International Journal of Antimicrobial Agents最新文献

Background: Carbapenem-resistant Escherichia coli (CREC) producing New Delhi metallo-beta-lactamase (NDM) poses a substantial threat to global public health. Prompt detection of CREC is essential for effective patient management and to curb the spread of resistance.

Objective: This study aims to establish a rapid and reliable detection method for NDM-producing CREC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) in conjunction with machine learning (ML) techniques.

Methods: Clinical isolates of E. coli were collected from the First Hospital of Jilin University's clinical laboratory from August 2018 to December 2022. PCR was employed to detect 23 prevalent resistance genes in the isolates. Protein profiles were analyzed by MALDI-TOF MS with a cooperative matrix consisting of (E)-propyl α-cyano-4-hydroxylcinnamylate (CHCA-C3) and α-cyano-4-hydroxycinnamic acid (CHCA). By comparative analysis of nine ML algorithms, the optimal Random Forest (RF) algorithm was identified and used to find the NDM specific ion peaks. Furthermore, the NDM gene was cloned into the standard E. coli strain ATCC 25922 to verify the reliability of these specific peaks.

Results: A total of 154 E. coli strains were categorized into three groups: 45 CREC strains, 58 extended-spectrum beta-lactamase (ESBL)-producing strains, and 51 non-CREC, non-ESBL strains. PCR amplification identified 12 resistance genes. The established ML model with RF algorithm exhibits excellent discriminative ability, achieving an AUC of 0.993 and an AP of 0.997. Four specific peaks (m/z 5132, m/z 5209, m/z 6350, and m/z 6371) of NDM were identified using the cooperative matrix. In contrast, the traditional CHCA matrix revealed no specific peaks. Furthermore, the specific peaks at m/z 5132 and m/z 5209 were detected in the MALDI-TOF MS spectra of the recombinant E. coli strain ATCC 25922-PZY01/NDM, which directly correlated with the expression of the NDM gene.

Conclusion: The integration of MALDI-TOF MS with ML techniques, facilitated by the cooperative matrix approach, has enabled the swift and precise identification of NDM-producing CREC. This advancement significantly enhances the effectiveness of clinical management and the control of hospital-acquired infections.

Objectives: To identify and characterise a novel KPC variant (KPC-271) and evaluate its molecular, phenotypic and fitness impacts in an ST15-KL19 Klebsiella pneumoniae strain.

Methods: Sequential K. pneumoniae isolates were obtained from a single patient undergoing ceftazidime-avibactam and carbapenem therapy. The following tests were performed: antimicrobial susceptibility testing; plasmid conjugation and transformation assays; bla_KPC cloning; whole-genome sequencing; and enzyme kinetic assays. Fitness costs were assessed using plasmid stability, growth curves and competition assays. The genetic environments of the bla_KPC were analysed using comparative genomics.

Results: KPC-271 harboured a D179Y substitution within the omega loop and an insertion (KDDKH) at Ambler position 269 within the 267-275 loop. Antimicrobial susceptibility testing of clinical isolates revealed ceftazidime MICs of >32 mg/L for both KPC-271 and KPC-2, ceftazidime-avibactam MICs of >64 vs. 1 mg/L, meropenem MICs of 2 vs. 64 mg/L, and imipenem MICs of 0.125 vs. 32 mg/L. Analysis of the kinetic parameters of KPC-271 compared to KPC-2 revealed enhanced ceftazidime hydrolysis and reduced avibactam inhibition with an increased IC₅₀ value, but diminished carbapenemase activity. Fitness assays indicated that bla_KPC-271 imposed a minimal cost, potentially conferring competitive advantages over bla_KPC-2. Genomic analysis revealed that the bla_KPC-271 was located within NTE_KPC-Ib-like elements on plasmids that were closely related to those in circulation in Shanghai.

Conclusions: KPC-271 mediates resistance to ceftazidime-avibactam while restoring carbapenem susceptibility without imposing a significant fitness burden. The localisation of bla_KPC-271 within mobile elements highlights its dissemination potential and underlines the need for continuous molecular surveillance and prudent antibiotic use.

Introduction: Gepotidacin is a new triazaacenaphthylene antibiotic approved for the treatment of female patients with uncomplicated urinary tract infections (uUTIs). Its bactericidal activity stems from its unique ability to inhibit both DNA gyrase and topoisomerase IV.

Methods: A systematic search was conducted in PubMed, Embase, Web of Science, and Scopus for relevant publications. US Food and Drug Administration (FDA) resistance breakpoints were used.

Results: An analysis of 23,711 isolates from 15 studies demonstrated a consistently low resistance to gepotidacin across various bacterial species and resistance phenotypes. Among Enterobacterales isolates, the resistance and intermediate category was 0%-6.8% and 0%-8%, respectively. For Gram-positive bacterial uropathogens, susceptibility to gepotidacin was 99.2% and 100% in 2 studies for Enterococcus faecalis isolates and ranged from 66.7% to 100% for Staphylococcus saprophyticus isolates. Resistance among extended-spectrum β-lactamase (ESBL)-producing Enterobacterales isolates ranged from 0% to 0.6%. Resistance among multidrug-resistant (MDR), defined as resistant to ≥3 relevant antibacterial classes, Gram-negative uropathogen isolates (323 MDR Escherichia coli, 27 MDR Klebsiella pneumoniae, and 21 MDR Proteus mirabilis in one study, as well as 244 MDR E. coli isolates in another study) was 0%. Similarly, resistance to gepotidacin was 0% in Enterobacterales isolates resistant to ampicillin, amoxicillin-clavulanic acid, mecillinam, cefadroxil, fluoroquinolones, fosfomycin, nitrofurantoin and trimethoprim-sulfamethoxazole.

Conclusion: Gepotidacin has very good antimicrobial activity against a variety of pathogens that cause uUTIs. Importantly, it retains activity against uropathogen isolates that exhibit resistance to other antibiotics commonly used for UTIs making it a useful addition to a physician's therapeutic arsenal.

Background: Fungal keratitis remains a leading cause of corneal blindness in tropical and subtropical regions. The limited corneal penetration of topical antifungals has prompted investigation into intracameral amphotericin B (ICAMB), which delivers higher intraocular concentrations beyond the corneal epithelium and stroma, although the corneal endothelium remains a pharmacologic barrier.

Objective: To systematically evaluate the efficacy and safety of ICAMB in fungal keratitis and synthesize current evidence from randomized, cohort, and case-series studies.

Methods: A PRISMA-guided systematic review and meta-analysis were conducted using PubMed, Scopus, Cochrane Library, and Google Scholar through May 2025. Eligible studies assessed ICAMB, alone or in combination with topical therapy, in confirmed or clinically suspected fungal keratitis. Outcomes included ulcer healing rate, mean healing time, visual acuity, hypopyon resolution, need for keratoplasty, and adverse events. Random-effects models and GRADE assessments were applied to evaluate pooled data and evidence quality.

Results: Seventeen studies (n = 491 eyes) were included. ICAMB significantly improved ulcer healing rate (OR 1.8, 95% CI 1.6-1.9, p < 0.001), shortened mean healing time by 4.3 days (95% CI -5.8 to -2.8, p < 0.001), and reduced hypopyon duration by 14.6 days (95% CI -17.4 to -11.8, p < 0.001). The requirement for therapeutic keratoplasty decreased significantly (logit event rate -0.71, p < 0.001). Improvement in visual acuity was modest but significant (standardized mean difference (SMD) 0.5, p < 0.001). Heterogeneity across analyses was low (I² < 10%), and GRADE evaluation indicated moderate-to-high certainty for efficacy and high certainty for safety. No ocular or systemic adverse events were reported at standard doses (≤10 µg/0.1 mL).

Conclusions: ICAMB was associated with improved healing and reduced surgical intervention in fungal keratitis without reported toxicity. Although the evidence is primarily observational, the consistency of effect across cohort and case-series data supports its potential role as an adjunctive therapy in severe or refractory fungal keratitis. The term conventional treatment in this context refers to standard topical antifungal therapy (e.g., natamycin, voriconazole). No data were available regarding species-level amphotericin susceptibility or Candida ocular surface disease comorbidity. Future trials should include standardized outcome definitions and controlled comparisons to validate these findings.

Klebsiella pneumoniae is an opportunistic pathogen responsible for both hospital and community acquired infections. It is broadly classified into classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp), with the latter being linked to increased mortality owing to its capacity for invasive and metastatic infections. The recent global emergence of carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKp) strains poses a serious and escalating public health threat worldwide. In this study, we conducted a comprehensive genomic analysis of all publicly available ST23 genomes (n = 1,622) from the NCBI database, collected between 1980 and 2024, to investigate the evolutionary dynamics and global dissemination of this emerging high-risk clone. We systematically analyzed antimicrobial resistance profiles, virulence factors, plasmid content, and phylogenetic relationships, with particular emphasis on the emerging CR-hvKp ST23-KL57 lineage. ST23 strains were identified in 42 countries, including 263 CR-hvKp ST23 strains (16.2% of the total), which were detected in 22 countries. Although both ST23-KL1 (n = 1,577) and ST23-KL57 (n = 45) belong to the same sequence type, phylogenetic analysis revealed substantial single nucleotide polymorphism (SNP) divergence, classifying them into two distinct sublineages (SLs): ST23-KL1 (SL23) and ST23-KL57 (SL218). The newly emerged ST23-KL57 strains exhibited higher levels of antimicrobial resistance, smaller genome sizes, lacked key chromosomal virulence loci (GIE492 and all_island), and were predominantly distributed in Europe. Notably, 77.8% of ST23-KL57 strains were identified as CR-hvKp, underscoring the alarming convergence of carbapenem resistance and hypervirulence. These findings reveal the emergence of a highly adaptive international clone and highlight the urgent need for enhanced global surveillance efforts and more granular sublineage-level genomic characterization to inform public health responses and clinical management.

Background: Daptomycin is increasingly used to treat Gram-positive infections, but carries a risk of muscle toxicity. Despite guideline recommendations, real-world adherence to safety monitoring remains poorly documented.

Objectives: To evaluate daptomycin prescribing practices and identify risk factors for muscle toxicity across three French university hospitals.

Methods: We conducted a retrospective multicenter study of adults (≥18 years) treated with daptomycin between June 2021 and May 2022. Data included demographics, treatment, monitoring, microbiology, and adverse events. Muscle toxicity was defined as an elevation of CK (> 5 upper normal value) and/or rhabdomyolysis, identified by explicit documentation in medical records. Logistic regression identified associated factors.

Results: We collected data from 1,407 patients (65.1% male; mean age 62.4 ± 16.5) treated with daptomycin during the study period, for a mean duration of 7.87 ± 7.05 days. Most patients (93.9%) received high-dose daptomycin, ≥8 mg/kg/day. Combination therapy was frequent (72%), mostly with β-lactams (91.8%). CK monitoring was reported in 34.2% of patients, muscle toxicity was reported in 4.9%, including rhabdomyolysis in 2.7%. Statins were co-prescribed without discontinuation in 15.6% of cases. In multivariate analysis, concomitant use of high-risk comedications, including statins and fibrates (OR [95% CI] = 6.68 [3.28-13.97], P<0.001) and obesity (OR 2.25 [1.07-4.72], P=0.03) were independently associated with muscle toxicity.

Conclusion: Despite widespread use of high-dose daptomycin, safety monitoring was inconsistent. Systematic CK testing and careful review of myotoxic co-medications are essential to mitigate adverse events in clinical practice.

The rising prevalence of drug resistance has emerged as a major obstacle to global tuberculosis (TB) control, necessitating the development of novel host-directed strategies. In this study, we conducted a cell-based screening of a G-protein-coupled receptor-related compound library and identified amodiaquine hydrochloride (CAS), a conventional antimalarial drug, as a potent inducer of autophagic killing of intracellular Mycobacterium tuberculosis (Mtb). Further mechanistic investigation revealed that CAS reduced the phosphorylation of PI3K, AKT and mTOR in Mtb-infected macrophages, thereby promoting ULK1 activation and autophagic induction. In vivo studies using the BALB/c mouse model demonstrated that CAS treatment significantly reduced bacterial load in lungs. Taken together, our findings highlight CAS as a novel host-directed therapeutic agent capable of enhancing the intracellular clearance of Mtb by triggering autophagy in macrophages.