OBJECTIVES We investigated transmission patterns and therapeutic options for Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) in Greek ICUs. METHODS CR-Kp isolates (N=271) were prospectively collected from patients in 17 Greek ICUs between 2021-2023 (INCREASE study, funded by Pfizer). Susceptibility profiles were determined by broth microdilution and genomes sequenced with Oxford Nanopore. RESULTS All isolates produced carbapenemases: 48% KPC, 20% NDM, 4.4% VIM, 27.6% multi-carbapenemase producers. Resistance to carbapenems, fluoroquinolones, aminoglycosides, and co-trimoxazole exceeded 90%, except for amikacin (73.4%) and colistin (46.5%). Aztreonam-avibactam and cefepime-zidebactam showed the highest susceptibility, 94.5% and 91.6% respectively, yet resistance was >10% among multi-carbapenemase producers. High levels of resistance to cefiderocol (41.7%) and cefepime-taniborbactam (21.4%) were detected. Aztreonam-avibactam resistance co-occurred with VEB-25 and a novel VEB variant. Predominant sequence types included ST39 (28.1%), ST11 (22.7%), and ST258 (18.4%). Time-scaled phylogenies demonstrated that following CG importation CR-Kp often acquired multiple carbapenemases. Over 88% of isolates were implicated in transmission clusters involving 1-8 ICUs across the country. CONCLUSIONS In Greek ICUs, CR-Kp appears to emerge via local plasmid acquisition and then spread within and between hospitals. While aztreonam-avibactam and cefepime-zidebactam remain promising treatment options, resistance among multi-carbapenemase producers and diagnostic gaps (notably for VEB variants) are concerning.
OBJECTIVES This study aimed to characterize recent linezolid susceptibility trends in Staphylococcus aureus and develop individualized dosing strategies for older adults. METHODS We analyzed Staphylococcus aureus isolates collected from 2023 to 2026 and linezolid concentrations from adults aged ≥ 65 years at four medical centers. A population pharmacokinetic model and Monte Carlo simulations evaluated dosing across age and estimated glomerular filtration rate (eGFR). RESULTS Among 506 isolates, geometric mean minimum inhibitory concentration (MIC) increased from 1.587 to 1.796mg/L; the proportion at 2mg/L increased from 69.2% to 82.2%, whereas values ≤ 1mg/L decreased from 30.8% to 16.7%. Pharmacokinetic analysis included 406 patients and 1,032 samples; age and eGFR influenced clearance. At MIC = 2mg/L, selected regimens achieved target attainment of 82.0%-95.3%, with 13.8%-27.4% above a trough concentration of 16mg/L. At MIC = 4mg/L, target attainment was 72.0%-94.5%, with 31.6%-66.1% above 16mg/L. CONCLUSIONS Linezolid MICs shifted towards 2mg/L, while age and eGFR contributed to exposure variability. MIC-informed model-informed precision dosing, early therapeutic drug monitoring, and haematological monitoring may help balance efficacy and toxicity. At MIC = 4mg/L, routine dose escalation should be avoided in favour of benefit-risk reassessment and consideration of alternative therapy. CLINICAL TRIAL REGISTRATION ChiCTR2100045707 (registered April 23, 2021).
