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Objectives. We performed a one-year prospective surveillance study on MRSA colonization within the five NICUs of the metropolitan area of Palermo, Italy. The purpose of the study was to assess epidemiology of MRSA in NICU from a network perspective. Methods. Transfer of patients between NICUs during 2014 was traced based on the annual hospital discharge records. In the period February 2014 – January 2015, in the NICU B, at the University teaching hospital, nasal swabs from all infants were collected weekly, whereas in the other four NICUs (A, C, D, E) at four week-intervals of time. MRSA isolates were submitted to antibiotic susceptibility testing, SCCmec typing, PCR to detect lukS-PV and lukF-PV (lukS/F-PV) genes and the gene encoding the toxic shock syndrome toxin (TSST-1), multilocus variable number tandem repeat fingerprinting (MLVF) and multilocus sequence typing (MLST). Results. In the period under study, 587 nasal swabs were obtained from NICU B, whereas 218, 180, 157 and 95 from NICUs A, C, D and E, respectively. Two groups of NICUs at high prevalence and low prevalence of MRSA colonization were recognized. Overall, 113 isolates of MRSA were identified from 102 infants. Six MLVF types (A-F) were detected, with type C being subdivided into five subtypes. Five sequence types (STs) were found with ST22-IVa being the most frequent type in all NICUs. All the MRSA molecular subtypes, except for ST1-IVa, were identified in NICU B. Conclusions. Our findings support the need to approach surveillance and infection control in NICU in a network perspective, prioritizing referral healthcare facilities.

Sindrome da microduplicazione 17p13.3, palatoschisi

NOSOCOMIAL INFECTIONS, EMERGING RESISTANCES SURVEILLANCE, NICU

TUBEROUS SCLEROSIS, GENOMIC REARRANGEMENT

15q13.3 microduplication syndrome, genomic rearrangment, gentotype-phenotype correlation

Candida spp., colonizzazione, UTIN

encefalopatia, disfunzione multirogano

Colonizzazione, MRSA, UTIN

Summary Background Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov ( NCT02790996 ). Findings Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding EU Seventh Framework Programme for research, technological development and demonstration.

BackgroundAntimicrobial resistance in neonatal intensive care unit (NICU) patients is a threat, due to the frequent use of antimicrobial treatment and invasive devices in fragile babies. Since 2014 an active surveillance program of multidrug-resistant Gram-negative bacteria (MDR-GNB) carriage has been in place in the five NICUs of Palermo, Italy. In 2017 an increase in the prevalence of MDR-GNB, and in particular of extended-spectrum β-lactamases-producingKlebsiella pneumoniae(ESBL-KP), was observed in “Civico” hospital NICU.AimTo assess the impact of a coordinated intervention strategy in achieving long-lasting reduction of MDR-GNB prevalence in the NICU.MethodsRectal swabs were obtained monthly and processed to detect MDR-GNB using standard methods. MDR-GNB were characterized by pulsed-field gel electrophoresis (PFGE). Since November 2017 the following intervention measures were applied: (a) two-months intensification of sample collection; (b) stakeholders meetings; (c) improvement of prevention measures and antimicrobial policies.FindingsDuring the intensified microbiological surveillance MDR-GNB and ESBL-KP were detected in rectal swabs (34.8%; 23.2%), nasal swabs (24.6%; 14.5%), oral swabs (14.5%; 5.4%), milk samples (32.1%; 17.9%), pacifiers swabs (30.8%; 17.9%) and from sub-intensive room surfaces. Thirteen ESBL-KP strains isolated from clinical and environmental samples showed identical PFGE patterns. The prevalence of MDR-GNB and ESBL-KP carriage significantly decreased in the year after intervention compared to the previous year (20.6% vs 62.2%;p p p ConclusionsMDR-GNB broadly circulate in NICU setting, they can colonize different body sites and spread through various vehicles. A coordinated strategy of multiple interventions with active cooperation between epidemiologists and clinicians in the NICU can effectively reduce their circulation and in particular the carriage of the most dangerous ESBL-KP strains.

Fungal infections are an important cause of morbidity and mortality in neonatal intensive care units (NICUs). The identifi-cation of specific risk factors supports pre-vention of candidemia in neonates. Effec-tive prophylactic strategies have recently become available, but the identification and adequate management of high-risk in-fants is still a priority. Prior colonization is a key risk factor for candidemia. For this reason, surveillance studies to monitor in-cidence, species distribution, and antifun-gal susceptibility profiles, are mandatory. Among 520 infants admitted to our NICU between January 2013 and December 2014, 472 (90.77%) were included in the study. Forty-eight out of 472 (10.17%) pa-tients tested positive for Candida spp. (C.), at least on one occasion. All the colonized patients tested positive for the rectal swab, whereas 7 patients also tested positive for the nasal swab. Fifteen out of 472 patients (3.18%) had more than one positive rec-tal or nasal swab during their NICU stay. Moreover, 9 out of 15 patients tested nega-tive at the first sampling, suggesting they acquired Candida spp. during their stay. Twenty-five of forty-eight (52.1%) colo-nized patients carried C.albicans and 15/48 (31.25%) C.parapsilosis. We identified as risk factors for Candida spp. colonization: antibiotic therapy, parenteral nutrition, the use of a central venous catheter, and nasogastric tube. Our experience suggests that effective microbiological surveillance can allow for implementing proper, effec-tive and timely control measures in a high-risk setting.

Introduction: Fungal infections are an important cause of increased morbidity and mortality in infants admitted to neonatal intensive care units (NICUs). In VLBW infants, Candida (C.) albicans is the third most common cause of neonatal late onset sepsis (LOS). The overall incidence of candidemia in NICU is increasing because of the longer survival and the invasive procedures related with the intensive care of extremely preterm infants. Prevention of candidemia in neonates is supported by the identification and adequate management of specific risk factors, including low birth weight, use of invasive devices, prolonged hospitalization and use of broad-spectrum antimicrobial agents. Effective prophylactic strategies have recently become available, but the identification of the best possible strategies to manage high-risk infants is still a priority. Prior colonization is a key risk factor for candidemia. For this reason, surveillance studies to monitor incidence, species distribution, and antifungal susceptibility profiles are mandatory. Materials and Methods: In 2013 and 2014, we performed a cohort, prospective surveillance study in our NICU, collecting weekly nasal and rectal swabs. For each patient, clinical and demographic data expected to affect Candida colonization were recorded. We evaluated Candida spp. colonization rate and assessed the related risk factors. Swabs were placed on Sabouraud agar and incubated at 30°C for 4 days. Candida growth on agar was confirmed by microscopic observation. Moreover, Candida spp. were identified through Candida chromogenic agar (ChromAgar Candida, Laboratorios Conda) and API® 20C AUX (Biomérieux). Statistical analysis was performed by EpiInfo (CDC software) using the chi square or the Fisher’s exact method, when indicated. We assumed as statistically significant a p-value < 0.05. Results: In this 2-year study, we enrolled 520 patients and we analyzed 1,259 nasal and 1,255 rectal swabs. From 472 out of 520 patients we collected complete microbiological, clinical and demographic data. 48 out of 472 (10.17%) patients tested positive for Candida spp. at least once. In particular, 26 patients tested positive for C. albicans, 16 for C. parapsilosis, 6 for C. glabrata and 1 each for C. guilliermondii and an environmental mold. All the colonized patients had their rectal samples positive, and 7 their nasal samples as well. 15 patients out of 472 (3.18%) had more than one rectal or nasal swab positive during their NICU stay. Importantly, 9 patients out of 15 tested negative at the first sampling, suggesting that they have acquired Candida spp. colonization during their stay. Table 1 summarizes data about risk factors for Candida colonization in the patients under study. No systemic infection by Candida spp. was reported during the study. Conclusion: Our experience suggest that an effective microbiological surveillance can allow for implementing proper, effective and timely control measures in a high-risk setting.

Colonization and infection by multidrug-resistant gram-negative bacilli (MDR GNB) in neonatal intensive care units (NICUs) are increasingly reported.We conducted a 5-year prospective cohort surveillance study in a tertiary NICU of the hospital "Paolo Giaccone," Palermo, Italy. Our objectives were to describe incidence and trends of MDR GNB colonization and the characteristics of the most prevalent organisms and to identify the risk factors for colonization. Demographic, clinical, and microbiological data were prospectively collected. Active surveillance cultures (ASCs) were obtained weekly. Clusters of colonization by extended spectrum β-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae were analyzed by conventional and molecular epidemiological tools.During the study period, 1152 infants were enrolled in the study. Prevalences of colonization by MDR GNB, ESBL-producing GNB and multiple species/genera averaged, respectively, 28.8%, 11.7%, and 3.7%. Prevalence and incidence density of colonization by MDR GNB and ESBL-producing GNB showed an upward trend through the surveillance period. Rates of ESBL-producing E coli and K pneumoniae colonization showed wide fluctuations peaking over the last 2 years. The only independent variables associated with colonization by MDR GNB and ESBL-producing organisms and multiple colonization were, respectively, the days of NICU stay (odds ratio [OR] 1.041), the days of exposure to ampicillin-sulbactam (OR 1.040), and the days of formula feeding (OR 1.031). Most clusters of E coli and K pneumoniae colonization were associated with different lineages. Ten out of 12 clusters had an outborn infant as their index case.Our study confirms that MDR GNB are an increasing challenge to NICUs. The universal once-a-week approach allowed us to understand the epidemiology of MDR GNB, to timely detect new clones and institute contact precautions, and to assess risk factors. Collection of these data can be an important tool to optimize antimicrobials use and control the emergence and dissemination of resistances in NICU.

Introduction Multidrug-resistant organisms are a serious public health problem, particularly in critical hospital wards such as the Neonatal Intensive Care Units (NICUs). Hospitalized neonates are at high risk for healthcare-associated infections leading to higher morbidity and mortality rates, because of their poor immune defences, frequent exposure to antibiotics, invasive procedures and contacts with healthcare-workers. Our study aimed to evaluate the prevalence of colonization by methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Gram-negatives (MDRGNs) and fungi in the five NICUs of the city of Palermo. Methods From February 2014 to January 2015, an active surveillance culture (ACS) program was set up in the five NICUs of Palermo (ARNAS Civico-NICU1, Ingrassia Hospital-NICU2, Villa Sofia-Cervello Hospital-NICU3, Buccheri La Ferla Hospital-NICU4 and AOUP "Paolo Giaccone"-NICU5). From each patient nasal and rectal swabs were monthly collected to look for MRSA, MDRGNs and fungi. Swabs were pre-incubated at 37°C overnight in BHI enrichment broth, and cultured on selective media. Suspected S. aureus colonies were confirmed by cefoxitin susceptibility testing. MDRGNs were selected by antibiotic disk screening and tested to detect extended-spectrum beta-lactamase” (ESBL) and carbapenemase-producing isolates. For fungal detection swabs were directly inoculated on chloramphenicol-Sabouraud dextrose agar plates and incubated at 30°C for 72 hrs. Yeast-like colonies were identified by subculturing on CHROMagar Candida and eventually confirmed by the API20CAUX test. Prevalence rates of colonization of the different NICUs were compared by the chi-square test. Results The average daily number of hospitalized patients was 16 in NICU1, 9 in NICU2, 21 in NICU3, 15 in NICU4, 11 in NICU5. Prevalence of MRSA colonization ranged between 3.6% in NICU3 and 28.8% in NICU4, showing statistically significant differences between the NICUs. Prevalence of colonization by MDRGNs ranged between 53.9% for NICU1 and 14% for NICU4 with statistically significant differences between the NICUs. The most frequently isolated MDRGN organisms were Klebsiella pneumoniae, Escherichia coli and Enterobacter spp., with a prevalence between 1.9% and 57.2% for ESBL-producing and between 0% and 3.5% for carbapenemase-producing isolates. Fungal colonization was never detected in NICU2, whilst the highest prevalence values were 7.2% for C. albicans in NICU4 and 5.9% for non-albicans Candida spp. in NICU5. Statistically significant differences were found. Discussion Spread of multidrug-resistant organisms proved to affect all the NICUs under investigation, with a higher prevalence of MRSA in NICUs 4 and 2 and a higher prevalence of MDRGNs in NICUs 1 and 5. Fungal colonization prevalence was different between the NICUs with NICU4 being more affected by C.albicans and NICU5 by non-albicans Candida spp. These differences could be attributable to different structural and organizational characteristics and the recurrent epidemic spread of some organisms by cross-transmission. The widespread dissemination of MRSA and ESBL producing isolates and the emergence of carbapenem-resistant Enterobacteriaceae require a continuous effort in implementing preventive measures, control interventions and staff training.

L’atresia intestinale tipo III B (apple peel) e la gastroschisi sono entrambe malformazioni congenite che necessitano di correzione chirurgica precoce in epoca neonatale. La loro associazione è un evento molto raro. Presentiamo il caso di un neonato a termine con l’associazione di atresia ileale apple-peel parziale e piccolo difetto della parete addominale anteriore, complicate con perforazione intestinale in utero e conseguente peritonite meconiale. Abbiamo riscontrato un’atresia parziale delle anse intestinali, coninteressamento dell’ileo terminale e risparmio del digiuno e di buona parte dell’ileo prossimale, difetto della parete addominale di piccole dimensioni e con poche anse erniate, malrotazione intestinale. L’ileo paralitico e le infezioni rappresentano le maggiori cause di morbidità e mortalità in età neonatale. Nel nostro caso, a dispetto del fenotipo “mild”, la prognosi è stata complicata dall’instaurarsi di un quadro di occlusione intestinale funzionale, determinata dalla peritonite chimica attribuibile al danno da contatto con fluido amniotico da un lato e meconio dall’altro. Intestinal atresia type III B (apple peel) and gastroschisis are both congenital malformations who require early surgical correction in neonatal age. Their association is very rare. We present the case of a full term infant with partial apple peel ileal atresia and a small defect of the anterior abdominal wall, complicated by in utero intestinal perforation and subsequent meconial peritonitis. We observed a partial atresia of small intestine, with involvement of terminal ileus savings of jejunum and a large part of the proximal ileum, small anterior abdominal wall defect with herniation of few bowel loops, intestinal malrotation. Paralytic ileus and infections are the main causes of morbidity and mortality at neonatal age. In our case, in spite of the mild phenotype, prognosis has been complicated by the onset of functional bowel obstruction, caused by chemical peritonitis resulting from contact with either amniotic fluid and meconium

Gastroschisis is an abdominal wall defect, typically located to the right of the umbilical cord, requiring an early surgical treatment shortly after birth. Affected patients can be identified during intrauterine life with US and should be delivered in referral hospitals where a multisciplinary approach can be provided, involving neonatologists, clinical geneticists, surgeons and other specialists. These patients require a complex management in Neonatal Intensive Care Unit (NICU) and a long term follow-up after discharge. Exceed the acute neonatal condition, gastroschisis has a good prognosis, if there are no overlapping complications, and it should be differentiated from omphalocele, burdened with worse prognosis, and other conditions in the wide spectrum of abdominal wall defects.