171 results found
Rawson TM, Hernandez B, Moore L, et al., 2020, A real-world evaluation of a Case-Based Reasoning algorithm to support antimicrobial prescribing decisions in acute care, Clinical Infectious Diseases, ISSN: 1058-4838
BackgroundA locally developed Case-Based Reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated.MethodsPrescribing recommendations made by a CBR algorithm were compared to decisions made by physicians in clinical practice. Comparisons were examined in two patient populations. Firstly, in patients with confirmed Escherichia coli blood stream infections (‘E.coli patients’), and secondly in ward-based patients presenting with a range of potential infections (‘ward patients’). Prescribing recommendations were compared against the Antimicrobial Spectrum Index (ASI) and the WHO Essential Medicine List Access, Watch, Reserve (AWaRe) classification system. Appropriateness of a prescription was defined as the spectrum of the prescription covering the known, or most-likely organism antimicrobial sensitivity profile.ResultsIn total, 224 patients (145 E.coli patients and 79 ward patients) were included. Mean (SD) age was 66 (18) years with 108/224 (48%) female gender. The CBR recommendations were appropriate in 202/224 (90%) compared to 186/224 (83%) in practice (OR: 1.24 95%CI:0.392-3.936;p=0.71). CBR recommendations had a smaller ASI compared to practice with a median (range) of 6 (0-13) compared to 8 (0-12) (p<0.01). CBR recommendations were more likely to be classified as Access class antimicrobials compared to physicians’ prescriptions at 110/224 (49%) vs. 79/224 (35%) (OR: 1.77 95%CI:1.212-2.588 p<0.01). Results were similar for E.coli and ward patients on subgroup analysis.ConclusionsA CBR-driven decision support system provided appropriate recommendations within a narrower spectrum compared to current clinical practice. Future work must investigate the impact of this intervention on prescribing behaviours more broadly and patient outcomes.
Matthews S, McKenna S, Malito E, et al., 2020, Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes, Computational and Structural Biotechnology Journal, Vol: 18, Pages: 650-660, ISSN: 2001-0370
Over 18 million disease cases and half a million deaths worldwide are estimated to be caused annually by Group A Streptococcus. A vaccine to prevent GAS disease is urgently needed. SpyCEP (Streptococcus pyogenes Cell-Envelope Proteinase) is a surface-exposed serine protease that inactivates chemokines, impairing neutrophil recruitment and bacterial clearance, and has shown promising immunogenicity in preclinical models. Although SpyCEP structure has been partially characterized, a more complete and higher resolution understanding of its antigenic features would be desirable prior to large scale manufacturing. To address these gaps and facilitate development of this globally important vaccine, we performed immunogenicity studies with a safety-engineered SpyCEP mutant, and comprehensively characterized its structure by combining X-ray crystallography, NMR spectroscopy and molecular dynamics simulations. We found that the catalytically-inactive SpyCEP antigen conferred protection similar to wild-type SpyCEP in a mouse infection model. Further, a new higher-resolution crystal structure of the inactive SpyCEP mutant provided new insights into this large chemokine protease comprising nine domains derived from two non-covalently linked fragments. NMR spectroscopy and molecular simulation analyses revealed conformational flexibility that is likely important for optimal substrate recognition and overall function. These combined immunogenicity and structural data demonstrate that the full-length SpyCEP inactive mutant is a strong candidate human vaccine antigen. These findings show how a multi-disciplinary study was used to overcome obstacles in the development of a GAS vaccine, an approach applicable to other future vaccine programs. Moreover, the information provided may also facilitate the structure-based discovery of small-molecule therapeutics targeting SpyCEP protease inhibition.
Jauneikaite E, Ferguson T, Mosavie M, et al., 2020, Staphylococcus aureus colonisation and acquisition of skin and soft tissue infection amongst Royal Marines recruits: A prospective cohort study, Clinical Microbiology and Infection, Vol: 26, Pages: 381.e1-381.e6, ISSN: 1198-743X
Objectives: Skin and soft tissue infections (SSTIs) are a serious health issue for military personnel. Of particular importance are those caused by MRSA and PVL-positive S. aureus (PVL-SA), as they have been associated with outbreaks of SSTIs. A prospective observational study was conducted in Royal Marines recruits to investigate the prevalence of PVL-SA carriage and any association with SSTIs.Methods: 1,012 RM recruits were followed through a 32-week training programme, with nose and throat swabs obtained at weeks 1, 6, 15 and 32. S. aureus isolates were characterised by antibiotic susceptibility testing, spa typing, presence of mecA/C and PVL genes. Retrospective review of the clinical notes for SSTI acquisition was conducted.Results: S. aureus colonisation decreased from week-1 to week-32 (41% to 26%, p<0.0001). Of 1,168 S. aureus isolates, 3/1168 (0.3%) were MRSA and 10/1168 (0.9%) PVL-positive (all MSSA) and 169/1168 (14.5%) were resistant to clindamycin. Isolates showed genetic diversity with 238 different spa types associated with 25 MLST clonal complexes. SSTIs were seen in 35% (351/989) of recruits with 3 training days lost per recruit. SSTI acquisition rate was reduced amongst persistent carriers (p<0.0283). Conclusions: Nose and throat carriage of MRSA and PVL-SA was low amongst recruits, despite a high incidence of SSTIs being reported particularly cellulitis. Carriage strains were predominantly MSSA with a marked diversity of genotypes. Persistent nose and/or throat carriage was not associated with SSTI acquisition. Putative person-to-person transmission within troops was identified based on spa typing requiring further research to confirm and explore potential transmission routes.
Parks T, Elliot K, Lamagni T, et al., 2020, Elevated risk of invasive group a streptococcal disease and host genetic variation in the human leukocyte antigen locus, Genes and Immunity, Vol: 21, Pages: 63-70, ISSN: 1466-4879
Invasive group A streptococcal (GAS) disease is uncommon but carries a high casefatality rate relative to other infectious diseases. Given the ubiquity of mild GASinfections, it remains unclear why healthy individuals will occasionally develop lifethreatening infections, raising the possibility of host genetic predisposition. Here, wepresent the results of a case-control study including 43 invasive GAS cases and1,540 controls. Using HLA imputation and linear mixed-models, we find each copy ofthe HLA-DQA1*01:03 allele associates with a two-fold increased risk of disease(odds ratio 2.3, 95% confidence interval 1.3-4.4, P=0.009), an association whichpersists with classical HLA typing of a subset of cases and analysis with analternative large control dataset with validated HLA data. Moreover, we propose theassociation is driven by the allele itself rather than the background haplotype. Overallthis finding provides impetus for further investigation of the immunogenetic basis ofthis devastating bacterial disease.
Collin SM, Lamb P, Jauneikaite E, et al., 2019, Hospital clusters of invasive Group B Streptococcal disease: a systematic review, Journal of Infection, Vol: 79, Pages: 521-527, ISSN: 0163-4453
Objectives: To characterize outbreaks of invasive Group B Streptococcal (iGBS) disease in hospitals.Methods: Systematic review using electronic databases to identify studies describing iGBS outbreaks/clusters or cross-infection/acquisition in healthcare settings where ‘cluster’ was defined as ≥2 linked cases. PROSPERO CRD42018096297.Results: Twenty-five references were included describing 30 hospital clusters (26 neonatal, 4 adult) in 11 countries from 1966 to 2019. Cross-infection between unrelated neonates was reported in 19 clusters involving an early-onset (<7 days of life; n = 3), late-onset (7–90 days; n = 13) index case or colonized infant (n = 3) followed by one or more late-onset cases (median serial interval 9 days (IQR 3–17, range 0–50 days, n = 45)); linkage was determined by phage typing in 3 clusters, PFGE/MLST/PCR in 8, WGS in 4, non-molecular methods in 4. Postulated routes of transmission in neonatal clusters were via clinical personnel and equipment, particularly during periods of crowding and high patient-to-nurse ratio. Of 4 adult clusters, one was attributed to droplet spread between respiratory cases, one to handling of haemodialysis catheters and two unspecified.Conclusions: Long intervals between cases were identified in most of the clusters, a characteristic which potentially hinders detection of GBS hospital outbreaks without enhanced surveillance supported by genomics.
Herbert R, Hatcher J, Jauneikaite E, et al., 2019, Two-year analysis of Clostridium difficile ribotypes associated with increased severity, Journal of Hospital Infection, Vol: 103, Pages: 388-394, ISSN: 0195-6701
BackgroundCertain Clostridium difficile ribotypes have been associated with complex disease phenotypes including recurrence and increased severity, especially the well-described hypervirulent ribotype RT027. In this study we set out to determine the pattern of ribotypes causing infection and association if any with severity.MethodsAll faecal samples submitted to a large diagnostic laboratory for C. difficile testing between 2011 and 2013 were subject to routine testing and cultured. All C. difficile isolates were ribotyped and associated clinical and demographic patient data were retrieved then linked to ribotyping data.ResultsA total of 86 distinct ribotypes were identified from 705 isolates of C. difficile. Ribotypes RT002 and RT015 were the most prevalent (22.5%, n=159). Only five isolates (0.7%) were the hypervirulent RT027. Ninety of 450 (20%) patients with clinical information available died within 30-days of C. difficile isolation. Ribotype RT220, one of the ten commonest ribotypes, was associated with elevated median C-reactive protein and significantly increased 30-day all-cause mortality when compared with ribotypes RT002 and RT015, and with all other ribotypes found in the study.ConclusionsA wide range of C. difficile ribotypes were responsible for C. difficile infection presentations. Although C. difficile-associated mortality has reduced in recent years, expansion of lineages associated with increased severity could herald increases in future mortality. Enhanced surveillance for emerging lineages such as RT220 that are associated with more severe disease is required, with genomic approaches to dissect pathogenicity.
Ellington MJ, Davies F, Jauneikaite E, et al., 2019, A multi-species cluster of GES-5 carbapenemase producing Enterobacterales linked by a geographically disseminated plasmid, Clinical Infectious Diseases, ISSN: 1058-4838
BACKGROUND: Early and accurate treatment of infections due to carbapenem-resistant organisms is facilitated by rapid diagnostics but rare resistance mechanisms can compromise detection. One year after a GES-5 carbapenemase-positive Klebsiella oxytoca infection was identified by whole genome sequencing (WGS) (later found to be part of a cluster of three cases), a cluster of 11 patients with GES-5-positive K. oxytoca was identified over 18 weeks in the same hospital.METHODS: Bacteria were identified by MALDI-TOF, antimicrobial susceptibility testing followed EUCAST guidelines. Ertapenem-resistant isolates were referred to Public Health England for characterization using PCR detection of GES, pulse-field gel electrophoresis (PFGE) and WGS for the second cluster.RESULTS: The identification of the first GES-5 K. oxytoca isolate was delayed, being identified on WGS. A GES-gene PCR informed the occurrence of the second cluster in real-time. In contrast to PFGE, WGS phylogenetic analysis refuted an epidemiological link between the two clusters; it also suggested a cascade of patient-to-patient transmission in the later cluster. A novel GES-5-encoding plasmid was present in K. oxytoca,E. coli and E. cloacae isolates from unlinked patients within the same hospital group and in human and wastewater isolates from three hospitals elsewhere in the UK.CONCLUSIONS: Genomic sequencing revolutionized the epidemiological understanding of the clusters, it also underlined the risk of covert plasmid propagation in healthcare settings and revealed the national distribution of the resistance-encoding plasmid. Sequencing results also informed and led to the ongoing use of enhanced diagnostic tests for detecting carbapenemases locally and nationally.
Lynskey NN, Jauneikaite E, Li H-K, et al., 2019, Emergence of dominant toxigenic M1T1 Streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological study, Lancet Infectious Diseases, Vol: 19, Pages: 1209-1218, ISSN: 1473-3099
BackgroundEngland is experiencing scarlet fever activity unprecedented in modern times. In 2016, England’s scarlet fever seasonal rise coincided with an unexpected elevation in invasive Streptococcus pyogenes infections. We describe the molecular-epidemiological investigation of these events and emergence of a new emm1 lineage.Methods We analysed changes in S. pyogenes emm-genotypes, and notifications of scarlet fever and invasive disease 2014-2016 using regional (North-West London) and national (England and Wales) data. We analysed genomes of 135 non-invasive and 552 invasive emm1 isolates from 2009-2016, and compared 2800 global emm1 sequences. Expression of Streptococcal pyrogenic exotoxin (Spe)A by sequenced non-invasive emm1 isolates was quantified.FindingsCoincident with national increases in scarlet fever and invasive disease notifications, emm1 S. pyogenes increased significantly, from 19% (28/147) of upper respiratory tract isolates in MarchMay 2015, to 32·6% (47/144) in the same period 2016 in North-West London (χ2 (1df)=7·024, p=0·008), and from 31% (183/587) of invasive isolates in March-May 2015, to 41·9% (267/637)in the same period 2016 nationally (χ2 (1df)=15·16, p=0·0001). Sequences of emm1 isolates from 2009-2016 demonstrated emergence of a new emm1 lineage (M1UK), with overlap of pharyngitis, scarlet fever, and invasive M1UK strains, that could be genotypically distinguished from pandemic emm1 isolates (M1global). Compared with M1global, median expression of SpeA increased 9-fold in M1UK isolates (M1global, median=20·9 ng/ml, IQ range=21.3; (M1UK, median=190·2 ng/ml, IQ3 range 31.5; Mann-Whitney p<0·001). M1UK expanded nationally to represent 84% (252/299) of all emm1 genomes in 2016; phylogenetic analysis of published datasets identified single M1UK isolates in Denmark and USA.
Turner CE, Holden MTG, Blane B, et al., 2019, The Emergence of Successful Streptococcus pyogenes Lineages through Convergent Pathways of Capsule Loss and Recombination Directing High Toxin Expression, MBIO, Vol: 10, ISSN: 2150-7511
Greer O, Shah NM, Sriskandan S, et al., 2019, Sepsis: precision-based medicine for pregnancy and the puerperium, International Journal of Molecular Sciences, Vol: 20, Pages: 1-18, ISSN: 1422-0067
Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.
Sharma H, Turner CE, Siggins MK, et al., 2019, Toxic shock syndrome toxin-1 evaluation and antibiotic impact in a transgenic model of staphylococcal soft tissue infection, mSphere, Vol: 4, ISSN: 2379-5042
Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo. HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression.
Davies F, Olme C, Lynskey N, et al., 2019, Streptococcal superantigen‐induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death and reduced immunoglobulin release, Clinical and Experimental Immunology, Vol: 197, Pages: 83-94, ISSN: 1365-2249
Streptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo‐pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co‐incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme‐linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA‐stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C‐X‐C chemokine receptor (CXCR)5 (CD185) expression, but up‐regulation of OX40 (CD134) and inducible T cell co‐stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen‐producing bacteria with a probable survival advantage.
Mosavie M, Blandy O, Jauneikaite E, et al., 2019, Sampling and diversity of Escherichia coli from the enteric microbiota in patients with Escherichia coli bacteraemia, BMC Research Notes, Vol: 12, ISSN: 1756-0500
ObjectiveThe increase in Escherichia coli bloodstream infections mandates better characterisation of the relationship between commensal and invasive isolates. This study adopted a simple approach to characterize E. coli in the gut reservoir from patients with either E. coli or other Gram-negative bacteraemia, or those without bacteraemia, establishing strain collections suitable for genomic investigation. Enteric samples from patients in the three groups were cultured on selective chromogenic agar. Genetic diversity of prevailing E. coli strains in gut microbiota was estimated by RAPD-PCR.ResultsEnteric samples from E. coli bacteraemia patients yielded a median of one E. coli RAPD pattern (range 1–4) compared with two (range 1–5) from groups without E. coli bacteraemia. Of relevance to large-scale clinical studies, observed diversity of E. coli among hospitalised patients was not altered by sample type (rectal swab or stool), nor by increasing the colonies tested from 10 to 20. Hospitalised patients demonstrated an apparently limited diversity of E. coli in the enteric microbiota and this was further reduced in those with E. coli bacteraemia. The reduced diversity of E. coli within the gut during E. coli bacteraemia raises the possibility that dominant strains may outcompete other lineages in patients with bloodstream infection.
Goldblatt J, Hoffland A, Lawrenson RA, et al., 2019, A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP, Journal of Immunology, Vol: 202, Pages: 3246-3255, ISSN: 1550-6606
To evade the immune system, the lethal human pathogen Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminal α-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage. We examined the in vitro migration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N terminus and preserved disulfide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C-terminal α-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whereas navigation of an fMLF gradient remained largely intact. We conclude, therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation because of a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
Reglinski M, Sriskandan S, Turner CE, 2019, Identification of two new core chromosome-encoded superantigens in Streptococcus pyogenes; speQ and speR, Journal of Infection, Vol: 78, Pages: 358-363, ISSN: 0163-4453
Superantigens are ubiquitous within the Streptococcus pyogenes genome, which suggests that superantigen-mediated T-cell activation provides a significant selective advantage. S. pyogenes can carry a variable complement of the 11 known superantigens. We have identified two novel S. pyogenes superantigens, denoted speQ and speR, adjacent to each other in the core-chromosome of isolates belonging to eleven different emm-types. Although distinct from other superantigens, speQ and speR were most closely related to speK and speJ, respectively. Recombinant SPEQ and SPER were mitogenic towards human peripheral blood mononuclear cells at ng/ml concentrations, and SPER was found to be more mitogenic than SPEQ.
Reglinski M, Sriskandan S, 2019, Treatment potential of pathogen-reactive antibodies sequentially purified from pooled human immunoglobulin, BMC Research Notes, Vol: 12, ISSN: 1756-0500
ObjectiveIntravenous immune globulin (IVIG), pooled from human blood, is a polyspecific antibody preparation that inhibits the super-antigenic proteins associated with streptococcal and staphylococcal toxic shock, and the Shiga toxin. In addition to this toxin-neutralising activity, IVIG contains other pathogen-reactive antibodies that may confer additional therapeutic benefits. We sought to determine if pathogen-reactive antibodies that promote opsonophagocytosis of different organisms can be sequentially affinity-purified from one IVIG preparation.ResultsAntibodies that recognise cell wall antigens of Streptococcus pyogenes, Staphylococcus aureus, and vancomycin-resistant enterococcus (VRE) were sequentially affinity-purified from a single preparation of commercial IVIG and opsonophagocytic activity was assessed using a flow cytometry assay of neutrophil uptake. Non-specific IgG-binding proteins were removed from the S. aureus preparations using an immobilised Fc fragment column, produced using IVIG cleaved with the Immunoglobulin G-degrading enzyme of S. pyogenes (IdeS). Affinity-purified anti-S. aureus and anti-VRE immunoglobulin promoted significantly higher levels of opsonophagocytic uptake by human neutrophils than IVIG when identical total antibody concentrations were compared, confirming activity previously shown for affinity-purified anti-S. pyogenes immunoglobulin. The opsonophagocytic activities of anti-S. pyogenes, anti-S. aureus, and anti-VRE antibodies that were sequentially purified from a single IVIG preparation were undiminished compared to antibodies purified from previously unused IVIG.
Hutchinson M, Sohal M, Layton M, et al., 2019, STEROID-FREE MANAGEMENT OF LIFE-THREATENING HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE CONTEXT OF SUSPECTED LYMPHOPROLIFERATIVE DISEASE AND INFECTION, Annual Conference of the British-Soceity-for-Rheumatology, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324
Rawson TM, Hernandez B, Moore L, et al., 2019, Supervised machine learning for the prediction of infection on admission to hospital: a prospective observational cohort study, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1108-1115, ISSN: 0305-7453
BackgroundInfection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital.MethodsAn SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160 203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored.ResultsOne hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21–98) years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20–0.40). ROC AUC was 0.84 (95% CI: 0.76–0.91).ConclusionsAn SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.
Blandy O, Honeyford K, Gharbi M, et al., 2019, Factors that impact on the burden of Escherichia coli bacteraemia: multivariable regression analysis of 2011-2015 data from West London, Journal of Hospital Infection, Vol: 101, Pages: 120-128, ISSN: 0195-6701
BackgroundThe incidence of Escherichia coli bacteraemia in England is increasing amid concern regarding the roles of antimicrobial resistance and nosocomial acquisition on burden of disease.AimTo determine the relative contributions of hospital-onset E. coli blood stream infection and specific E. coli antimicrobial resistance patterns to the burden and severity of E. coli bacteremia in West London.MethodsPatient and antimicrobial susceptibility data were collected for all cases of E. coli bacteraemia between 2011 and 2015. Multivariable logistic regression was used to determine the association between the category of infection (hospital or community-onset) and length of stay, intensive care unit admission, and 30-day all-cause mortality.FindingsE. coli bacteraemia incidence increased by 76% during the study period, predominantly due to community-onset cases. Resistance to quinolones, third-generation cephalosporins, and aminoglycosides also increased over the study period, occurring in both community- and hospital-onset cases. Hospital-onset and non-susceptibility to either quinolones or third-generation cephalosporins were significant risk factors for prolonged length of stay, as was older age. Rates of mortality were 7% and 12% at 7 and 30 days, respectively. Older age, a higher comorbidity score, and bacteraemia caused by strains resistant to three antibiotic classes were all significant risk factors for mortality at 30 days.ConclusionMultidrug resistance, increased age, and comorbidities were the main drivers of adverse outcome. The rise in E. coli bacteraemia was predominantly driven by community-onset infections, and initiatives to prevent community-onset cases should be a major focus to reduce the quantitative burden of E. coli infection.
Leonard A, Wright A, Saavedra-Campos M, et al., 2019, Severe group A streptococcal infections in mothers and their newborns in London and the South East, 2010-2016: assessment of risk and audit of public health management, BJOG: An International Journal of Obstetrics and Gynaecology, Vol: 126, Pages: 44-53, ISSN: 1470-0328
ObjectiveWe describe cases of invasive group A Streptococcus (iGAS) in mothers or neonates and assess management according to national guidelines, which recommend administering antibiotics to both mother and neonate if either develops iGAS infection within 28 days of birth and investigation of clusters in maternity units.DesignCross‐sectional retrospective study.Setting and populationNotified confirmed iGAS cases in either mothers or neonates with onset within 28 days of birth in London and the South East of England between 2010 and 2016MethodReview of public health records of notified cases.Main outcome measuresIncidence and onset time of iGAS in postpartum mothers and babies, proportion given prophylaxis, maternity unit clusters within 6 months.ResultsWe identified 134 maternal and 21 neonatal confirmed iGAS infections. The incidence (in 100 000 person years) of iGAS in women within 28 days postpartum was 109 (95% CI 90–127) compared with 1.3 in other females aged 15–44. For neonates the incidence was 1.5 (95% CI 9–23). The median onset time was 2 days postpartum [interquartile range (IQR) 0–5 days] for mothers and 12 days (IQR 7–15 days) for neonates. All eligible mothers and most (109, 89%) eligible neonates received chemoprophylaxis. Of 20 clusters (59 cases of GAS and iGAS) in maternity units, two clusters involved possible transmission. However, in 6 of 15 clusters, GAS isolates were not saved for comparison even after relevant guidance was issued.ConclusionsiGAS infection remains a potential postpartum risk. Prophylaxis among neonates and storage of isolates from maternity cases can be improved.
Parks T, Wilson C, Curtis N, et al., 2018, Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis., Clinical Infectious Diseases, Vol: 67, Pages: 1434-1436, ISSN: 1058-4838
We evaluated the effect of adjunctive intravenous immunoglobulin (IVIG) on mortality in clindamycin-treated streptococcal toxic shock syndrome patients using a meta-analysis. In association with IVIG, mortality fell from 33.7% to 15.7% (risk ratio 0.46, 95% confidence intervals 0.26-0.83, p=0.010) with remarkable consistency across the single randomised and four non-randomised studies.
Mearkle R, Balasegaram S, Sriskandan S, et al., 2018, Familial transmission of emm12 group A streptococcus, Emerging Infectious Diseases, Vol: 24, Pages: 2133-2134, ISSN: 1080-6040
Jauneikaite E, Kapatai G, Davies F, et al., 2018, Serial clustering of late onset group B streptococcal infections in the neonatal unit - a genomic re-evaluation of causality, Clinical Infectious Diseases, Vol: 67, Pages: 854-860, ISSN: 1058-4838
Background. Invasive Group B streptococcus (GBS) is a major cause of serious neonatal infection. Current strategies to reduce early onset GBS disease have no impact on late onset disease (LOD). Although GBS is a normal part of the enteric microbiota in healthy term infants, LOD cases arising in the neonatal intensive care unit setting raise questions about mode of acquisition.Methods. Enhanced surveillance for any case of late onset GBS sepsis admitted to a level 3, 24-bed neonatal intensive care unit over a 2 year period was instituted following a cluster of four cases. All late onset GBS isolates were serotyped and genomes sequenced. Rectal screening of neonates for GBS was undertaken weekly. Healthcare workers and parents were not screened.Results. Over 24 months, a total of 12 late onset invasive GBS episodes were identified (incidence 0.6/1000 live births). Genomic analysis revealed that 11/12 GBS isolates (92%) were linked to at least one other LOD isolate. Four isolates from the first cluster were serotype V, resistant to macrolides and lincosamides, providing early evidence of a common source. Sequencing confirmed isolates were indistinguishable, or distinguishable by 1 SNP, from each other, and distinct from contemporary serotype V GBS. Although a common environmental source was not identified, prompt infection prevention interventions were instituted and no further serotype V GBS infections arose. Prospective surveillance identified three further clusters of LOD due to serotypes Ia, Ib, and III, leading to re-evaluation of interventions required for preventing GBS LOD. Conclusion. Acquisition routes for LOD GBS in the neonatal unit are poorly understood; such cases may not necessarily be sporadic. Within this neonatal unit, our data suggest that a single case of LOD GBS sepsis should be considered a potential nosocomial transmission event warranting prompt investigation, heightened infection prevention vigilance and action where required.
Shallcross L, Mentzer A, Rahman S, et al., 2018, Cohort study protocol: Bioresource in Adult Infectious Diseases (BioAID), Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Introduction: Infectious diseases have a major impact on morbidity and mortality in hospital. Microbial diagnosis remains elusive for most cases of suspected infection which impacts on the use of antibiotics. Rapid advances in genomic technologies combined with high-quality phenotypic data have great potential to improve the diagnosis, management and clinical outcomes of infectious diseases. The aim of the Bioresource in Adult Infectious Diseases (BioAID) is to provide a platform for biomarker discovery, trials and clinical service developments in the field of infectious diseases, by establishing a registry linking clinical phenotype to microbial and biological samples in adult patients who attend hospital with suspected infection.Methods and analysis: BioAID is a cohort study which employs deferred consent to obtain an additional 2.5mL RNA blood sample from patients who attend the Emergency Department (ED) with suspected infection when they undergo peripheral blood culture sampling. Clinical data and additional biological samples including DNA, serum and microbial isolates are obtained from BioAID participants during hospital admission. Participants are also asked to consent to be recalled for future studies. BioAID aims to recruit 10,000 patients from 5-8 sites across England. Since February 2014 >4000 individuals have been recruited to the study. The final cohort will be characterised using descriptive statistics including information on the number of cases that can be linked to biological and microbial samples to support future research studies. Ethical approval and section 251 exemption have been obtained for BioAID researchers to seek deferred consent from patients from whom a RNA specimen has been collected. Samples and meta-data obtained through BioAID will be made available to researchers worldwide following submission of an application form and research protocol. Conclusions: BioAID will support a range of study designs spanning discovery science
Taylor E, Sriskandan S, Woodford N, et al., 2018, High prevalence of 16S rRNA methyltransferases among carbapenemase-producing Enterobacteriaceae in the UK & Ireland, International Journal of Antimicrobial Agents, Vol: 52, Pages: 278-282, ISSN: 0924-8579
The emergence of 16S rRNA methyltransferases (16S RMTases) worldwide is a growing concern due to their ability to confer high-level resistance (MICs >256 mg/L) to all clinically-relevant aminoglycosides. As the occurrence of 16S RMTases in the United Kingdom has not been investigated to date, we screened 806 Enterobacteriaceae isolates displaying high-level aminoglycoside resistance (amikacin, gentamicin and tobramycin MICs ≥64, ≥32 and ≥32 mg/L, respectively) for 16S RMTases either by analysing whole-genome sequence (WGS) data (which were available for 449 isolates) or by PCR. A total of 94.5% (762/806) pan-aminoglycoside resistant Enterobacteriaceae were positive for one or more 16S RMTase genes; armA was the most common (340, 44.6%) followed by rmtC (146, 19.2%), rmtF (137, 18.0%), rmtB (87, 11.4%) and various two gene combinations (52, 6.8%). Most (93.4%; 712/762) 16S RMTase producers also carried acquired carbapenemase genes, with blaNDM the most common (592/712; 83.1%). Additionally, high-risk bacterial clones associated with blaNDM were identified in the subset of isolates with WGS data. These included E. coli sequence types (STs) 405 [21.8%, 19/87], 167 [20.7%, 18/87] 410 [12.6%, 11/87] and K. pneumoniae STs 14 [35.6%, 112/315], 231 [15.6%, 49/315] and 147 [10.5%, 33/315]. These accounted for 4.2% [15/358], 5.0% [18/358], 3.1% [11/358], 28.2% [101/358], 3.1% [11/358] and 7.0% [25/358] blaNDM-producing isolates, respectively. This study shows that 16S RMTases occur in the UK & Ireland and carbapenemases are particularly prevalent in 16S RMTase-producing Enterobacteriaceae. This association poses a risk to the treatment of multidrug-resistant Gram-negative infections in the clinical setting.
Lamb LE, Siggins MK, Scudamore C, et al., 2018, Impact of contusion injury on intramuscular emm1 group A-Streptococcus infection and Lymphatic spread, Virulence, Vol: 9, Pages: 1074-1084, ISSN: 2150-5594
Invasive group A Streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of around 20%. Cases occasionally arise in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new murine model of contusion, we determined the impact of contusion on iGAS bacterial burden and phenotype. Calibrated mild blunt contusion did not provide a focus for initiation or seeding of GAS that was detectable following systemic GAS bacteremia, but instead enhanced GAS migration to the local draining lymph node following GAS inoculation at the same time and site of contusion. Increased migration to lymph node was associated with emergence of mucoid bacteria, although was not specific to mucoid bacteria. In one study, mucoid colonies demonstrated a significant increase in capsular hyaluronan that was not linked to a covRS or rocA mutation, but to a deletion in the promoter of the capsule synthesis locus, hasABC, resulting in a strain with increased fitness for lymph node migration. In summary, in the mild contusion model used, we could not detect seeding of muscle by GAS. Contusion promoted bacterial transit to the local lymph node. The consequences of contusion-associated bacterial lymphatic migration may vary depending on the pathogen and virulence traits selected.
Lamb L, Zhi X, Alam F, et al., 2018, Modelling invasive group A streptococcal disease using bioluminescence, BMC Microbiology, Vol: 18, ISSN: 1471-2180
Background:The development of vaccines and evaluation of novel treatment strategies for invasive group A streptococcal (iGAS) disease requires suitable models of human infection that can be monitored longitudinally and are preferably non-invasive. Bio-photonic imaging provides an opportunity to reduce use of animals in infection modelling and refine the information that can be obtained, however the range of bioluminescent GAS strains available is limited. In this study we set out to develop bioluminescent iGAS strains for use in in vivo pneumonia and soft tissue disease models.Results:Using clinical emm1, emm3, and emm89 GAS strains that were transformed with constructs carrying the luxABCDE operon, growth and bioluminescence of transformed strains were characterised in vitro and in vivo.Emm3 and emm89 strains expressed detectable bioluminescence when transformed with a replicating plasmid and light production correlated with viable bacterial counts in vitro, however plasmid instability precluded use in the absence of antimicrobial pressure. Emm89 GAS transformed with an integrating construct demonstrated stable bioluminescence that was maintained in the absence of antibiotics. Bioluminescence of the emm89 strain correlated with viable bacterial counts both in vitro and immediately following infection in vivo. Although bioluminescence conferred a detectable fitness burden to the emm89 strain during soft tissue infection in vivo, it did not prevent dissemination to distant tissues.Conclusion:Development of stably bioluminescent GAS for use in vitro and in vivo models of infection should facilitate development of novel therapeutics and vaccines while also increasing our understanding of infection progression and transmission routes.
Jones S, Moreland NJ, Zancolli M, et al., 2018, Development of an opsonophagocytic killing assay for group a streptococcus, Vaccine, Vol: 36, Pages: 3756-3763, ISSN: 0264-410X
Group A Streptococcus (GAS) or Streptococcus pyogenes is responsible for an estimated 500,000 deaths worldwide each year. Protection against GAS infection is thought to be mediated by phagocytosis, enhanced by bacteria-specific antibody. There are no licenced GAS vaccines, despite many promising candidates in preclinical and early stage clinical development, the most advanced of which are based on the GAS M-protein. Vaccine progress has been hindered, in part, by the lack of a standardised functional assay suitable for vaccine evaluation. Current assays, developed over 50 years ago, rely on non-immune human whole blood as a source of neutrophils and complement. Variations in complement and neutrophil activity between donors result in variable data that is difficult to interpret. We have developed an opsonophagocytic killing assay (OPKA) for GAS that utilises dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in current assays. We have standardised the OPKA for several clinically relevant GAS strain types (emm1, emm6 and emm12) and have shown antibody-specific killing for each emm-type using M-protein specific rabbit antisera. Specificity was demonstrated by pre-incubation of the antisera with homologous M-protein antigens that blocked antibody-specific killing. Additional qualifications of the GAS OPKA, including the assessment of the accuracy, precision, linearity and the lower limit of quantification, were also performed. This GAS OPKA assay has the potential to provide a robust and reproducible platform to accelerate GAS vaccine development.
Edwards RJ, Pyzio M, Gierula M, et al., 2018, Proteomic analysis at the sites of clinical infection with invasive Streptococcus pyogenes, Scientific Reports, Vol: 8, ISSN: 2045-2322
Invasive Streptococcus pyogenes infections are rare, with often-unexplained severity. Prompt diagnosis is desirable, as deaths can occur rapidly following onset and there is an increased, but preventable, risk to contacts. Here, proteomic analyses of clinical samples from invasive human S. pyogenes infections were undertaken to determine if novel diagnostic targets could be detected, and to augment our understanding of disease pathogenesis. Fluid samples from 17 patients with confirmed invasive S. pyogenes infection (empyema, septic arthritis, necrotising fasciitis) were analysed by proteomics for streptococcal and human proteins; 16/17 samples had detectable S. pyogenes DNA. Nineteen unique S. pyogenes proteins were identified in just 6/17 samples, and 15 of these were found in a single pleural fluid sample including streptococcal inhibitor of complement, trigger factor, and phosphoglycerate kinase. In contrast, 469 human proteins were detected in patient fluids, 177 (38%) of which could be identified as neutrophil proteins, including alpha enolase and lactotransferrin which, together, were found in all 17 samples. Our data suggest that streptococcal proteins are difficult to detect in infected fluid samples. A vast array of human proteins associated with leukocyte activity are, however, present in samples that deserve further evaluation as potential biomarkers of infection.
Sharma H, Smith D, Turner CE, et al., 2018, Clinical and Molecular Epidemiology of Staphylococcal Toxic Shock Syndrome in the United Kingdom, Emerging Infectious Diseases, Vol: 24, Pages: 258-266, ISSN: 1080-6040
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