BACKGROUND:Carbapenem-resistant Enterobacterales (CRE) bloodstream infections are associated with high mortality and limited treatment options. This study aimed to characterize CRE epidemiology, identify risk factors for 30-day mortality, and evaluate the impact of appropriate combination therapy on mortality in patients with CRE bacteremia using treatment regimens prior to the adoption of novel β-lactam/β-lactamase inhibitors. METHODS:This multicenter retrospective cohort study was conducted across 13 teaching hospitals in Korea. All notified CRE-positive cases (n=8,687) were analyzed descriptively, while all clinical outcome analyses were confined to patients with monomicrobial CRE bacteremia (n=358). Antibiotic appropriateness was independently evaluated by infectious disease specialists, and inverse probability of treatment weighting (IPTW) was applied to adjust for confounding between treatment groups. RESULTS:Blood-positive specimens accounted for 12.4% of all CRE-positive cases, a proportion that has increased over time. Among the bacteremia cohort, the 30-day mortality was 34.1%. Independent predictors of 30-day mortality included higher qSOFA score (Odds Ratio [OR]=1.57; 95% Confidence Interval [CI] 1.22-2.01; P<0.001) and septic shock (OR=5.17; 95% CI 3.03-8.81; P<0.001). Combination therapy showed no overall survival advantage after IPTW adjustment. However, a significant mortality benefit was observed with definitive colistin-based combination therapy (adjusted OR=0.42; 95% CI 0.18-0.98; P=0.044) and in those with a high comorbidity burden (CCI ≥6; adjusted OR=0.34; 95% CI 0.12-0.98; P=0.046), though not in KPC-producing K. pneumoniae subgroup. Among KPC-producing K. pneumoniae isolates, amikacin and colistin retained high in vitro activity. CONCLUSIONS:In CRE bacteremia, combination therapy did not confer a uniform survival advantage, but was associated with lower mortality in patients receiving colistin-based regimens and those with high comorbidity burden. Sustained antimicrobial stewardship and continuous susceptibility surveillance of blood isolates remain essential for optimizing patient outcomes in settings where novel agents are limited.
Klebsiella pneumoniae ranks at the top of the WHO priority pathogen list. The convergence of carbapenem resistance with hypervirulence is exhausting pathogen-directed therapy. Host-directed therapy (HDT) offers a structural alternative: because it acts on host targets, it is largely indifferent to the carbapenemases that confer resistance.K. pneumoniae remodels the host immune microenvironment through four mechanisms: suppressing NF-κB/MAPK/interferon signaling, blunting inflammasome and oxidative-burst effectors, reprogramming macrophages into the intracellular M(Kp) sanctuary, and depleting the lymphocyte compartment. These are now well characterized; their therapeutic corollary has not been assembled.We map each evasion node onto pharmacological agents and natural products, graded by evidence directness. Four strategies carry direct evidence in carbapenem-resistant or multidrug-resistant K. pneumoniae: recombinant IL-22, L-arginine, autophagy-inducing sensitization, and T-cell correction. Two principles govern deployment: resistance-agnostic efficacy against carbapenemases, and a directional, phase-dependent hazard, whereby modulators can help in one phase or compartment and harm in another.Most claims remain graded as K. pneumoniae (not necessarily resistant) or extrapolated from sepsis/oncology, with only four nodes directly evidenced in resistant isolates; this is a hypothesis-generating map, not a validated algorithm. Key caveats: hypervirulent CRKP represses autophagy, potentially reversing agonists validated only in non-hypervirulent isolates; most natural products favor M2 polarization that may reinforce persistence; and antibiotics antagonize microbiota-restoring interventions, requiring sequential use. Individual biomarkers already carry preliminary clinical stratification value: mHLA-DR and the neutrophil-to-lymphocyte ratio have validated thresholds for immunoparalysis, and an inverted CD4/CD8 ratio is documented in CRKP cohorts; what remains unvalidated is their integration into a continuous, multi-marker intervention-window score. We convert residual gaps into a structured research agenda.
INTRODUCTION:Vancomycin is standard therapy for vancomycin-susceptible Enterococcus faecium bloodstream infection (VSE-BSI). Nephrotoxicity or patient-specific constraints may lead clinicians to use linezolid or daptomycin. METHODS:This retrospective study investigated the efficacy and safety of linezolid/daptomycin (n=83) versus vancomycin (n=134) in patients with VSE-BSI in 3 French hospitals (November 2015-April 2023). The primary outcome was treatment failure, defined as a composite of clinical failure, microbiological failure, 30-day all-cause mortality, and 90-day VSE-BSI recurrence. Risk factors for treatment failure and association between treatment and 30-day mortality were assessed. RESULTS:Overall treatment failure was 54% (52% vs 57%; p=0.49). Linezolid/daptomycin was not associated with higher risk of treatment failure (odds ratio (OR) 1.22, 95% confidence interval (CI) [0.57-2.62], p=0.61), unlike sepsis (OR 3.11, 95% CI [1.12-8.59], p=0.03) and baseline C-reactive protein (OR 1.01, 95% CI [1.00-1.01], p=0.01). The 30-day mortality was significantly higher in the linezolid/daptomycin group (45% vs 28%; risk ratio 1.57, 95% CI [1.10-2.25], p=0.02) but not after adjustment for confounding factors (hazard ratio 0.6, 95% CI [0.40-1.00], p=0.07). CONCLUSION:Linezolid or daptomycin was not independently associated with treatment failure. However, residual confounding and heterogeneity between these agents preclude conclusions of equivalence or causality. Linezolid or high-dose daptomycin may be considered when vancomycin is unsuitable.
OBJECTIVE:To elucidate the drug resistance characteristics, epidemiological distribution, and molecular mechanisms of third-generation cephalosporin-resistant Salmonella from animal sources in China during 2016-2024. METHODS:Antimicrobial susceptibility testing, serotyping, and whole-genome sequencing (WGS) were employed. RESULTS:Salmonella exhibited the highest resistance rate to ampicillin (91.9%), followed by sulfisoxazole (87.4%) and tetracycline (83.1%). Among these, strains producing extended-spectrum β-lactamases (ESBLs) accounted for 67.1% and were widely prevalent in chickens and ducks; their dominant resistance gene, blaCTX-M-55, is closely associated with IncI2 and is co-driven by ISEcp1, ISKpn26, IS150, and IS103. 6.2% of the strains carried cephalosporinases (AmpC), primarily from chickens, with blaCMY-59 associated with ISEcp1 as the predominant genotype. An additional 27.1% carried other β-lactamases, mostly from pigs, with the predominant genotype being blaTEM-1 associated with IS406. Notably, the carbapenemase gene blaNDM-1/5 was detected only in strains producing other β-lactamases and was associated with ISSbol and ISRor2. Serotype distribution showed that S. Kentucky predominantly carried ESBLs and AmpC, while S. Enteritidis was dominated by other β-lactamases. Phylogenetic analysis revealed that serotype is the primary factor determining the structure of Salmonella clonal groups, and the acquisition of resistance to third-generation cephalosporins in Salmonella may depend on both clonal transmission and horizontal gene transfer. CONCLUSION:This study is the first to untangle the differences in animal distribution and serotype associations of third-generation cephalosporin-resistant Salmonella over the past decade and to elucidate, at the genomic level, the formation mechanisms and transmission pathways underlying different resistance phenotypes.
Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus harbored by fruit bats (Pteropodidae). The virus spreads through zoonotic spillover via intermediate animal hosts or contaminated environments, and through human-to-human transmission. Since its emergence in 1998, NiV has triggered recurrent outbreaks across South and Southeast Asia, with case-fatality rates of 40-75%. Two genotypes (NiV-M and NiV-B) differ in transmissibility and pathogenicity. WHO-listed as a priority pathogen, NiV has no approved vaccines or antiviral therapeutics. The virus gains entry into host cells through Ephrin-B2/B3 receptors, and evades innate immunity via non-structural proteins (V, W, C) and structural proteins. These evasion strategies disrupt multiple nodes in type I and II interferon (IFN-I/II) signaling pathways, including suppression of RIG-I/MAVS and inhibition of STAT1/STAT2 nuclear translocation, and dysregulation of NF-κB activation. Finally, these mechanisms facilitate viral replication and systemic dissemination. Infection also elicits adaptive immunity, including neutralizing antibodies against viral glycoproteins (G and F) and durable virus-specific CD4⁺ and CD8⁺ T-cell responses. Fatal outcomes correlate with high early viremia, delayed or insufficient antibody production, and dysregulated innate and adaptive immunity. In affected organs, particularly the brain, persistent cytokine storm driven predominantly by CXCL10 recruits inflammatory infiltrates and amplifies immunopathological damage. Current intervention strategies include vaccine candidates (ChAdOx1 Nipah B, mRNA-1215, HeV-sG) and antiviral approaches such as nucleoside analogs, monoclonal antibodies, and fusion inhibitors. This review comprehensively synthesizes current knowledge on NiV epidemiology, pathogenesis, and countermeasure development, providing a conceptual framework to interpret its exceptional virulence and prioritize targets for effective outbreak control.
BACKGROUND:The association between fluoroquinolones (FQs) and peripheral neuropathy (PN) poses a severe challenge to patient safety. This study aimed to characterize PN signals for ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin using large-scale pharmacovigilance databases and explore potential mechanisms. METHODS:Pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS, 2004-2025) were analyzed and corroborated with the Canada Vigilance Adverse Reaction Database (CVARD). Signal detection utilized four disproportionality algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). Time-to-onset, subgroup analysis, and logistic regression were performed on FAERS data to identify clinical patterns. Network toxicology was employed to explore potential mechanisms. RESULTS:In FAERS (n=6,451), all FQs exhibited significant signals across all four algorithms. In the CVARD validation set, signals were confirmed for ciprofloxacin, levofloxacin, and moxifloxacin, while ofloxacin did not reach significance due to limited data. Within FAERS, ciprofloxacin (OR=2.71) and levofloxacin (OR=1.88) exhibited significantly higher reporting odds compared to moxifloxacin (p<0.001). PN onset was typically rapid (median 4-5 days). Logistic regression identified extended treatment duration and concomitant nitrofurantoin use as important factors associated with higher reporting odds. Mechanistic exploration suggested a potential association with pathways such as neuroactive ligand-receptor interaction. CONCLUSION:This study provides a comprehensive pharmacovigilance characterization of FQ-associated PN, revealing significant differences in reporting frequencies among FQs. These results underscore the need for a careful benefit-risk assessment when prescribing FQs, particularly for long-term oral therapy, and highlight the importance of further research to validate these associations.
BACKGROUND:Antimicrobial resistance (AMR) poses a critical threat to child health, particularly in resource-limited settings. A comprehensive assessment of the AMR-related mortality burden in children under five is needed to inform global strategies. METHODS:We conducted a secondary analysis of the Global Burden of Disease (GBD) 2021 estimates, extracting AMR-associated and AMR-attributable mortality data for children under five from 1990 to 2021, with projections to 2050. Analyses included historical trends, pathogen- and syndrome-specific burdens, and future projections under a reference scenario and two alternative scenarios. The alternative scenarios included a scenario assuming future drug development that targets Gram-negative pathogens (Gram-negative drug scenario) and a scenario assuming future improvements in health-care quality and access to appropriate antimicrobials (better care scenario). RESULTS:In 2021, AMR was associated with 0.84 million (95% UI 0.64-1.04) and attributable to 0.19 million (0.14-0.24) deaths globally in children under five, reflecting a substantial decline since 1990. Substantial regional disparities persisted, with Sub-Saharan Africa bearing the highest burden. Streptococcus pneumoniae accounted for largest number of AMR-associated deaths, while Klebsiella pneumoniae accounted for largest number of AMR-attributable deaths. Bloodstream infections and lower respiratory infections accounted for the majority of AMR-related mortality. For AMR-attributable deaths, key pathogen-drug combinations included beta-lactam-resistant S. pneumoniae, methicillin-resistant Staphylococcus aureus, and carbapenem-resistant Acinetobacter baumannii. Projections to 2050 indicate a continued decline. From 2025 to 2050, the better care scenario was projected to avert an estimated 10.65 million deaths, substantially exceeding the 1.09 million deaths averted under the Gram-negative drug scenario. CONCLUSIONS:Despite a declining global trend, AMR remains a pressing cause of mortality in children under five, marked by severe inequity. The persistent burden from multidrug-resistant Gram-negative pathogens underscores the need for comprehensive strategies that extend beyond antibiotic development, prioritizing improved healthcare access, infection prevention, and vaccination, especially in high-burden regions.
Antibiotic resistance in Helicobacter pylori is an important factor in the ineffectiveness of eradication regimens. The rate of resistance is not constant and varies widely by region and over time. Resistance is mainly due to point mutations in target genes like 23S rRNA (clarithromycin), gyrA/gyrB (fluoroquinolones), rdxA/frxA (metronidazole), and PBP1 (amoxicillin). Moreover, multi-drug resistance is mediated by efflux proteins (e.g., HefA, RND proteins), biofilm formation, and phase-variable epigenetics like DNA methylation, which regulate virulence and stress response. Immune evasion by the bacterium involves Toll-like receptor modulation, cytokine (IL-1β, TNF-α, IL-8) dysregulation, miRNA (e.g., miR-146, miR-155) modification, and persistent epigenetic field defects post-eradication, which may result in carcinogenesis via NF-κB and STAT3 signaling. H. pylori also induces gastric microbiome dysbiosis, with reduced microbial diversity, increased pro-inflammatory species, and extragastric manifestations like iron deficiency anemia, metabolic syndrome, and neurological complications. Microbiome-directed therapies, such as probiotics (Lactobacillus, Bifidobacterium), have been demonstrated to increase eradication success to 78-88%. Machine learning algorithms, including XGBoost and CNNs, accurately predict resistance from genomic sequences with over 90% sensitivity, integrating multi-omics for personalized therapy. Efflux pumps are key in multidrug resistance, while host epigenetics plays a role in bacterial persistence. Approaches include susceptibility testing, bismuth quadruple therapy, and novel adjuncts such as fecal microbiota transplantation. Prompt and personalized eradication is essential in overcoming antimicrobial resistance and preventing oncogenic transformation.
Vancomycin continuous infusion (CI) has been associated with lower nephrotoxicity. This study compared a 3-minute bolus/standard infusion comparator (SI) with 24-hour CI in a validated rat model. Male Sprague-Dawley rats (n=14) received a target total dose of 150 mg/kg as a 3-minute intravenous bolus followed by a 24-hour saline infusion (SI, n=7) or as an initial loading administration followed by continuous infusion to 24 hours (CI, n=7). Urine and serial plasma samples were collected, and terminal whole-kidney homogenates were assayed for vancomycin. Day 1 urine output increased from baseline in SI animals (19.4 vs 8.9 mL/24 h; p<0.001) but not in CI animals (12.4 vs 10.1 mL/24 h; p=0.446). Urinary KIM-1 and clusterin excretion increased on Day 1 in SI compared with baseline and CI (both p<0.001). Median AUC0-24h was 354.1 mg·h/L (IQR, 277.1-427.0) with SI and 379.9 mg·h/L (IQR, 337.7-500.9) with CI (exact Wilcoxon W=28; p=0.710). Whole-kidney vancomycin concentrations were numerically higher with SI (88.02 ± 85.12 vs 27.97 ± 18.74 µg/g; p=0.11). Urinary KIM-1 showed a four-parameter sigmoidal relationship with whole-kidney vancomycin concentration (R²=0.62). Continuous infusion was associated with lower biomarker-defined renal tubular stress and lower whole-kidney drug accumulation without a detectable difference in total systemic AUC0-24h.
The World Health Organization has listed antibiotic resistance as one of the top ten health threats. There is an urgent need to analyze the resistance mechanism to develop novel anti-infection strategies. Fatty acids have been reported to promote antibiotic resistance; however, the underlying mechanism is complex and requires further exploration. To address this, we investigated the effect of sodium oleate-mediated resistance by proteomics. The present study corroborated that sodium oleate decreased the sensitivity of E. coli to gentamicin being visualized by fluorescence imaging, bacterial survival curve and minimum inhibitory concentration (MIC) assays. Proteomic profiles after treatment with gentamicin or sodium oleate were significantly different, with a number of proteins significantly changing. Pathway enrichment analysis showed that fatty acid biosynthesis and the stress response were upregulated under gentamicin treatment, whereas sodium oleate upregulated fatty acid degradation, amino acids metabolism, siderophore transmembrane transporter activity and enterobactin biosynthetic process. The addition of sodium oleate increased the expression levels of genes involved in the fatty acid degradation pathway by qPCR. Additionally, sodium linoleate and sodium palmitate also reduced bacterial sensitivity to gentamicin. The higher level of acetyl-CoA was found, and acetic acid/sodium acetate also reduced bacterial sensitivity to gentamicin, which was associated with protein acetylation. Moreover, sodium oleate caused a decrease in membrane potential and porin permeability, thereby affecting gentamicin uptake. This study provides new insights of fatty acid-mediated resistance, which may contribute to the development of novel strategies for addressing antibiotic resistance.
INTRODUCTION:Treatment of vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) in patients with haematological malignancies remains challenging, with the optimal dosing regimen of the highly protein bound daptomycin uncertain. METHODS:Patients with haematological malignancies receiving contemporary daptomycin doses for confirmed VREfm BSIs had total daptomycin steady-state concentrations measured. Population pharmacokinetic (popPK) modelling and Monte Carlo simulations were performed to predict probabilities of target attainment (PTA). Targets utilised were fAUC24h,ss/MIC >27.43 or >81.87 (efficacy) and trough (Cmin) levels ≥24.3 mg/L or ≥60 mg/L (toxicity). fAUC was estimated using unbound fractions of 0.07, 0.10 and 0.14. RESULTS:Ten patients contributed 30 daptomycin concentrations. A two-compartment model, with creatinine clearance and lean body weight as covariates best described the data. Simulations showed that PTA increased as protein binding (PB) estimates decreased. 1200 mg was the only dose able to achieve PTA>90% for MICs of 4 mg/L when targeting fAUC24h,ss/MIC >27.43, PB 86%. PTA >90% was achievable for MICs ≤1 mg/L with doses ≥10 mg/kg or doses ≥850 mg daily (fAUC24h,ss/MIC>81.87, PB 86%). No doses achieved PTA >90% for MICs >4 mg/L for either efficacy target. Cmin increased with fixed and mg/kg dosing. CONCLUSION:In patients with VREfm BSIs with underlying haematological malignancies, PTA for daptomycin efficacy increases inversely to PB. Fixed 1200 mg doses may achieve desired PTA for higher MIC isolates (4 mg/L) in patients with lower albumin, however Cmin increases with daptomycin dose. Dosing strategies supported by therapeutic drug monitoring are recommended to optimise efficacy and minimise toxicity.
