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Nosocomial acquisition and transmission of vancomycin-resistant Enterococcus faecium (VREfm) is the driver for E. faecium carriage in hospitalized patients, which, in turn, is a risk factor for invasive infection in immunocompromised patients. In the present study, we provide a comprehensive picture of E. faecium transmission in an entire sampled patient population using a sequence-driven approach. We prospectively identified and followed 149 haematology patients admitted to a hospital in England for 6 months. Patient stools (n = 376) and environmental swabs (n = 922) were taken at intervals and cultured for E. faecium. We sequenced 1,560 isolates (1,001 stool, 559 environment) and focused our genomic analyses on 1,477 isolates (95%) in the hospital-adapted clade A1. Of 101 patients who provided two or more stool samples, 40 (40%) developed E. faecium carriage after admission based on culture, compared with 64 patients (63%) based on genomic analysis (73% VREfm). Half of 922 environmental swabs (447, 48%) were positive for VREfm. Network analysis showed that, of 111 patients positive for the A1 clade, 67 had strong epidemiological and genomic links with at least one other patient and/or their direct environment, supporting nosocomial transmission. Six patients (3.4%) developed an invasive E. faecium infection from their own gut-colonizing strain, which was preceded by nosocomial acquisition of the infecting isolate in half of these. Two informatics approaches (subtype categorization to define phylogenetic clusters and the development of an SNP cut-off for transmission) were central to our analyses, both of which will inform the future translation of E. faecium sequencing into routine outbreak detection and investigation. In conclusion, we showed that carriage and environmental contamination by the hospital-adapted E. faecium lineage were hyperendemic in our study population and that improved infection control measures will be needed to reduce hospital acquisition rates.

Background Klebsiella pneumoniae is a human, animal, and environmental commensal and a leading cause of nosocomial infections, which are often caused by multiresistant strains. We evaluate putative sources of K. pneumoniae that are carried by and infect hospital patients. Methods We conducted a 6-month survey on 2 hematology wards at Addenbrooke’s Hospital, Cambridge, United Kingdom, in 2015 to isolate K. pneumoniae from stool, blood, and the environment. We conducted cross-sectional surveys of K. pneumoniae from 29 livestock farms, 97 meat products, the hospital sewer, and 20 municipal wastewater treatment plants in the East of England between 2014 and 2015. Isolates were sequenced and their genomes compared. Results Klebsiella pneumoniae was isolated from stool of 17/149 (11%) patients and 18/922 swabs of their environment, together with 1 bloodstream infection during the study and 4 others over a 24-month period. Each patient carried 1 or more lineages that was unique to them, but 2 broad environmental contamination events and patient–environment transmission were identified. Klebsiella pneumoniae was isolated from cattle, poultry, hospital sewage, and 12/20 wastewater treatment plants. There was low genetic relatedness between isolates from patients/their hospital environment vs isolates from elsewhere. Identical genes encoding cephalosporin resistance were carried by isolates from humans/environment and elsewhere but were carried on different plasmids. Conclusion We identified no patient-to-patient transmission and no evidence for livestock as a source of K. pneumoniae infecting humans. However, our findings reaffirm the importance of the hospital environment as a source of K. pneumoniae associated with serious human infection., A One Health genomic survey of Klebsiella pneumoniae demonstrated transmission between patients and their ward environment but no evidence to implicate livestock as a source of K. pneumoniae or their mobile genetic elements encoding antibiotic resistance.

Allogeneic haemopoietic cell transplant (allo-HCT) may be curative in acute myeloid leukaemia (AML) in second complete remission (CR2) but the impact of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain. The Acute Leukaemia Working Party of the European Society for Blood and Bone Marrow Transplantation Registry studied an AML CR2 cohort characterised by age ≥ 18 years, first allo-HCT 2007–2016, available cytogenetic profile at diagnosis, donors who were matched family, volunteer unrelated with HLA antigen match 10/10 or 9/10 or haplo-identical. The 1879 eligible patients included 1010 (54%) MAC allo-HCT recipients. In patients

Klebsiella pneumoniae is a human, animal and environmental commensal and a leading cause of nosocomial infections, which are often caused by multi-resistant strains that are challenging to treat. We conducted a One Health evaluation of putative sources of K. pneumoniae that are carried by, and infect hospital patients. This combined data from a six-month study on two haematology wards at Addenbrooke’s Hospital, Cambridge, in 2015 to isolate K. pneumoniae from stool, blood and the environment, and a cross-sectional survey of K. pneumoniae from 29 livestock farms, 97 meat products, the hospital sewer and 20 municipal wastewater treatment plants in the East of England between 2014 and 2015. K. pneumoniae was isolated from stools of 17/149 (11%) patients and 18/922 swabs of their environment, together with one patient bloodstream infection during the study and 4 others over a 24-month period. Each patient carried one or more lineages that was unique to them, but two broad environmental contamination events and patient-environmental transmission were identified. K. pneumoniae was isolated from cattle and poultry, hospital sewage and 12/20 wastewater plants. There was low genetic relatedness between isolates from patients/their hospital environment versus isolates from elsewhere. Identical genes encoding cephalosporin resistance were carried by isolates from different reservoirs, but were carried on different plasmids by isolates from patients/their environment versus elsewhere. We identified no patient-to-patient transmission and no evidence for livestock as a source of K. pneumoniae infecting humans, but our findings reaffirm the importance of the hospital environment as a source of K. pneumoniae associated with serious human infection.

Virus infection is a major cause of morbidity and mortality following allogeneic haematopoietic stem cell transplant (HSCT), with up to 1 in 4 deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post HSCT, the innate anti-viral immune response is the first line of defence against invading viruses. Several novel innate viral sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analysed a panel of innate viral sensor genes in HSCT patients, and assessed whether differences in innate anti-viral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patient without active infections, and healthy volunteers were highly homogenous. Although IFNα expression was upregulated in actively-infected patients relative to controls, a corresponding upregulation of innate viral sensor expression was not observed. IFNα stimulation of patient peripheral blood mononuclear cells (PBMCs) in-vitro showed intact IFNα signaling, but actively-infected patients’ PBMCs had reduced upregulation of innate viral sensors. We show that the aberrant IFNα responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor upregulation in HSCT patients following viral infection.

Background Enterococcus faecium is a leading cause of hospital-acquired infection, particularly in the immunocompromised. Here, we use whole genome sequencing of E. faecium to study within-host evolution and the transition from gut carriage to invasive disease. Methods We isolated and sequenced 180 E. faecium from four immunocompromised patients who developed bloodstream infection during longitudinal surveillance of E. faecium in stool and their immediate environment. Results A phylogenetic tree based on single nucleotide polymorphisms (SNPs) in the core genome of the 180 isolates demonstrated several distinct clones. This was highly concordant with the population structure inferred by Bayesian methods, which contained four main BAPS (Bayesian Analysis of Population Structure) groups. The majority of isolates from each patient resided in a single group, but all four patients also carried minority populations in stool from multiple phylogenetic groups. Bloodstream isolates from each case belonged to a single BAPS group, which differed in all four patients. Analysis of 87 isolates (56 from blood) belonging to a single BAPS group that were cultured from the same patient over 54 days identified 30 SNPs in the core genome (nine intergenic, 13 non-synonymous, eight synonymous), and 250 accessory genes that were variably present. Comparison of these genetic variants in blood isolates versus those from stool or environment did not identify any variants associated with bloodstream infection. The substitution rate for these isolates was estimated to be 128 (95% confidence interval 79.82 181.77) mutations per genome per year, more than ten times higher than previous estimates for E. faecium. Within-patient variation in vancomycin resistance associated with vanA was common and could be explained by plasmid loss, or less often by transposon loss. Conclusions These findings demonstrate the diversity of E. faecium carriage by individual patients and significant within-host diversity of E. faecium, but do not provide evidence for adaptive genetic variation associated with invasion. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0507-0) contains supplementary material, which is available to authorized users.

Supplementary figures. (PDF 920 kb)

Nosocomial acquisition and transmission of vancomycin-resistant Enterococcus faecium (VREfm) is the driver for E. faecium carriage in hospitalized patients, which, in turn, is a risk factor for invasive infection in immunocompromised patients. In the present study, we provide a comprehensive picture of E. faecium transmission in an entire sampled patient population using a sequence-driven approach. We prospectively identified and followed 149 haematology patients admitted to a hospital in England for 6 months. Patient stools (n = 376) and environmental swabs (n = 922) were taken at intervals and cultured for E. faecium. We sequenced 1,560 isolates (1,001 stool, 559 environment) and focused our genomic analyses on 1,477 isolates (95%) in the hospital-adapted clade A1. Of 101 patients who provided two or more stool samples, 40 (40%) developed E. faecium carriage after admission based on culture, compared with 64 patients (63%) based on genomic analysis (73% VREfm). Half of 922 environmental swabs (447, 48%) were positive for VREfm. Network analysis showed that, of 111 patients positive for the A1 clade, 67 had strong epidemiological and genomic links with at least one other patient and/or their direct environment, supporting nosocomial transmission. Six patients (3.4%) developed an invasive E. faecium infection from their own gut-colonizing strain, which was preceded by nosocomial acquisition of the infecting isolate in half of these. Two informatics approaches (subtype categorization to define phylogenetic clusters and the development of an SNP cut-off for transmission) were central to our analyses, both of which will inform the future translation of E. faecium sequencing into routine outbreak detection and investigation. In conclusion, we showed that carriage and environmental contamination by the hospital-adapted E. faecium lineage were hyperendemic in our study population and that improved infection control measures will be needed to reduce hospital acquisition rates.

Supplementary figures. (PDF 920 kb)

BACKGROUND: Klebsiella pneumoniae is a human, animal, and environmental commensal and a leading cause of nosocomial infections, which are often caused by multiresistant strains. We evaluate putative sources of K. pneumoniae that are carried by and infect hospital patients. METHODS: We conducted a 6-month survey on 2 hematology wards at Addenbrooke's Hospital, Cambridge, United Kingdom, in 2015 to isolate K. pneumoniae from stool, blood, and the environment. We conducted cross-sectional surveys of K. pneumoniae from 29 livestock farms, 97 meat products, the hospital sewer, and 20 municipal wastewater treatment plants in the East of England between 2014 and 2015. Isolates were sequenced and their genomes compared. RESULTS: Klebsiella pneumoniae was isolated from stool of 17/149 (11%) patients and 18/922 swabs of their environment, together with 1 bloodstream infection during the study and 4 others over a 24-month period. Each patient carried 1 or more lineages that was unique to them, but 2 broad environmental contamination events and patient-environment transmission were identified. Klebsiella pneumoniae was isolated from cattle, poultry, hospital sewage, and 12/20 wastewater treatment plants. There was low genetic relatedness between isolates from patients/their hospital environment vs isolates from elsewhere. Identical genes encoding cephalosporin resistance were carried by isolates from humans/environment and elsewhere but were carried on different plasmids. CONCLUSION: We identified no patient-to-patient transmission and no evidence for livestock as a source of K. pneumoniae infecting humans. However, our findings reaffirm the importance of the hospital environment as a source of K. pneumoniae associated with serious human infection.