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PURPOSE: We aimed to explore the prevalence and within-host evolution of resistance in polymyxin-heteroresistant carbapenem-resistant Klebsiella pneumoniae (PHR-CRKP) in critically ill patients. METHODS: We performed an epidemiological analysis of consecutive patients with PHR-CRKP from clinical cases. Our study investigated the within-host resistance evolution and its clinical significance during polymyxin exposure. Furthermore, we explored the mechanisms underlying the dynamic evolution of polymyxin resistance at both subpopulation and genetic levels, involved population analysis profile test, time-killing assays, competition experiments, and sanger sequencing. Additionally, comparative genomic analysis was performed on 713 carbapenemase-producing K. pneumoniae strains. RESULTS: We enrolled 109 consecutive patients, and PHR-CRKP was found in 69.7% of patients without previous polymyxin exposure. 38.1% of PHR-CRKP isolates exhibited polymyxin resistance and led to therapeutic failure in critically ill scenarios. An increased frequency of resistant subpopulations was detected during PHR-CRKP evolution, with rapid regrowth of resistant subpopulations under high polymyxin concentrations, and a fitness cost in an antibiotic-free environment. Mechanistic analysis revealed that diverse mgrB insertions and pmrB hypermutations contributed to the dynamic changes in polymyxin susceptibility in dominant resistant subpopulations during PHR evolution, which were validated by comparative genomic analysis. Several deleterious mutations (e.g. pmrBLeu82Arg, pmrBSer85Arg) were firstly detected during PHR-CRKP evolution. Indeed, specific sequence types of K. pneumoniae demonstrated unique deletions and deleterious mutations. CONCLUSIONS: Our study emphasizes the high prevalence of pre-existing heteroresistance in CRKP, which can lead to polymyxin resistance and fatal outcomes. Hence, it is essential to continuously monitor and observe the treatment response to polymyxins in appropriate critically ill scenarios.
RESUMO
Background: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most commonly encountered pathogens among burn patients incurring substantial morbidity and mortality. To investigate the epidemiology and features of MRSA in burn wound infections, we conducted a 10-year retrospective study on MRSA isolated from burn patients with burn wound infections from southeast China from 2013 to 2022. Methods: One hundred MRSA isolates (10 isolates each year) from burn wound infection among burn patients from 2013 to 2022 were randomly selected and enrolled. In addition to the clinical data of the 100 burn patients, MRSA isolates were characterized by antimicrobial susceptibility testing, detection of toxin genes, and molecular typing. Results: The median time from the onset of burns and admission to MRSA detected was 13 and 5 days, respectively. No MRSA isolate was found resistant to quinupristin/dalfopristin, linezolid, and vancomycin. Toxin gene seg was found most frequently (90%) followed by sea (70%) and eta (64%). CC8 (74%), ST239 (70%), and SCCmec III (72%) were the most common CC, ST, and SCCmec types, respectively. Conclusion: ST239-III (70%) was the predominant clone found in MRSA from burn wound infection among burn patients in southeast China. ST239-III was less found from 2018 to 2022. A higher diversity of MRSA clones was observed in these recent 5 years than that from 2013 to 2017.