Salvage Strategy for Long-Term Central Venous Catheter-Associated Staphylococcus aureus Infections in Children

Introduction: Current international guidelines strongly recommend catheter removal in case of S. aureus central line-associated bloodstream infection (CLASBI), but a catheter salvage strategy may be considered in children given age-related specificities. No data is available regarding the outcome of this strategy in children. This study aims to evaluate catheter salvage strategy in children with S. aureus CLABSI, and to determine treatment failure rates and associated risk factors.Methods: We retrospectively analyzed data for all children <18 years having S. aureus CLABSI on a long-term central venous catheter in a tertiary hospital from 2010 to 2014. We defined catheter salvage strategy as a central venous catheter left in place ≥3 days after initiation of empiric treatment for suspected bacteremia, and catheter salvage strategy failure as the persistence or relapse of bacteremia with a S. aureus strain harboring the same antibiotic susceptibility pattern, or the occurrence or the worsening of local or systemic infectious complication between 72 h and 28 days after the first positive blood culture.Results: During the study period, 49 cases of S. aureus CLABSI on long-term central venous catheters were observed in 41 children (including 59% with long-term parenteral nutrition) and 6 (15%) isolates were resistant to methicillin. A catheter salvage strategy was chosen in 37/49 (76%) cases and failed in 12/37 (32%) cases. Initial presence of bloodstream co-infection, serum concentration of vancomycin under the targeted value and inadequate empiric treatment were significantly associated with catheter salvage therapy failure.Conclusions: The catheter salvage strategy of S. aureus CLABSI on a long-term central venous catheter was frequent in the studied hospital and failed only in one third of cases

Ongoing diphtheria outbreak in Yemen: a cross-sectional and genomic epidemiology study.

BACKGROUND: An outbreak of diphtheria, declared in Yemen in October, 2017, is ongoing. We did a cross-sectional study to investigate the epidemiological, clinical, and microbiological features of the outbreak. METHODS: Probable cases of diphtheria that were defined clinically and recorded through a weekly electronic diseases early warning system (from 2017, week 22, to 2020, week 17) were used to identify trends of the outbreak (we divided the epidemic into three time periods: May 29, 2017, to June 10, 2018; June 11, 2018, to June 3, 2019; and June 4, 2019, to April 26, 2020). We used the line list of diphtheria reports for governorate-level descriptions. Vaccination coverage was estimated using the 2017 and 2018 annual reports by the national Expanded Programme on Immunization. To confirm cases biologically, Corynebacterium diphtheriae was isolated and identified from throat swabs using standard microbiological culture and identification procedures. We assessed differences in the temporal and geographical distributions of cases, including between different age groups. For in-depth microbiological analysis, tox gene and species-specific rpoB real-time PCR, Illumina genomic sequencing, antimicrobial susceptibility analysis (disk diffusion, E-test), and the Elek diphtheria toxin production test were done on confirmed cases. We used genomic data for phylogenetic analyses and to estimate the nucleotide substitution rate. FINDINGS: The Yemen diphtheria outbreak affected almost all governorates (provinces), with 5701 probable cases and 330 deaths recorded up to April 26, 2020. We collected clinical data for 888 probable cases with throat swab samples referred for biological confirmation, and genomic data for 42 positive cases, corresponding to 43 isolates (two isolates from one culture were included due to distinct colony morphologies). The median age of patients was 12 years (range 0·2-80). The proportion of cases in children aged 0-4 years was reduced during the second time period, after a vaccination campaign, compared with the first period (19% [95% CI 18-21] in the first period vs 14% [12-15] in the second period, p<0·0001). Among 43 tested isolates, 39 (91%) produced the diphtheria toxin and two had low level (0·25 mg/L) antimicrobial resistance to penicillin. We identified six C diphtheriae phylogenetic sublineages, four of which are genetically related to isolates from Saudi Arabia, Eritrea, and Somalia. Inter-sublineage genomic variations in genes associated with antimicrobial resistance, iron acquisition, and adhesion were observed. The predominant sublineage (30 [70%] of 43 isolates) was resistant to trimethoprim and was associated with unique genomic features, more frequent neck swelling (p=0·0029) and a younger age of patients (p=0·060) compared with the other sublineages. Its evolutionary rate was estimated at 1·67 × 10-6 substitutions per site per year, placing its most recent common ancestor in 2015, and indicating silent circulation of C diphtheriae in Yemen before the outbreak was declared. INTERPRETATION: In the Yemen outbreak, C diphtheriae shows high phylogenetic, genomic, and phenotypic variation. Laboratory capacity and real-time microbiological monitoring of diphtheria outbreaks need to be scaled up to inform case management and transmission control of diphtheria. Catch-up vaccination might have provided some protection to the targeted population (children aged 0-4 years). FUNDING: National Centre of the Public Health Laboratories (Yemen), Institut Pasteur, and the French Government Investissement d'Avenir Programme. TRANSLATION: For the Arabic translation of the abstract see Supplementary Materials section

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

Background: Corynebacterium diphtheriae, the agent of diphtheria, is a genetically diverse bacterial species. Although antimicrobial resistance has emerged against several drugs including first-line penicillin, the genomic determinants and population dynamics of resistance are largely unknown for this neglected human pathogen. Methods: Here, we analyzed the associations of antimicrobial susceptibility phenotypes, diphtheria toxin production, and genomic features in C. diphtheriae. We used 247 strains collected over several decades in multiple world regions, including the 163 clinical isolates collected prospectively from 2008 to 2017 in France mainland and overseas territories. Results: Phylogenetic analysis revealed multiple deep-branching sublineages, grouped into a Mitis lineage strongly associated with diphtheria toxin production and a largely toxin gene-negative Gravis lineage with few toxin-producing isolates including the 1990s ex-Soviet Union outbreak strain. The distribution of susceptibility phenotypes allowed proposing ecological cutoffs for most of the 19 agents tested, thereby defining acquired antimicrobial resistance. Penicillin resistance was found in 17.2% of prospective isolates. Seventeen (10.4%) prospective isolates were multidrug-resistant (≥ 3 antimicrobial categories), including four isolates resistant to penicillin and macrolides. Homologous recombination was frequent (r/m = 5), and horizontal gene transfer contributed to the emergence of antimicrobial resistance in multiple sublineages. Genome-wide association mapping uncovered genetic factors of resistance, including an accessory penicillin-binding protein (PBP2m) located in diverse genomic contexts. Gene pbp2m is widespread in other Corynebacterium species, and its expression in C. glutamicum demonstrated its effect against several beta-lactams. A novel 73-kb C. diphtheriae multiresistance plasmid was discovered. Conclusions: This work uncovers the dynamics of antimicrobial resistance in C. diphtheriae in the context of phylogenetic structure, biovar, and diphtheria toxin production and provides a blueprint to analyze re-emerging diphtheria

Circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries

Reported incidence of pertussis in the European Union (EU) and the European Economic Area (EEA) varies and may not reflect the real situation, while vaccine-induced protection against diphtheria and tetanus seems sufficient. We aimed to determine the seroprevalence of DTP antibodies in EU/EEA countries within the age groups of 40-49 and 50-59 years. Eighteen countries collected around 500 samples between 2015 and 2018 (N = 10,302) which were analysed for IgG-DTP specific antibodies. The proportion of sera with pertussis toxin antibody levels ≥100 IU/mL, indicative of recent exposure to pertussis was comparable for 13/18 countries, ranging between 2.7-5.8%. For diphtheria the proportion of sera lacking the protective level (</p

The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water.

BACKGROUND: Having conquered water surfaces worldwide, the semi-aquatic bugs occupy ponds, streams, lakes, mangroves, and even open oceans. The diversity of this group has inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders our ability to more thoroughly investigate the molecular mechanisms underlying the processes of adaptation and diversification within this group. RESULTS: Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome; the first water strider genome to be sequenced thus far. The size of the G. buenoi genome is approximately 1,000 Mb, and this sequencing effort has recovered 20,949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to a water surface lifestyle. These expansions may affect key processes associated with growth, vision, desiccation resistance, detoxification, olfaction and epigenetic regulation. Strikingly, the G. buenoi genome contains three insulin receptors, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes affecting with opsin genes may be associated with wavelength sensitivity shifts in opsins, which is likely to be key in facilitating specific adaptations in vision for diverse water habitats. CONCLUSIONS: Our findings suggest that local gene duplications might have played an important role during the evolution of water striders. Along with these findings, the sequencing of the G. buenoi genome now provides us the opportunity to pursue exciting research opportunities to further understand the genomic underpinnings of traits associated with the extreme body plan and life history of water striders

The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water

Background: Having conquered water surfaces worldwide, the semi-aquatic bugs occupy ponds, streams, lakes, mangroves, and even open oceans. The diversity of this group has inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders our ability to more thoroughly investigate the molecular mechanisms underlying the processes of adaptation and diversification within this group. Results: Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome; the first water strider genome to be sequenced thus far. The size of the G. buenoi genome is approximately 1,000Mb, and this sequencing effort has recovered 20,949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to a water surface lifestyle. These expansions may affect key processes associated with growth, vision, desiccation resistance, detoxification, olfaction and epigenetic regulation. Strikingly, the G. buenoi genome contains three insulin receptors, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes affecting with opsin genes may be associated with wavelength sensitivity shifts in opsins, which is likely to be key in facilitating specific adaptations in vision for diverse water habitats. Conclusions: Our findings suggest that local gene duplications might have played an important role during the evolution of water striders. Along with these findings, the sequencing of the G. buenoi genome now provides us the opportunity to pursue exciting research opportunities to further understand the genomic underpinnings of traits associated with the extreme body plan and life history of water striders

Signalisation de TLR2, organisation et variabilité de la réponse immunitaire innée

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Genomic epidemiology and strain taxonomy of Corynebacterium diphtheriae

International audienceBackground Corynebacterium diphtheriae is highly transmissible and can cause large diphtheria outbreaks where vaccination coverage is insufficient. Sporadic cases or small clusters are observed in high-vaccination settings. The phylogeography and short timescale evolution of C. diphtheriae are not well understood, in part due to a lack of harmonized analytical approaches of genomic surveillance and strain tracking. Methods We combined 1,305 genes with highly reproducible allele calls into a core genome multilocus sequence typing (cgMLST) scheme. We analyzed cgMLST genes diversity among 602 isolates from sporadic clinical cases, small clusters or large outbreaks. We defined sublineages based on the phylogenetic structure within C. diphtheriae and strains based on the highest number of cgMLST mismatches within documented outbreaks. We performed time-scaled phylogenetic analyses of major sublineages. Results The cgMLST scheme showed high allele call rate in C. diphtheriae and the closely related species C. belfantii and C. rouxii . We demonstrate its utility to delineate epidemiological case clusters and outbreaks using a 25 mismatches threshold, and reveal a number of cryptic transmission chains, most of which are geographically restricted to one or a few adjacent countries. Subcultures of the vaccine strain PW8 differed by up to 20 cgMLST mismatches. Phylogenetic analyses revealed short timescale evolutionary gain or loss of the diphtheria toxin and biovar-associated genes. We devised a genomic taxonomy of strains and deeper sublineages (defined using a 500 cgMLST mismatches threshold), currently comprising 151 sublineages, only a few of which are geographically widespread based on current sampling. The cgMLST genotyping tool and nomenclature was made publicly accessible at https://bigsdb.pasteur.fr/diphtheria . Conclusions Standardized genome-scale strain genotyping will help tracing transmission and geographic spread of C. diphtheriae . The unified genomic taxonomy of C. diphtheriae strains provides a common language for studies into the ecology, evolution and virulence heterogeneity among C. diphtheriae sublineages

Determining Factors for Pertussis Vaccination Policy: A Study in Five EU Countries

International audiencePertussis vaccination policy varies across Europe, not only in the type of vaccine—whole cell (wP) vs. acellular (aP1/2/3/5)—but also in the schedule and recommendation for parents. This study aims to investigate the determining factors for the type of vaccine, immunization schedule and maternal immunization recommendation. From March to May 2019, experts in national health agencies and major academic or research institutions from Denmark, France, Poland, Sweden and the UK were invited to a semi-structured interview. Thematic analysis was performed on the transcripts using a codebook formulated by three coders. Inter-coder agreement was assessed. Fifteen expert interviews were conducted. The identified driving factors for pertussis vaccine policy were classified into three domains: scientific factors, sociological factors, and pragmatic factors. The determining factors for the type of vaccine were prescriber’s preference, concern of adverse events following immunization (AEFI), effectiveness, and consideration of other vaccine components in combined vaccines. The determining factors for infant schedule were immunity response and the potential to improve coverage and timeliness. The determining factors for maternal immunization were infant mortality and public acceptability. To conclude, socio-political and pragmatic factors were, besides scientific factors, important in determining the pertussis vaccine type, schedule of childhood immunization and recommendations for parents

Myostatin inactivation increases myotube size through regulation of translational initiation machinery

International audienceMyostatin deficiency leads in skeletal muscle overgrowth but the precise molecular mechanisms underlying this hypertrophy are not well understood. In this study, to gain insight into the role of endogenous myostatin in the translational regulation, we used an in vitro model of cultured satellite cells derived from myostatin knock-out mice. Our results show that myostatin knock-out myotubes are larger than control myotubes and that this phenotype is associated with an increased activation of the Akt/mTOR signaling pathway, a known regulator of muscle hypertrophy. These results demonstrate that hypertrophy due to myostatin deficiency is preserved in vitro and suggest that myostatin deletion results in an increased protein synthesis. Accordingly, the rates of global RNA content, polysome formation and protein synthesis are all increased in myostatin-deficient myotubes while they are counteracted by the addition of recombinant myostatin. We furthermore demonstrated that genetic deletion of myostatin stimulates cap-dependent translation by positively regulating assembly of the translation preinitiation complex. Together the data indicate that myostatin controls muscle hypertrophy in part by regulating protein synthesis initiation rates, that is, translational efficiency