[Impact of the healthcare pathway on the rate of obstetrical interventions in small for gestational age fetuses (IATROPAG Study)]. / Impact du parcours de soins sur le taux d'interventions obstétricales dans la prise en charge des fœtus petit pour l'âge gestationnel (Étude IATROPAG).

BACKGROUND: While previous studies have demonstrated an improvement in implementation of clinical practices and an improved neonatal prognosis when growth restricted fetuses were followed within a standardized healthcare pathway, the objective of this study was to assess the prevalence of obstetric interventions in small-for-gestational-age (SGA) fetuses followed within a standardized care pathway compared to a traditional care pathway. METHODS: We conducted a retrospective study between 2015 and 2017, in a type III maternity hospital in Lyon, in a population of SGA fetuses, considered as such in case of antenatal diagnosis of fetal weight<10th percentile but>3rd centile without umbilical Doppler abnormality during antenatal surveillance and without ultrasound argument suggesting intrauterine growth retardation (IUGR). We collected the gestational age at diagnosis, obstetrical events and prevention of preterm delivery (antenatal corticosteroids), gestation age at birth, the method of delivery (spontaneous or induced), indication of induction, the method of birth (spontaneous, instrumental extraction or caesarean section), and the immediate neonatal outcome including cord pH, Apgar score at 5minutes, birth weight and fetal sex. After diagnosis, the choice of the pathway was left to the practitioner depending on their habit, their ability to manage the follow-up and their organizational constraints. RESULTS: Over the study period, and after exclusion of IUGR, 96 SGA were followed up in the traditional pathway and 106 SGA were followed up in the standardized pathway P=0.75. The traditional pathway showed in multivariate analysis a higher prevalence of antenatal corticosteroid therapy for SGA (16,6%) between 2015 and 2017 with OR 7.3 95% CI [1.41-38.43] when compared to the standardized pathway (3,7%). Similarly, the traditional pathway proposes a higher prevalence of induction of labor (54,1%) than the standardized pathway (33,9%) between 2015 and 2017 with OR 3.19 95% CI [1.70-7.80]. The "a posteriori" post-hoc power of the study is 82.9%. CONCLUSION: This study confirms the absence of excessive obstetrical intervention in the SGA population when followed in a standardized healthcare pathway. The latter would reduce unnecessary obstetrical interventions while respecting the intrinsic neonatal prognosis of small for gestational age fetuses.

Clinical impact of vancomycin heteroresistance in staphylococcal strains involved in neonatal sepsis: Discussion of a case report.

Heteroresistance to vancomycin (HRV) represents a decreased susceptibility to vancomycin and is frequently observed in multidrug-resistant coagulase-negative staphylococci. The clinical significance of such heteroresistance is controversial, but several failures of vancomycin therapy have been related to HRV, especially in the neonatal population. Here we report the case of a preterm neonate, born at 26 weeks of gestation, who developed sepsis due to a multidrug-resistant HRV Staphylococcuscapitis isolate. Bacteremia persisted despite adequate vancomycin serum concentration and catheter removal. The patient finally recovered after replacing vancomycin by linezolid. Through this case report, we would like to alert clinicians of the potential clinical impact of HRV and to discuss the lack of therapeutic alternatives in neonates.

Staphylococcus capitis and NRCS-A clone: the story of an unrecognized pathogen in neonatal intensive care units.

BACKGROUND: In neonatal intensive care units (NICUs), nosocomial late-onset sepsis (LOS), mostly due to coagulase negative staphylococci, constitute a major cause of death or impairment. Staphylococcus capitis, usually considered as a poorly virulent species, has been reported as a cause of LOS. OBJECTIVES: To review data regarding S. capitis neonatal LOS and the features of isolates involved. SOURCES: PubMed was searched up to August 2018 to retrieve studies on the topic; the keywords used were 'S. capitis', 'neonate', 'neonatal ICU', 'bloodstream infection' and 'late onset sepsis'. CONTENT: Published data highlight the worldwide endemicity of a single S. capitis clone, named NRCS-A, specifically involved in LOS. NRCS-A harbours a multidrug resistance profile (including resistance to the usual first-line antibiotics used in NICUs). It is also able to adapt under vancomycin selective pressure that could confer an advantage for its implantation and dissemination in NICUs where this selective pressure is high. Moreover, a severe morbidity has been observed in NRCS-A-related LOS. The NICU environment, and especially incubators, constitute reservoirs of NRCS-A from which it could diffuse inside the setting. Finally, the virulome and resistome of S. capitis NRCS-A contain many genes potentially implicated in its specific epidemiology and pathophysiology, including the gene nsr that may be involved in its fitness and implantation in neonatal gut flora. IMPLICATIONS: S. capitis must be considered as a true pathogen in neonates. The decreased susceptibility to vancomycin may be involved in failure of vancomycin therapy. Further studies are needed to better manage its diffusion inside each NICU but also worldwide.

Vancomycin treatment is a risk factor for vancomycin-nonsusceptible Staphylococcus capitis sepsis in preterm neonates.

OBJECTIVES: Multidrug-resistant, vancomycin-nonsusceptible Staphylococcus capitis is an emerging cause worldwide of late-onset sepsis (LOS) in preterm neonates. The pathophysiology and risk factors for S. capitis-related LOS are poorly understood, but we hypothesized that S. capitis LOS follows translocation from the gut microbiota rather than catheter invasion. The objective of this study was to investigate the risk factors of S. capitis LOS and gut colonization. METHODS: We conducted a prospective single-centre cohort study of patients hospitalized in a tertiary-care unit (Lyon, France) from June 2011 to January 2012. S. capitis gut colonization was determined weekly from stool cultures. The determinants of gut colonization and LOS were established by multivariate Cox proportional hazards models. RESULTS: Eighty-three (36.2%) of 229 patients had S. capitis-positive stool culture, and 28 (12.2%) developed S. capitis LOS during hospitalization. Independent risk factors for S. capitis LOS included prior administration of vancomycin independent of a previous LOS episode (hazard ratio 6.44, 95% confidence interval 2.15-19.3, p 0.001) and low birth weight (hazard ratio 0.72 per 100 g increase, 95% confidence interval 0.55-0.95, p 0.02). The prior administration of vancomycin was also an independent risk factor for S. capitis colonization (hazard ratio 3.45, 95% confidence interval 2.07-5.76, p <0.001), particularly in the first week of life and in noncolonized neonates. CONCLUSIONS: Neonates treated with vancomycin are at a higher risk of LOS caused by vancomycin-nonsusceptible S. capitis. The use of vancomycin in neonates must urgently be optimized to limit the selection of vancomycin-nonsusceptible strains, for which alternative antibiotics are lacking.

Emergence and dissemination of a linezolid-resistant Staphylococcus capitis clone in Europe.

Objectives: We investigated the epidemiological, clinical, microbiological and genetic characteristics of linezolid-resistant (LZR) Staphylococcus capitis isolates from French ICUs, and compared them with LZR S. capitis isolates from other European countries. Methods: All LZR isolates were subjected to antimicrobial susceptibility testing (AST) and the presence of cfr and optrA genes as well as mutations in the 23S rRNA and ribosomal proteins were investigated using specific PCR with sequencing. The genetic relationship between isolates was investigated using PFGE and WGS. Epidemiological data concerning LZR S. capitis were collected retrospectively in French microbiology laboratories. Results: Twenty-one LZR isolates were studied: 9 from France, 11 from Greece and 1 from Finland. All were resistant to methicillin and aminoglycosides. In addition, this unusual AST profile was identified in S. capitis isolates from seven French hospitals, and represented up to 12% of the S. capitis isolates in one centre. A G2576T mutation in 23S rRNA was identified in all isolates; cfr and optrA genes were absent. All isolates belonged to the same clone on the basis of their PFGE profiles, whatever their geographical origin. WGS found at most 212 SNPs between core genomes of the LZR isolates. Conclusions: We identified and characterized an LZR S. capitis clone disseminated in three European countries, harbouring the same multiple resistance and a G2576T mutation in the 23S rRNA. The possible unrecognized wider distribution of this clone, belonging to a species classically regarded as a low-virulence skin colonizer, is of major concern not least because of the increasing use of oxazolidinones.

Genome Sequences of Multiresistant Staphylococcus capitis Pulsotype NRCS-A and Methicillin-Susceptible S. capitis Pulsotype NRCS-C.

Here, we report the draft genome sequences of methicillin-susceptible Staphylococcus captis pulsotype NCRS-C (CR02 strain) and multiresistant Staphylococcus captis pulsotype NCRS-A (CR07 strain).

Wide geographical dissemination of the multiresistant Staphylococcus capitis NRCS-A clone in neonatal intensive-care units.

Nosocomial late-onset sepsis represents a frequent cause of morbidity and mortality in preterm neonates. The Staphylococcus capitis clone NRCS-A has been previously described as an emerging cause of nosocomial bacteraemia in French neonatal intensive-care units (NICUs). In this study, we aimed to explore the possible unrecognized dissemination of this clone on a larger geographical scale. One hundred methicillin-resistant S. capitis strains isolated from neonates (n = 86) and adult patients (n = 14) between 2000 and 2013 in four different countries (France, Belgium, the UK, and Australia) were analysed with SmaI pulsed-field gel electrophoresis (PFGE) and dru typing. The vast majority of NICU strains showed the NRCS-A pulsotype and the dt11c type (96%). We then randomly selected 14 isolates (from neonates, n = 12, three per country; from adult patients, n = 2), considered to be a subset of representative isolates, and performed further molecular typing (SacII PFGE, SCCmec typing, and multilocus sequence typing-like analysis), confirming the clonality of the S. capitis strains isolated from neonates, despite their distant geographical origin. Whole genome single-nucleotide polymorphism-based phylogenetic analysis of five NICU isolates (from the different countries) attested to high genetic relatedness within the NRCS-A clone. Finally, all of the NRCS-A strains showed multidrug resistance (e.g. methicillin and aminoglycoside resistance, and decreased vancomycin susceptibility), with potential therapeutic implications for infected neonates. In conclusion, this study represents the first report of clonal dissemination of methicillin-resistant coagulase-negative Staphylococcus clone on a large geographical scale. Questions remain regarding the origin and means of international spread, and the reasons for this clone's apparent predilection for neonates.

Genome Sequences of Four Staphylococcus capitis NRCS-A Isolates from Geographically Distant Neonatal Intensive Care Units.

Staphylococcus capitis pulsotype NRCS-A was previously reported as a frequent cause of late-onset sepsis in neonatal intensive care units (NICUs) worldwide. Here, we report the whole-genome shotgun sequences of four S. capitis pulsotype NCRS-A strains, CR03, CR04, CR05, and CR09, isolated from Belgium, Australia, the United Kingdom, and France, respectively.

Adaptation to vancomycin pressure of multiresistant Staphylococcus capitis NRCS-A involved in neonatal sepsis.

OBJECTIVES: The Staphylococcus capitis clone NRCS-A has recently been described as a frequent cause of late-onset sepsis (LOS) in pre-term neonates worldwide. Representatives of this clone exhibit non-susceptibility to vancomycin, the first-line agent used in LOS. Cases of prolonged S. capitis LOS despite vancomycin treatment have been reported. We investigated whether NRCS-A strains exhibit faster adaptation to vancomycin pressure as compared with other staphylococci. METHODS: Strains of S. capitis NRCS-A, S. capitis non-NRCS-A and Staphylococcus epidermidis (n = 2 each, all with vancomycin MICs ≤2 mg/L) and the prototype vancomycin-heteroresistant Staphylococcus aureus Mu3 were subcultured daily for 15 days with 0.25-32 mg/L vancomycin. Regression coefficients of daily log2 MICs on time were used to estimate the kinetics of resistance development. Changes in bacterial cell-wall thickness were measured by transmission electron microscopy. To assess the stability of resistance and the emergence of cross-resistance, vancomycin, teicoplanin, daptomycin and linezolid MICs were measured before and after vancomycin treatment, as well as after nine additional subcultures without antibiotics. RESULTS: All strains developed a stable resistance to vancomycin, but this occurred significantly faster in S. capitis NRCS-A than in S. capitis non-NRCS-A (P < 0.001) and other species (P < 0.0001). Vancomycin resistance in S. capitis NRCS-A was associated with significant cell-wall thickening and an increase in MICs of daptomycin and teicoplanin, but not linezolid. CONCLUSIONS: S. capitis NRCS-A rapidly adapts to vancomycin pressure as compared with potential niche competitors, a feature that might contribute to its success in neonatal ICUs where vancomycin is widely prescribed.

Non-contiguous finished genome sequence of Staphylococcus capitis CR01 (pulsetype NRCS-A).

Staphylococcus capitis is a coagulase-negative staphylococcus (CoNS) commonly found in the human microflora. Recently, a clonal population of Staphylococcus capitis (denominated NRCS-A) was found to be a major cause of late-onset sepsis (LOS) in several neonatal intensive care units in France. Here, we report the complete genome sequence and annotation of the prototype Staphylococcus capitis NCRS-A strain CR01. The 2,504,472 bp long genome (1 chromosome and no plasmids) exhibits a G+C content of 32.81%, and contains 2,468 protein-coding and 59 tRNA genes and 4 rRNA genes.

Characterization of a novel composite staphylococcal cassette chromosome mec (SCCmec-SCCcad/ars/cop) in the neonatal sepsis-associated Staphylococcus capitis pulsotype NRCS-A.

Multiresistant Staphylococcus capitis pulsotype NRCS-A has been reported to be a major pathogen causing nosocomial bacteremia in preterm infants. We report that the NRCS-A strain CR01 harbors a novel 60.9-kb composite staphylococcal cassette chromosome mec (SCCmec) element, composed of an SCCmec with strong homologies to Staphylococcus aureus ST398 SCCmec and of an SCCcad/ars/cop harboring resistance genes for cadmium, arsenic, and copper. Whole-genome-based comparisons of published S. capitis strains suggest that strain CR01 acquired the two elements independently.

[Management of late-onset sepsis due to coagulase-negative staphylococci in neonatal intensive care units]. / Actualités sur la prise en charge des infections néonatales nosocomiales tardives à staphylocoque à coagulase négative.

Coagulase-negative staphylococci (CoNS) are the most frequent cause of late-onset sepsis (LOS) in neonatal intensive care units (NICUs). Staphylococcus epidermidis is usually considered the most prevalent CoNS in this setting. However, recent reports have identified Staphylococcus capitis, another CoNS, as an emerging cause of bacteremia in NICU wards. S. capitis is the main cause of LOS in several NICUs in France, whereas this species is rarely found in adult patients from the same hospitals. S. capitis isolates from NICU infants share several striking features: they all belong to the same pulsed-field gel electrophoresis type, designated as NRCS-A, which indicates their clonal relatedness; their resistance profile reflects adaptation to antimicrobial agents specifically used in NICUs, including resistance to beta-lactams and aminoglycosides but not to fluoroquinolones, and reduced susceptibility to vancomycin; and they are associated with more severe LOS than those caused by other CoNS. The molecular characterization of NICU S. capitis isolates from several countries has shown that S. capitis NRCS-A strains have disseminated in both Western Europe (France, the United Kingdom, and Belgium) and Australia. The dissemination of such multiresistant strains imposes difficult therapeutic choices on pediatricians. As a consequence of the recent strengthening of the French and European guidelines that regulate the interpretation of clinical vancomycin susceptibility in staphylococci, a non-negligible proportion of NICU CoNS isolates (including S. capitis as well as other CoNS species) that were usually reported as vancomycin-susceptible are now categorized as vancomycin-resistant. In such cases, practitioners are faced with uncomfortable alternatives: the continued use of vancomycin in spite of the pathogen being unambiguously reported as resistant to this molecule and the use of antimicrobial agents such as linezolid or daptomycin that retain an in vitro efficacy against CoNS but whose use in neonates has not received approval by the healthcare authorities. To cope with this emerging challenge, clinical investigations of the relative tolerance and efficacy of vancomycin, linezolid, and daptomycin in NICU infants infected with these newly reported vancomycin-resistant CoNS are urgently needed.

[Late onset Ondine syndrome: literature review on a case report]. / Syndrome d'Ondine à révélation tardive : revue de la littérature à propos d'un cas.

Ondine syndrome is the central congenital hypoventilation syndrome (CCHS) caused by the mutation of the PHOX2B gene. In late onset cases, the symptomatology often appears after an acute event (infection, general anesthesia, drug intake), increasing hypoventilation. We report a case of late onset Ondine curse in a 9-year-old girl. The diagnosis was made based on a hypercapnic coma complicating a respiratory infection caused by Mycoplasma pneumoniae and was confirmed by genetic testing. In the patient's history we found symptoms that had not been noted (e.g., enuresis, morning headache, adynamia), attesting to chronic hypoventilation. Through this observation, we review the literature on CCHS, notably late onset cases, which are rare and insidious, emphasizing the pre-existing hypoventilation symptoms in this child. This case underlines the need for all practitioners not to trivialize these symptoms so as to decrease the current delay in diagnosis for late onset CCHS and to introduce optimal care as soon as possible.

Retention of enteropathogenicity by viable but nonculturable Escherichia coli exposed to seawater and sunlight.

The effect of natural sunlight on culturability and persistence of pathogenicity of Escherichia coli was examined in the field, i.e., in the Morlaix Estuary, France, using an enterotoxigenic strain of Escherichia coli H10407. Results showed that E. coli responds to the estuarine diurnal solar cycle by entering the viable but nonculturable state upon exposure to sunlight. That is, direct counts of viable cells remained stable without significant change, but E. coli cells remained fully culturable only when exposed to seawater in control chambers in the dark, i.e., without solar irradiation. The effect of sunlight on the pathogenicity of E. coli H10407 was studied, using both the rabbit intestinal loop assay and ganglioside-enzyme-linked immunosorbent assay (GM1-ELISA), a sensitive procedure for testing for production of enterotoxin. Results of the GM1-ELISA demonstrated that strains of E. coli, after exposure to sunlight and entering the viable but nonculturable state, as well as culturable E. coli, retained pathogenicity, i.e., produced enterotoxin. The GM1-ELISA is concluded to be more sensitive than the rabbit intestinal loop assay for analysis of enterotoxin in natural water samples.