Diverse Role of blaCTX-M and Porins in Mediating Ertapenem Resistance among Carbapenem-Resistant Enterobacterales.

Among carbapenem-resistant Enterobacterales (CRE) are diverse mechanisms, including those that are resistant to meropenem but susceptible to ertapenem, adding further complexity to the clinical landscape. This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) Escherichia coli and Klebsiella pneumoniae CRE across five hospitals in San Antonio, Texas, USA, from 2012 to 2018. The majority of the CRE isolates were non-carbapenemase producers (NCP; 54%; 41/76); 56% of all NCP isolates had an ErMs phenotype. Among ErMs strains, E. coli comprised the majority (72%). ErMs strains carrying blaCTX-M had, on average, 9-fold higher copies of blaCTX-M than CP-ErMs strains as well as approximately 4-fold more copies than blaCTX-M-positive but ertapenem- and meropenem-susceptible (EsMs) strains (3.7 vs. 0.9, p < 0.001). Notably, carbapenem hydrolysis was observed to be mediated by strains harboring blaCTX-M with and without a carbapenemase(s). ErMs also carried more mobile genetic elements, particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p < 0.0001). MGE- ISVsa5 was uniquely more abundant in ErMs than either EsMs or ErMr strains, with over 30 more average ISVsa5 counts than both phenotype groups (p < 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, our findings characterize both collaborative and independent efforts between blaCTX-M and OmpC in ErMs strains, indicating the need to reappraise the term "non-carbapenemase (NCP)", particularly for strains highly expressing blaCTX-M. To improve outcomes for CRE-infected patients, future efforts should focus on mechanisms underlying the emerging ErMs subphenotype of CRE strains to develop technologies for its rapid detection and provide targeted therapeutic strategies.

Molecular Rapid Diagnostics Improve Time to Effective Therapy and Survival in Patients with Vancomycin-Resistant Enterococcus Bloodstream Infections.

Delays in appropriate antibiotic therapy are a key determinant for deleterious outcomes among patients with vancomycin-resistant Enterococcus (VRE) bloodstream infections (BSIs). This was a multi-center pre/post-implementation study, assessing the impact of a molecular rapid diagnostic test (Verigene® GP-BC, Luminex Corporation, Northbrook, IL, USA) on outcomes of adult patients with VRE BSIs. The primary outcome was time to optimal therapy (TOT). Multivariable logistic and Cox proportional hazard regression models were used to determine the independent associations of post-implementation, TOT, early vs. delayed therapy, and mortality. A total of 104 patients with VRE BSIs were included: 50 and 54 in the pre- and post-implementation periods, respectively. The post- vs. pre-implementation group was associated with a 1.8-fold faster rate to optimized therapy (adjusted risk ratio, 1.841 [95% CI 1.234-2.746]), 6-fold higher likelihood to receive early effective therapy (<24 h, adjusted odds ratio, 6.031 [2.526-14.401]), and a 67% lower hazards for 30-day in-hospital mortality (adjusted hazard ratio, 0.322 [0.124-1.831]), after adjusting for age, sex, and severity scores. Inversely, delayed therapy was associated with a 10-fold higher risk of in-hospital mortality (aOR 10.488, [2.497-44.050]). Reduced TOT and in-hospital mortality were also observed in subgroups of immunosuppressed patients in post-implementation. These findings demonstrate that the addition of molecular rapid diagnostic tests (mRDT) to clinical microbiology and antimicrobial stewardship practices are associated with a clinically significant reduction in TOT, which is associated with lower mortality for patients with VRE BSIs, underscoring the importance of mRDTs in the management of VRE infections.

Metformin Attenuates Inflammatory Responses and Enhances Antibody Production in an Acute Pneumonia Model of Streptococcus pneumoniae.

Metformin may potentially reverse various age-related conditions; however, it is unclear whether metformin can also mitigate or delay the deterioration of immunological resilience that occurs in the context of infections that are commonly observed in older persons. We examined whether metformin promotes the preservation of immunological resilience in an acute S. pneumoniae (SPN) infection challenge in young adult mice. Mice were fed metformin (MET-alone) or standard chow (controls-alone) for 10 weeks prior to receiving intratracheal inoculation of SPN. A subset of each diet group received pneumococcal conjugate vaccine at week 6 (MET + PCV and control + PCV). Compared to controls-alone, MET-alone had significantly less infection-associated morbidity and attenuated inflammatory responses during acute SPN infection. Metformin lowered the expression of genes in the lungs related to inflammation as well as shorter lifespan in humans. This was accompanied by significantly lower levels of pro-inflammatory cytokines (e.g., IL6). MET + PCV vs. control + PCV manifested enhanced SPN anticapsular IgM and IgG levels. The levels of SPN IgM production negatively correlated with expression levels of genes linked to intestinal epithelial structure among MET + PCV vs. control + PCV groups. Correspondingly, the gut microbial composition of metformin-fed mice had a significantly higher abundance in the Verrucomicrobia, Akkermansia muciniphila, a species previously associated with beneficial effects on intestinal integrity and longevity. Together, these findings indicate metformin's immunoprotective potential to protect against infection-associated declines in immunologic resilience.

Predominance of Non-carbapenemase Producing Carbapenem-Resistant Enterobacterales in South Texas.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) pose a significant global public health threat. Resistance among CRE is particularly complex, owing to numerous possible resistance mechanisms and broad definitions. We aimed to characterize the clinical and molecular profiles of CRE in the South Texas region. MATERIALS AND METHODS: We compared the clinical, genotypic, and phenotypic profiles of carbapenemase producing Enterobacterales (CPE) with those of non-carbapenemase producers (NCPE) isolated from South Texas, United States between 2011 and 2019. Molecular characteristics and resistance mechanisms were analyzed using whole-genome sequences. RESULTS: The majority (59%) of the CRE isolates were NCPE while 41% of isolates harbored carbapenemases, predmonantly bla KPC-type. The most common CPE was Klebsiella pneumoniae while majority of Enterobacter cloacae and Escherichia coli were NCPE Among K. pneumoniae, the clonal group 307 has emerged as a predmoninant group and was associated with as many CRE infections as the previous common clonal group 258. Patients with NCPE compared to CPE infections were associated with higher antimicrobial exposure prior to culture collection (days of therapy, 795 vs. 242; p < 0.001) and emergency department visits within past 90 days (22% vs. 4%; p = 0.011). The all cause 30-day mortality was 21%. CONCLUSIONS: This study highlights the diversity of resistance mechanisms underlying CRE in South Texas, with 59% not harboring a carbapenemase. Individuals with NCPE infections were more likely to have had prior antimicrobial therapy and emergency department visits compared to those with CPE. Identification and distinction of these mechanisms by rapid identification of species and carbapenemase would allow for optimal treatment and infection control efforts.

Gut Microbiome: Profound Implications for Diet and Disease.

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual's starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.