International Journal of Antimicrobial Agents最新文献

Background: The study aimed to assess the clinical and economic impact of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli bacteremic UTIs (Ec-BUTI) and to evaluate the possibility of developing antimicrobial stewardship interventions.

Methods: Retrospective single-center cohort study included all consecutive episodes of Ec-BUTI requiring hospitalization from September 2020 to February 2023.

Primary outcome: clinical failure.

Secondary outcome: hospital resource consumption, length of stay, 30-day recurrence and mortality, and 90-day readmissions. Antimicrobial stewardship interventions were evaluated. A propensity score matching analysis was performed.

Results: 310 E. coli-BUTI episodes were included; 86 caused by ESBL-producing strains. The ESBL group had greater comorbidity burden than the non-ESBL group (median Charlson index 4 [IQR 2-6] vs. 2 [IQR 1-4]; p<0.001) and more frequent inappropriate empirical therapy (40.7% vs. 3.6%; p<0.001). Overall, an intravenous-to-oral switch was made within the first week in 172 (55.5%) episodes. In the ESBL group, an oral switch was made in 17 patients (19.7%), while no oral option was available in 48 (55.8%) based on susceptibility results. After adjustment, ESBL was not significantly associated with clinical failure (aOR 1.85, 95% CI 0.33-10.48), recurrence (aOR 1.98, 95% CI 0.70-5.62) or mortality (aHR 2.12, 95% CI 0.43-10.38). However, ESBL-producing Ec-BUTI was associated with longer stays (p=0.014), higher pharmacy costs (p<0.001) and independently increased overall hospitalization costs by a median of €1,493 (p=0.022).

Conclusions: ESBL-producing Ec-BUTI was associated with greater healthcare resource consumption and costs, though not with worse clinical outcomes. These findings highlight the economic impact of antimicrobial resistance, and support antimicrobial stewardship.

Comprehensive global assessments of antimicrobial resistance (AMR) mortality in lower respiratory infections (LRIs) are limited. Using data from the Global Burden of Disease 2021 study, we analyzed the global and regional burden of AMR-associated and AMR-attributable LRI mortality from 1990 to 2021. The analysis covered 74 pathogen-drug combinations. Trends in age-standardized mortality rates (ASMRs) were quantified using the estimated annual percentage change (EAPC). In 2021, AMR was associated with 1.64 million (95% uncertainty interval [UI]: 1.44, 1.84) global LRI deaths and directly attributable to 0.40 million (0.34, 0.46). Although ASMRs declined significantly from 1990 to 2021 (EAPC: -2.31 for AMR-associated, -2.05 for AMR-attributable), the absolute burden shifted markedly by age, with substantial reductions in children under five contrasting with rising deaths among adults ≥60 years. Globally, males exhibited a higher mortality burden than females, although the magnitude and statistical significance of this disparity varied by age group. Sub-Saharan Africa experienced the highest regional burden. Six pathogens-Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli-accounted for >92.1% of deaths. While resistance of S. pneumoniae to trimethoprim-sulfamethoxazole and macrolides contributed the most AMR-associated deaths globally, β-lactam resistance emerged as the leading cause of AMR-attributable deaths. This burden was driven by resistant strains of S. pneumoniae, alongside critical Gram-negative pathogens including A. baumannii, K. pneumoniae, and P. aeruginosa. These findings highlight successful reductions in pediatric AMR mortality and reveal urgent gaps in addressing Gram-negative resistance, the growing geriatric burden, and pervasive disparities. Equitable vaccine access, enhanced diagnostics, and targeted interventions are critical to mitigating the global AMR burden in LRIs.

Introduction: Ceftazidime is a mainstay in the treatment of neonatal sepsis. However, the lack of pharmacokinetic data regarding its blood-cerebrospinal fluid (CSF) penetration in neonates hinders accurate exposure assessment and dose optimization for patients with concomitant central nervous system infections.

Methods: A population pharmacokinetic (PPK) model was established using plasma and CSF samples from 69 neonates using NLME software. Model predictive performance was validated using goodness-of-fit plots, bootstrapping, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were employed to optimize dosing regimens, targeting a probability of target attainment (PTA) ≥90%.

Results: A two-compartment plasma-CSF model was developed, with body weight and eGFR identified as significant covariates for ceftazidime clearance. Simulations indicated that a 50 mg/kg q8h regimen (30-minute infusion) achieved ≥ 90% PTAs for bloodstream infections (MIC ≤ 4 mg/L) in neonates weighing 2-5 kg with an eGFR of 15-60 mL/min/1.73m². Achieving similar PTAs in the CSF for MIC = 4 mg/L requires a 4-hour extended infusion. For higher CSF MICs (MIC = 8 mg/L), 150 mg/kg/day or less cannot achieve the desired pharmacodynamic targets (PTAs < 90%), regardless of infusion modality.

Conclusion: This study developed a PPK model of ceftazidime in plasma and CSF. The dosing regimen of 50 mg/kg q8h (30-minute infusion) is suitable for treating most cases of neonatal sepsis caused by susceptible Enterobacterales in neonates with normal body weight and renal function. For CSF infections with MICs up to 4 mg/L, extended infusion is recommended. Precise dosing should be tailored to the developmental maturity, renal function, and pathogen susceptibility.

Highly pathogenic avian influenza H5N1 continues to pose a serious zoonotic and pandemic threat due to its increasing cross-species transmission and high virulence in humans. Despite the availability of vaccines and antivirals for seasonal influenza, effective prophylactic and treatment options for H5N1 remain limited. Herein we explore the potential action of monoclonal antibodies (mAbs) against H5N1, focusing on those with demonstrated efficacy in animal models. Most of these mAbs target conserved hemagglutinin epitopes and function as broad neutralizing fusion/entry inhibitors; notably, CR9114 targets both groups 1 and 2 influenza A strains as well as B lineages. Other mAbs prevent viral release by targeting neuraminidase, and those directed against the M2 ectodomain and nucleoprotein function through Fc receptor-mediated pathways. These mAbs have shown robust protection against lethal H5N1 challenge in mice, ferrets, and/or non-human primates. Compounds such as CR6261, MEDI8852, and TCN-032 have been evaluated in clinical trials for seasonal influenza, yielding encouraging safety and pharmacokinetics results and notably, no reported emergence of resistance. Despite these positive results their clinical development was prematurely discontinued. Integrating these highly effective mAbs into our H5N1 pandemic preparedness arsenal is a logical next step to provide a robust prophylactic and therapeutic option at the early stages of an outbreak. Future efforts must address regulatory and logistical barriers, invest in stockpiling and emergency use protocols, and support adaptive clinical trial frameworks to ensure rapid deployment when needed.

Objective: To define the epidemiology, antimicrobial resistance phenotypes, and genomic mechanisms of ceftazidime/avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) across China.

Methods: We conducted multicenter surveillance (2021-2024) across 26 tertiary hospitals in 19 provinces. Isolates underwent identification, broth microdilution AST, and whole-genome sequencing with genomic analyses. In KPC-2 only CZA-resistant isolates, bla_KPC-2 expression and copy number were quantified, and porin/efflux mutations and expression were evaluated.

Results: Among 4739 isolates, 101 (2.1%) were CZA-resistant CRKP, mainly older male inpatients with lower-respiratory infections. NDM predominated (55.4%); dual NDM+KPC producers showed the broadest, highest-level resistance. Tigecycline remained most active (3%), while resistance to other agents was generally ≥37%. Genomic analysis revealed substantial resistance burdens (mean 15.4 ARGs; 4.1 plasmids per isolate), with ST11 predominating (42.6%) and concentrated in a major cluster linked to KL64/KL47 and IncF replicons; hypervirulence markers were absent. Among nine (8.9%) KPC-2-only CZA-resistant isolates, high-MIC strains showed significantly higher bla_KPC-2 expression and copy number; susceptibility was restored in 8/9 isolates with 8 mg/L avibactam. Stepwise induction demonstrated increasing bla_KPC-2 expression with rising MICs. In addition, 8/9 isolates carried OmpK35/OmpK36 and/or AcrA/B alterations, and efflux inhibition with PABN reduced MICs by ≥4-fold in 6/9 isolates.

Conclusion: CZA-resistant CRKP in China are uncommon but widely distributed, driven mainly by epidemic ST11-KL64/KL47 lineages with extensive multidrug resistance and no convergence with classical hypervirulence. In the small subset of KPC-2-only isolates, resistance correlated with increased bla_KPC-2 expression/copy number and efflux involvement, with frequent co-occurrence of porin structural variants.

Objective: We aimed to identify factors associated with vancomycin trough concentration (VTC) target non-attainment in critically ill adults using a stratified approach.

Methods: This retrospective cohort study included 342 ICU patients with vancomycin plasma trough concentrations from September 2014 and December 2022. Patients were categorized by VTCs: subtherapeutic (<10 μg/mL), target (10-20 μg/mL), or supratherapeutic (>20 μg/mL). The clinical characteristics, concentration distributions, and patient outcomes were compared. Multinomial logistic regression and stratified analyses identified risk factors for non-attainment concentration (subtherapeutic and supratherapeutic subgroups). Network pharmacology was employed to analyze the mechanisms of potential drugs specifically associated with vancomycin-associated acute kidney injury (VA-AKI).

Results: Overall, VTC target attainment was 27.19% (93/342), with inter-ICU variability. Stratified analysis revealed distinct predictors: in the model comparing subtherapeutic with therapeutic VTCs, younger age (p=0.020), lower BUN (p=0.011), and higher eGFR (p=0.008) were associated with subtherapeutic levels; in the model comparing supratherapeutic with therapeutic VTCs, glucocorticoid use (p=0.012) and lower eGFR (p=0.006) were associated with supratherapeutic levels. 3 genes (AR, IL6, SERPINA6) involved in glucocorticoids and VA-AKI signaling pathways. Bacterial eradication was highest in the target group (65.59%), and the clinical improvement was better than that of the supratherapeutic group (p=0.006).

Conclusion: The predictors of non-attainment of vancomycin target trough concentrations are concentration-specific: younger age, lower BUN, and higher eGFR predispose to subtherapeutic levels, whereas glucocorticoid use and lower eGFR predispose to supratherapeutic levels. Achieving target VTC is beneficial for optimal efficacy. Our study may provide insights for promoting target vancomycin trough concentrations.

The gut mycobiome influences adipose tissue thermogenesis and obesity. Amphotericin B (AmB) has been shown to improve steatohepatitis in mice fed a high-fat diet (HFD). The objective of this study was to examine the effects of AmB on diet-induced obesity and the resulting gut mycobiome dysbiosis in mice. Male C57BL/6 mice were fed a normal-fat diet or an HFD, with HFD-mice receiving either no treatment or AmB gavage. After 11 weeks, adipose indexes, lipid levels, tissue histology, gene expression, and the gut mycobiome composition were analyzed. Key fungal species in lipid metabolism were isolated from mouse cecal contents by culture, and their cholesterol-lowering potential was assessed in vitro. AmB treatment of HFD-mice decreased body weight and epididymal fat mass, increased the brown fat index, improved serum cholesterol profiles, and decreased adipocyte size. It upregulated the thermogenic genes peroxisome proliferator-activated receptor γ (PPARγ), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), and uncoupling protein 1 (UCP1) in adipose tissue, improved colon barrier integrity (elevated the levels of Occludin and Muc2), and altered the gut mycobiome composition by increasing the abundance of Rhodotorula and decreasing that of Aspergillus. Rhodotorula was identified as a keystone taxon. An isolated strain, R. mucilaginosa DM2025, demonstrated cholesterol-lowering capacity in vitro. AmB ameliorates HFD-induced obesity by improving lipid metabolism, promoting adipose tissue browning and thermogenesis, and modulating the gut mycobiome. R. mucilaginosa may be a keystone species in the regulation of obesity.