Risk Factors for Necrotizing Enterocolitis:A Prospective Multicenter Case-Control Study

BACKGROUND: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. OBJECTIVE: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. METHODS: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age </=30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. RESULTS: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. CONCLUSIONS: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants:a multicenter cohort study

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003). Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored.What is Known:• Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis.• The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated.What is New:• Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged.• A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants:a multicenter cohort study

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age &lt; 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (&gt; 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (&gt; 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003). Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored.What is Known:• Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis.• The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated.What is New:• Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged.• A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (&gt;72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.</p

Preclinical detection of non-catheter related late-onset sepsis in preterm infants by fecal volatile compounds analysis : a prospective, multi-center cohort study

Background: Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiological role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC. Methods: In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter–related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry. Results: In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter–related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11). Conclusions: Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology

Human milk as a tool against infection in preterm infants.

Growing evidence favors the use of human milk for the feeding of preterm infants based on its many beneficial effects, including on infectious-related outcomes. However, contaminated human milk can act as the vehicle of transmission for a number of infections. Pasteurization inactivatesmost bacteria and viruses in the milk but likewise affects the immunological and nutritional quality of the milk. As a result of these effects,we hypothesized that short term infection-related benefits of human milk feeding for very low-birth-weight infants are decreased by the processof pasteurization. Furthermore, we aimed to evaluate the impact of typeof enteral feeding, comparing raw and pasteurized mother´s own milk andformula milk, on the colonization of the intestinal microbiota, which plays an important role in the protection against invasive infections. Chapter 1, the introduction of this thesis, gives an overview of the benefits of human milk in reduction of infection-related morbidity in preterm infants, the intestinal microflora and its relationto infection, the hazards of microbial contamination and quality control of expressed maternal milk and the effects of pasteurization. Furthermore, the outline and aims of the thesis are described. In chapter 2, we document the diversity in current practices for the use of human milk in neonatal intensive care units in Belgium and Luxembourg, especially regarding storage and processing procedures. In chapter 3, we focus on clinical management issues on the use of expressed mother´s own milk in the neonatal intensive care unit and apply the principles of hazard analysis and critical control points on the handling of expressed mother´s own milk. In chapter 4, the first randomized controlled trial on pasteurization of mother´s own milk for very low-birth-weight infants shows that pasteurization does not significantly reduce therisk of serious infectious morbidity. On the contrary, there is a trendtowards a lower incidence of bloodstream infections in infants assignedto receive raw, untreated expressed milk. Intestinal colonization patterns of staphylococci, the most frequent causative microorganism of nosocomial sepsis, is not associated with the type of enteral feeding, as wasdescribed in chapter 5. In addition, we found that, in most patients exhibiting a bloodstream infection, intestinal colonization retrieves a predominant strain that is different from the one recovered from the blood. We speculate that, in case of staphyolococcal invasive infection, an endogenous portal of entry plays a minor role. The in vitro effects of Holder pasteurization on the immunological quality of maternal milk are further described in chapter 6. In chapter 6a, we found a low mannose binding lectin activity in human milk, without difference between pasteurized and non-pasteurized milk. On the other hand, pasteurization significantly reduces the soluble CD14 concentration in expressed human milk. In chapter 6b, we focused on the effect of pasteurization on the antibacterial properties of human milk. In milk samples inoculated with Staphylococcus aureus or Escherichia coli, growth inhibition is significantly lower in the pasteurized milk compared to raw milk. The results of this thesis suggest that pasteurization of mother´s own milk is not an effective strategy to minimise the risk of serious infectious morbidity; minimizing exogenous bacterial contamination of expressed milk, using the HACCP approach, has priority.status: publishe

Dosing guidelines of aminoglycosides in neonates: a balance between physiology and feasibility

Once daily dosing of aminoglycosides has been introduced and validated in non-neonatal patient cohorts. This is because aminoglycosides display peak concentration dependent bacterial killing, have a postantibiotic effect and adaptive resistance. In addition, this strategy reduces toxicity. Although aminoglycosides are also frequently administered to neonates, there is still debate about how to integrate and extrapolate these extended interval dosing regimens into dosing schedules tailored for neonates. There is a growing body of knowledge on aminoglycoside disposition and its covariates (e.g. asphyxia, ibuprofen or indomethacin exposure, serum creatinine, sepsis, dose accuracy) in neonates. In essence, integration of developmental physiology with clinical pharmacology unveils a discrepancy between aspects related to either body composition (higher distribution volume necessitates higher dose, to attain peak concentration) or to elimination clearance (lower renal clearance necessitates prolonged time interval between administrations). Such discrepancy can be solved by introducing more complex dosing guidelines (based on weight, postnatal age, serum creatinine, ibuprofen, asphyxia) in neonates. However, the introduction of more complex dosing guidelines should be balanced with its clinical feasibility. At least, there are reports that these more complex dosing guidelines result in a higher incidence of dosing errors. Besides errors in prescription, these errors also relate to the number of dilutions or manipulations needed before the prescribed dose can be administered. Since an integrated approach is needed, we discuss in this overview both the available pharmacokinetic data in support of the use of extended dosing regimens in neonates as well as the strategies suggested to reduce dosing errors.status: publishe

Effect of pasteurisation on the mannose-binding lectin activity and the concentration of soluble CD14 in human milk

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Intestinal Colonization Patterns of Staphylococci in Preterm Infants in Relation to Type of Enteral Feeding and Bacteremia

Abstract Objective: This study investigated the intestinal colonization with staphylococci in very low birth weight infants in relation to the type of enteral feeding and evaluated the intestine as potential source for staphylococcal bacteremia. Patients and Methods: Infants born in the Level III neonatal intensive care unit of a university hospital with a gestational age below 32 weeks and/or birth weight below 1,500 g were included in a prospective, observational study. The infants received either preterm formula or mother's own milk, with random allocation to raw or pasteurized milk. Precise viable staphylococcal counts of serial fecal specimens were examined in the first 8 weeks of life. In the case of bloodstream infection, fecal and blood isolates of staphylococci were compared by antibiotypes or pulsed-field gel electrophoresis. Results: One hundred fifty neonates, with a mean of 29 weeks of gestation and 1,260 g at birth, had 1,045 fecal samples analyzed and were found to be heavy carriers of staphylococci in the intestine with 10(6)-10(7) colony-forming units/g of feces from the first week of life. Colonization rate and patterns were not different in relation to the type of enteral feeding. In nearly 80% of 42 patients exhibiting a staphylococcal bloodstream infection, intestinal colonization retrieved a predominant strain that was different from the one recovered from the blood. Conclusions: In very low birth weight infants, predominance of staphylococci in the gut is not related to the type of enteral feeding. An endogenous origin of staphylococcal bloodstream infection seems to play a minor role.status: publishe

Impact of pasteurization on the antibacterial properties of human milk

Growing evidence favours the use of human milk for the feeding of preterm newborns based on its many beneficial effects. Despite the many benefits, human milk has been associated as a possible vehicle of transmission for a number of infections. Although pasteurization of human milk can diminish the risk of neonatal infection, it also significantly reduces the concentrations of immunological components in human milk due to thermal damage. In order to evaluate the impact of pasteurization on the antibacterial properties of human milk, we aimed to compare the capacity of raw and pasteurized human milk to inhibit bacterial proliferation. Therefore, a single milk sample was collected from ten healthy lactating mothers. Each sample was divided into two aliquots; one aliquot was pasteurized, while the other was kept raw. Both aliquots were inoculated either with Escherichia coli or Staphylococcus aureus and incubated at 37 °C during 8 h. Viable colony counts from the inoculated samples were performed at regular time points to compare the bacterial growth in both forms of breast milk. Relative to the tryptic soy broth control sample, both raw and pasteurized milk samples exhibited an inhibitory effect on the growth of E. coli and S. aureus. Compared with the raw portion, growth inhibition was significantly lower in the pasteurized milk at every time point beyond T0 (after 2, 4 and 8 h of incubation) (p = 0.0003 for E. coli and p < 0.0001 for S. aureus).status: publishe

Subcutaneous palivizumab (synagis) administration in an infant with congenital type 2B von Willebrand disease

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