Antimicrobial Agents and Chemotherapy最新文献

There is limited evidence on the recommended voriconazole (VCZ) concentration ranges for prophylactic versus therapeutic use, and the factors influencing individualized dosing in young children remain insufficiently characterized. This retrospective study analyzed the clinical data from pediatric patients (2-17 years) at Peking University People's Hospital from September 2020 to December 2024. The aim was to define optimal concentration thresholds for prophylaxis and treatment and identify sources of pharmacokinetic variability across age groups to support individualized dosing in children. In the exposure-effect study, VCZ trough concentration (C_min) was significantly correlated with clinical efficacy. VCZ C_min ≥0.41 mg/L and C_min ≥1.115 mg/L were proven to be significant predictors of prophylactic and therapeutic dosing success, respectively. For pharmacokinetic analysis, patients were stratified into three age groups: Group 1 (2 to <6 years), Group 2 (6 to <12 years), and Group 3 (≥12 years). The final multiple regression analysis showed that affecting factors, including sex, moderate-to-severe inflammation, cytochrome P450 2C19 (CYP2C19) metabolic phenotype, and coadministration, explained 34.5%, 23.4%, and 47.6% of the variability in VCZ exposure in three groups, respectively. This study investigated pediatric patients with hematologic malignancies to define exposure-response differences between therapeutic and prophylactic VCZ regimens and identify age-related determinants of exposure variability. Overall, the findings support the use of individualized, age-appropriate dosing strategies to optimize VCZ exposure in children.

Carbapenem-resistant gram-negative ventriculitis is a life-threatening infection with limited treatment options. H. Jiang, Y. Hu, J. Cai, J. Zhang, et al. (Antimicrob Agents Chemother 70:e00943-25, 2026, https://doi.org/10.1128/aac.00943-25) describe two patients with this condition who were successfully treated with intraventricular polymyxin B. Their report highlights uneven antibiotic distribution within the ventricles, the influence of cerebrospinal fluid drainage on intraventricular drug concentrations, and cure with intraventricular polymyxin B alone. These findings raise important questions about optimal intraventricular antimicrobial dosing and whether concurrent intravenous therapy is needed in healthcare-associated ventriculitis.

RNA interference (RNAi) therapeutics targeting hepatitis B virus (HBV) RNAs and monoclonal antibodies (mAbs) targeting HBV surface antigen (HBsAg) represent potential strategies for enabling functional cure in chronic HBV patients. Tobevibart (VIR-3434) is an investigational, Fc-engineered human mAb that targets HBsAg with pan-genotypic neutralizing activity. Elebsiran (VIR-2218) is an investigational small interfering RNA targeting a conserved region of the HBV genome. The in vitro antiviral activity of elebsiran was assessed in HBV-infected primary human hepatocytes and hepatoma cells and showed potent inhibition of viral markers HBeAg (EC₅₀ of 2.5 nM and 53.7 pM, respectively) and HBsAg (EC₅₀ of 1.4 nM and 66.5 pM, respectively). Tobevibart and elebsiran activity in vivo was determined using two well-established HBV mouse models: AAV-HBV transduced C57BL/6 mice and human liver-chimeric mice. Mice were treated with a monotherapy or a combination of muHBC34 (the murinized parental mAb of tobevibart) and elebsiran at different doses. In both models, the mouse surrogate of tobevibart or elebsiran monotherapy was effective in reducing blood HBsAg levels. Combined treatment improved suppression of HBsAg (maximum mean reductions of 2.81 log in the AAV-HBV model and 2.51 log in human liver-chimeric mice) and HBV DNA over monotherapy. Tobevibart and elebsiran have been tested in clinical trials for the treatment of chronic hepatitis B and chronic hepatitis Delta.

Enterococcal bacteremia is a common healthcare-associated infection, associated with significant morbidity and mortality, with the emergence of vancomycin-resistant enterococci further complicating treatment and clinical outcomes. Despite this, long-term estimates of population-based incidence and antimicrobial resistance trends are limited. We aim to describe the burden of enterococcal bacteremia in Victoria, Australia (population 7.0 million), over a 35-year period. We conducted a retrospective analysis of laboratory-confirmed enterococcal bacteremia episodes voluntarily reported to the Victorian Hospital Pathogen Surveillance Scheme database from 1988 to 2022. Population-based incidence was estimated using inverse probability weighting to adjust for inconsistent hospital participation. Incidence per 10,000 hospital admissions was determined for the period 2011-2022. Antimicrobial resistance was calculated as the annual proportion of resistant isolates among all tested isolates. Overall, 11,157 enterococcal bacteremia episodes were identified, mainly Enterococcus faecalis (n = 6,915, 61.9%) and Enterococcus faecium (n = 3,558, 31.9%). Incidence increased from <3 episodes/100,000 population in 1988 to >10 by 2022. Incidence per 10,000 hospital admissions within Victoria has also increased from 2.8 in 2011 to 4 in 2022. Although E. faecalis remained mostly susceptible to tested antibiotics, E. faecium showed persistently high levels of vancomycin resistance, ranging from 50.7% (n = 69/136) to 66.5% (n = 139/209) over the past decade. Increasing incidence and high rates of vancomycin resistance among E. faecium highlight the ongoing clinical and public health challenge posed by enterococcal bacteremia. Applying statistical modeling to account for variability in hospital participation improves the certainty of incidence measures and strengthens the evidence for true increase in disease burden.

Antimicrobial resistance (AMR) poses a critical and growing global health threat, directly causing millions of deaths, with China bearing a significant burden. Understanding the provincial dynamics and multifactorial one health drivers of AMR, especially amidst the transformative 2019-2023 coronavirus disease 2019 (COVID-19) pandemic, remains crucial but underexplored. This comprehensive study investigated the spatiotemporal patterns and multisectoral drivers of methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Klebsiella pneumoniae (CRKP), and carbapenem-resistant Acinetobacter baumannii (CRAB) prevalence across Chinese provinces using a robust 2019-2023 panel data set. Utilizing spatial autocorrelation (Global Moran's I) and a multimodel approach, including panel fixed-effects regression, least absolute shrinkage and selection operator, and random forest, we identified robust drivers across healthcare, agricultural, environmental, and socioeconomic domains. Significant positive spatial autocorrelation was found for CRKP (Moran's I = 0.225; P < 0.05) and CRAB (Moran's I = 0.159; P < 0.05), indicating geographical clustering, whereas MRSA exhibited no significant pattern. Pathogen-specific drivers emerged. MRSA prevalence was linked to livestock inventory and PM2.5; CRKP to healthcare expenditure and pig inventory; and CRAB to healthcare expenditure and hospital beds, alongside counterintuitive negative associations with population aging and average length of hospital stay. The direct annual effect of COVID-19 was not statistically significant. We conclude that Chinese AMR is a spatially heterogeneous challenge driven by complex one health factors. A striking "paradox of progress" suggests higher healthcare capacity correlates with dangerously increased carbapenem-resistant pathogens, emphasizing the urgent need for robust infection prevention and control. The pandemic's influence was predominantly indirect. These findings demand multisectoral, regionally tailored AMR strategies integrating healthcare, agricultural, and environmental policies for effective control.

Brucellosis, caused by Brucella spp., is a globally zoonotic disease that results in substantial economic losses and public health concerns. Although antibiotic-resistant Brucella strains have been reported worldwide, the current status and underlying mechanisms of resistance among Chinese isolates remain poorly characterized. In this study, we analyzed 636 clinical human isolates of B. melitensis from China using genomic sequencing, transcriptomic sequencing, and neural network prediction to identify key determinants and mechanisms of antibiotic resistance. Functional validations were performed using gene editing and protein-protein interaction assays. We found a gradual increase in resistance to trimethoprim-sulfamethoxazole (SXT) among Chinese isolates in recent years, despite the absence of known antibiotic resistance genes. Comparative genomic analyses between high- and low-minimum inhibitory concentration (MIC) isolates revealed specific single nucleotide polymorphisms (SNPs) that were present only in high-MIC isolates. Transcriptomic analysis demonstrated that high-MIC and low-MIC isolates activated distinct metabolic pathways in response to SXT exposure. Notably, genes influenced by specific SNPs exhibited opposing expression patterns after SXT treatment. Gene-editing experiments revealed that deletion of the glycoside hydrolase family 25 (GH25) gene, which was identified through SNP analysis, was associated with SXT resistance and notably altered Brucella energy metabolism, although it did not impact virulence in host cells. Further, we identified a direct interaction between GH25 and XylF. Collectively, our study reveals a novel genetic mechanism driving SXT resistance in B. melitensis. These findings highlight the critical need for vigilant surveillance of antibiotic resistance to mitigate public health risks associated with the potential widespread emergence of antibiotic resistance.

Identifying the genetic relatedness of resistant bacterial pathogens in healthcare settings can help identify undetected transmission events and outbreaks. However, current methods are time- and resource-intensive. We evaluated a rapid neighbor typing method paired with long-read sequencing for assessment of genetic relatedness. Utilizing a data set of primary clinical samples and published isolate data from two outbreaks of Escherichia coli, we applied genomic neighbor typing of long-read sequence data to rapidly estimate genetic relatedness. We assessed the correlation between neighbor typing predicted genetic distance and pairwise genetic distance from short-read draft whole genomes for all sample pairs. Predicted genetic trees using neighbor typing were compared to reference genetic trees generated using mash distances and maximum-likelihood (ML) methods to assess the extent of agreement, along with metrics of cluster similarity (cluster comparability and Baker's gamma index [BGI]) and tree topology similarity (generalized Robinson-Foulds [GRF] metric). For all three data sets, we found strong correlations between the reference methods and predicted genetic distances (Spearman's rho = 0.75-0.95, P < 0.001), which improved when using a lineage score-informed approach (Spearman's rho = 0.93-0.94, P < 0.001). Predicted genetic trees and clusters from neighbor typing were comparable to those generated using either mashtree or an ML method, with a range of cluster comparability of 85.8-99.5%, BGIs of 0.8-0.95, and GRF values of 0.34-0.8. Pairing the neighbor typing method with long-read sequencing can enable accurate predictions of the relatedness of E. coli samples and isolates, and could potentially be used as a rapid outbreak surveillance tool.

Contezolid is a novel oxazolidinone antibiotic for the treatment of gram-positive bacteria, which are one of the most common pathogens of pneumonia. We conducted a prospective, single-center, open-label study to evaluate the clinical and microbiological efficacy, safety profile, and pulmonary epithelial lining fluid (ELF) penetration characteristics of contezolid in adult pneumonia patients. Sparse blood samples and bronchoalveolar lavage fluid samples were collected from patients after multiple oral doses of 800 mg of contezolid twice a day. Pharmacokinetic parameters were calculated by developing population pharmacokinetic (PopPK) modeling, and probability of target attainment was evaluated by Monte Carlo simulations. The study enrolled 15 patients (mean age 55 years) with primarily community-acquired pneumonia. Contezolid achieved a clinical cure rate of 80.0% and a bacterial clearance rate of 71.4%. Oral contezolid was well tolerated, and no drug-related adverse effects were observed in any of the subjects. The mean area under the concentration-time curve (AUC_{₀-₁₂,ss}) was estimated by the PopPK model to be 33.06 mg·h/L in ELF and 71.95 mg·h/L in plasma. Assuming a plasma protein binding rate of 90% based on literature data, the ELF-to-free plasma AUC_0-12,ss ratio was 4.50. When the minimum inhibitory concentration was ≤4 mg/L, 800 mg of contezolid q12h could achieve the optimal therapeutic target in the plasma of patients with pneumonia. This study demonstrates that contezolid achieved excellent pulmonary penetration in adult patients with pneumonia.

HIV-1 treatment has advanced with various antiretroviral regimens. Although efavirenz (EFV)-based regimens have been widely used, current guidelines recommend integrase strand transfer inhibitor (INSTI)-based therapy as first-line. However, INSTI may cause weight gain and adverse lipid changes, creating new unmet metabolic needs. Novel agents like ainuovirine (ANV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), may offer effective virological suppression (VS) with improved tolerability, but their long-term real-world safety and effectiveness remain unclear. This was a multicenter, retrospective observational cohort study. Virologically suppressed adults on a tenofovir disoproxil fumarate (TDF)/3TC+EFV regimen were either switched to TDF/3TC+ANV (ANV group) based on the physician's discretion or continued on TDF/3TC+EFV (EFV group). Baseline demographic and clinical data were collected, and participants were followed for 48 weeks. The primary effectiveness outcome was the proportion of patients achieving HIV-1 RNA levels below the limit of quantification (LOQ) at week 48. Secondary outcomes included absolute or percentage changes from baseline in CD4+ T-cell count, CD4+/CD8+ ratio. Key secondary safety outcomes included absolute changes from baseline in body weight, BMI, fasting lipid profiles (total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C]), and parameters of liver and renal function. A total of 350 participants who completed the 48-week follow-up were included, comprising 170 patients in the ANV group and 180 patients who remained on EFV. At week 48, the proportion of VS was 96.5% in the ANV group and 96.1% in the EFV group (difference: 1.00 percentage points; 95% CI: -2.77 to 2.77), confirming non-inferiority. No significant differences in CD4+ T-cell recovery or CD4+/CD8+ ratios were observed. The ANV group experienced significantly less weight gain than the EFV group (estimated treatment difference [ETD]: -0.79 kg; P < 0.001). A corresponding trend in BMI change was observed but did not reach statistical significance. ANV also led to more favorable lipid changes, including a significant reduction in total cholesterol (ETD: -0.52 mmol/L; P < 0.001) and triglycerides (ETD: -0.83 mmol/L; P < 0.001) compared to EFV. Liver and renal function profiles remained stable in both groups. Switching from EFV- to an ANV-based regimen effectively maintained VS and led to improved metabolic parameters, including less weight gain and a more favorable lipid profile. As an alternative switch strategy, the ANV-based regimen may be a more beneficial option for people living with HIV (PLWH) who are at high risk of weight-related or dyslipidemia-associated comorbidities.

High-dose continuous infusion of cefepime is frequently employed in ICU patients with a creatinine clearance above 60 mL/min. The CEFTOX study aimed to investigate whether this regimen could lead to cefepime overexposure and cefepime-induced neurotoxicity (CIN) in a cohort of severe trauma and brain-injured patients. This retrospective cohort study included patients from a Level 1 Trauma Center who received a continuous infusion of 6 g/day of cefepime and had a therapeutic drug monitoring (TDM) within 24-48 h of treatment initiation. They were divided into three groups based on creatinine clearance: mild renal impairment (60-90 mL/min), normal clearance (90-150 mL/min), and augmented renal clearance (ARC) (>150 mL/min). The primary outcome was cefepime overexposure. A key secondary outcome was CIN. One hundred and sixty-two critically ill patients were included: 84 with ARC, 62 with normal renal clearance, and 16 with mild renal impairment. Cefepime overexposure occurred in 72 (44.4%) patients. While 50% of patients with normal renal clearance experienced overexposure, the rate was higher in those with mild renal impairment (87.5%) and lower in those with ARC (32.1%; P < 0.0001). In the ARC group, age > 33 years was a risk factor for overexposure (odds ratio [OR] 3.76; 95% CI [1.30-10.95]; P = 0.01), while sepsis was a protective factor (OR 0.30; 95% CI [0.11-0.83]; P = 0.02). CIN was observed in 24% of overexposed patients when TDM results were obtained ≤48 h compared to 57.4% when results were delayed >48 h (P = 0.006). These results highlight the need for early TDM and individualized dose adjustment to avoid CIN.