A microbiological and genomic perspective of globally collected Escherichia coli from adults hospitalized with invasive E. coli disease.

OBJECTIVES: Escherichia coli can cause infections in the urinary tract and in normally sterile body sites leading to invasive E. coli disease (IED), including bacteraemia and sepsis, with older populations at increased risk. We aimed to estimate the theoretical coverage rate by the ExPEC4V and 9V vaccine candidates. In addition, we aimed at better understanding the diversity of E. coli isolates, including their genetic and phenotypic antimicrobial resistance (AMR), sequence types (STs), O-serotypes and the bacterial population structure. METHODS: Blood and urine culture E. coli isolates (n = 304) were collected from hospitalized patients ≥60 years (n = 238) with IED during a multicentric, observational study across three continents. All isolates were tested for antimicrobial susceptibility, O-serotyped, whole-genome sequenced and bioinformatically analysed. RESULTS: A large diversity of STs and of O-serotypes were identified across all centres, with O25b-ST131, O6-ST73 and O1-ST95 being the most prevalent types. A total of 45.4% and 64.7% of all isolates were found to have an O-serotype covered by the ExPEC4V and ExPEC9V vaccine candidates, respectively. The overall frequency of MDR was 37.4% and ST131 was predominant among MDR isolates. Low in-patient genetic variability was observed in cases where multiple isolates were collected from the same patient. CONCLUSIONS: Our results highlight the predominance of MDR O25b-ST131 E. coli isolates across diverse geographic areas. These findings provide further baseline data on the theoretical coverage of novel vaccines targeting E. coli associated with IED in older adults and their associated AMR levels.

Clinical presentation and antimicrobial resistance of invasive Escherichia coli disease in hospitalized older adults: a prospective multinational observational study.

BACKGROUND: Clinical data characterizing invasive Escherichia coli disease (IED) are limited. We assessed the clinical presentation of IED and antimicrobial resistance (AMR) patterns of causative E. coli isolates in older adults. METHODS: EXPECT-2 (NCT04117113) was a prospective, observational, multinational, hospital-based study conducted in patients with IED aged ≥ 60 years. IED was determined by the microbiological confirmation of E. coli from blood; or by the microbiological confirmation of E. coli from urine or an otherwise sterile body site in the presence of requisite criteria of systemic inflammatory response syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick SOFA (qSOFA). The primary outcomes were the clinical presentation of IED and AMR rates of E. coli isolates to clinically relevant antibiotics. Complications and in-hospital mortality were assessed through 28 days following IED diagnosis. RESULTS: Of 240 enrolled patients, 80.4% had bacteremic and 19.6% had non-bacteremic IED. One-half of infections (50.4%) were community-acquired. The most common source of infection was the urinary tract (62.9%). Of 240 patients, 65.8% fulfilled ≥ 2 SIRS criteria, and 60.4% had a total SOFA score of ≥ 2. Investigator-diagnosed sepsis and septic shock were reported in 72.1% and 10.0% of patients, respectively. The most common complication was kidney dysfunction (12.9%). The overall in-hospital mortality was 4.6%. Of 299 E. coli isolates tested, the resistance rates were: 30.4% for trimethoprim-sulfamethoxazole, 24.1% for ciprofloxacin, 22.1% for levofloxacin, 16.4% for ceftriaxone, 5.7% for cefepime, and 4.3% for ceftazidime. CONCLUSIONS: The clinical profile of identified IED cases was characterized by high rates of sepsis. IED was associated with high rates of AMR to clinically relevant antibiotics. The identification of IED can be optimized by using a combination of clinical criteria (SIRS, SOFA, or qSOFA) and culture results.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

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.

Clostridioides difficile infection (CDI): A pan-European multi-center cost and resource utilization study, results from the Combatting Bacterial Resistance in Europe CDI (COMBACTE-CDI).

OBJECTIVES: Clostridioides difficile infection (CDI) is one of the leading nosocomial infections worldwide, resulting in a significantly increasing burden on the healthcare systems. However, Pan-European data about cost and resource utilization of CDI treatment do not exist. METHODS: A retrospective analysis within the Combatting Bacterial Resistance in Europe CDI project was conducted based on resource costs for inpatient treatment and productivity costs. Country-specific cost values were converted to EURO referred to 1 January, 2019 values. Differences in price levels for healthcare services among the participating countries were adjusted by using an international approach of the Organisation for Economic Co-operation and Development. As the study focused on patients with recurrent CDI, the observed study population was categorized into (a) patients with CDI but without CDI recurrence (case group), (b) patients with CDI recurrence (recurrence group), and (c) patients without CDI (control group). RESULTS: Overall, 430 hospitalized patients from 12 European countries were included into the analysis between July 2018 and November 2018. Distribution of mean hospital length of stay and mean overall costs per patient between the case group, recurrence group, and control group were as follows: 22 days (95% CI 17-27 days) vs. 55 days (95% CI 17-94 days) vs. 26 days (95% CI 22-31 days; p 0.008) and € 15 242 (95% CI 10 593-19 891) vs. € 52 024 (95% CI 715-103 334) vs. € 21 759 (95% CI 16 484-27 035; p 0.010), respectively. The CDI recurrence rate during the observational period was 18%. Change escalation in CDI medication (OR 3.735) and treatment in an intensive care unit (OR 5.454) were found to be the most important variables associated with increased overall costs of patients with CDI. CONCLUSIONS: Treatment of patients with recurrent CDI results in a significant burden. Prevention of CDI recurrences should be in focus of daily patient care to identify the most cost-effective treatment strategy.

Postoperative Staphylococcus aureus Infections in Patients With and Without Preoperative Colonization.

Importance: Staphylococcus aureus surgical site infections (SSIs) and bloodstream infections (BSIs) are important complications of surgical procedures for which prevention remains suboptimal. Contemporary data on the incidence of and etiologic factors for these infections are needed to support the development of improved preventive strategies. Objectives: To assess the occurrence of postoperative S aureus SSIs and BSIs and quantify its association with patient-related and contextual factors. Design, Setting, and Participants: This multicenter cohort study assessed surgical patients at 33 hospitals in 10 European countries who were recruited between December 16, 2016, and September 30, 2019 (follow-up through December 30, 2019). Enrolled patients were actively followed up for up to 90 days after surgery to assess the occurrence of S aureus SSIs and BSIs. Data analysis was performed between November 20, 2020, and April 21, 2022. All patients were 18 years or older and had undergone 11 different types of surgical procedures. They were screened for S aureus colonization in the nose, throat, and perineum within 30 days before surgery (source population). Both S aureus carriers and noncarriers were subsequently enrolled in a 2:1 ratio. Exposure: Preoperative S aureus colonization. Main Outcomes and Measures: The main outcome was cumulative incidence of S aureus SSIs and BSIs estimated for the source population, using weighted incidence calculation. The independent association of candidate variables was estimated using multivariable Cox proportional hazards regression models. Results: In total, 5004 patients (median [IQR] age, 66 [56-72] years; 2510 [50.2%] female) were enrolled in the study cohort; 3369 (67.3%) were S aureus carriers. One hundred patients developed S aureus SSIs or BSIs within 90 days after surgery. The weighted cumulative incidence of S aureus SSIs or BSIs was 2.55% (95% CI, 2.05%-3.12%) for carriers and 0.52% (95% CI, 0.22%-0.91%) for noncarriers. Preoperative S aureus colonization (adjusted hazard ratio [AHR], 4.38; 95% CI, 2.19-8.76), having nonremovable implants (AHR, 2.00; 95% CI, 1.15-3.49), undergoing mastectomy (AHR, 5.13; 95% CI, 1.87-14.08) or neurosurgery (AHR, 2.47; 95% CI, 1.09-5.61) (compared with orthopedic surgery), and body mass index (AHR, 1.05; 95% CI, 1.01-1.08 per unit increase) were independently associated with S aureus SSIs and BSIs. Conclusions and Relevance: In this cohort study of surgical patients, S aureus carriage was associated with an increased risk of developing S aureus SSIs and BSIs. Both modifiable and nonmodifiable etiologic factors were associated with this risk and should be addressed in those at increased S aureus SSI and BSI risk.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

COMBACTE LAB-Net: building a European laboratory network for clinical trials on anti-infectives.

LAB-Net, the laboratory network of COMBACTE, has established itself as an indispensable network for clinical trials in infectious diseases that plays a crucial part across 30 clinical studies not only within, but also outside the COMBACTE consortium. Since its official launch in January 2013, LAB-Net has expanded more than threefold and in Q4 2020 it encompasses 841 labs across 41 countries in Europe. In addition, LAB-Net has crossed the European borders and collaborates with more than 300 laboratories spread across the globe. The tight collaboration with partners within COMBACTE and beyond contributed tremendously to the growth of LAB-Net over the years. A sustainable infrastructure beyond COMBACTE-NET is needed to ensure the smooth handover and continuity of the achievements made by the project.

Preparedness of European diagnostic microbiology labs for detection of SARS-CoV-2, March 2020.

BACKGROUND: To track the European spread of SARS-CoV-2, decentralized testing became necessary and test capacity needed to be expanded outside reference laboratories rapidly. METHODS: We assessed via an online questionnaire the preparedness of European hospital laboratories for detection of SARS-CoV-2 and listed the main drawbacks for implementation. RESULTS: Forty-five percent of the surveyed labs had a test in place by March 26th which is well into the first wave of the pandemic in most countries. CONCLUSIONS: The main implementation barriers for introduction of a SARSCoV-2 molecular assay in European diagnostic laboratories were availability of positive controls and a specificity panel.

Antimicrobial resistance rates in gram-positive bacteria do not drive glycopeptides use.

Surveillance data are considered essential to appropriate empiric antibiotic therapy and stewardship. The objective of this study was to determine if a change in the rates of antibiotic resistance impacts antibiotic use in European hospitals. Glycopeptides use was selected to study the correlation between resistance rates and antibiotic use because of the restricted spectrum against resistant gram positive bacteria. PubMed, ECDC databases and national/regional surveillance systems were searched to identify glycopeptides´ consumption in defined daily dose per 1000 inhabitant-days (DID) and rate of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE) in bloodstream infections (BSIs) in European countries between 1997 and 2015. Time trends were studied and associations between DID and BSI resistance rates were tested using multi-level mixed effect models. To account for the gap in the publication and dissemination of the yearly resistance data, a 2-year lag in the resistance rates was applied. Data on glycopeptides´ DID and resistance rates of target microorganisms in blood cultures were identified among 31 countries over a 19-year period. Glycopeptides use significantly increased (p<0·0001) while rates of MRSA BSIs decreased in majority of the countries (p<0·0001) and MRCoNS and VRE BSIs remained stable. Variation in glycopeptides' DID was not associated with variation in BSIs due to MRSA (p = 0·136) and VRE (p = 0·613). After adjusting for MRCoNS and VRE resistance rates, among 21 countries, 11 (52%) had a concordant and 10 (48%) a discordant trend in yearly glycopeptides´ DID and MRSA BSI rates. No correlation was found between resistance rates and DID data even among 8 countries with more than 5% decrease in MRSA rates over time. (RC -0·009, p = 0·059). Resistance rate of MRSA, MRCoNS, and VRE BSIs does not impact DID of glycopeptides in European hospitals. This finding is key to redefining the role and structure of antimicrobial surveillance and stewardship programmes.