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Factors behind the prevalence of carbapenem-resistant Klebsiella pneumoniae in pediatric wards.

ABSTRACT:

Abstract

The emergence of carbapenem-resistant Enterobacteriaceae made the treatment difficult, which has become a significant issue of public health. A sharp increase of carbapenem-resistance rate in Klebsiella pneumoniae was observed in a maternity and child health care hospital in Zunyi, China, in 2014.In 2015 to 2016, carbapenem-resistant Klebsiella pneumoniae (CRKp) isolated from all the clinical samples were analyzed to identify the carbapenem-resistance genes. They were then fingerprinted in order to determine their genetic relationship. Clinical data such as usage of imipenem in 2012 to 2016 and the nosocomial infection surveillance data were analyzed.Thirty-five isolates of CRKp out of 4328 various pathogens were obtained, and blaNDM-1 was identified to be the most common resistant gene present in the CRKp isolates. The fingerprint analysis identified 15 major clusters of CRKp isolates. The bacteria with close proximity relationship tended to be from the same wards. However, a few CRKp isolates from different wards were found to be genetically highly related. The clinical data showed a significantly higher usage of carbapenems in 2012 to 2013 before the CRKp rate sharply increased in 2014. The nosocomial infection surveillance showed an unexpectedly high rate of failures to meet the requirement of the hospital environment hygiene and hand hygiene in the neonatal ward.The increasing isolation rate of CRKp was associated with poorly regulated usage of carbapenems, impropriate medical practices, and the poor hospital environmental hygiene and hand hygiene.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8428699 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A diverse, antibiotic-naive microbiota prevents highly antibiotic-resistant microbes, including carbapenem-resistant Klebsiella pneumoniae (CR-Kp), from achieving dense colonization of the intestinal lumen. Antibiotic-mediated destruction of the microbiota leads to expansion of CR-Kp in the gut, markedly increasing the risk of bacteremia in vulnerable patients. While preventing dense colonization represents a rational approach to reduce intra- and interpatient dissemination of CR-Kp, little is known about pathogen-associated factors that enable dense growth and persistence in the intestinal lumen. To identify genetic factors essential for dense colonization of the gut by CR-Kp, we constructed a highly saturated transposon mutant library with >150,000 unique mutations in an ST258 strain of CR-Kp and screened for in vitro growth and in vivo intestinal colonization in antibiotic-treated mice. Stochastic and partially reversible fluctuations in the representation of different mutations during dense colonization revealed the dynamic nature of intestinal microbial populations. We identified genes that are crucial for early and late stages of dense gut colonization and confirmed their role by testing isogenic mutants in in vivo competition assays with wild-type CR-Kp Screening of the transposon library also identified mutations that enhanced in vivo CR-Kp growth. These newly identified colonization factors may provide novel therapeutic opportunities to reduce intestinal colonization by CR-Kp IMPORTANCE Klebsiella pneumoniae is a common cause of bloodstream infections in immunocompromised and hospitalized patients, and over the last 2 decades, some strains have acquired resistance to nearly all available antibiotics, including broad-spectrum carbapenems. The U.S. Centers for Disease Control and Prevention has listed carbapenem-resistant K. pneumoniae (CR-Kp) as an urgent public health threat. Dense colonization of the intestine by CR-Kp and other antibiotic-resistant bacteria is associated with an increased risk of bacteremia. Reducing the density of gut colonization by CR-Kp is likely to reduce their transmission from patient to patient in health care facilities as well as systemic infections. How CR-Kp expands and persists in the gut lumen, however, is poorly understood. Herein, we generated a highly saturated mutant library in a multidrug-resistant K. pneumoniae strain and identified genetic factors that are associated with dense gut colonization by K. pneumoniae This study sheds light on host colonization by K. pneumoniae and identifies potential colonization factors that contribute to high-density persistence of K. pneumoniae in the intestine.

Project description:Carbapenem-resistantKlebsiella pneumoniae(CR-Kp) is significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract, where the bacterium is usually present at low density, but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood. Nevertheless, gaining such knowledge could lead to innovative intervention strategies for addressing colonization and infection. Here, we adopted anin vivomodel to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis, and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, the concentration of oxidative species and amino acids was increased in the mouse intestine following treatment. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were particularly upregulated, however their deletion did not impair CR-Kp fitness in vivoupon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein CRP as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, CRP deletion in CR-Kp resulted in strongly impaired gut colonization, but this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance towards bacterial fitness remains cryptic. Further analyses utilizing this model may identify key factors to tackle the intestinal stage of CR-Kp colonization.

Project description:Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality, only a subset of patients acquiring CRKP extraintestinal colonization will develop clinical infection. Here, we sought to ascertain the relative importance of patient characteristics and CRKP genetic background in determining patient risk of infection. Machine learning models classifying colonization versus infection were built using whole-genome sequences and clinical metadata from a comprehensive set of 331 CRKP extraintestinal isolates collected across 21 long-term acute-care hospitals over the course of a year. Model performance was evaluated based on area under the receiver operating characteristic curve (AUROC) on held-out test data. We found that patient and genomic features were predictive of clinical CRKP infection to similar extents (AUROC interquartile ranges [IQRs]: patient = 0.59 to 0.68, genomic = 0.55 to 0.61, combined = 0.62 to 0.68). Patient predictors of infection included the presence of indwelling devices, kidney disease, and length of stay. Genomic predictors of infection included presence of the ICEKp10 mobile genetic element carrying the yersiniabactin iron acquisition system and disruption of an O-antigen biosynthetic gene in a sublineage of the epidemic ST258 clone. Altered O-antigen biosynthesis increased association with the respiratory tract, and subsequent ICEKp10 acquisition was associated with increased virulence. These results highlight the potential of integrated models including both patient and microbial features to provide a more holistic understanding of patient clinical trajectories and ongoing within-lineage pathogen adaptation.IMPORTANCE Multidrug-resistant organisms, such as carbapenem-resistant Klebsiella pneumoniae (CRKP), colonize alarmingly large fractions of patients in regions of endemicity, but only a subset of patients develop life-threatening infections. While patient characteristics influence risk for infection, the relative contribution of microbial genetic background to patient risk remains unclear. We used machine learning to determine whether patient and/or microbial characteristics can discriminate between CRKP extraintestinal colonization and infection across multiple health care facilities and found that both patient and microbial factors were predictive. Examination of informative microbial genetic features revealed variation within the ST258 epidemic lineage that was associated with respiratory tract colonization and increased rates of infection. These findings indicate that circulating genetic variation within a highly prevalent epidemic lineage of CRKP influences patient clinical trajectories. In addition, this work supports the need for future studies examining the microbial genetic determinants of clinical outcomes in human populations, as well as epidemiologic and experimental follow-ups of identified features to discern generalizability and biological mechanisms.

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Factors behind the prevalence of carbapenem-resistant Klebsiella pneumoniae in pediatric wards.

Abstract

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