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.
BACKGROUND Streptococcus pyogenes (Group A Streptococcus, GAS) is a major global pathogen. While macrolide resistance has been studied, large-scale analyses of overall antimicrobial resistance (AMR) in GAS across geographic datasets remain limited. This study aimed to comprehensively investigate AMR in GAS over more than a century. METHODS A total of 47,689 high-quality S. pyogenes genomes from 59 countries, collected between 1900 and 2025 (predominantly post-1990), underwent quality control. Multilocus sequence typing and in silico prediction of AMR determinants using AMRFinderPlus v4.2.5 were performed. Temporal trends were analyzed via quasibinomial regression. Phenotypic susceptibility data from 310 isolates were interpreted using CLSI 2023 breakpoints. RESULTS GAS showed high genomic conservation (mean genome size, ∼1.81 Mb; ∼1,705 coding sequences). The non-macrolide resistome was dominated by tetracycline and aminoglycoside-associated genes, with tet(M) being the most prevalent (20.96%), followed by aph(3')-IIIa (8.50%), sat4 (8.30%), and ant(6)-Ia (7.69%). Overtime, the prevalence of sat4, aph(3')-IIIa, ant(6)-Ia, and tet(M) increased significantly, whereas that of tet(L), tet(O), and pbp2x_P601L declined (P < 0.05). Reduced susceptibility to selected β-lactams (cefuroxime, imipenem, meropenem) was sporadic (3-10%), primarily linked to pbp2x_P601L, whereas penicillin retained near-universal activity (99.7% susceptibility). Typical β-lactamase genes were rare and geographically restricted. Phenotypic resistance was detected for tetracycline (6%) and trimethoprim-sulfamethoxazole (4%), with 13% showing intermediate susceptibility to trimethoprim-sulfamethoxazole. CONCLUSIONS S. pyogenes remains highly susceptible to penicillin and other β-lactams. Resistance is mainly associated with tetracycline and aminoglycoside genes, which show dynamic changes over time due to ongoing selection pressures.
OBJECTIVES Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of infectious diseases. We analyzed the recent trends in molecular epidemiology of MRSA in northern Japan. METHODS MRSA isolates from all types of clinical specimens were genetically classified by MLST and typing schemes of SCCmec, spa, coa, and agr. Antimicrobial susceptibility was measured by broth microdilution test, and resistance/virulence determinants were detected by multiplex/uniplex PCR, and sequencing as required. RESULTS A total of 321 MRSA isolates were collected during the 6-month period in 2025, and differentiated into three major clonal groups, clonal complex 1-SCCmec IV (CC1-IV)-coa-VIIa (62%), CC5-II-coa-IIa (27%), and CC8-IV-coa-IIIa (6%). The proportion of CC1-IV in 2025 increased significantly compared with that in 2011-2014 (<10%), associated with the decrease in CC5-II, while CC8-IV showed persistently low prevalence. CC1 isolates comprised a predominant ST1 and minor ST2725 and ST2764, with dominant spa-type t1784. Most CC5 MRSA consisted of ST5 (64%) and ST764 (35%), with half of ST764 isolates carrying arginine catabolic mobile element (ACME) type II'. Panton-Valentine leukocidine (PVL) genes were detected in ST8-IVa/spa-t008 with ACME-I (USA300 clone), ST22-IV with tst-1 (ST22-PT clone), ST1232 (CC398)-V, and ST10821 (ST8-single locus variant)-IVa. PVL-negative ST8 with SCCmec-IVl (CAMRSA/J clone, n=7) was found to harbor novel enterotoxin gene se01/sel30. As rare clones in Japan, ST5-IV (n=2) and ST5-VI (n=1) were identified in this study. CONCLUSIONS This study revealed the recent clonal shift of major MRSA in northern Japan, along with the occurrence of presumptive emerging clones.
