International Journal of Antimicrobial Agents最新文献

Recurrent Clostridioides difficile infection (rCDI) is a global health threat and receives increased attention. Berberine (BBR), a natural pentacyclic isoquinoline alkaloid, has been used as a cost-effective treatment for intestinal infections in Asia for many years. However, its effect on rCDI is not clear yet. The efficacy and the underlying mechanisms of BBR were evaluated in vancomycin-dependent rCDI mouse model and intestinal organoids model. Our findings revealed that BBR treatment alleviated the severity and increased survival rate in rCDI mice. Mechanistically, BBR alleviated intestinal epithelial damage with higher Occludin expression, suppressed some inflammatory pathways and reduced the level of inflammatory factors in both cecum and serum. Moreover, the 16s rRNA sequencing analysis indicated that BBR reshaped the gut microbiota by increasing the abundance of Firmicutes and reducing the abundance of Proteobacteria. At genus level, BBR treatment increased levels of Blautia and Bilophila, and reduced levels of Proteus. In addition, acetic acid, one of the short-chain fatty acids (SCFAs), was also increased after BBR treatment in rCDI mice. Collectively, BBR exerted a protective effect in rCDI via multiple underlying mechanisms, which deserve further investigation as a potential drug candidate for alleviating rCDI.

Intracellular microbes are actively present in various tumor types in low biomass and play a major role in metastasis. Eliminating intracellular microbes on a cellular level with precision remains a challenge. To address this issue, we designed a screening pipeline to characterize intracellular microbes and their interaction with host cells. We used host and microbial in-vitro lab based constant and reproducible model, host as (mammalian cancer HeLa) and microbial strain as (Escherichia coli 25922). To study the pharmacological impact on intracellular bacterial load, we used antibiotics (ampicillin, roxithromycin, ciprofloxacin) and chemotherapy drugs (doxorubicin and cisplatin) as external stimuli for both host and microbes. We found that increasing pharmacological stress does not increase microbial load inside the host cells. Eliminations of intracellular bacteria was done by using Permutation Orthogonal Arrays (POA), where we acquired optimal drug combination in particular sequence of drugs, which reduced 90-95% of intracellular microbial load. Proteomic analysis reveals that upon the invasion of Escherichia coli 25922, HeLa cells enriched ATP production pathways to activate intermediate filaments, which should be investigated closely via in-vivo models.

Background: Plasma protein binding (PPB) is a critical factor in drug therapy and understanding free compound exposure across preclinical and clinical species is vital for developing new antibiotics. Optimizing beta-lactam dosing based on unbound drug concentrations has garnered significant interest, yet comprehensive data on how inter-species differences in protein binding affect the attainment of targeted unbound concentrations remain sparse.

Methods: This study aimed to examine the protein binding of three beta-lactams: cefiderocol, ceftriaxone, and temocillin using human, bovine, and rat plasma. Total and unbound beta-lactam concentrations were measured through ultrafiltration. An interspecies comparison of PPB was conducted to evaluate variability in protein binding across the different species.

Results: The findings revealed that PPB was highest in human plasma for all three beta-lactam antibiotics tested. In rat plasma, PPB was higher for cefiderocol and ceftriaxone compared to bovine plasma, while bovine plasma exhibited higher PPB for temocillin compared to rat plasma.

Conclusion: Significant variability in protein binding was observed among and between different species for the tested drugs. The study highlights substantial interspecies differences in the plasma protein binding of cefiderocol, ceftriaxone, and temocillin. Our findings indicate the need for careful consideration of species-specific PPB in the optimization of beta-lactam dosing and the development of new pharmaceuticals.

Objectives: This study aimed to investigate the "seesaw effect" of daptomycin (DAP) and ceftobiprole (BPR) on DAP-resistant (DAP-R) methicillin-resistant Staphylococcus aureus (MRSA) isolates.

Methods: Broth microdilution minimum inhibitory concentrations (MICs) of DAP and BPR were tested for laboratory-derived and clinical DAP-R MRSA isolates to estimate the "seesaw effect". Time-kill curves for seven representative DAP-R isolates were obtained using DAP and BPR to validate their synergistic activity in vitro. Whole genome sequencing as well as deletion and complementation of the mprF gene were performed to investigate the mechanisms of the "seesaw effect".

Results: The BPR MICs decreased by half-fold in DAP-R MRSA isolates. The synergistic effect of DAP and BPR against representative clinical and community-associated MRSA (CA-MRSA) isolates was demonstrated in time-kill analyses, showing that synergistic activity was preferred in CA-MRSA compared with hospital-associated MRSA. The mprF mutations were identified in isolates exhibiting the "seesaw effect". These mutations increased the DAP MIC while decreasing the BPR MIC.

Conclusions: The "seesaw effect" between DAP and BPR was prevalent among DAP-R MRSA isolates. This phenomenon was associated with the mprF mutations of MRSA.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a major contributor to healthcare-associated infections globally. This study presents a molecular epidemiological analysis of 628 non-duplicate CRPA isolates collected over five years (2018-2022) from a hospital in Henan Province, China, with 256 isolates from before the COVID-19 pandemic and 372 during the pandemic. Only 26.59% of isolates carried carbapenemases, predominantly GES-14, and carbapenemase diversity decreased during the pandemic. However, the diversity of CRPA sequence types (STs) increased, with ST235 and ST244 emerging as the most prevalent clones. The Antibiotic resistance genes (ARGs) number carried by CRPA isolates significantly decreased during the pandemic (p < 0.05), with notable differences in 24 ARGs and 14 virulence factors (VFs) between pre-pandemic and pandemic periods (χ² test, p < 0.05). O11 was the predominant serotype across all periods. Global analysis revealed a significant reduction in ARGs in strains from China and Australia (p < 0.01) during the pandemic, while an increase was observed in the United States, Singapore, and Spain. Analysis of the global epidemic clones ST244 and ST235 indicated that ARGs in ST244 P. aeruginosa increased significantly during the pandemic, whereas no significant changes were observed in ST235 strains. This study provides essential insights for developing clinical strategies against CRPA infections.

Objectives: Critical illness and organ support such as extracorporeal membrane oxygenation (ECMO) may influence antimicrobial pharmacokinetics. This study investigated cefiderocol pharmacokinetics in critically-ill patients receiving ECMO to understand if standard dosing achieves optimal exposure.

Methods: Cefiderocol was prescribed according to approved package insert recommendations based on creatinine clearance (CrCL). Blood sampling was performed at steady-state. Protein binding was determined by ultrafiltration. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. The fT>MIC for each patient was assessed at MICs of 4, 8, and 16 mg/L. Total AUC_24h was calculated to evaluate comparative exposure to non-ECMO patients.

Results: Five patients receiving 1.5g q8h to 2g q6h dosing regimens were enrolled. Three patients received venous-arterial and two veno-venous ECMO [mean flow rate of 3.9 (range: 2.7-4.9) L/min]. A two-compartment model fitted the data best with mean ± standard deviation estimates for clearance (CL), volume of the central compartment (V), K₁₂ and K₂₁ of 2.3 ± 0.5 L/h, 4.8 ± 2.3 L, 5.1 ± 2.8 h^-1, and 3.9 ± 3.3 h^-1, respectively. Mean protein binding was 41% (range: 31-50%). Prescribed dosing regimens achieved 100% fT>MIC up to 16 mg/L for all patients, with a total steady-state AUC_24h of 2501 (range: 1631-3276) mg/L*h.

Conclusions: These are the first data to describe cefiderocol pharmacokinetics in critically-ill patients undergoing ECMO. The currently labeled dosing recommendations based on CrCL in these patients were well tolerated and achieved 100% fT>MIC against susceptible bacteria and AUC exposures similar to values in non-ECMO patients.

Hand-foot-and-mouth disease (HFMD) is widespread in the world. Severe HFMD can lead to complications like pneumonia, encephalitis, myocarditis, transverse myelitis and even death. Since HFMD is caused by at least 20 types of enteroviruses, there is an urgent need for broad-spectrum antiviral drugs to help control the spread of HFMD outbreaks. Type I interferon (IFN), as an indispensable part of the immune response, plays a key role in the inhibition of the enterovirus replication cycle without species specificity, and regulation of the innate immune system by inducing the activation of the IFN-stimulated genes. Here, the interplay of enteroviruses and type I IFN was systematically summarized, including pathways for the activation and evasion of type I IFN. Besides, we proposed promising anti-enterovirus agents with therapeutic potential.

Recently, the number of carbapenem-resistant Citrobacter spp.(CRC) have been on the rise. In this study, we collected CRCs from humans, animals, and water environments to examine their epidemiological distribution and resistance characteristics. Total of 171 CRCs were isolated from diverse Chinese provinces between 2016 and 2023. All strains are classified into seven Citrobacter species, C. freundii is the most common (76.02%), with ST116 and ST22 being the predominant strains. Among all strains, 63.16% carried bla_NDM-1, and 41.52% carried bla_KPC-2. Hospital wastewater was the primary source of CRCs harboring two carbapenemase genes, with the most prevalent combination being bla_NDM-1 and bla_KPC-2 (85.71%, 24/28). All strains showed multiple drug resistance, with over 95% resistant to various carbapenems. Transconjugation experiments showed that carbapenemase genes in the majority of CRCs were located on the plasmids and can be transferred to the recipient strains. According to the phylogenetic analysis, clonal transmission was observed among a few CRCs. Multiple mobile genetic elements mediate the spread and prevalence of carbapenem resistance in Citrobacter spp..