Risk of death in Klebsiella pneumoniae bloodstream infections is associated with specific phylogenetic lineages.

BACKGROUND: Klebsiella pneumoniae species complex (KpSC) bloodstream infections (BSIs) are associated with considerable morbidity and mortality, particularly in elderly and multimorbid patients. Multidrug-resistant (MDR) strains have been associated with poorer outcome. However, the clinical impact of KpSC phylogenetic lineages on BSI outcome is unclear. METHODS: In an 18-month nationwide Norwegian prospective study of KpSC BSI episodes in adults, we used whole-genome sequencing to describe the molecular epidemiology of KpSC, and multivariable Cox regression analysis including clinical data to determine adjusted hazard ratios (aHR) for death associated with specific genomic lineages. FINDINGS: We included 1078 BSI episodes and 1082 bacterial isolates from 1055 patients. The overall 30-day case-fatality rate (CFR) was 12.5%. Median patient age was 73.4, 61.7% of patients were male. Median Charlson comorbidity score was 3. Klebsiella pneumoniae sensu stricto (Kp) (79.3%, n = 858/1082) and K. variicola (15.7%, n = 170/1082) were the dominating phylogroups. Global MDR-associated Kp clonal groups (CGs) were prevalent (25.0%, n = 270/1082) but 78.9% (n = 213/270) were not MDR, and 53.7% (n = 145/270) were community acquired. The major findings were increased risk for death within 30 days in monomicrobial BSIs caused by K. variicola (CFR 16.9%, n = 21; aHR 1.86, CI 1.10-3.17, p = 0.02), and global MDR-associated Kp CGs (CFR 17.0%, n = 36; aHR 1.52, CI 0.98-2.38, p = 0.06) compared to Kp CGs not associated with MDR (CFR 10.1%, n = 46). CONCLUSION: Bacterial traits, beyond antimicrobial resistance, have a major impact on the clinical outcome of KpSC BSIs. The global spread of MDR-associated Kp CGs is driven by other mechanisms than antibiotic selection alone. Further insights into virulence determinants, and their association with phylogenetic lineages are needed to better understand the epidemiology of KpSC infection and clinical outcome.

Community carriage of ESBL-producing Escherichia coli and Klebsiella pneumoniae: a cross-sectional study of risk factors and comparative genomics of carriage and clinical isolates.

The global prevalence of infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) is increasing, and for Escherichia coli, observations indicate that this is partly driven by community-onset cases. The ESBL-E population structure in the community is scarcely described, and data on risk factors for carriage are conflicting. Here, we report the prevalence and population structure of fecal ESBL-producing E. coli and Klebsiella pneumoniae (ESBL-Ec/Kp) in a general adult population, examine risk factors, and compare carriage isolates with contemporary clinical isolates. Fecal samples obtained from 4,999 participants (54% women) ≥40 years in the seventh survey of the population-based Tromsø Study, Norway (2015, 2016), were screened for ESBL-Ec/Kp. In addition, we included 118 ESBL-Ec clinical isolates from the Norwegian surveillance program in 2014. All isolates were whole-genome sequenced. Risk factors associated with carriage were analyzed using multivariable logistic regression. ESBL-Ec gastrointestinal carriage prevalence was 3.3% [95% confidence interval (CI) 2.8%-3.9%, no sex difference] and 0.08% (0.02%-0.20%) for ESBL-Kp. For ESBL-Ec, travel to Asia was the only independent risk factor (adjusted odds ratio 3.46, 95% CI 2.18-5.49). E. coli ST131 was most prevalent in both collections. However, the ST131 proportion was significantly lower in carriage (24%) versus clinical isolates (58%, P < 0.001). Carriage isolates were genetically more diverse with a higher proportion of phylogroup A (26%) than clinical isolates (5%, P < 0.001), indicating that ESBL gene acquisition occurs in a variety of E. coli lineages colonizing the gut. STs commonly related to extraintestinal infections were more frequent in clinical isolates also carrying a higher prevalence of antimicrobial resistance, which could indicate clone-associated pathogenicity.IMPORTANCEESBL-Ec and ESBL-Kp are major pathogens in the global burden of antimicrobial resistance. However, there is a gap in knowledge concerning the bacterial population structure of human ESBL-Ec/Kp carriage isolates in the community. We have examined ESBL-Ec/Kp isolates from a population-based study and compared these to contemporary clinical isolates. The large genetic diversity of carriage isolates indicates frequent ESBL gene acquisition, while those causing invasive infections are more clone dependent and associated with a higher prevalence of antibiotic resistance. The knowledge of factors associated with ESBL carriage helps to identify patients at risk to combat the spread of resistant bacteria within the healthcare system. Particularly, previous travel to Asia stands out as a major risk factor for carriage and should be considered in selecting empirical antibiotic treatment in critically ill patients.

Detection of Klebsiella pneumoniae human gut carriage: a comparison of culture, qPCR, and whole metagenomic sequencing methods.

Klebsiella pneumoniae is an important opportunistic healthcare-associated pathogen and major contributor to the global spread of antimicrobial resistance. Gastrointestinal colonization with K. pneumoniae is a major predisposing risk factor for infection and forms an important hub for the dispersal of resistance. Current culture-based detection methods are time consuming, give limited intra-sample abundance and strain diversity information, and have uncertain sensitivity. Here we investigated the presence and abundance of K. pneumoniae at the species and strain level within fecal samples from 103 community-based adults by qPCR and whole metagenomic sequencing (WMS) compared to culture-based detection. qPCR demonstrated the highest sensitivity, detecting K. pneumoniae in 61.2% and 75.8% of direct-fecal and culture-enriched sweep samples, respectively, including 52/52 culture-positive samples. WMS displayed lower sensitivity, detecting K. pneumoniae in 71.2% of culture-positive fecal samples at a 0.01% abundance cutoff, and was inclined to false positives in proportion to the relative abundance of other Enterobacterales present. qPCR accurately quantified K. pneumoniae to 16 genome copies/reaction while WMS could estimate relative abundance to at least 0.01%. Quantification by both methods correlated strongly with each other (Spearman's rho = 0.91). WMS also supported accurate intra-sample K. pneumoniae sequence type (ST)-level diversity detection from fecal microbiomes to 0.1% relative abundance, agreeing with the culture-based detected ST in 16/19 samples. Our results show that qPCR and WMS are sensitive and reliable tools for detection, quantification, and strain analysis of K. pneumoniae from fecal samples with potential to support infection control and enhance insights in K. pneumoniae gastrointestinal ecology.

What is the context?Klebsiella pneumoniae is a major cause of healthcare-associated infections and a key contributor to the spread of resistance to last-line antimicrobials.Gastrointestinal colonization by K. pneumoniae is a risk factor for developing infection and can facilitate the spread of antimicrobial resistance.Culture-based detection may lack sensitivity and is ill-suited to detecting within-sample K. pneumoniae abundance and diversity.Developing molecular methods to improve K. pneumoniae abundance and strain diversity detection are essential in understanding human gut colonization and ecology.What is new? We compared culture-based detection of K. pneumoniae within human fecal samples to two molecular-based techniques: 1) qPCR, which amplifies K. pneumoniae species complex-specific DNA targets with high sensitivity, and 2) whole metagenomic sequencing (WMS), which sequences the entire DNA content of complex microbial communities.Our findings show:qPCR had the highest sensitivity, detecting K. pneumoniae in all (52/52) culture-positive samples and 11/51 and 23/47 culture-negative samples, using a direct-fecal and culture-sweep method, respectively. qPCR could accurately quantify K. pneumoniae to 16 genome copies/reaction.WMS had lower sensitivity, positive in 37/52 culture-positive samples, and demonstrated false positives arising from closely related bacterial species. Relative abundance estimates could be performed to 0.01%.WMS performed accurate strain-level detection of K. pneumoniae to 0.1% relative abundance and could detect within-sample strain diversity.What is the impact?qPCR and WMS are valid methods for the detection and characterization of colonizing K. pneumoniae with potential to enhance our understanding of the gastrointestinal ecology of this important pathogen.

Gastrointestinal carriage of Klebsiella pneumoniae in a general adult population: a cross-sectional study of risk factors and bacterial genomic diversity.

Antibiotic resistant Klebsiella pneumoniae is a leading public health threat and gastrointestinal carriage is an established risk factor for subsequent infections during hospitalization. Our study contributes new knowledge of risk factors for gastrointestinal carriage and the genomic population structure of K. pneumoniae colonizing humans in a representative sample of a general population in a community setting. Altogether, 2,975 participants (54% women) >40 y in the population-based Tromsø Study: Tromsø7, Norway (2015-2016) were included. Fecal samples were screened for K. pneumoniae, which were characterized using whole-genome sequencing. Risk factors for carriage were analyzed using multivariable logistic regression on data from questionnaires and the Norwegian Prescription Database. Prevalence of K. pneumoniae gastrointestinal carriage was 16.3% (95% CI 15.0-17.7, no gender difference). Risk factors associated with carriage included age ≥60 y, travel to Greece or Asia past 12 months (adjusted odds ratio 1.49, 95% CI 1.11-2.00), Crohn's disease/ulcerative colitis (2.26, 1.20-4.27), use of proton pump inhibitors (1.62, 1.18-2.22) and non-steroidal anti-inflammatory drugs past 6 months (1.38, 1.04-1.84), and antibiotic use the last month (1.73, 1.05-2.86). Prevalence was higher among those having used combinations of drug classes and decreased over time with respect to preceding antibiotic use. The K. pneumoniae population was diverse with 300 sequence types among 484 isolates distributed across four phylogroups. Only 5.2% of isolates harbored acquired resistance and 11.6% had virulence factors. Identification of risk factors for gastrointestinal carriage allows for identification of individuals that may have higher risk of extraintestinal infection during hospitalization. The findings that specific diseases and drugs used were associated with carriage show an impact of these possibly through modulating the human gut microbiota promoting colonization. The diverse population structure of carriage isolates reflects the ecologically adaptive capacity of the bacterium and challenges for vaccine prospects and the identification of reservoirs as a potential source for human colonization.

Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study.

Objectives: To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods: A prospective, multicentre, observational cohort study of women aged ≥16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration: Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results: The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for ≤5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions: Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production.

[Referral to the pediatric dialysis unit -- the earlier the better?]. / Zuweisung an die Kinderdialyse -- Ist früher besser?

Whereas recent research has demonstrated clear evidence for beneficial effects of early referral to the nephrologist in chronic renal insufficiency in adults, no such data exist for the pediatric population. In this study, we therefore correlated patient age and residual renal function at first presentation to a specialized pediatric nephrologist with the extent of secondary uremic complications and the further course of renal function. From March 2003 until March 2004, 43 children (34 boys, aged 10.1 +/- 6.3 yrs) with congenital-urologic (n = 26), congenital-nephrologic (n = 13) or acquired (n = 4) renal diseases had been followed for 3.9 yrs (14 days to 17.5 yrs) at the Kinderdialyse Wien, with a residual renal function of 35 +/- 20.5 ml/min/1.73 m(2) at first presentation. With regards to uremic secondary complications, the majority of children exhibited involvement of at least two systems at first presentation. Thereafter, children with congenital diseases who were referred to the specialized pediatric nephrology unit within the first year of live demonstrated a significantly better course of residual renal function (1.8% vs -0.7%, p = 0.034) than children who were referred later. These data confirm recent registry reports on chronic renal insufficiency in children. Only about a third of the children of our population were presented to a specialized pediatric nephrology center within their first year of life (despite a congenital disease in 90% of them). Thus, therapeutic interventions might be currently offered at a delayed time point in the majority of children.