BACKGROUND:Carbapenemase-producing Enterobacterales, particularly New Delhi metallo-β-lactamase (NDM) producers, are spreading rapidly in European hospitals despite reinforced control measures. Risk factors specifically associated with hospital carriage of NDM-producing Enterobacterales in France remain poorly defined. We aimed to identify factors independently associated with in-hospital NDM carriage. METHODS:We performed a retrospective, single centre, 1:2 matched case -control study at Avicenne University Hospital (Paris, France) over 2024. Cases were patients with NDM-producing Enterobacterales identified at least three days after admission. Each case was matched to two controls hospitalized in the same ward, during the same period, with a comparable length of stay and at least two negative rectal screenings. Clinical, demographic, and epidemiological variables were analyzed using conditional logistic regression. RESULTS:Seventy-two cases were matched to 144 controls. In multivariable analysis, NDM carriage was independently associated with a Charlson comorbidity index ≥5 (adjusted odds ratio [aOR] 2.84, 95% CI 1.30-6.19), prior surgery (aOR 2.92, 95% CI 1.47-8.44), endoscopic procedures during hospitalization (aOR 3.52, 95% CI 1.47-8.44), recent travel abroad (aOR 3.58, 95% CI 1.41-9.13), and hospitalization in two or more epidemic wards during the same year (aOR 5.85, 95% CI 1.84-18.55). CONCLUSION:Carriage of NDM-producing Enterobacterales results from the interplay between patient vulnerability, invasive procedures, international exposure, and intra-hospital transmission dynamics. These findings support targeted screening strategies and reinforced infection prevention measures for high-risk patients, particularly those undergoing invasive procedures or transferred between epidemic wards.

Levofloxacin is a valuable antibiotic in the treatment of bone and joint infections. Due to the known risk of treatment failure and bacterial resistance, the development of tools facilitating pharmacokinetic/pharmacodynamic parameter monitoring to inform precision dosing is needed. Therefore, we assessed the use of Bayesian estimation to predict AUC0-24 and Cmax of levofloxacin under various sampling scenarios realistic in clinical routine. Furthermore, we developed a free web-based application allowing model-informed precision dosing. All published population pharmacokinetic models of ofloxacin and levofloxacin in bone and joint infections were researched and their predictive performance was compared using a real-life data cohort. We used simulated data to validate the robustness of various scenarios for Bayesian estimation of AUC0-24 and Cmax with up to three samples, including the potential impact of an incorrectly reported sampling time at peak concentration. Relative bias and relative root mean square error were estimated to assess accuracy and precision, respectively. One of the three published levofloxacin models showed negligible mean relative prediction error (0.02 ± 0.09). We modified it to a closed form approximation to facilitate the implementation in the application. The 2-sample scenario (T0h-T3h) allowed accurate and precise AUC0-24 estimations for 500 mg q12h and 750 mg q24h dosing regimens. None of the tested scenarios allowed a satisfactory estimation of Cmax. We finally developed and validated a free web-based application (https://levoshiny.iame-research.center/) using the selected model. The Shiny application will be useful in clinical practice to individualize dose regimens based on the AUC0-24 obtained using the proposed limited sampling strategy.

Background: Enterobacterales are among the most frequent causes of healthcare-associated infections and are increasingly affected by antimicrobial resistance. Antibiotic use disrupts the gut microbiota, facilitating colonization by multidrug-resistant organisms, including carbapenemase-producing Enterobacterales (CPE). While animal studies have suggested that certain antibiotic classes may increase the risk of CPE acquisition, clinical data identifying which classes are most implicated remain limited. Methods: We conducted a single-center, retrospective case-control study (2021–2024) comparing antibiotic prescriptions in patients who acquired CPE with those in controls hospitalized in the same unit and during the same risk period but who did not acquire CPE. The objective of this study was to identify which antibiotic classes or pharmacological properties are associated with the acquisition of carbapenemase-producing Enterobacterales (CPE) in hospitalized patients. Results: During the study period, 35 cases and 70 controls were included. Most cases acquired NDM-type metalloenzymes. Before the risk period, 55 patients had received antibiotic therapy. Univariate analysis identified an association between CPE acquisition and the prescription of fluoroquinolones and antibiotics excreted in bile. During the risk period, only metronidazole prescription was significantly associated with CPE acquisition. Our study has several limitations, including the small sample size, the single-center retrospective design, and the lack of molecular typing (e.g., WGS) to confirm potential clonal transmission. Conclusions: In this preliminary study, metronidazole use was associated with an increased risk of CPE acquisition during risk periods. However, these results should be interpreted cautiously and need to be confirmed in larger, multicenter studies. The high exposure of patients to multiple antibiotic classes highlights the importance of strict antibiotic stewardship policies in the current era of global CPE dissemination.

BACKGROUND:Carbapenem-resistant strains of Pseudomonas aeruginosa (CRPA) have become a major health care concern in many countries, against which anti-infective strategies are limited and which require adequate infection control interventions. Knowing the different modes of transmission of CRPA in intensive care units (ICUs) would be helpful to adapt the means of prevention. METHODS:The aim of this retrospective case-control study was conducted between January 1, 2017 and February 28, 2022 to identify the risk factors for the acquisition of CRPA in ICUs. RESULTS:During the study period, 147 patients were included (49 cases and 98 controls). Among the 49 patients, 31 (63%) acquired CRPA in clusters and 18 (37%) sporadically. A univariate analysis showed that 4 variables were associated with CRPA acquisition, including (1) prior antibiotic prescriptions, (2) admission to rooms 203 and 207, (3) severity of illness at admission, and (4) use of mechanical ventilation. Multivariate analysis identified 3 factors of CRPA acquisition, including admission to room 203 (odds ratio [OR] = 29.5 [3.52-247.09]), previous antibiotic therapy (OR = 3.44 [1.02-11.76]), and severity of condition at admission (OR = 1.02 [1-1.04]). CONCLUSIONS:Our study suggests the role of a contaminated environment in the acquisition of CRPA in the ICU, along with antibiotic use.

AbstractEscherichia coliis both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostics, prevention and treatment is still lacking. We used a collection of 1282 BSI and commensalE. coliisolates collected in France over a 17-year period (2000-2017) and we compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity increased steadily from 23% in 1980 to 46% in 2010. Together our findings imply thatE. coliexhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.

In recent years, the diagnosis of bloodstream infections has been complemented by rapid microbiological methods, unattainable to most clinical laboratories in resource-limited settings. We evaluated the impact of their shortage on antibiotic therapy adequacy. We conducted a prospective multicenter cohort study including 150 adult Gram-negative bacilli bacteremia episodes, evenly distributed across three university hospitals: one in Lebanon, a resource-limited setting, and two in France, a resource-rich setting. Previous colonization by multidrug-resistant organisms (MDRO) was significantly more prevalent among the Lebanese than the French group of patients (16/50 vs. 5/100; p < 0.01). Bloodstream infections by carbapenemase-producing Enterobacterales and other MDRO were higher among the Lebanese than the French group of patients (25/50 vs. 12/100; p < 0.01). For the French group, rapid identification of species and mechanisms of resistance significantly shortened turnaround time for definitive laboratory diagnosis and increased antibiotic therapy adequacy. No statistically significant differences were noted in targeted antibiotic therapy between the two groups. This study suggests that, in settings where bacterial resistance is prevalent, rapid microbiological methods have not provided any additional value. The clinical and economic impact of rapid microbiological methods will likely depend on local CPE, VRE, and other MDRO epidemiology and are areas for future research.

Multidrug-resistant Gram-negative bacteria-related infections have become a real public health problem and have exposed the risk of a therapeutic impasse. In recent years, many new antibiotics have been introduced to enrich the therapeutic armamentarium. Among these new molecules, some are mainly of interest for the treatment of the multidrug-resistant infections associated with Pseudomonas aeruginosa (ceftolozane/tazobactam and imipenem/relebactam); others are for carbapenem-resistant infections associated with Enterobacterales (ceftazidime/avibactam, meropenem/vaborbactam); and finally, there are others that are effective on the majority of multidrug-resistant Gram-negative bacilli (cefiderocol). Most international guidelines recommend these new antibiotics in the treatment of microbiologically documented infections. However, given the significant morbidity and mortality of these infections, particularly in the case of inadequate therapy, it is important to consider the place of these antibiotics in probabilistic treatment. Knowledge of the risk factors for multidrug-resistant Gram-negative bacilli (local ecology, prior colonization, failure of prior antibiotic therapy, and source of infection) seems necessary in order to optimize antibiotic prescriptions. In this review, we will assess these different antibiotics according to the epidemiological data.

Magréault, Sophie PharmD, PhD; Charbit, Judith MD; Berkane, Narimane MD; Jaureguy, Françoise PharmD, PhD; Carbonnelle, Etienne MD, PhD; Cosson, Emmanuel MD, PhD; Jullien, Vincent PharmD, PhD; Bihan, Hélène MD, PhD Author Information

This paper evaluates the impact of playing the educational 'BacteriaGame' on student engagement and learning in comparison with a traditional lecture approach, as well as utilizing student feedback. The fight against antibiotic resistance has become a true global public health challenge of gargantuan proportions. Amongst the myriad of approaches being explored to tackle this predicament, one strategy involves enhancing prescriber knowledge and in particular their basic knowledge of medical bacteriology. Yet, as we well know in medical microbiology teachings, traditional lectures can be arduous, attempting to cram in a vast array of information in a limited time. An alternative solution to improve student engagement and enhance learning outcomes is to utilize educational games in complementary approach. Such games are an effective means of inspiring students to learn, encouraging self-assessment, and injecting diversity into the teaching process. To this end, we have developed and evaluated an educational card game, the 'BacteriaGame,' aimed at our medical students in medical bacteriology. Designed for students at the basic level, it serves as activity at the end of their apprenticeship to their bacteriology education. Additionally, it can also be used as a review tool by more advanced students, with teachers able to impart additional knowledge as the game progresses. We also use it in continuous training of medical laboratory staff. In this study, we evaluated the game at various stages of medical education, collecting feedback and analysing its impact on knowledge acquisition, comparing it to traditional lectures. Feedback from the majority of students revealed that the rules were clear, the game was enjoyable, and neither too lengthy nor too challenging. The integration of 'BacteriaGame' into their future training piqued their interest. In terms of learning outcomes, we discovered a significant increase in knowledge acquisition among those who used the game (P < .05). 'BacteriaGame' is now published by the French Society of Microbiology (SFM) and distributed in all medical and pharmacy schools thanks to a funding of the French Health Ministry. An English edition of the game is also available for international use as a physical copy to be purchased from the SFM. This will allow a large-scale distribution to colleagues who would like to use this game in their teaching.

Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostic, prevention and treatment is still lacking. We used a collection of 912 BSI and 370 commensal E. coli isolates collected in France over a 17-year period (2000-2017). We compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity continuously increased through 1980, 2000, to 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.

Therapeutic drug monitoring (TDM) of antibiotics (ATB) in patients with serious bacterial infections allows optimization of the efficacy of the treatment while reducing the risk of toxicity. Notably, early measurement of plasma beta-lactam concentration has been shown to be associated with reduced mortality in intensive care patients. In this context, a rapid, robust, and accurate assay method is essential for daily TDM.A fully automated procedure for quantification of the plasma concentrations of ten ATB was developed. The ATB were divided into two calibration pools, with Pool 1: aztreonam, ceftobiprole, cefoxitin, avibactam, tazo-bactam and Pool 2: metronidazole, ceftriaxone, daptomycin, ceftolozane, moxifloxacin. Sample preparation consisting of acetonitrile plasma protein precipitation and H20 dilution was applied to all analytes. This pro-cedure was carried out by an automated sample preparation system directly coupled to a liquid chromatography -tandem mass spectrometry (LC-MS/MS) system. Since the instrument extracts sample n while sample n-1 is in the LC-MS/MS system, the delay between obtaining the results for two samples corresponds to the analytical run time, which is less than 7 min.The method was validated according to the Food and Drug Administration guidelines. The method was sen-sitive (lower limit of quantification 0.1-1 mg/L, depending on the ATB), accurate (intra/inter-assay bias-14.8 to 14.2 %) and precise (intra/inter-assay CVs 1.27 to 16.3 %). Application of the TDM assay was illustrated by the report of an intensive care patient treated with the ceftazidime/aztreonam/avibactam combination. Four assays were performed in 8 days with results returned within 24 h to quickly manage the dose regimen in this patient.An automated, simple, rapid, robust LC-MS/MS analysis was developed and validated for the simultaneous quantification of plasma concentrations of 10 ATB and was applied with success to perform TDM. This method provides a shorter turnaround time than classic sample batch-based analytical methods.

Bacterial resistance to antibiotics continues to be a global public health problem. The choice of the most effective antibiotic and the use of an adapted dose in the initial phase of the infection are essential to limit the emergence of resistance. This will depend on (i) the isolated bacteria and its resistance profile, (ii) the pharmacodynamic (PD) profile of the antibiotic used and its level of toxicity, (iii) the site of infection, and (iv) the pharmacokinetic (PK) profile of the patient. In order to take account of both parameters to optimize the administered treatment, a minimal inhibitory concentration (MIC) determination associated with therapeutic drug monitoring (TDM) and their combined interpretation are required. The objective of this narrative review is thus to suggest microbiological, pharmacological, and/or clinical situations for which this approach could be useful. Regarding the microbiological aspect, such as the detection of antibiotic resistance and its level, the preservation of broad-spectrum β-lactams is particularly discussed. PK-PD profiles are relevant for difficult-to-reach infections and specific populations such as intensive care patients, cystic fibrosis patients, obese, or elderly patients. Finally, MIC and TDM are tools available to clinicians, who should not hesitate to use them to manage their patients.

Background: Sepsis caused by multi-drug-resistant Gram-negative bacilli lead physicians to prescribe broad-spectrum antibiotic therapy, such as carbapenems. Rapid susceptibility testing can help with the rational use of antibiotics. The aim of this study was to measure the clinical impact associated with rapid reporting of Beta-Lacta test (BLT) directly on blood cultures positive with Gram-negative bacilli. Methods: In an observational, multicentric, prospective study, we included patients with sepsis caused by Enterobacterales observed on Gram staining of the positive blood cultures. BLT and antimicrobial susceptibility testing (AST) were performed directly on the blood cultures. Clinical impact was measured on the proportion of patients for whom the probabilistic antibiotic therapy was modified according to BLT, including patients receiving carbapenem. Results: 170 patients were included, of whom 44 (25.9%) were receiving inadequate empirical antibiotic therapy. Among them, 27 (15.9%) benefited from an early modification, according to the BLT results. Among 126 (74.1%) patients receiving appropriate probabilistic antibiotic therapy, we modified the antibiotic therapy for 28 (16.5%) of them, including 4/14 (28.5%) de-escalation from carbapenem to a third-generation cephalosporin. Conclusions: Implementation of BLT performed directly on blood cultures allowed us to rapidly modify the empirical antibiotic therapy for about one-third of patients with sepsis caused by Enterobacterales.

The incidence of extra pelvic infections due to vaginal microflora bacteria has increased as growth media and methods of isolation have improved. However, bone infections seem to be still relatively rare, and little is known about their risk factors, clinical presentation, treatment and final outcome. We describe here a spondylodiscitis due to Gardnerella vaginalis , Atopobium vaginae , Peptostreptococcus indolicus and Prevotella amnii , anaerobic bacteria from vaginal microbiota. Our patient had no obvious predisposing factor and recovered after antibiotic treatment. To our knowledge, this case is the first reported spondylodiscitis caused by polymicrobial vaginal flora in a healthy, immunocompetent woman.

In the context of increasing antimicrobial resistance in Enterobacterales, the management of these UTIs has become challenging. We retrospectively assess the prevalence of antimicrobial resistance in Enterobacterales isolates recovered from urinary tract samples in France, between 1 September 2017, to 31 August 2018. Twenty-six French clinical laboratories provided the susceptibility of 134,162 Enterobacterales isolates to 17 antimicrobials. The most frequent species were E. coli (72.0%), Klebsiella pneumoniae (9.7%), Proteus mirabilis (5.8%), and Enterobacter cloacae complex (2.9%). The overall rate of ESBL-producing Enterobacterales was 6.7%, and ranged from 1.0% in P. mirabilis to 19.5% in K. pneumoniae, and from 3.1% in outpatients to 13.6% in long-term care facilities. Overall, 4.1%, 9.3% and 10.5% of the isolates were resistant to cefoxitin, temocillin and pivmecillinam. Cotrimoxazole was the less active compound with 23.4% resistance. Conversely, 4.4%, 12.9%, and 14.3% of the strains were resistant to fosfomycin, nitrofurantoin, and ciprofloxacin. However, less than 1% of E. coli was resistant to fosfomycin and nitrofurantoin. We identified several trends in antibiotics resistances among Enterobacterales isolates recovered from the urinary tract samples in France. Carbapenem-sparing drugs, such as temocillin, mecillinam, fosfomycin, cefoxitin, and nitrofurantoin, remained highly active, including towards ESBL-E.

In a prospective, nationwide study in France of Escherichia coli responsible for pneumonia in patients receiving mechanical ventilation, we determined E. coli antimicrobial susceptibility, phylotype, O-type, and virulence factor gene content. We compared 260 isolates with those of 2 published collections containing commensal and bacteremia isolates. The preponderant phylogenetic group was B2 (59.6%), and the predominant sequence type complex (STc) was STc73. STc127 and STc141 were overrepresented and STc95 underrepresented in pneumonia isolates compared with bacteremia isolates. Pneumonia isolates carried higher proportions of virulence genes sfa/foc, papGIII, hlyC, cnf1, and iroN compared with bacteremia isolates. Virulence factor gene content and antimicrobial drug resistance were higher in pneumonia than in commensal isolates. Genomic and phylogenetic characteristics of E. coli pneumonia isolates from critically ill patients indicate that they belong to the extraintestinal pathogenic E. coli pathovar but have distinguishable lung-specific traits.

Les infections à EBLSE en réanimation nécessitent une prise en charge globale incluant le choix des traitements les plus efficaces, l’adaptation des doses et des modalités thérapeutiques et l’évacuation des collections abcédées lorsque cela est possible. La seule classe thérapeutique actuellement disponible, et qui reste active, est celle des carbapénèmes. Aussi, cette classe reste le traitement probabiliste de choix en cas de suspicion d’infection à EBLSE. L’utilisation d’« alternatives » aux carbapénèmes n’est possible qu’en cas de documentation microbiologique et sur les données de l’antibiogramme. Elles ne peuvent être utilisées que chez des patients hémodynamiquement stables. L’arrivée dans l’arsenal thérapeutique de nouvelles molécules associant des bêtalactamines aux inhibiteurs de bêtalactamase permet d’envisager de nouvelles approches.