Meiji Pharmaceutical University

Carbapenem-resistant Acinetobacter baumannii (CRAb) is designated by the World Health Organization as a critical priority pathogen, and most clinical CRAb isolates are multidrug-resistant (MDRA). However, an in vivo mouse imaging model of infection using clinical MDRA isolates has not been curated. Using antibiotic resistance genes as plasmid selection markers is incompatible with antimicrobial drug evaluation and prevents their application to MDRA isolates. To overcome this limitation, we constructed a firefly luciferase plasmid using tellurite resistance genes as non-antibiotic selection markers, enabling luminescence in multiple clinical MDRA isolates without altering susceptibility. Using a mouse pneumonia model and near-infrared luciferin derivative (TokeOni), we achieved noninvasive visualization of lung colonization by clinical MDRA isolates. Luminescence dynamics during treatment mirrored the in vitro minimum inhibitory concentration and survival outcomes, providing a therapeutic response readout. This platform overcomes a major bottleneck in MDR pathogen imaging and supports the evaluation of infection dynamics and drug efficacy.

Background/Objectives: Oral microbial homeostasis is crucial for overall health. Nonetheless, the relationship between probiotics and the oral environment remains unclear. This study investigated the association between continuous consumption of yogurt containing Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (LbR1 yogurt), salivary antimicrobial proteins (AMPs), tongue-coating microbiota, and upper respiratory tract infection (URTI) frequency. Methods: This observational study was conducted on 53 nursing home care workers, categorized into a group who consumed LbR1 yogurt daily for over 1 year (n = 40, yogurt group) and a non-intake group (n = 13, non-yogurt group). Salivary and tongue-coating samples were collected. Results: The yearly URTI frequency was lower in the yogurt group than in the non-yogurt group (p = 0.003). The salivary β-defensin-2 (HBD2) and β-defensin-3 (HBD3) flow rates were higher in the yogurt group than in the non-yogurt group (p = 0.02 and p = 0.0009, respectively). Fusobacterium nucleatum (F. nucleatum) ssp. animalis abundance was lower in the yogurt group than in the non-yogurt group (p = 0.04). Bayesian network analysis indicated an association between yogurt consumption and the yearly URTI frequency and salivary HBD2 and HBD3 flow rates. Conclusions: Continuous consumption of LbR1 yogurt was associated with elevated salivary HBD2 and HBD3, reduced abundance of F. nucleatum ssp. animalis, and decreased URTI frequency. Thus, LbR1 yogurt intake is associated with modulated oral immunity and microbiota, suggesting a potential link to reduced URTIs. However, as an observational pilot study, its results should be interpreted with caution.

Advanced non-squamous non-small cell lung cancer has a poor prognosis, and immune checkpoint inhibitors (ICIs) plus platinum-based combination chemotherapy is the first-line treatment. Atezolizumab, an ICI, has three regimens: atezolizumab + carboplatin (CBDCA) + paclitaxel + bevacizumab [ABCP], atezolizumab + CBDCA + nab-paclitaxel (nab-PTX) [A + CnP], and atezolizumab + CBDCA + pemetrexed [A + CbP]. However, clinical trials directly comparing these regimens have not been reported, and the differences in adverse events have not been fully clarified. We calculated the reporting odds ratio (ROR), a measure of adverse drug reaction (ADR) signals, using the FDA Adverse Event Reporting System (FAERS) to compare the major ADRs of ABCP, A + CnP, and A + CbP regimens. The ROR (95% confidence interval [CI]) for rash and hypersensitivity-related adverse events was 2.06 (1.81-2.34) for ABCP, 0.81 (0.42-1.56) for A + CnP, and 0.57 (0.37-0.87) for A + CbP; the signal was only detected for the ABCP regimen. In acute kidney injury (AKI), it was ABCP: 1.24 (0.89-1.73), A + CnP: 1.16 (0.37-3.60), and A + CbP: 1.76 (1.06-2.93), and signal was detected only for the A + CbP regimen. Contrarily, signals were detected for colitis, drug-induced liver injury, and pneumonitis for all regimens. Rash and hypersensitivity-related adverse events and AKI were more frequently reported with the ABCP and A + CbP regimens, respectively. These observations may help generate hypotheses regarding regimen-specific adverse event profiles and support future studies toward individualized chemotherapy.

Introduction. Biofilms are a primary form of device-associated infections and typically exhibit high tolerance to antimicrobial agents. In biofilms formed by multiple microbial species, microorganisms may show even greater tolerance, complicating treatment. There is evidence that meropenem (MEPM) tolerance in Escherichia coli is increased in dual-species biofilms with Candida albicans, and effective treatments have not been established.Hypothesis/Gap Statement. If the presence of viable C. albicans increases the MEPM tolerance of E. coli in mature biofilms, then the killing of C. albicans will attenuate the MEPM tolerance of E. coli.Aim. We evaluated the effectiveness of various antifungal combination treatments against dual-species biofilms of E. coli and C. albicans in vitro and in vivo.Methodology. The reduction in the number of viable cells in dual-species mature biofilms formed by E. coli and C. albicans was evaluated after treatment with a combination of antifungal drugs (fluconazole, amphotericin B and micafungin) and MEPM. In addition, the in vivo effects of combination therapy were assessed using a silkworm biofilm infection model.Results. The combination of amphotericin B and MEPM reduced the viable cell counts of both E. coli and C. albicans within dual-species biofilms. In contrast, the combination of fluconazole and MEPM did not reduce the viable cell count of either species, whereas the combination of micafungin and MEPM reduced C. albicans only. The reduction in viable C. albicans counts by micafungin was less than that by amphotericin B, suggesting that micafungin did not affect the tolerance of E. coli. The combination of amphotericin B and MEPM also reduced the viable cell counts of both E. coli and C. albicans in the in vivo model.Conclusion. These findings suggest that the combination of amphotericin B and antibacterial agents is a potential treatment option to reduce the C. albicans-induced bacterial tolerance for catheter-related infections involving C. albicans co-infection.

Multicomponent reactions, which involve the reaction of three or more components in a single step to efficiently produce a new molecular structure, have received growing attention in a range of research areas. In this study, four- and five-component reactions incorporating alkenes, carboxylic acids, alkyl radicals, and nitriles are developed for the imidoalkylation of alkenes with perfect regioselectivity. More specifically, this approach involves a photoredox reaction based on a catalytic indirect reductive quenching system. Various drug molecules and amino acids were demonstrated to be compatible substrates for this reaction, thereby enabling the synthesis of multifunctionalized derivatives. Notably, five individual components were assembled with perfect regioselectivity via the reaction of a radical species in the presence of a polarity-matched alkene. Mechanistic studies and density functional theory calculations suggested that this multicomponent reaction involves a cascade of Ritter-type substitutions and Mumm rearrangements. This method exhibits immense potential for use in the creation of structurally diverse and biologically relevant molecules with defined connectivities, thereby holding promise for applications in drug discovery and materials science.

BackgroundAlthough the incidence of amikacin (AMK)-resistant Mycobacterium avium complex (MAC) pulmonary disease (PD) is suspected to have increased, limited data are available on AMK-resistant MAC-PD. This study evaluated the risk factors associated with AMK resistance, the molecular characteristics of the AMK-resistant isolates, and treatment outcomes of patients with AMK-resistant MAC-PD.MethodsThis retrospective case–control study included 73 patients with severe and refractory MAC-PD who had a history of aminoglycoside drug use. Patients with initial and repeat AMK minimum inhibitory concentration (MIC) ≥64 μg·mL−1 were classified as AMK-resistant. To clarify the clinical outcomes and prognosis, an observational study was conducted. 21 patients with AMK resistance (AMK-resistant) and 52 controls (AMK-susceptible) were analysed.ResultsIn all cases of AMK resistance where previous isolates were available, the AMK MICs were elevated compared to the levels prior to aminoglycoside administration. In the multivariate analysis of risk factors, clarithromycin resistance (OR 6.31, 95% CI 1.68–23.7) and >12 months of total duration of aminoglycoside use (OR 4.69, 95% CI 1.09–20.2) were identified as independent risk factors for AMK resistance. 12 (57%) out of 21 AMK-resistant isolates were found to have mutations in the rrs region. There was a significant difference between the AMK-resistant and AMK-susceptible groups in terms of worsening outcomes, including the introduction of home oxygen therapy (38% versus 12%; p=0.01) and 3-year mortality (33% versus 10%; p=0.02).ConclusionsBetter management strategies for patients with severe and refractory MAC-PD are crucial. This includes placing a strong emphasis on preventing AMK resistance.