Microbiological Epidemiology of Invasive Infections Due to Non-Beta-Hemolytic Streptococci, France, 2021.

Non-beta-hemolytic streptococci (NBHS), also referred to as viridans streptococci, represent an underestimated cause of human invasive diseases. Their resistance to antibiotics, including beta-lactam agents, often complicate their therapeutic management. A prospective multicenter study was conducted by the French National Reference Center for Streptococci between March and April 2021 to describe the clinical and microbiological epidemiology of invasive infections due to NBHS, excluding pneumococcus. A total of 522 NBHS invasive cases were collected. Distribution among streptococcal groups was: Streptococcus anginosus (33%), Streptococcus mitis (28%), Streptococcus sanguinis (16%), Streptococcus bovis/equinus (15%), Streptococcus salivarius (8%), and Streptococcus mutans (<1%). Median age of infection was 68 years old (range <1 day to 100 years). Cases were more frequent in male patients (gender ratio M/F 2.1:1) and manifested mainly as bacteremia without focus (46%), intra-abdominal infections (18%) and endocarditis (11%). All isolates were susceptible to glycopeptides and displayed low-level inherent gentamicin resistance. All isolates of the S. bovis/equinus, S. anginosus, and S. mutans groups were susceptible to beta-lactams. Conversely, nonsusceptibility to beta-lactams was found in 31%, 28%, and 52% of S. mitis, S. salivarius, and S. sanguinis isolates, respectively. The screening for beta-lactam resistance using the recommended one unit benzylpenicillin disk screening failed to detect 21% of resistant isolates (21/99). Last, overall resistance rates to the alternative anti-streptococcal molecules clindamycin and moxifloxacin were 29% (149/522) and 1.6% (8/505), respectively. IMPORTANCE NBHS are recognized as opportunistic pathogens particularly involved in infections of the elderly and immunocompromised patients. This study underlines their importance as common causes of severe and difficult-to-treat infections such as endocarditis. Although species of the S. anginosus and S. bovis/equinus groups remain constantly susceptible to beta-lams, resistance in oral streptococci exceeds 30% and screening techniques are not fully reliable. Therefore, accurate species identification and antimicrobial susceptibility testing by MICs determination appears essential for the treatment of NBHS invasive infections, together with continued epidemiological surveillance.

Group B Streptococcus (GBS) Invasive Infections in Women of Childbearing Age, France, 2012-2020: GBS CC-17 Hypervirulence in Intrapartum Infections.

Group B Streptococcus (GBS) is the leading cause of neonatal infections and an important pathogen in pregnancy. However, the features of pregnancy-associated infections are poorly reported. We analyzed 336 cases of GBS invasive infections in women aged 18-50 years, including 242 (72.0%) pregnancy-associated infections. In pregnancy, most cases were intra-amniotic infections (55.8%), occurred preterm (61.3%), and were associated with obstetrical and neonatal complications (81.7%). The GBS clone CC-17 (18.8% of the cases) was overrepresented intrapartum (35.2%; odds ratio, 5.1 [95% confidence interval, 1.6-19.3]). This work highlights the burden of GBS and of the CC-17 clone infections during pregnancy.

Invasive group B Streptococcus infections in non-pregnant adults: a retrospective study, France, 2007-2019.

OBJECTIVES: Group B Streptococcus (GBS) (Streptococcus agalactiae) is a pathogen of growing importance in adults. The objective of this study was to describe the features of invasive infections by GBS in non-pregnant adults. METHODS: GBS infections were reported to the national reference centre for streptococci. Clinical information was abstracted from questionnaires. Capsular typing, identification of the hypervirulent CC-17 clone, and antibiotic susceptibility testing were performed for all GBS isolates. Multi-locus sequence typing and assignment to clonal complexes (CCs) was performed on a representative sample of 324 isolates. RESULTS: In total, 1960 GBS invasive infections were analysed from 2007 to 2019. The median age at onset was 71 years old (range 18-103). The main manifestation was bacteraemia without focus (54.5%). Meningitis was more frequent in patients under 40 (26/180, 14.4% versus 78/1780, 4.4%, p < 0.0001). Capsular types Ia, Ib, II, III and V accounted for 91.0% of the cases (1786/1960). CC-1, -10, -17, -19 and -23 accounted for 96.3% (312/324) of the cases. Capsular type III and CC-17 were overrepresented in meningitis (38/104, 36.5%, p < 0.001 and 22/104, 21.2%, p 0.01, respectively). All isolates were susceptible to ß-lactam antibiotics. Resistance to erythromycin (32.7%) and clindamycin (26.3%) remained stable, whereas decreased susceptibility to fluoroquinolones increased, reaching 2.7% in 2019 (p for trend 0.002). CONCLUSIONS: This work highlights the susceptibility of the elderly to GBS infections and differences in the clinical manifestations according to the patients' age and GBS type. In agreement with worldwide reports on emerging multidrug-resistant GBS, it reinforces the need for a continued surveillance of GBS epidemiology.

Persistence of group B Streptococcus vaginal colonization and prevalence of hypervirulent CC-17 clone correlate with the country of birth: a prospective 3-month follow-up cohort study.

To identify factors associated with vaginal colonization and persistence by group B Streptococcus (GBS) and by the hypervirulent neonatal CC-17 clone in late pregnancy and after delivery, a multicentre prospective observational cohort with 3-month follow-up was established in two university hospitals, Paris area, France. Pregnant women were recruited when antenatal screening for GBS vaginal colonization at 34-38 weeks of gestational age was positive. Vaginal samples were analysed by conventional culture methods at antenatal screening, delivery, and 21 and 60 days following delivery. Identification of the hypervirulent neonatal GBS CC-17 was performed. Colonization was defined as persistent when all vaginal samples were positive for GBS. A total of 754 women were included. GBS vaginal colonization was persistent in 63% of the cases (95% CI 59%-67%). Persistent colonization was more likely in women born in Sub-Saharan Africa compared with women born in France (OR = 1.88, 95% CI 1.05-3.52), and GBS CC-17 was overrepresented in women born in Sub-Saharan Africa (OR = 2.09, 95% CI 1.20-3.57). Women born in Sub-Saharan Africa are at higher risk for GBS vaginal persistence than women born in France. This observation correlates with an increased prevalence of the hypervirulent GBS CC-17 in the former group, which likely reflect variations linked to ethnicity and vaginal community-state types and might account for the increased susceptibility of black neonates to GBS infections.

Multidrug-Resistant Hypervirulent Group B Streptococcus in Neonatal Invasive Infections, France, 2007-2019.

We analyzed group B Streptococcus (GBS) neonatal invasive infections reported during 2007-2019 in France. The hypervirulent clonal complex (CC) 17 GBS was responsible for 66% (827/1,262) of cases. The role of CC17 GBS increased over time (p for trend = 0.0001), together with the emergence of a multidrug-resistant CC17 GBS sublineage.

Risk Factors for Infant Colonization by Hypervirulent CC17 Group B Streptococcus: Toward the Understanding of Late-onset Disease.

BACKGROUND: In infants, the mode of acquisition of CC17 group B Streptococcus (GBS), the hypervirulent clone responsible for late-onset disease (LOD), remains elusive. METHODS: In a prospective multicenter study in France, we evaluated GBS colonization in mother-baby pairs with 2 months of follow-up between 2012 and 2015. Criteria included positivity for GBS colonization at antenatal screening or at delivery. Maternal vaginal samples and infant oral cavity and stool samples were analyzed at delivery, 21 ± 7 days (D21), and 60 ± 7 days (D60) post-delivery. RESULTS: A total of 890 mother-baby pairs were analyzed. GBS colonized 7%, 21%, and 23% of the infants at birth, D21, and D60, respectively, of which 10%, 11%, and 13% were identified as CC17 GBS. Concordance between maternal and infant GBS type was 96%. At D21, the main risk factors for infant colonization by GBS were simultaneous maternal colonization of the vagina (odds ratio [OR], 4.50; 95% confidence interval [CI], 1.69-15.61) and breast milk (OR, 7.93; 95% CI, 3.81-17.14). Importantly, 38% (95% CI, 23%-56%) of infants colonized by CC17 GBS appeared colonized for the first time at D60 vs 18% (95% CI, 14%-24%; P < .049) of infants colonized by non-CC17 GBS. Multivariate analysis showed a higher risk for de novo infant colonization by CC17 at D60 than by other GBS (OR, 2.45; 95% CI, 1.02-5.88). CONCLUSIONS: The high incidence of CC17 GBS in LOD is likely due to an enhanced post-delivery mother-to-infant transmission.

bPeaks: a bioinformatics tool to detect transcription factor binding sites from ChIPseq data in yeasts and other organisms with small genomes.

Peak calling is a critical step in ChIPseq data analysis. Choosing the correct algorithm as well as optimized parameters for a specific biological system is an essential task. In this article, we present an original peak-calling method (bPeaks) specifically designed to detect transcription factor (TF) binding sites in small eukaryotic genomes, such as in yeasts. As TF interactions with DNA are strong and generate high binding signals, bPeaks uses simple parameters to compare the sequences (reads) obtained from the immunoprecipitation (IP) with those from the control DNA (input). Because yeasts have small genomes (<20 Mb), our program has the advantage of using ChIPseq information at the single nucleotide level and can explore, in a reasonable computational time, results obtained with different sets of parameter values. Graphical outputs and text files are provided to rapidly assess the relevance of the detected peaks. Taking advantage of the simple promoter structure in yeasts, additional functions were implemented in bPeaks to automatically assign the peaks to promoter regions and retrieve peak coordinates on the DNA sequence for further predictions of regulatory motifs, enriched in the list of peaks. Applications of the bPeaks program to three different ChIPseq datasets from Saccharomyces cerevisiae, Candida albicans and Candida glabrata are presented. Each time, bPeaks allowed us to correctly predict the DNA binding sequence of the studied TF and provided relevant lists of peaks. The bioinformatics tool bPeaks is freely distributed to academic users. Supplementary data, together with detailed tutorials, are available online: http://bpeaks.gene-networks.net.

Mutations of CEP83 cause infantile nephronophthisis and intellectual disability.

Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.

Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia.

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.