Objectives: This study aimed to elucidate the molecular epidemiology, virulence factors, and antimicrobial resistance profiles of Staphylococcus aureus isolated from children with osteomyelitis and septic arthritis (OM-SA) in China. Methods: A total of 68 S. aureus isolates were collected from paediatric patients with OM-SA in Shanghai, China, with 100 strains from children with other infections serving as controls. We performed a systematic analysis on all strains by integrating clinical metadata, whole-genome sequencing, and antimicrobial susceptibility testing. Results: Among S. aureus isolates from OM-SA cases, CC22-t309 was the dominant clone (32.3%), followed by CC59-t437 (17.6%). The prevalence of CC22-t309 in OM-SA was much higher than that in the control (32.3% vs. 8.0%, P < 0.001). OM-SA patients with CC22-t309 infection presented much higher inflammatory markers than those infected with other clones ( P < 0.05). Notably, CC22-t309 from OM-SA exhibited higher carriage of virulence factors, including Panton–Valentine leukocidin ( pvl , 100%), collagen adhesin ( cna , 86.4%), and fibronectin-binding proteins ( fnbA/B , 77.3%), compared with other clones ( pvl , 0∼66.7%; cna , 0∼13.8%; fnbA/B , 0∼24.1%; P < 0.05). Within CC22-t309 clone, the carriage of pvl, fnbB and fnbA showed no difference between OM-SA and control group ( pvl : 100% vs. 87.5%; fnbB : 77.3% vs. 85.7%; fnbA: 77.3% vs. 37.5%; P > 0.05). However, the prevalence of cna in OM-SA was significantly higher than that in the control group (86.4% vs. 37.5%, P = 0.015). Furthermore, CC22-t309 isolates displayed a multidrug-resistant phenotype against β -lactams, macrolides, and lincosamides. Conclusion: We identify the hypervirulent and multidrug-resistant CC22-t309 as a high-risk S. aureus lineage associated with paediatric OM-SA.
Colistin is a last-resort antibiotic used to treat infections caused by multidrug-resistant Gram-negative pathogens, including Klebsiella pneumoniae . Resistance to colistin can be explained by canonical mechanisms involving chromosomal mutations that activate lipid A modification pathways or by acquisition of plasmid-mediated mcr genes. These mechanisms modify the net charge of the bacterial outer membrane, reducing the binding affinity of colistin. However, an increasing number of genomic surveillance studies report colistin-resistant K. pneumoniae isolates that lack detectable alterations in known resistance mechanisms. This genotype–phenotype discordance suggests that additional regulatory mechanisms may contribute to colistin resistance. This review evaluates the hypothesis that mutation-independent regulatory changes within the PhoP/PhoQ–PmrA/PmrB–CrrA/CrrB signalling network may alter the output of lipid A modification pathways in isolates lacking detectable canonical resistance determinants. This model remains to be experimentally validated. The role of small regulatory RNAs (sRNAs) as potential post-transcriptional modulators of regulatory networks involved in envelope remodelling and antimicrobial susceptibility is explored as a potential explanation for this genotype–phenotype discordance. Finally, experimental approaches including transcriptomics, RNA–RNA interaction mapping, and functional validation are discussed as strategies to study sRNA-mediated regulatory networks. Understanding these regulatory mechanisms may help explain unresolved resistance phenotypes and refine antimicrobial resistance surveillance frameworks.
Background: Cefiderocol is a siderophore cephalosporin with potent activity against carbapenem-resistant gramme-negative bacteria (CR-GNB). While monotherapy is recommended for susceptible Enterobacterales and Pseudomonas aeruginosa , the role of cefiderocol-based combination therapy remains uncertain. We conducted a systematic review of preclinical and clinical evidence supporting cefiderocol combination regimens. Methods: MEDLINE, ESCMID global and IDWeek sources (January 2015–January 2025) were systematically searched for in vitro, in vivo, and clinical studies evaluating cefiderocol-based combinations. Randomised trials, observational studies and preclinical synergy studies were included. An exploratory random-effects meta-analysis compared cefiderocol monotherapy with combination therapy for mortality, clinical cure and microbiological eradication. Results: Sixty-seven studies were included (34 in vitro , 5 in vivo and 31 clinical). Preclinical data showed enhanced cefiderocol activity when combined with β-lactamase inhibitors, tetracyclines and selected β-lactams, with in vivo models supporting improved bacterial killing and survival for selected combinations. Clinical studies were heterogeneous and frequently confounded. Combination therapy showed no consistent advantage over monotherapy for clinical cure or microbiological eradication, while mortality estimates were highly variable. Conclusions: Cefiderocol combinations show biologically plausible synergy in preclinical models, but current clinical evidence is limited and largely observational, failing to identify combinations that reliably improve patient-centred outcomes.
Background Cefiderocol is a siderophore cephalosporin with potent activity against carbapenem-resistant gramme-negative bacteria (CR-GNB). While monotherapy is recommended for susceptible Enterobacterales and Pseudomonas aeruginosa, the role of cefiderocol-based combination therapy remains uncertain. We conducted a systematic review of preclinical and clinical evidence supporting cefiderocol combination regimens. Methods MEDLINE, ESCMID global and IDWeek sources (January 2015–January 2025) were systematically searched for in vitro, in vivo, and clinical studies evaluating cefiderocol-based combinations. Randomised trials, observational studies and preclinical synergy studies were included. An exploratory random-effects meta-analysis compared cefiderocol monotherapy with combination therapy for mortality, clinical cure and microbiological eradication. Results Sixty-seven studies were included (34 in vitro, 5 in vivo and 31 clinical). Preclinical data showed enhanced cefiderocol activity when combined with β-lactamase inhibitors, tetracyclines and selected β-lactams, with in vivo models supporting improved bacterial killing and survival for selected combinations. Clinical studies were heterogeneous and frequently confounded. Combination therapy showed no consistent advantage over monotherapy for clinical cure or microbiological eradication, while mortality estimates were highly variable. Conclusions Cefiderocol combinations show biologically plausible synergy in preclinical models, but current clinical evidence is limited and largely observational, failing to identify combinations that reliably improve patient-centred outcomes.
