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1.
Clin Infect Dis ; 2020 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-32246143

RESUMEN

BACKGROUND: A locally developed Case-Based Reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated. METHODS: Prescribing 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. RESULTS: In 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. CONCLUSIONS: A 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.

2.
Genes Immun ; 21(1): 63-70, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31462703

RESUMEN

Invasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1540 controls. Using HLA imputation and linear mixed models, we find each copy of the HLA-DQA1*01:03 allele associates with a twofold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4, P = 0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.

3.
mBio ; 10(6)2019 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-31822586

RESUMEN

Gene transfer and homologous recombination in Streptococcus pyogenes has the potential to trigger the emergence of pandemic lineages, as exemplified by lineages of emm1 and emm89 that emerged in the 1980s and 2000s, respectively. Although near-identical replacement gene transfer events in the nga (NADase) and slo (streptolysin O) loci conferring high expression of these toxins underpinned the success of these lineages, extension to other emm genotype lineages is unreported. The emergent emm89 lineage was characterized by five regions of homologous recombination additional to nga-slo, including complete loss of the hyaluronic acid capsule synthesis locus hasABC, a genetic trait replicated in two other leading emm types and recapitulated by other emm types by inactivating mutations. We hypothesized that other leading genotypes may have undergone similar recombination events. We analyzed a longitudinal data set of genomes from 344 clinical invasive disease isolates representative of locations across England, dating from 2001 to 2011, and an international collection of S. pyogenes genomes representing 54 different genotypes and found frequent evidence of recombination events at the nga-slo locus predicted to confer higher toxin genotype. We identified multiple associations between recombination at this locus and inactivating mutations within hasAB, suggesting convergent evolutionary pathways in successful genotypes. This included common genotypes emm28 and emm87. The combination of no or low capsule and high expression of nga and slo may underpin the success of many emergent S. pyogenes lineages of different genotypes, triggering new pandemics, and could change the way S. pyogenes causes disease.IMPORTANCE Streptococcus pyogenes is a genetically diverse pathogen, with over 200 different genotypes defined by emm typing, but only a minority of these genotypes are responsible for the majority of human infection in high-income countries. Two prevalent genotypes associated with disease rose to international dominance following recombination of a toxin locus that conferred increased expression. Here, we found that recombination of this locus and promoter has occurred in other diverse genotypes, events that may allow these genotypes to expand in the population. We identified an association between the loss of hyaluronic acid capsule synthesis and high toxin expression, which we propose may be associated with an adaptive advantage. As S. pyogenes pathogenesis depends both on capsule and toxin production, new variants with altered expression may result in abrupt changes in the molecular epidemiology of this pathogen in the human population over time.

4.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-31671794

RESUMEN

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.

5.
J Infect ; 79(6): 521-527, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31733233

RESUMEN

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.

6.
Clin Infect Dis ; 2019 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-31746994

RESUMEN

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.

7.
mSphere ; 4(5)2019 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-31597722

RESUMEN

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 Vß 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.IMPORTANCE Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium Staphylococcus aureus, mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.


Asunto(s)
Antibacterianos/uso terapéutico , Toxinas Bacterianas/genética , Enterotoxinas/genética , Choque Séptico/microbiología , Infecciones de los Tejidos Blandos/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Superantígenos/genética , Animales , Citocinas , Modelos Animales de Enfermedad , Femenino , Antígenos HLA-DQ/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Choque Séptico/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad
8.
Lancet Infect Dis ; 19(11): 1209-1218, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31519541

RESUMEN

BACKGROUND: Since 2014, England has seen increased 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. METHODS: We analysed changes in S pyogenes emm genotypes, and notifications of scarlet fever and invasive disease in 2014-16 using regional (northwest London) and national (England and Wales) data. Genomes of 135 non-invasive and 552 invasive emm1 isolates from 2009-16 were analysed and compared with 2800 global emm1 sequences. Transcript and protein expression of streptococcal pyrogenic exotoxin A (SpeA; also known as scarlet fever or erythrogenic toxin A) in sequenced, non-invasive emm1 isolates was quantified by real-time PCR and western blot analyses. FINDINGS: Coincident with national increases in scarlet fever and invasive disease notifications, emm1 S pyogenes upper respiratory tract isolates increased significantly in northwest London in the March to May period, from five (5%) of 96 isolates in 2014, to 28 (19%) of 147 isolates in 2015 (p=0·0021 vs 2014 values), to 47 (33%) of 144 in 2016 (p=0·0080 vs 2015 values). Similarly, invasive emm1 isolates collected nationally in the same period increased from 183 (31%) of 587 in 2015 to 267 (42%) of 637 in 2016 (p<0·0001). Sequences of emm1 isolates from 2009-16 showed emergence of a new emm1 lineage (designated M1UK)-with overlap of pharyngitis, scarlet fever, and invasive M1UK strains-which could be genotypically distinguished from pandemic emm1 isolates (M1global) by 27 single-nucleotide polymorphisms. Median SpeA protein concentration in supernatant was nine-times higher among M1UK isolates (190·2 ng/mL [IQR 168·9-200·4]; n=10) than M1global isolates (20·9 ng/mL [0·0-27·3]; n=10; p<0·0001). M1UK expanded nationally to represent 252 (84%) of all 299 emm1 genomes in 2016. Phylogenetic analysis of published datasets identified single M1UK isolates in Denmark and the USA. INTERPRETATION: A dominant new emm1 S pyogenes lineage characterised by increased SpeA production has emerged during increased S pyogenes activity in England. The expanded reservoir of M1UK and recognised invasive potential of emm1 S pyogenes provide plausible explanation for the increased incidence of invasive disease, and rationale for global surveillance. FUNDING: UK Medical Research Council, UK National Institute for Health Research, Wellcome Trust, Rosetrees Trust, Stoneygate Trust.

9.
BMC Res Notes ; 12(1): 335, 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31196206

RESUMEN

OBJECTIVE: The 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. RESULTS: Enteric 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.


Asunto(s)
Bacteriemia/microbiología , Infecciones por Escherichia coli/microbiología , Escherichia coli/genética , Heces/microbiología , Microbioma Gastrointestinal/genética , Variación Genética , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Estudios de Cohortes , Escherichia coli/clasificación , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Reacción en Cadena de la Polimerasa/métodos , Técnica del ADN Polimorfo Amplificado Aleatorio/métodos , Reproducibilidad de los Resultados
10.
BMC Res Notes ; 12(1): 228, 2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30992057

RESUMEN

OBJECTIVE: Intravenous 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. RESULTS: Antibodies 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.


Asunto(s)
Anticuerpos Antibacterianos/farmacología , Inmunoglobulinas Intravenosas/química , Neutrófilos/efectos de los fármacos , Proteínas Opsoninas/farmacología , Fagocitosis/efectos de los fármacos , Anticuerpos Antibacterianos/aislamiento & purificación , Antígenos Bacterianos/química , Antígenos Bacterianos/inmunología , Pared Celular/química , Cromatografía de Afinidad/métodos , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Neutrófilos/citología , Neutrófilos/inmunología , Proteínas Opsoninas/aislamiento & purificación , Cultivo Primario de Células , Staphylococcus aureus/química , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad , Streptococcus pyogenes/química , Streptococcus pyogenes/inmunología , Streptococcus pyogenes/patogenicidad , Enterococos Resistentes a la Vancomicina/química , Enterococos Resistentes a la Vancomicina/inmunología , Enterococos Resistentes a la Vancomicina/patogenicidad
11.
J Immunol ; 202(11): 3246-3255, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31010851

RESUMEN

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.


Asunto(s)
Glicosaminoglicanos/metabolismo , Heparina/metabolismo , Interleucina-8/metabolismo , Neutrófilos/inmunología , Péptido Hidrolasas/metabolismo , Infecciones Estreptocócicas/inmunología , Streptococcus pyogenes/fisiología , Animales , Células Cultivadas , Humanos , Ratones , Unión Proteica , Ingeniería de Proteínas , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo
12.
J Infect ; 78(5): 358-363, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30796950

RESUMEN

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.

14.
Wellcome Open Res ; 3: 97, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30345383

RESUMEN

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, biomarker validation, disease pathogenesis and epidemiological analyses of clinical infection syndromes.

15.
Clin Infect Dis ; 67(9): 1434-1436, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-29788397

RESUMEN

We evaluated the effect of intravenous immunoglobulin (IVIG) on mortality in clindamycin-treated streptococcal toxic shock syndrome using a meta-analysis. In association with IVIG, mortality fell from 33.7% to 15.7% with remarkable consistency across the single randomized and four nonrandomized studies.


Asunto(s)
Clindamicina/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Choque Séptico/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Humanos , Choque Séptico/mortalidad , Infecciones Estreptocócicas/mortalidad , Streptococcus pyogenes , Resultado del Tratamiento
16.
Vaccine ; 36(26): 3756-3763, 2018 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-29776751

RESUMEN

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.


Asunto(s)
Inmunoensayo/métodos , Viabilidad Microbiana , Proteínas Opsoninas/sangre , Fagocitosis , Infecciones Estreptocócicas/inmunología , Streptococcus pyogenes/inmunología , Streptococcus pyogenes/fisiología , Animales , Anticuerpos Antibacterianos/sangre , Línea Celular , Proteínas del Sistema Complemento/inmunología , Humanos , Inmunoensayo/normas , Neutrófilos/inmunología , Conejos , Sensibilidad y Especificidad
17.
Sci Rep ; 8(1): 5950, 2018 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-29654237

RESUMEN

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.


Asunto(s)
Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/genética , Biomarcadores/metabolismo , ADN Bacteriano/genética , Humanos , Proteómica/métodos , Infecciones Estreptocócicas/genética
18.
Int J Antimicrob Agents ; 52(2): 278-282, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29596903

RESUMEN

The emergence of 16S rRNA methyltransferases (16S RMTases) worldwide is a growing concern due to their ability to confer high-level resistance (minimum inhibitory concentrations (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 polymerase chain reaction. 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 Escherichia 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 and 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.


Asunto(s)
Proteínas Bacterianas/genética , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Klebsiella pneumoniae/genética , Metiltransferasas/genética , ARN Ribosómico 16S/genética , beta-Lactamasas/genética , Aminoglicósidos/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Humanos , Irlanda/epidemiología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Metiltransferasas/metabolismo , Pruebas de Sensibilidad Microbiana , Plásmidos/química , Plásmidos/metabolismo , Prevalencia , Reino Unido/epidemiología , Secuenciación Completa del Genoma , beta-Lactamasas/metabolismo
19.
Clin Infect Dis ; 67(6): 854-860, 2018 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-29509833

RESUMEN

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 LOD is viewed as a sporadic event in the community, LOD arising within the neonatal intensive care unit (ICU) raises questions about mode of acquisition. Methods: Following a cluster of 4 GBS LOD cases, enhanced surveillance for all GBS LOD was undertaken over 2 years in the neonatal ICU supported by neonatal rectal screening. GBS isolates were serotyped and genome-sequenced. Results: Twelve 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. Isolates from the first cluster were serotype V, resistant to macrolides and lincosamides, and sequencing confirmed isolates were indistinguishable, or distinguishable by only one SNP difference, from each other. Rectal carriage was rare. Prospective surveillance identified three further clusters of LOD due to serotypes Ia (3 cases), Ib (2 cases), and III (2 cases), that would not have been identified without surveillance and genome sequencing, leading to a re-evaluation of interventions required to prevent GBS LOD. Conclusion: Acquisition routes for LOD GBS in the neonatal ICU are poorly understood; cases may not necessarily be sporadic. Within this neonatal ICU, 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.


Asunto(s)
Unidades de Cuidado Intensivo Neonatal , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/epidemiología , Streptococcus agalactiae/genética , Bacteriemia/epidemiología , Análisis por Conglomerados , Genómica , Humanos , Incidencia , Recién Nacido , Tamizaje Neonatal , Filogenia , Estudios Prospectivos , Factores de Riesgo , Serogrupo , Streptococcus agalactiae/aislamiento & purificación , Reino Unido/epidemiología , Secuenciación Completa del Genoma
20.
Emerg Infect Dis ; 24(2)2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29350159

RESUMEN

Staphylococcal toxic shock syndrome (TSS) was originally described in menstruating women and linked to TSS toxin 1 (TSST-1)-producing Staphylococcus aureus. Using UK national surveillance data, we ascertained clinical, molecular and superantigenic characteristics of TSS cases. Average annual TSS incidence was 0.07/100,000 population. Patients with nonmenstrual TSS were younger than those with menstrual TSS but had the same mortality rate. Children <16 years of age accounted for 39% of TSS cases, most caused by burns and skin and soft tissue infections. Nonmenstrual TSS is now more common than menstrual TSS in the UK, although both types are strongly associated with the tst+ clonal complex (CC) 30 methicillin-sensitive S. aureus lineage, which accounted for 49.4% of all TSS and produced more TSST-1 and superantigen bioactivity than did tst+ CC30 methicillin-resistant S. aureus strains. Better understanding of this MSSA lineage and infections in children could focus interventions to prevent TSS in the future.


Asunto(s)
Epidemiología Molecular , Choque Séptico/epidemiología , Choque Séptico/microbiología , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Enterotoxinas/genética , Enterotoxinas/metabolismo , Humanos , Vigilancia de la Población , Estudios Retrospectivos , Staphylococcus aureus/metabolismo , Superantígenos/genética , Superantígenos/metabolismo , Reino Unido/epidemiología
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