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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.

Antimicrobial resistance is a major concern. Epidemiological studies have demonstrated direct relationships between antibiotic consumption and emergence/dissemination of resistant strains. Within the last decade, authors confounded spectrum activity and ecological effects and did not take into account several other factors playing important roles, such as impact on anaerobic flora, biliary elimination and sub-inhibitory concentration. The ecological impact of antibiotics on the gut microbiota by direct or indirect mechanisms reflects the breaking of the resistance barrier to colonization. To limit the impact of antibiotic therapy on gut microbiota, consideration of the spectrum of activity and route of elimination must be integrated into the decision. Various strategies to prevent (antimicrobial stewardship, action on residual antibiotics at colonic level) or cure dysbiosis (prebiotic, probiotic and fecal microbiota transplantation) have been introduced or are currently being developed.

Background: Meropenem–vaborbactam (MEM-VAB) is a novel carbapenem-beta-lactamase-inhibitor combination that demonstrates activity against carbapenem-resistant (CR) Gram-negative bacteria, and more specifically KPC-producers, since vaborbactam is an effective inhibitor of KPC enzymes in vitro. This study aimed to describe the initial uses and efficacy of MEM-VAB for compassionate treatment during the first 21 months following its early access in France. Method: A national multicenter retrospective study was conducted, including all patients who received at least one dose of MEM-VAB between 20 July 2020, and 5 April 2022. Clinical characteristics and outcomes were collected using a standardized questionnaire. The minimum inhibitory concentration (MIC) of antimicrobials, and complete genome sequencing of bacteria were performed when bacterial isolates were available. Results: Ultimately, 21 patients from 15 French hospitals were included in the study. The main indication for MEM-VAB treatment was respiratory tract infections (n = 9). The targeted bacteria included Pseudomonas aeruginosa (n = 12), Klebsiella pneumoniae (n = 3), Enterobacter spp (n = 3), Citrobacter freundii (n = 1), Escherichia coli (n = 1), and Burkholderia multivorans (n = 1). Overall, no significant advantage of vaborbactam over meropenem alone was observed across all strains of P. aeruginosa in terms of in vitro susceptibility. However, MEM-VAB demonstrated a notable impact, compared to carbapenem alone, on the MIC for the two KPC-3-producing K. pneumoniae and B. multivorans. Conclusions: MEM-VAB seems effective as a salvage treatment in compassionate use, but vaborbactam was shown to lack benefits compared to meropenem in treating P. aeruginosa-related infections. Therefore, it is crucial to compare meropenem to MEM-VAB MICs, particularly for P. aeruginosa, before prescribing MEM-VAB.

(1) Background: We describe a model of primary mild-Clostridioides difficile infection (CDI) in a naïve host, including gut microbiota analysis, weight loss, mortality, length of colonization. This model was used in order to describe the kinetics of humoral (IgG, IgM) and mucosal (IgA) immune responses against toxins (TcdA/TcdB) and surface proteins (SlpA/FliC). (2) Methods: A total of 105 CFU vegetative forms of C. difficile 630Δerm were used for challenge by oral administration after dysbiosis, induced by a cocktail of antibiotics. Gut microbiota dysbiosis was confirmed and described by 16S rDNA sequencing. We sacrificed C57Bl/6 mice after different stages of infection (day 6, 2, 7, 14, 21, 28, and 56) to evaluate IgM, IgG against TcdA, TcdB, SlpA, FliC in blood samples, and IgA in the cecal contents collected. (3) Results: In our model, we observed a reproducible gut microbiota dysbiosis, allowing for C. difficile digestive colonization. CDI was objectivized by a mean weight loss of 13.1% and associated with a low mortality rate of 15.7% of mice. We observed an increase in IgM anti-toxins as early as D7 after challenge. IgG increased since D21, and IgA anti-toxins were secreted in cecal contents. Unexpectedly, neither anti-SlpA nor anti-FliC IgG or IgA were observed in our model. (4) Conclusions: In our model, we induced a gut microbiota dysbiosis, allowing a mild CDI to spontaneously resolve, with a digestive clearance observed since D14. After this primary CDI, we can study the development of specific immune responses in blood and cecal contents.

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.

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.

Ventilator-associated pneumonia is a frequent cause of ICU-acquired infections. These infections are associated with high morbidity and mortality. The increase in antibiotic resistance, particularly among Gram-negative bacilli, makes the choice of empiric antibiotic therapy complex for physicians. Multidrug-resistant organisms (MDROs) related infections are associated with a high risk of initial therapeutic inadequacy. It is, therefore, necessary to quickly identify the bacterial species involved and their susceptibility to antibiotics. New diagnostic tools have recently been commercialized to assist in the management of these infections. Moreover, the recent enrichment of the therapeutic arsenal effective on Gram-negative bacilli raises the question of their place in the therapeutic management of these infections. Most national and international guidelines recommend limiting their use to microbiologically documented infections. However, many clinical situations and, in particular, the knowledge of digestive or respiratory carriage by MDROs should lead to the discussion of the use of these new molecules, especially the new combinations with beta-lactamase inhibitors in empirical therapy. In this review, we present the current epidemiological data, particularly in terms of MDRO, as well as the clinical and microbiological elements that may be taken into account in the discussion of empirical antibiotic therapy for patients managed for ventilator-associated pneumonia.

Overconsumption of antibiotics in hospitals has led to policy implementation, including the control of antibiotic prescriptions. The impact of these policies on the evolution of antimicrobial resistance remains uncertain. In this work, we review the possible limits of such policies and focus on the need for a more efficient approach. Establishing a causal relationship between the introduction of new antibiotics and the emergence of new resistance mechanisms is difficult. Several studies have demonstrated that many resistance mechanisms existed before the discovery of antibiotics. Overconsumption of antibiotics has worsened the phenomenon of resistance. Antibiotics are responsible for intestinal dysbiosis, which is suspected of being the source of bacterial resistance. The complexity of the intestinal microbiota composition, the impact of the pharmacokinetic properties of antibiotics, and the multiplicity of other factors involved in the acquisition and emergence of multidrug-resistant organisms, lead us to think that de-escalation, in the absence of studies proving its effectiveness, is not the solution to limiting the spread of multidrug-resistant organisms. More studies are needed to clarify the ecological risk caused by different antibiotic classes. In the meantime, we need to concentrate our efforts on limiting antibiotic prescriptions to patients who really need it, and work on reducing the duration of these treatments.