Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection.

OBJECTIVES: Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. METHODS: A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. RESULTS: Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole. CONCLUSIONS: This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.

The portrayal of antimicrobial resistance in Bangladeshi newspapers during 2010-2021: Toward understanding the narrative.

BACKGROUND: Antimicrobial resistance (AMR) is a major global public health crisis and around the last decade, newspapers were one of the main sources of public dissemination of information for so. This study highlights how Bangladeshi mainstream newspapers represented AMR-related news and how they created the narrative of AMR in Bangladesh. METHODS: We conducted both quantitative and qualitative content analysis on 275 AMR-related news articles published in the twelve highest circulated dailies (January 2010 to September 2021). We divided the articles into report, opinion, and editorials and analyzed how their contents built the narrative of AMR in Bangladesh. RESULTS: Bangladeshi newspapers reported misuse of antibiotics by the consumers the most (32.2%), followed by selling without prescriptions (29%), and over-prescription by the health providers (26.1%). There were hardly any news reports describing the impact of pharmaceutical companies in prescribing and selling antibiotics. Around 45% of the news articles were event-oriented. Moreover, they suggested inadequate recommendations to battle AMR. CONCLUSION: Valid, consistent, and reliable AMR news coverage can play a crucial role in creating mass awareness, making providers accountable, and supporting national action plan in mitigating AMR threat. The Bangladeshi journalists interested in reporting AMR-issues should focus on disseminating more Bangla articles with scientific information, and reporting causes and recommendations responsibly.

Antibiotic Prescribing Practices for Treating COVID-19 Patients in Bangladesh.

Although national and international guidelines have strongly discouraged use of antibiotics to treat COVID-19 patients with mild or moderate symptoms, antibiotics are frequently being used. This study aimed to determine antibiotics-prescribing practices among Bangladeshi physicians in treating COVID-19 patients. We conducted a cross-sectional survey among physicians involved in treating COVID-19 patients. During September-November 2021, data were collected from 511 respondents through an online Google Form and hardcopies of self-administered questionnaires. We used descriptive statistics and a regression model to identify the prevalence of prescribing antibiotics among physicians and associated factors influencing their decision making. Out of 511 enrolled physicians, 94.13% prescribed antibiotics to COVID-19 patients irrespective of disease severity. All physicians working in COVID-19-dedicated hospitals and 87% for those working in outpatient wards used antibiotics to treat COVID-19 patients. The majority (90%) of physicians reported that antibiotics should be given to COVID-19 patients with underlying respiratory conditions. The most prescribed antibiotics were meropenem, moxifloxacin, and azithromycin. Our study demonstrated high use of antibiotics for treatment of COVID-19 patients irrespective of disease severity and the duty ward of study physicians. Evidence-based interventions to promote judicious use of antibiotics for treating COVID-19 patients in Bangladesh may help in reducing an overuse of antibiotics.

Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection.

Fecal microbiota transplantation (FMT) is a successful therapeutic strategy for treating recurrent Clostridioides difficile infection. Despite remarkable efficacy, implementation of FMT therapy is limited and the mechanism of action remains poorly understood. Here, we demonstrate a critical role for the immune system in supporting FMT using a murine C. difficile infection system. Following FMT, Rag1 heterozygote mice resolve C. difficile while littermate Rag1-/- mice fail to clear the infection. Targeted ablation of adaptive immune cell subsets reveal a necessary role for CD4+ Foxp3+ T-regulatory cells, but not B cells or CD8+ T cells, in FMT-mediated resolution of C. difficile infection. FMT non-responsive mice exhibit exacerbated inflammation, impaired engraftment of the FMT bacterial community and failed restoration of commensal bacteria-derived secondary bile acid metabolites in the large intestine. These data demonstrate that the host's inflammatory immune status can limit the efficacy of microbiota-based therapeutics to treat C. difficile infection.

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality.

Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.

Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages.

Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a "default" Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.