Predictors of Mortality of Streptococcal Bacteremia and the Role of Infectious Diseases Consultation: A Retrospective Cohort Study.

BACKGROUND: Streptococcal bacteremia is associated with high mortality. Thia study aims to identify predictors of mortality among patients with streptococcal bacteremia. METHODS: This retrospective study was conducted at the Lausanne University Hospital, Switzerland, and included episodes of streptococcal bacteremia among adult patients from 2015 to 2023. RESULTS: During the study period, 861 episodes of streptococcal bacteremia were included. The majority of episodes were categorized in the Mitis group (348 episodes; 40%), followed by the Pyogenic group (215; 25%). Endocarditis was the most common source of bacteremia (164; 19%). The overall 14-day mortality rate was 8% (65 episodes). The results from the Cox multivariable regression model showed that a Charlson comorbidity index >4 (P .001; hazard ratio [HR], 2.87; confidence interval [CI]: 1.58-5.22), Streptococcus pyogenes (P = .011; HR, 2.54;CI: 1.24-5.21), sepsis (P < .001; HR, 7.48; CI: 3.86-14.47), lower respiratory tract infection (P = .002; HR, 2.62; CI: 1.42-4.81), and absence of source control interventions within 48 hours despite being warranted (P = .002; HR, 2.62; CI: 1.43-4.80) were associated with 14-day mortality. Conversely, interventions performed within 48 hours of bacteremia onset, such as infectious diseases consultation (P < .001; HR, 0.29; CI: .17-.48) and appropriate antimicrobial treatment (P < .001; HR, .28; CI: .14-.57), were associated with improved outcome. CONCLUSIONS: Our findings underscore the pivotal role of infectious diseases consultation in guiding antimicrobial treatment and recommending source control interventions for patients with streptococcal bacteremia.

Evaluation of the 2023 Duke-ISCVID and 2023 Duke-ESC Clinical Criteria for the Diagnosis of Infective Endocarditis in a Multicenter Cohort of Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: The Duke criteria for infective endocarditis (IE) diagnosis underwent revisions in 2023 by the European Society of Cardiology (ESC) and the International Society for Cardiovascular Infectious Diseases (ISCVID). This study aims to assess the diagnostic accuracy of these criteria, focusing on patients with Staphylococcus aureus bacteremia (SAB). METHODS: This Swiss multicenter study conducted between 2014 and 2023 pooled data from three cohorts. It evaluated the performance of each iteration of the Duke criteria by assessing the degree of concordance between definite S. aureus IE (SAIE) and the diagnoses made by the Endocarditis Team (2018-23) or IE expert clinicians (2014-17). RESULTS: Among 1344 SAB episodes analyzed, 486 (36%) were identified as cases of SAIE. The 2023 Duke-ISCVID and 2023 Duke-ESC criteria demonstrated improved sensitivity for SAIE diagnosis (81% and 82%, respectively) compared to the 2015 Duke-ESC criteria (75%). However, the new criteria exhibited reduced specificity for SAIE (96% for both) compared to the 2015 criteria (99%). Spondylodiscitis was more prevalent among patients with SAIE compared to those with SAB alone (10% vs 7%, P = .026). However, when patients meeting the minor 2015 Duke-ESC vascular criterion were excluded, the incidence of spondylodiscitis was similar between SAIE and SAB patients (6% vs 5%, P = .461). CONCLUSIONS: The 2023 Duke-ISCVID and 2023 Duke-ESC clinical criteria show improved sensitivity for SAIE diagnosis compared to 2015 Duke-ESC criteria. However, this increase in sensitivity comes at the expense of reduced specificity. Future research should aim at evaluating the impact of each component introduced within these criteria.

Eyes Wide Shut: A Cohort Study Questioning the Role of Fundoscopy in Infective Endocarditis Diagnosis.

In this retrospective/prospective study, we assessed the role of fundoscopy in 711 episodes with suspected infective endocarditis (IE); 238 (33%) had IE. Ocular embolic events (retinal emboli or chorioretinitis/endophthalmitis) and Roth spots were found in 37 (5%) and 34 (5%) episodes, respectively, but had no impact on IE diagnosis.

Evaluation of the 2023 Duke-International Society of Cardiovascular Infectious Diseases Criteria in a Multicenter Cohort of Patients With Suspected Infective Endocarditis.

BACKGROUND: Since publication of Duke criteria for infective endocarditis (IE) diagnosis, several modifications have been proposed. We aimed to evaluate the diagnostic performance of the Duke-ISCVID (International Society of Cardiovascular Infectious Diseases) 2023 criteria compared to prior versions from 2000 (Duke-Li 2000) and 2015 (Duke-ESC [European Society for Cardiology] 2015). METHODS: This study was conducted at 2 university hospitals between 2014 and 2022 among patients with suspected IE. A case was classified as IE (final IE diagnosis) by the Endocarditis Team. Sensitivity for each version of the Duke criteria was calculated among patients with confirmed IE based on pathological, surgical, and microbiological data. Specificity for each version of the Duke criteria was calculated among patients with suspected IE for whom IE diagnosis was ruled out. RESULTS: In total, 2132 episodes with suspected IE were included, of which 1101 (52%) had final IE diagnosis. Definite IE by pathologic criteria was found in 285 (13%), 285 (13%), and 345 (16%) patients using the Duke-Li 2000, Duke-ESC 2015, or the Duke-ISCVID 2023 criteria, respectively. IE was excluded by histopathology in 25 (1%) patients. The Duke-ISCVID 2023 clinical criteria showed a higher sensitivity (84%) compared to previous versions (70%). However, specificity of the new clinical criteria was lower (60%) compared to previous versions (74%). CONCLUSIONS: The Duke-ISCVID 2023 criteria led to an increase in sensitivity compared to previous versions. Further studies are needed to evaluate items that could increase sensitivity by reducing the number of IE patients misclassified as possible, but without having detrimental effect on specificity of Duke criteria.

Evaluation of the HANDOC score and the 2023 ISCVID and ESC Duke clinical criteria for the diagnosis of infective endocarditis among patients with streptococcal bacteremia.

BACKGROUND: Streptococci are a common cause of infective endocarditis (IE). We aimed to evaluate the performance of the HANDOC score to identify patients at high-risk for IE and the Duke clinical criteria of the European Society of Cardiology (ESC; 2015 and 2023 versions) and the 2023 version from the International Society of Cardiovascular Infectious Diseases (ISCVID) in diagnosing IE among patients with streptococcal bacteremia. METHODS: This retrospective study included adult patients with streptococcal bacteremia hospitalized at Lausanne University Hospital. Episodes were classified as IE by the Endocarditis Team. A HANDOC score >2 classified patients as high-risk for IE. RESULTS: Among 851 episodes with streptococcal bacteremia, IE was diagnosed in 171 episodes (20%). Among 607 episodes with non-beta-hemolytic streptococci, 213 (35%) had HANDOC scores >2 points; 132 (22%) had IE. The sensitivity of the HANDOC score to identify episodes at high-risk for IE was 95% (90-98%), the specificity 82% (78-85%), and the NPV 98% (96-99%). 2015 Duke-ESC, 2023 Duke-ISCVID, and 2023 Duke-ESC clinical criteria classified 114 (13%), 145 (17%), and 126 (15%) episodes as definite IE, respectively. Sensitivity for the 2015 Duke-ESC, 2023 Duke-ISCVID, and 2023 Duke-ESC clinical criteria was calculated at 65% (57-72%), 81% (74-86%), and 73% (65-79%), respectively, with specificity at 100% (98-100%), 99% (98-100%), and 99% (98-100%), respectively. CONCLUSIONS: The HANDOC score showed an excellent NPV to identify episodes at high-risk for IE. Among the different versions of the Duke criteria, the 2023 Duke-ISCVID version fared better for the diagnosis of IE among streptococcal bacteremia.

Comparison of the 2015 and 2023 European Society of Cardiology versions of the Duke criteria among patients with suspected infective endocarditis.

BACKGROUND: Diagnosing infective endocarditis (IE) poses a significant challenge. This study aimed to compare the diagnostic accuracy of the 2015 and 2023 Duke clinical criteria introduced by the European Society of Cardiology (ESC) in a cohort of patients suspected of having IE. METHODS: Conducted retrospectively at two Swiss University Hospitals between 2014-2023, the study involved patients with suspected IE. Each hospitals' Endocarditis Team categorized case as either IE or not IE. The performance of each iteration of the Duke-ESC clinical criteria was assessed based on the agreement between definite IE and the diagnoses made by the Endocarditis Team. RESULTS: Among the 3127 episodes with suspected IE, 1177 (38%) were confirmed to have IE. Using the 2015 Duke-ESC clinical criteria, 707 (23%) episodes were deemed definite IE, with 696 (98%) receiving a final IE diagnosis. With the 2023 Duke-ESC clinical criteria, 855 (27%) episodes were classified as definite IE, of which 813 (95%) were confirmed as IE. The 2015 and 2023 Duke-ESC clinical criteria categorized 1039 (33%) and 1034 (33%) episodes, respectively, as possible IE. Sensitivity for the 2015 Duke-ESC and the 2023 Duke-ESC clinical criteria was calculated at 59% (95% CI: 56-62%), and 69% (66-72%), respectively, with specificity at 99% (99-100%), and 98% (97-98%), respectively. CONCLUSIONS: The 2023 ESC criteria demonstrated significant improvements in sensitivity compared to the 2015 version, although one-third of episodes were classified as possible IE by both versions.

Heterogeneity in practices to reduce the risk of transmission of Clostridioides difficile in healthcare settings: a survey of ESCMID Study Group for Clostridioides difficile (ESGCD) members.

Clostridioides difficile is a leading cause of healthcare-associated infections. The main objective was to assess the current landscape of CDI infection prevention and control (IPC) practices. An anonymous survey of IPC practices for CDI was conducted between July 25 and October 31, 2022. Precautions for symptomatic patients were applicable for 75.9% and were discontinued 48 h minimum after the resolution of diarrhea for 40.7% of respondents. Daily cleaning of CDI patients' rooms was reported by 23 (42.6%). There was unexpected heterogeneity in IPC practices regarding the hospital management of CDI.

Predictors of mortality of Pseudomonas aeruginosa bacteraemia and the role of infectious diseases consultation and source control; a retrospective cohort study.

PURPOSE: To determine predictors of mortality among patients with Pseudomonas aeruginosa bacteraemia. METHODS: Retrospective study. SETTING: This study conducted at the Lausanne University Hospital, Switzerland included adult patients with P. aeruginosa bacteraemia from 2015 to 2021. RESULTS: During the study period, 278 episodes of P. aeruginosa bacteraemia were included. Twenty (7%) isolates were multidrug-resistant. The most common type of infection was low respiratory tract infection (58 episodes; 21%). Sepsis was present in the majority of episodes (152; 55%). Infectious diseases consultation within 48 h of bacteraemia onset was performed in 203 (73%) episodes. Appropriate antimicrobial treatment was administered within 48 h in 257 (92%) episodes. For most episodes (145; 52%), source control was considered necessary, with 93 (64%) of them undergoing such interventions within 48 h. The 14-day mortality was 15% (42 episodes). The Cox multivariable regression model showed that 14-day mortality was associated with sepsis (P 0.002; aHR 6.58, CI 1.95-22.16), and lower respiratory tract infection (P < 0.001; aHR 4.63, CI 1.78-12.06). Conversely, interventions performed within 48 h of bacteraemia onset, such as infectious diseases consultation (P 0.036; HR 0.51, CI 0.27-0.96), and source control (P 0.009; aHR 0.17, CI 0.47-0.64) were associated with improved outcome. CONCLUSION: Our findings underscore the pivotal role of early infectious diseases consultation in recommending source control interventions and guiding antimicrobial treatment for patients with P. aeruginosa bacteraemia.

Risk of embolic events before and after antibiotic treatment initiation among patients with left-side infective endocarditis.

PURPOSE: Embolic events (EEs) are a common complication of left-side infective endocarditis (IE). The aim of the present study was to identify risk factors for the occurrence of EEs before or after antibiotic treatment instauration among patients with definite or possible IE. METHODS: This retro-prospective study was conducted at the Lausanne University Hospital, Lausanne, Switzerland, from January 2014 to June 2022. EEs and IE were defined according to modified Duke criteria. RESULTS: A total of 441 left-side IE episodes were included (334: 76% were definite and 107; 24% possible IE). EE were diagnosed in 260 (59%) episodes; in 190 (43%) before antibiotic treatment initiation and 148 (34%) after. Central nervous system (184; 42%) was the most common site of EE. Multivariable analysis identified S. aureus (P 0.022), immunological phenomena (P < 0.001), sepsis (P 0.027), vegetation size ≥ 10 mm (P 0.003) and intracardiac abscess (P 0.022) as predictors of EEs before antibiotic treatment initiation. For EEs after antibiotic treatment initiation, multivariable analysis revealed vegetation size ≥ 10 mm (P < 0.001), intracardiac abscess (P 0.035) and prior EE (P 0.042), as independent predictors of EEs, while valve surgery (P < 0.001) was associated with lower risk for EEs. CONCLUSIONS: We reported a high percentage of EEs among patients with left-side IE; vegetation size, intracardiac abscess, S. aureus and sepsis were independently associated with the occurrence of EEs. In addition to antibiotic treatment, early surgery led to further decrease in EEs incidence.

Role of Cerebral Imaging on Diagnosis and Management in Patients With Suspected Infective Endocarditis.

BACKGROUND: Cerebral embolic events (CEEs) are common complications of infective endocarditis (IE), and their presence can modify diagnosis and therapeutic plans. The aim of the present study was to assess the role of cerebral imaging (Cer-Im) on diagnosis and management of patients with suspected IE. METHODS: This study was conducted at the Lausanne University Hospital, Lausanne, Switzerland, from January 2014 to June 2022. CEEs and IE were defined according to modified Duke criteria of the European Society of Cardiology (ESC) guidelines. RESULTS: Among 573 patients with IE suspicion and Cer-Im, 239 (42%) patients had neurological symptoms. At least 1 CEE was found in 254 (44%) episodes. Based on Cer-Im findings, episodes were reclassified from rejected to possible or from possible to definite IE in 3 (1%) and 25 (4%) patients, respectively (0% and 2% in asymptomatic patients, respectively). Among the 330 patients with possible or definite IE, at least 1 CEE was found in 187 (57%) episodes. A new surgical indication (in association with left-side vegetation >10 mm) was established in 74/330 (22%) IE patients and 30/155 (19%) asymptomatic IE patients, respectively. CONCLUSIONS: Cer-Im in asymptomatic patients with IE suspicion showed limited potential for improving the diagnosis of IE. In contrast, performing Cer-Im in asymptomatic patients with IE may be useful for decision making, because Cer-Im findings led to the establishment of new operative indication for valvular surgery in one fifth of patients according to ESC guidelines.

Predictors of mortality of Staphylococcus aureus bacteremia among patients hospitalized in a Swiss University Hospital and the role of early source control; a retrospective cohort study.

S. aureus bacteremia is associated with high mortality. The aim was to identify predictors of mortality among patients with S. aureus bacteremia and evaluate the role of early source control. This retrospective study was conducted at the Lausanne University Hospital, Switzerland. All episodes of S. aureus bacteremia among adult patients from 2015 to 2021 were included. During the study period, 839 episodes of S. aureus bacteremia were included, of which 7.9% were due to methicillin-resistant isolates. Bacteremias were related to bone or joint infections (268; 31.9%), followed by bacteremia of unknown origin (158; 18.8%), proven endocarditis (118; 14.1%) and lower-respiratory tract infections (79; 9.4%). Overall 28-day mortality was 14.5%. Cox multivariate regression model showed that Charlson comorbidity index > 5 (P < 0.001), nosocomial bacteremia (P 0.019), time to blood culture positivity ≤ 13 h (P 0.004), persistent bacteremia for ≥ 48 h (P 0.004), sepsis (P < 0.001), bacteremia of unknown origin (P 0.036) and lower respiratory tract infection (P < 0.001) were associated with 28-day mortality, while infectious diseases consultation within 48 h from infection onset (P < 0.001) was associated with better survival. Source control was warranted in 575 episodes and performed in 345 episodes (60.0%) within 48 h from infection onset. Results from a second multivariate analysis confirmed that early source control (P < 0.001) was associated with better survival. Mortality among patients with S. aureus bacteremia was high and early source control was a key determinant of outcome. Infectious diseases consultation within 48 h played an important role in reducing mortality.

Clinical significance of concomitant bacteriuria in patients with Staphylococcus aureus bacteraemia.

This retrospective study, conducted at Lausanne University Hospital (2015-2021), compared Staphylococcus aureus bacteraemia (SABA) patients with or without concomitant bacteriuria (SABU). Among 448 included bacteraemic patients, 62 (13.8%) had S. aureus concurrently isolated from urine. In multivariate analysis, there was a significant difference in the odds of community-onset bacteraemia (P 0.030), malignancy (P 0.002), > 1 pair of positive blood cultures (P 0.037), and persistent bacteraemia for at least 48 h (P 0.045) in patients with concurrent SABU. No difference concerning mortality was found. On the other hand, SABU was associated with higher rates of SABA recurrence after antibiotic cessation.

Core genome multilocus sequence typing of Clostridioides difficile to investigate transmission in the hospital setting.

PURPOSE: Traditional epidemiological investigations of healthcare-associated Clostridioides difficile infection (HA-CDI) are often insufficient. This study aimed to evaluate a procedure that includes secondary isolation and genomic typing of single toxigenic colonies using core genome multilocus sequence typing (cgMLST) for the investigation of C. difficile transmission. METHODS: We analyzed retrospectively all toxigenic C. difficile-positive stool samples stored at the Lausanne University Hospital over 6 consecutive months. All isolates were initially typed and classified using a modified double-locus sequence typing (DLST) method. Genome comparison of isolates with the same DLST and clustering were subsequently performed using cgMLST. The electronic administrative records of patients with CDI were investigated for spatiotemporal epidemiological links supporting hospital transmission. A comparative descriptive analysis between genomic and epidemiological data was then performed. RESULTS: From January to June 2021, 86 C. difficile isolates were recovered from thawed samples of 71 patients. Thirteen different DLST types were shared by > 1 patient, and 13 were observed in single patients. A genomic cluster was defined as a set of isolates from different patients with ≤ 3 locus differences, determined by cgMLST. Seven genomic clusters were identified, among which plausible epidemiological links were identified in only 4/7 clusters. CONCLUSION: Among clusters determined by cgMLST analysis, roughly 40% included unexplained HA-CDI acquisitions, which may be explained by unidentified epidemiological links, asymptomatic colonization, and/or shared common community reservoirs. The use of DLST, followed by whole genome sequencing analysis, is a promising and cost-effective stepwise approach for the investigation of CDI transmission in the hospital setting.

Temporal changes in fecal microbiota of patients infected with COVID-19: a longitudinal cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a multifaceted disease potentially responsible for various clinical manifestations including gastro-intestinal symptoms. Several evidences suggest that the intestine is a critical site of immune cell development, gut microbiota could therefore play a key role in lung immune response. We designed a monocentric longitudinal observational study to describe the gut microbiota profile in COVID-19 patients and compare it to a pre-existing cohort of ventilated non-COVID-19 patients. METHODS: From March to December 2020, we included patients admitted for COVID-19 in medicine (43 not ventilated) or intensive care unit (ICU) (14 ventilated) with a positive SARS-CoV-2 RT-PCR assay in a respiratory tract sample. 16S metagenomics was performed on rectal swabs from these 57 COVID-19 patients, 35 with one and 22 with multiple stool collections. Nineteen non-COVID-19 ICU controls were also enrolled, among which 14 developed ventilator-associated pneumonia (pneumonia group) and five remained without infection (control group). SARS-CoV-2 viral loads in fecal samples were measured by qPCR. RESULTS: Although similar at inclusion, Shannon alpha diversity appeared significantly lower in COVID-19 and pneumonia groups than in the control group at day 7. Furthermore, the microbiota composition became distinct between COVID-19 and non-COVID-19 groups. The fecal microbiota of COVID-19 patients was characterized by increased Bacteroides and the pneumonia group by Prevotella. In a distance-based redundancy analysis, only COVID-19 presented significant effects on the microbiota composition. Moreover, patients in ICU harbored increased Campylobacter and decreased butyrate-producing bacteria, such as Lachnospiraceae, Roseburia and Faecalibacterium as compared to patients in medicine. Both the stay in ICU and patient were significant factors affecting the microbiota composition. SARS-CoV-2 viral loads were higher in ICU than in non-ICU patients. CONCLUSIONS: Overall, we identified distinct characteristics of the gut microbiota in COVID-19 patients compared to control groups. COVID-19 patients were primarily characterized by increased Bacteroides and decreased Prevotella. Moreover, disease severity showed a negative correlation with butyrate-producing bacteria. These features could offer valuable insights into potential targets for modulating the host response through the microbiota and contribute to a better understanding of the disease's pathophysiology. TRIAL REGISTRATION: CER-VD 2020-00755 (05.05.2020) & 2017-01820 (08.06.2018).

Post­COVID­19 Syndrome in Outpatients: a Cohort Study.

BACKGROUND: After mild COVID-19, some outpatients experience persistent symptoms. However, data are scarce and prospective studies are urgently needed. OBJECTIVES: To characterize the post-COVID-19 syndrome after mild COVID-19 and identify predictors. PARTICIPANTS: Outpatients with symptoms suggestive of COVID-19 with (1) PCR-confirmed COVID-19 (COVID-positive) or (2) SARS-CoV-2 negative PCR (COVID-negative). DESIGN: Monocentric cohort study with prospective phone interview between more than 3 months to 10 months after initial visit to the emergency department and outpatient clinics. MAIN MEASURES: Data of the initial visits were extracted from the electronic medical file. Predefined persistent symptoms were assessed through a structured phone interview. Associations between long-term symptoms and PCR results, as well as predictors of persistent symptoms among COVID-positive, were evaluated by multivariate logistic regression adjusted for age, gender, smoking, comorbidities, and timing of the survey. KEY RESULTS: The study population consisted of 418 COVID-positive and 89 COVID-negative patients, mostly young adults (median age of 41 versus 36 years in COVID-positive and COVID-negative, respectively; p = 0.020) and healthcare workers (67% versus 82%; p = 0.006). Median time between the initial visit and the phone survey was 150 days in COVID-positive and 242 days in COVID-negative patients. Persistent symptoms were reported by 223 (53%) COVID-positive and 33 (37%) COVID-negative patients (p = 0.006) and proportions were stable among the periods of the phone interviews. Overall, 21% COVID-positive and 15% COVID-negative patients (p = 0.182) attended care for this purpose. Four surveyed symptoms were independently associated with COVID-19: fatigue (adjusted odds ratio 2.14, 95% CI 1.04-4.41), smell/taste disorder (26.5, 3.46-202), dyspnea (2.81, 1.10-7.16), and memory impairment (5.71, 1.53-21.3). Among COVID-positive, female gender (1.67, 1.09-2.56) and overweight/obesity (1.67, 1.10-2.56) were predictors of persistent symptoms. CONCLUSIONS: More than half of COVID-positive outpatients report persistent symptoms up to 10 months after a mild disease. Only 4 of 14 symptoms were associated with COVID-19 status. The symptoms and predictors of the post-COVID-19 syndrome need further characterization as this condition places a significant burden on society.

How to Manage Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa is a pathogen frequently encountered in healthcare-associated infections and immunocompromised patients. In bacteremia, this pathogen is associated with higher mortality than other Gram-negative pathogens. This increase in mortality was also found globally for multi-resistant compared to susceptible strains. Several factors have been associated with the development of resistance: previous ICU stay, use of carbapenems, and comorbidities were identified in multivariate analysis. In the therapeutic choice, previous antibiotic treatment remains the strongest driver suggesting a potential resistant strain. These risk factors will decide whether multi-resistant strains must be considered in the empiric coverage. For susceptible strains, a single agent can be used, ß-lactams are usually the first choice. Associations do not provide any advantage on mortality. Optimization of pharmacokinetic/pharmacodynamic parameters, such as prolonged infusion (for time-dependent antibiotics), increased dosage (for concentration-dependent antibiotics), and therapeutic drug monitoring, also influences the outcome. The increasing number of resistant strains led the clinician to use either recently approved new molecules but also associations. For multi-resistant strains, new molecules such as ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol have shown an adequate activity against P. aeruginosa. Older molecules like colistin and fosfomycin are also used in this indication. The complexity of the resistance and consequences on a larger scale of antibiotic prescription will probably lead to more individualized prescriptions.

[Phage therapy for respiratory infections]. / Phagothérapie pour traiter les infections respiratoires.

The crisis of antibiotic resistance represents a global public health challenge, affecting particularly patients with respiratory infections. The use of (bacterio)phages for the treatment of bacterial infections (phage therapy) seems safe but its effectiveness has not yet been proven by controlled clinical trials. Nevertheless, phage therapy is regaining interest, encouraged by published cases treated successfully with personalized phage combinations as well as significant advances at a preclinical level. Standardized approaches in phage production and treatment administration, as well as future translational studies, are needed to improve our understanding and explore the potential of phage therapy.

La crise de l'antibiorésistance représente un enjeu considérable en santé publique, touchant particulièrement les patients avec des infections respiratoires. L'utilisation des (bactério)phages pour le traitement des infections bactériennes semble sécuritaire mais son efficacité n'a pas encore été formellement démontrée dans des essais cliniques contrôlés. La phagothérapie regagne de l'intérêt comme traitement personnalisé pour les patients qui ne répondent pas aux traitements standards, comme en témoignent les multiples cas publiés ainsi que des découvertes significatives au niveau préclinique. Des approches standardisées concernant la production et l'administration des phages ainsi que des études translationnelles sont nécessaires afin d'améliorer notre compréhension et d'explorer le potentiel de la phagothérapie.

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors.

Bacterial pathogens often subvert the innate immune system to establish a successful infection. The direct inhibition of downstream components of innate immune pathways is particularly well documented but how bacteria interfere with receptor proximal events is far less well understood. Here, we describe a Toll/interleukin 1 receptor (TIR) domain-containing protein (PumA) of the multi-drug resistant Pseudomonas aeruginosa PA7 strain. We found that PumA is essential for virulence and inhibits NF-κB, a property transferable to non-PumA strain PA14, suggesting no additional factors are needed for PumA function. The TIR domain is able to interact with the Toll-like receptor (TLR) adaptors TIRAP and MyD88, as well as the ubiquitin-associated protein 1 (UBAP1), a component of the endosomal-sorting complex required for transport I (ESCRT-I). These interactions are not spatially exclusive as we show UBAP1 can associate with MyD88, enhancing its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes both cytokine and TLR receptor signalling, highlighting a novel strategy for innate immune evasion.

Establishment of a French surveillance system of Clostridiodes difficile infection: Comparison of patient's characteristics with other national and European data.

INTRODUCTION: The magnitude and scope of Clostridioides difficile infection (CDI) has changed with an increase in incidence and severity. The epidemiology of CDI is not well known in France due to difficulties to conduct large continuous surveillance. The objectives were to compare the characteristics of patients with CDI collected through repeated point prevalence survey via DIFTEC™, a free electronic tool, with those from previous French or European studies. METHODS: DIFTEC™ was developed to evaluate epidemiological burden, diagnostic strategies and management of CDI in France. National and European guidelines were used for definitions. A literature review of studies conducted in Western Europe on CDI and published between January 2008 and May 2018 was done to compare their data with those included in the DIFTEC™ database. RESULTS: From January 2016, to December 2017, 455 CDI episodes from 22 French hospitals were included. Most of CDI cases were health-care associated (HCA) (78%). The comparison between included patients and French literature data showed that the rates of previous antibiotics exposure, crude mortality and recurrence were not statistically different. However HCA-CDI was significantly more frequent in the DIFTEC™ study. Gender distribution, recurrence and crude mortality rates were not statistically different compared to European data. HCA-CDI was more frequent in the DIFTEC™ study whereas previous treatment with proton pump inhibitors and antibiotics were significantly higher in European studies. DISCUSSION: These results illustrated the added value of a new tool for increasing the reliable knowledge of CDI in France based on epidemiological surveillance implemented in health-care settings.

Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial.

BACKGROUND: Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown. OBJECTIVES: To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI. METHODS: In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1-5; once daily on alternate days, Days 7-25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ±âŸ1, 12 ±âŸ1 and 25/26, and post-dose stool samples obtained on Days 5 ±âŸ1, 12 ±âŸ1 and 26 ±âŸ1. RESULTS: Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ±âŸ1 and Day 25/26 were 0.0252 (0.0038-0.1220) mg/L and 0.0069 (0-0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142-0.3250) mg/L and 0.0206 (0-0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ±âŸ1 were 272.5 (0-524) mg/kg and 280.5 (0-1120) mg/kg, respectively. CONCLUSIONS: EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ±âŸ1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.