 24 TVRE provided evidence for transmissions of TVRE, also across different wards., Conclusions: Tigecycline exposure is the main risk factor for TVRE carriage. VRE/TVRE- and Candida-BSI are associated with worse clinical outcome. Hospital transmission of TVRE may occur despite strict contact precautions, whereas both antimicrobial stewardship and infection control interventions are of high importance to prevent emergence and spread of TVRE., Competing Interests: Declaration of Competing Interest The authors declare that they have authors must disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. The detailed COI disclosure statement of each author is given below: Dr. Kessel reports grants from Basilea, grants from Correvio, outside the submitted work. Dr. Bender has nothing to disclose. Prof. Dr. Werner has nothing to disclose. Mr. Griskaitis has nothing to disclose. Prof. Dr. Herrmann has nothing to disclose. Mrs. Lehn has nothing to disclose. Prof. Dr. Serve has nothing to disclose. Prof. Dr. Dr. Zacharowski reports grants from AbbVie Deutschland GmbH & Co. KG, grants from B. Braun Melsungen AG, grants from MSD Sharp & Dohme GmbH, grants from Orion Pharma GmbH, grants from Fresenius Kabi Deutschland GmbH, outside the submitted work. Prof. Dr. Zeuzem reports Honoraria for lectures and consultancies: Abbvie, Gilead, Intercept, Janssen, Merck. Prof. Dr. Vehreschild has served at the speakers' bureau of Akademie für Infektionsmedizin, Ärztekammer Nordrhein, Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance and Pfizer, received research funding from 3 M, Evoinik, Glycom, Astellas Pharma, DaVolterra, Gilead Sciences, MaaT Pharma, Merck/MSD, Morphochem, Organobalance, Seres Therapeutics and is a consultant to Alb-Fils Kliniken GmbH, Arderypharm, Astellas Pharma, Ferring, DaVolterra, MaaT Pharma and Merck/MSD. Prof. Dr. Wichelhaus has nothing to disclose. Prof. Dr. Kempf has nothing to disclose. Dr. Hogardt reports grants from Gilead Sciences, the German Cystic Fibrosis Foundation, the Krimser Foundation and honoraria for lectures and consultancies from Chiesi GmbH, and Thieme Publisher Group, outside the submitted work., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail., Methods: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list., Results: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0-1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died., Conclusions: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients., Competing Interests: Philip G. Ferstl, Consultancies: SNIPR Biome. Wolf O. Bechstein: Consultancies/speaker fees: Astellas, Chiesi, Gore Deutschland, Medupdate GmbH, MCI, MCN, Novartis. Michael Hogardt, Grants: Gilead, Kirmser Foundation, German CF Foundation; Speaker’s fees: Thieme Science, Chiesi GmbH. Haitham Mutlak, Speaker’s fees: Orion Pharma, Löwenstein Medical, Pfizer, Getinge. Christoph Stephan, Speaker’s fees: AbbVie, LÄK-Hessen, Gilead, Hexal, Janssen, MSD, Pfizer, Roche, TAD, ViiV; Consultancies: AbbVie, Gilead, Janssen, MSD, ViiV. Nina Weiler, Consultancy: Astellas and Novartis, Travel support: AbbVie, Astellas, Biotest, and Novartis. Jonel Trebicka, Speaker’s fees and/or consultancies: Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical. Stefan Zeuzem: Speaker’s fees: Abbvie, Gilead, Merck/MSD, Consultancy: Abbvie, Gilead, Intercept, Janssen. Oliver Waidmann, Consultancies: Amgen, Bayer, BMS, Celgene, Eisai, Incyte, Ipsen, Merck Serono, MSD, Novartis, Roche, Servier, Shire; Speaker’s fees: Bayer, BMS, Celgene, Eisai, Ipsen, Novartis, Roche, Shire; Travel support: Abbvie, Bayer, BMS, Gilead, Ipsen, Merck; Grants: Basilea, Incyte, Else Kröner-Fresenius-Stiftung, Medac, Merck Serono, MSD. Martin-Walter Welker, Consultancies / speaker’s fees: AbbVie, Amgen, Bayer, Chiesis, BMS, Gilead, Novartis, Roche; Travel Support: AbbVie, Astellas, Bayer, BMS, Novartis, Janssen, Roche. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Wound-healing disorders are common complications in bilateral reduction mammaplasty. Traditional electrosurgical devices generate large amounts of thermal energy, often causing extensive thermal-related collateral tissue damage. This study aimed to retrospectively analyse the operative performance of a novel low-thermal plasma dissection device (pulsed electron avalanche knife-PEAK PlasmaBlade™) compared with traditional electrosurgery. Twenty patients with breast hypertrophy were randomly treated with PEAK PlasmaBlade™ on one breast and conventional electrosurgery on the other. Primary outcome measures were resection weight, drain duration, total drainage volume, and drain output on the first postoperative day. Breasts treated with PEAK PlasmaBlade™ had significantly higher resection weights (728.0 ± 460.1 g vs 661.6 ± 463.4 g; P = .038), significantly lower drain output on the first postoperative day (15.9 ± 15.2 mL vs 27.6 ± 23.5 mL; P = .023), and significantly lower drain durations (2.8 ± 1.0 days vs 3.3 ± 1.0 days; P = .030). Mean total drainage volume was lower where breast reduction was performed with PEAK PlasmaBlade™, but this difference was not significant. No major complications occurred, but wound-healing disorders were documented in almost one-third of the patients (35.0%, n = 7). The PEAK PlasmaBlade™ seems to be superior to conventional electrosurgery for bilateral reduction mammaplasty in terms of tissue damage and wound healing., (© 2020 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections., Materials and Methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study., Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0-19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6-30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002)., Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JS reports personal fees from Bristol-Myers & Squibb, personal fees from Novartis, personal fees from Roche, outside the submitted work. RL has nothing to disclose. OB has nothing to disclose. SS has nothing to disclose. WG has nothing to disclose. MJGTV has served at the speakers’ bureau of Akademie für Infektionsmedizin, Ärztekammer Nordrhein, Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and Uniklinik Freiburg / Kongress und Kommunikation, received research funding from 3M, Astellas Pharma, DaVolterra, Gilead Sciences, MaaT Pharma, Merck/MSD, Morphochem, Organobalance, Seres Therapeutics, and is a consultant to Alb-Fils Kliniken GmbH, Ardeypharm, Astellas Pharma, Berlin Chemie, DaVolterra, Ferring, MaaT Pharma and Merck/MSD. TW has nothing to disclose. CR has nothing to disclose. SG has nothing to disclose. VK reports grants and personal fees from DFG Germany (DFG FG 2251), grants and personal fees from EU Marie Sklodowska-Curie (#765042), during the conduct of the study. PK has nothing to disclose. SS has nothing to disclose. CB has nothing to disclose. MSe reports personal fees from Lilly, personal fees from Astra-Zeneca, personal fees from Bristol-Myers & Squibb, personal fees from Merck Sharp & Dohme, personal fees from Pfizer, personal fees from Takeda, personal fees from Roche, personal fees from AbbVie, personal fees from Boehringer Ingelheim, personal fees from Celgene, personal fees from Novartis, outside the submitted work. SK has nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.