Treatment of infections caused by multi-drug-resistant Gram-negative bacilli: A practical approach by the Italian (SIMIT) and French (SPILF) Societies of Infectious Diseases.

INTRODUCTION: The emergence of multi-drug-resistant Gram-negative bacilli and the development of new antibiotics have complicated the selection of optimal regimens. International guidelines are valuable tools, but are limited by the scarcity of high-quality randomized trials in many situations. METHODS: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, an updated literature review and open discussions. RESULTS: The panel reached consensus for the following 'first choices': (i) cefepime for ventilator-acquired pneumonia due to AmpC ß-lactamase-producing Enterobacterales; (ii) the ß-lactam/ß-lactamase inhibitor combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; (iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion) for complicated urinary tract infections (cUTIs) caused by extended-spectrum ß-lactamase-producing Enterobacterales with piperacillin-tazobactam minimum inhibitory concentration (MIC) ≤8 mg/L; (iv) high-dose cefepime for cUTIs due to AmpC ß-lactamase-producing Enterobacterales other than Enterobacter spp. if cefepime MIC ≤2 mg/L; (v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to third-generation cephalosporin-resistant Enterobacterales; (vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo-ß-lactamase-producing Enterobacterales; (vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii; (viii) meropenem-vaborbactam for BSIs caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales; and (ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa. CONCLUSIONS: These expert choices were based on the necessary balance between antimicrobial stewardship principles and the need to provide optimal treatment for individual patients in each situation.

18F-FDG-Based Radiomics and Machine Learning: Useful Help for Aortic Prosthetic Valve Infective Endocarditis Diagnosis?

BACKGROUND: Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) results in better sensitivity for prosthetic valve endocarditis (PVE) diagnosis, but visual image analysis results in relatively weak specificity and significant interobserver variability. OBJECTIVES: The primary objective of this study was to evaluate the performance of a radiomics and machine learning-based analysis of 18F-FDG PET/CT (PET-ML) as a major criterion for the European Society of Cardiology score using machine learning as a major imaging criterion (ESC-ML) in PVE diagnosis. The secondary objective was to assess performance of PET-ML as a standalone examination. METHODS: All 18F-FDG-PET/CT scans performed for suspected aortic PVE at a single center from 2015 to 2021 were retrospectively included. The gold standard was expert consensus after at least 3 months' follow-up. The machine learning (ML) method consisted of manually segmenting each prosthetic valve, extracting 31 radiomics features from the segmented region, and training a ridge logistic regressor to predict PVE. Training and hyperparameter tuning were done with a cross-validation approach, followed by an evaluation on an independent test database. RESULTS: A total of 108 patients were included, regardless of myocardial uptake, and were divided into training (n = 68) and test (n = 40) cohorts. Considering the latter, PET-ML findings were positive for 13 of 22 definite PVE cases and 3 of 18 rejected PVE cases (59% sensitivity, 83% specificity), thus leading to an ESC-ML sensitivity of 72% and a specificity of 83%. CONCLUSIONS: The use of ML for analyzing 18F-FDG-PET/CT images in PVE diagnosis was feasible and beneficial, particularly when ML was included in the ESC 2015 criteria. Despite some limitations and the need for future developments, this approach seems promising to optimize the role of 18F-FDG PET/CT in PVE diagnosis.

Expert consensus on monitoring antimicrobial stewardship in French nursing homes using assessed reimbursement database indicators.

Objectives: Monitoring the appropriateness of antibiotic prescriptions with indicators based on reimbursement data is required to guide antibiotic stewardship (AMS) interventions in nursing homes (NHs). Quantity metrics (QMs) monitor the volume of prescriptions while proxy indicators (PIs) reflect the appropriateness of antibiotic use. Our objectives were: (i) to provide a relevant consensual set of indicators to be used in French NHs; and (ii) to assess the feasibility of their implementation at the national and local scale. Methods: Nine French professional organizations implicated in AMS in NHs were asked to nominate at least one member to create a national expert panel of 20 physicians. Twenty-one recently published QMs and 11 PIs were assessed by the expert panel. Indicators were evaluated using a RAND-modified Delphi procedure comprising two online surveys and a videoconference meeting. Indicators were kept in the final list if >70% of stakeholders validated their relevance for estimating the volume (QMs) and appropriateness (PIs) of prescriptions. Results: Of the 21 QM indicators submitted to the panel, 14 were selected, describing the consumption of antibiotics overall (n = 3), broad-spectrum (n = 6) and second-line antibiotics (n = 2). The three remaining QMs evaluated the route of administration (n = 1) and urine culture prescriptions (n = 2). Ten PIs (six modified, two rejected, one new) were selected to assess the appropriateness of prescriptions for urinary tract infections (n = 2), seasonal variations in prescriptions (n = 2), repeated prescriptions of fluoroquinolones (n = 1), cephalosporins' route of administration (n = 1), duration of treatment (n = 1), rate of second-line antibiotics (n = 1), co-prescriptions with non-steroidal anti-inflammatory drugs (n = 1), and flu vaccine coverage (n = 1). The panel was in favour of using these indicators for regional and facility level AMS programmes (91%), feedback to NH prescribers (82%), benchmarking by health authorities (55%) and public reporting at the facility level (9%). Conclusions: This consensual list of indicators, covering a wide range of frequent clinical situations, may be used as part of the French national AMS strategy for monitoring antibiotic prescriptions in NHs at the national and local levels. Regional AMS networks might manage this selected list to guide personalized action plans with concrete objectives of reducing the quantity and improving the quality of antibiotic prescriptions.

Qualitative assessment of the national initiative to implement antimicrobial stewardship centres in French administrative regions.

BACKGROUND: In May 2020, the French Ministry of Health funded the creation of regional antimicrobial stewardship (AMS) coordination centres (CRAtb) in preparation for the new national framework for the prevention of antimicrobial resistance. This study aimed to assess through qualitative methods the implementation process, the activities carried out, and the interactions with other regional stakeholders of the newly created CRAtb. METHODS: We conducted a mixed-method study based on a cross-sectional survey and semi-structured interviews by French regions among implemented CRAtb. Of the eight eligible French regions with an existing CRAtb, seven participated to the online survey. Regional partners involved in AMS from the eight regions were interviewed between September 2021 and April 2022. The survey questionnaire addressed, through closed questions, the organization of the CRAtb, articulation with other regional actors involved in AMS and infection prevention and control (IPC), and AMS activities. The semi-structured interviews approached the implementation and the role of CRAtb, and the collaboration of other AMS and IPC stakeholders. Interview transcripts were analysed using thematic content analysis methodology. RESULTS: AMS activities carried out by CRAtb were mainly focusing on hospitals (n = 3), primary care (n = 2) and nursing homes (n = 1). Education mostly relied on training days and AMS help lines, communication on websites and newsletters. CRAtb members reported still being more engaged in providing advice to professionals for individual antibiotic treatments rather than collective-level AMS activities. Interactions were frequent between CRAtb, IPC regional centres and health authorities, but rarely involved other stakeholders. Interviews were performed with 28 professionals involved in AMS from eight regions. Pre-existing networks and working relationships in AMS and more broadly facilitated the implementation of CRAtb. Streamlining and decompartmentalizing IPC and AMS regional activities were considered a way to optimise the prevention of antimicrobial resistance across sectors. The engagement with liberal health professionals was identified as a significant obstacle for CRAtb. CONCLUSIONS: Two years after the launch of a new national framework, the implementation of CRAtb appeared complex in most regions. An integrative model joining IPC and AMS efforts, relying on existing networks, with engagement from liberal health profession organisations may be the next pivotal step.

Assessment of Factors Associated With Community-Acquired Extended-Spectrum ß-Lactamase-Producing Escherichia coli Urinary Tract Infections in France.

Importance: Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli is considered a leading pathogen contributing to the global burden of antimicrobial resistance. Objective: To better understand factors associated with the heterogeneity of community-acquired ESBL-producing E coli urinary tract infections (UTIs) in France. Design, Setting, and Participants: This cross-sectional study performed from January 1 to December 31, 2021, was based on data collected via PRIMO (Surveillance and Prevention of Antimicrobial Resistance in Primary Care and Nursing Homes), a nationwide clinical laboratory surveillance system in France. Strains of E coli isolated from community urine samples from January 1 to December 31, 2019, from 59 administrative departments of metropolitan France were included. Main Outcomes and Measures: Quasi-Poisson regression models were used to assess the associations between several ecological factors available on government and administration websites between 2010 and 2020 (demographic population structure, living conditions, baseline health care services, antibiotic consumptions, economic indicators, animal farming density, and environmental characteristics) and the number of ESBL-producing E coli strains isolated from urine samples of individuals with community-acquired UTI in 2019. Results: Among 444 281 E coli isolates from urine samples tested in 1013 laboratories, the mean prevalence of ESBL-producing E coli was 3.0% (range, 1.4%-8.8%). In an adjusted model, the number of community-acquired ESBL-producing E coli UTIs in each department was positively associated with the percentage of children younger than 5 years (adjusted ß1 coefficient, 0.112 [95% CI, 0.040-0.185]; P = .004), overcrowded households (adjusted ß1 coefficient, 0.049 [95% CI, 0.034 to 0.062]; P < .001), consumption of fluoroquinolones (adjusted ß1 coefficient, 0.002 [95% CI, 0.001-0.002]; P < .001), and tetracyclines (adjusted ß1 coefficient, 0.0002 [0.00004 to 0.00039]; P = .02), and poultry density (adjusted ß1 coefficient, 0.0001 [95% CI, 0.0001-0.0002]; P < .001). The social deprivation index (adjusted ß1 coefficient, -0.115 [95% CI, -0.165 to -0.064]; P < .001) and the proportion of water surface area (adjusted ß1 coefficient, -0.052 [-0.081 to -0.024]; P = .001) were negatively associated with a higher number of community-acquired ESBL-producing E coli UTIs. Conclusions and Relevance: The findings of this cross-sectional study suggest that multiple human health, animal health, and environmental factors are associated with the occurence of community-acquired ESBL E coli UTI. Strategies to mitigate ESBL in the community should follow the One Health approach and address the role played by fluoroquinolones, tetracycline use, poultry density, overcrowded households, and preschool-aged children.

Cochleovestibular involvement in patients with Fabry disease: data from the multicenter cohort FFABRY.

PURPOSE: Fabry disease (FD) is a lysosomal storage disease responsible for cochleovestibular involvement. Exact prevalence and pathophysiological mechanisms behind ENT affections are still poorly known. Treating FD with enzyme replacement therapy (ERT) does not seem to significantly improve the ENT symptoms, while the impact of migalastat has yet to be determined. METHODS: We carried out a retrospective multi-centre study on 47 patients from the FFABRY cohort who had an ENT consultation in the context of their FD. The information collected were as follows: clinical examination, videonystagmoscopy, pure-tone speech audiometry, videonystagmography or VHIT (Video Head Impulse Test). Severe hearing loss was defined as greater than 70 dB. RESULTS: The median age of our cohort was 52 years with a non-negligible proportion of non-classic variants and female carriers. 72.3% of the patients complained of at least one of the following symptoms: hearing loss, tinnitus or vertigo. Pure-tone audiometry was abnormal in 61.7% of the patients (29/47), while speech audiometry was abnormal for 41.7% of the patients. The age of the patients and hypertrophic cardiomyopathy were significantly associated with the existence of an anomaly in pure-tone audiometry results. Severe hearing loss (> 70 dB) was significantly more common in male patients. DISCUSSION: Hearing loss is particularly frequent in FD and is not limited to classic phenotypes. Close ENT follow-up is essential for Fabry patients to detect those who might benefit from hearing aid. Further studies are needed to define the impact of migalastat on cochleovestibular symptoms.

Circulating Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Contribute to Sepsis-Induced Immunosuppression in Patients During Septic Shock.

BACKGROUND: Septic shock remains a major cause of death that can be complicated by long-term impairment in immune function. Among regulatory T (Treg) cells, the tumor necrosis factor receptor 2 positive (TNFR2pos) Treg-cell subset endorses significant immunosuppressive functions in human tumors and a sepsis mouse model but has not been investigated during septic shock in humans. METHODS: We prospectively enrolled patients with septic shock hospitalized in intensive care units (ICU). We performed immunophenotyping and functional tests of CD4+ T cells, Treg cells, and TNFR2pos Treg cells on blood samples collected 1, 4, and 7 days after admission to ICU. RESULTS: We investigated 10 patients with septic shock compared to 10 healthy controls. Although the proportions of circulating Treg cells and TNFR2pos Treg-cell subsets were not increased, their CTLA4 expression and suppressive functions in vitro were increased at 4 days of septic shock. Peripheral blood mononuclear cells from healthy donors cultured with serum from septic shock patients had increased CTLA4 expression in TNFR2pos Treg cells compared to TNFR2neg Treg cells. CONCLUSIONS: In patients with septic shock, CTLA4 expression and suppressive function were increased in circulating TNFR2pos Treg cells. We identify TNFR2pos Treg cells as a potential attractive target for therapeutic intervention.

Switch from parenteral to oral antibiotics for brain abscesses: a retrospective cohort study of 109 patients.

OBJECTIVES: Brain abscess is one of the most serious diseases of the CNS and is associated with high morbidity and mortality. With regard to the lack of data supporting an optimal therapeutic strategy, this study aimed to explore the prognostic factors of brain abscess, putting emphasis on the impact of therapeutic decisions. METHODS: We retrospectively included patients hospitalized for brain abscess during a period of 13 years. Comorbidities (Charlson scale), clinical presentation, microbiology culture, radiological features and therapeutic management were collected. Glasgow Outcome Scale (GOS) at 3 months and length of hospital stay were, respectively, the main and the secondary outcomes. Logistic regression was used to determine factors associated with outcome independently. RESULTS: Initial Glasgow Coma Scale (GCS) ≤14 and comorbidities (Charlson scale ≥2) were associated with poor neurological outcome while oral antibiotic switch was associated with better neurological outcome. Oral switch did not appear to be associated with an unfavourable evolution in the subset of patients without initial neurological severity (GCS >14) on admission. Duration of IV regimen and time to oral switch were associated with the length of inpatient stay. CONCLUSIONS: This study confirms the role of GCS and comorbidities as prognostic factors and presents reassuring data regarding the safety of oral switch for the antibiotic treatment of brain abscesses. Oral switch could prevent catheter-induced iatrogenic complications and allow a higher quality of life for patients.