Staphylococcus capitis isolated from bloodstream infections: a nationwide 3-month survey in 38 neonatal intensive care units

To increase the knowledge about S. capitis in the neonatal setting, we conducted a nationwide 3-month survey in 38 neonatal intensive care units (NICUs) covering 56.6% of French NICU beds. We demonstrated 14.2% of S. capitis BSI (S.capBSI) among nosocomial BSIs. S.capBSI incidence rate was 0.59 per 1000 patient-days. A total of 55.0% of the S.capBSIs were late onset catheter-related BSIs. The S. capitis strains infected preterm babies (median gestational age 26 weeks, median birth weight 855 g). They were resistant to methicillin and aminoglycosides and belonged to the NRCS-A clone. Evolution was favorable in all but one case, following vancomycin treatment.


Introduction
Catheter-related bloodstream infections (CRBSI) are associated with increased rates of morbidity in intensive care unit patients and in neonates [1]. The prevention of the avoidable part of CRBSIs is a public health priority [2,3]. In this context, since 2019, all French hospitals and clinics are encouraged to participate in an annual 3-month survey of CRBSI coordinated by the national infection control SPIADI network. Over the last two decades, multidrug-resistant Staphylococcus capitis has been increasingly reported as a major agent responsible for CRBSI in preterm babies [4]. Therapeutic failures likely due to heteroresistance to vancomycin in this bacteria [5] and local epidemics have been identified and investigated in NICUs [5][6][7]. S. capitis seems to be particularly welladapted to the NICU environment, possibly in connection with its ability to produce biofilm [8,9]. However, the neonate contamination routes remain obscure. Recent studies performed in distinct parts of the world have demonstrated a single lineage within the S. capitis species, named NRCS-A, responsible for invasive neonatal infections worldwide [10,11]. The mechanisms that have driven the global dissemination of this clone have not yet been elucidated. We report the results of the 3-month nationwide BSI survey conducted during the first quarter of 2019 in the largest series of NICUs located in 38 French hospitals. We present clinical data related to the neonates suffering from BSI, and the incidence rates and major characteristics of the neonatal BSIs. In addition, using molecular methods, we characterized the isolates responsible for S. capitis BSIs to establish whether or not they belong to the NRCS-A clone. We provide new data that increase the knowledge about S. capitis in the current neonatal setting.

Study design
The surveillance program involved a 3-month survey of all cases of nosocomial BSI between January 1 and April 30 2019. The survey covered 33,971 intensive care patient-days (PD). Nosocomial BSIs were defined according to international definitions (CDC). The variables studied included clinical data (i.e., sex, gestational age, birth weight, death within 7 days of BSI diagnosis), major characteristics of the BSI such as the portal of entry (skin [primitive cutaneous form or superinfection of a skin breach], lungs, urine, intravascular device, or digestive tract), and for catheterrelated BSI, the time lag between the insertion of the catheter, and the appearance of the clinical signs of the BSI. The BSI incidence rates were calculated per 1000 PD. Ethical approval of the surveillance program was obtained at the national level from the Réseau de Prévention des Infections Associées aux Soins.
Microbiological study PFGE was used as a typing technique [12].
Statistical data The data were analyzed with R software. Chisquare tests and Fisher's exact test (two-tailed) were used to test associations, and a P value of 0.05 was considered significant.
Characteristics of the infected neonates The gestational age of the infected neonates ranged between 24 and 41 weeks (median value 28), and their birth weight ranged between 455 and 4050 g (median value 1100); 15.6% of the neonates died during the 7-day period after the diagnosis of the BSI. BSIs involving S. aureus, Enterobacteriaceae, and Enterococci were associated with the highest prevalence of early death among i n f e c t e d n e o n a t e s ( 2 9 . 4 , 2 9 . 2 , a n d 1 4 . 3 % f o r Enterobacteriaceae-, S. aureus-, and Enterococci-associated BSIs, respectively). The prevalence of BSI in the neonates with the a gestational age ≥ 33 weeks and a birth weight > 1500 g differed according to the bacteria ( S. capitis BSI characteristics and antibiotic susceptibility of S. capitis strains Twenty BSIs were associated with S. capitis (14.2%), resulting in a mean incidence of 0.59 per 1000 PD, ranging between 0 and 2.24 according to centers  (Fig. 2). Regarding the three NICUs that reported several S. capitis-BSI cases, the strains isolated in a same center shared the same pattern in two cases. In addition, the strains isolated from three distinct centers located in two distant French regions shared the same pattern.

Discussion
This nationwide study adds several elements to the available data on S. capitis responsible for neonatal BSI.
We provide a first mean incidence of S. capitis BSIs in French NICUs. S. capitis BSIs currently involve an average of one neonate per 1700 PD, which is lower than that observed for S. aureus and S. epidermidis, but higher than that of Enterobacteriaceae in the population of neonates surveyed. Our findings confirm S. capitis as a significant agent responsible for nosocomial BSI in the neonatal setting [10,11,13].
Second, such as S. epidermidis and S. haemolyticus, we showed that S. capitis preferentially infects the more fragile neonates and thus confirmed that S. capitis is an opportunistic pathogen, devoid of great virulence potential. Concordant with previous studies [13], all the S. capitis strains responsible for BSIs displayed resistance to methicillin and gentamicin, but remained susceptible to vancomycin. S. capitis-BSIs have been taken into account by the clinicians, and vancomycin probably played a crucial role in the recovery of neonates.
Third, we identified one particularity distinguishing S. capitis among the bacteria associated with CRBSI cases. Our study reveals a doubled lag time between insertion of the catheter and the first signs of the BSI involving S. capitis when compared with other bacteria. The absence of early infection likely excludes a contamination of the catheter at the time of its insertion, but rather indicates that the contamination of the catheter may have occurred following catheter manipulations among neonates presenting the longest periods of catheterization. Finally, the molecular analysis of a large part of the S. capitis strains indicates that they belong to the multidrugresistant NRCS-A clone and highly suggests likely epidemic phenomena among the NICUs presenting the highest incidence rates of S. capitis BSIs.

Conclusion
Our data confirm the clone NRCS-A particularly well-suited to the neonatal setting and its cumbersome epidemiology [10,11,13]. In most NICUs, S. capitis BSIs remain relatively infrequent among neonates, but concern primarily the most fragile ones. In order to better determine the factors involved in the occurrence of these infections, monitoring of BSIs should be continued and complemented by a systematic investigation when several cases are identified over a 3-month period in the same NICU.
Authors' contribution MD conducted the study, SDS performed the molecular typing, RM conducted the statistical analysis, FG designed and developed the website for data collection and analysis, SLV participated with the data analysis, NVDM designed and conducted the study and wrote the manuscript.
All the others are participating members from each of the 41 NICUs (the infection control practitioner, the microbiologist, and the clinician responsible for the NICU). They collected the data and strains.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval The nationwide survey was conducted under the control of the national agency Santé Public France and with the authorization by the CNIL (a national committee for data protection). Ethical review and approval was not required for the study on human participants in accordance with the French national legislation and institutional requirements.
Informed consent In each participating hospital, a quality commitment charter was signed by the general director and the infection control physician. Patients were informed and ask for consent about the 3-month national survey.
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