Late-onset Sepsis In Preterm Infants Research Articles

Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants.

ObjectiveLate onset sepsis (LOS) contributes to mortality and morbidity in preterm infants. We tested the hypotheses that microbes causing LOS originate from the gut, and that distortions in the gut microbial community increases subsequent risk of LOS.Study DesignWe examined the gut microbial community in prospectively collected stool samples from preterm infants with LOS and an equal number of age-matched controls at two sites (Cincinnati, OH and Birmingham, AL), by sequencing the bacterial 16S rDNA. We confirmed our findings in a subset of infants by whole genome shotgun sequencing, and analyzed the data using R and LEfSe.ResultsInfants with LOS in Cincinnati, as compared to controls, had less abundant Actinobacteria in the first samples after birth (median 18 days before sepsis onset), and less abundant Pseudomonadales in the last samples collected prior to LOS (median 8 days before sepsis onset). Infants with LOS in Birmingham, as compared to controls, had no differences identified in the first sample microbial communities, but Lactobacillales was less abundant in the last samples prior to LOS (median 4 days before sepsis onset). Sequencing identified detectable levels of the sepsis-causative organism in stool samples prior to disease onset for 82% of LOS cases.ConclusionsTranslocation of gut microbes may account for the majority of LOS cases. Distortions in the fecal microbiota occur prior to LOS, but the form of distortion depends on timing and site. The microbial composition of fecal samples does not predict LOS onset in a generalizable fashion.

Pentoxifylline therapy for late-onset sepsis in preterm infants: a randomized controlled trial.

The role of pentoxifylline (PTX) in reducing mortality associated with neonatal sepsis is not well established. We aimed to assess the efficacy and safety of PTX as an adjunct to antibiotics on mortality and morbidity in preterm infants with late-onset sepsis (LOS). Double blind, randomized controlled trial was conducted on 120 preterm infants with LOS. They were randomly assigned to receive either intravenous PTX 5 mg/kg/hr for 6 hours on 6 successive days or placebo. Death before hospital discharge was our primary outcome and secondary outcomes were length of hospital stay, duration of respiratory support, duration of antibiotics use, short-term morbidity of preterm infants, tumor necrosis factor-alpha concentrations, C-reactive protein concentrations, and adverse effects of PTX. A total of 120 infants were enrolled, 60 in each group, 78 (65%) infants had confirmed and 42 (35%) had suspected LOS. There were no significant differences between groups regarding mortality [6 (10%) in PTX vs. 10 (16.5%) in placebo, P = 0.44], short-term morbidity and combined mortality and/or short-term morbidity [18 (30%) vs. 24 (40%), P = 0.23]. PTX therapy was associated with significant reduction of serum tumor necrosis factor-alpha and C-reactive protein concentrations. The length of hospital stay, durations of respiratory support and antibiotic therapy were significantly shorter in the PTX group. Patients in PTX group had less need for vasopressors, lower incidence of metabolic acidosis, disseminated intravascular coagulopathy and thrombocytopenia. No adverse effects to PTX were reported. PTX has a beneficial adjuvant effect to antibiotic therapy in preterm infants with LOS without significant impact on neonatal mortality and morbidity.

Staphylococcus epidermidis Bacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways.

Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking. Wild-type and TLR2-deficient (TLR2-/-) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2-/- mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

Development of a multiplex real-time PCR assay for the rapid diagnosis of neonatal late onset sepsis

The diagnosis of late onset sepsis (LOS), a severe condition with high prevalence in preterm infants, is hampered by the suboptimal sensitivity and long turnaround time of blood culture. Detection of the infecting pathogen directly in blood by PCR would provide a much more timely result. Unfortunately, PCR-based assays reported so far are labor intensive and often lack direct species identification. Therefore we developed a real-time multiplex PCR assay tailored to LOS diagnosis which is easy-to-use, is applicable on small blood volumes and provides species-specific results within 4h. Species-specific PCR assays were selected from literature or developed using bioinformatic tools for the detection of the most prevalent etiologic pathogens: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus spp., Streptococcus agalactiae, Escherichia coli, Pseudomonas aeruginosa, Klebsiella spp. and Serratia marcescens. The PCR assays showed 100% specificity, full coverage of the target pathogens and a limit of detection (LOD) of ≤10CFUeq./reaction. These LOD values were maintained in the multiplex format or when bacterial DNA was isolated from blood. Clinical evaluation showed high concordance between the multiplex PCR and blood culture. In conclusion, we developed a multiplex PCR that allows the direct detection of the most important bacterial pathogens causing LOS in preterm infants.

Culture‐proven neonatal sepsis in preterm infants in a neonatal intensive care unit over a 7 year period: Coagulase‐negative Staphylococcus as the predominant pathogen

The aim of this study was to determine the causative agents in early, late- and very late-onset sepsis in preterm infants. The demographic features, risk factors, clinical and laboratory findings in sepsis types were also defined. A total of 151 preterm infants with culture-proven neonatal sepsis were enrolled in this prospective study. The infants were classified into three groups with regard to the onset of sepsis: early onset sepsis (EOS), late-onset sepsis (LOS) and very late-onset sepsis (VLOS). A sepsis screen including whole blood count, blood smear, infection markers and cultures was performed before initiating antibiotic therapy. EOS, LOS and VLOS groups consisted of 23, 86 and 42 infants, respectively. Coagulase-negative staphylococci (CONS) was the most common organism in all sepsis groups. The main factors associated with EOS included presence of premature rupture of membranes, antibiotic use in pregnancy and choriamnionitis. Previous antibiotic use was the main factor associated with LOS, while low birthweight was the main factor in infants with VLOS. Although mortality rate due to Gram-negative bacteria and fungi was higher, CONS was an important cause of mortality in infants with LOS and VLOS. CONS was found to be the most common causative organism in three sepsis types in preterm neonates. Although the mortality rate due to CONS was lower in EOS, it was an important cause of mortality in LOS and VLOS. CONS seems to be the main pathogen in neonatal sepsis in developing countries, as in developed countries.

Distortions in Development of Intestinal Microbiota Associated with Late Onset Sepsis in Preterm Infants

Late onset sepsis (LOS) is a major contributor to neonatal morbidity and mortality, especially in premature infants. Distortions in the establishment of normal gut microbiota, commensal microbes that colonize the digestive tract, might increase the risk of LOS via disruption of the mucosal barrier with resultant translocation of luminal contents. Correlation of distortions of the intestinal microbiota with LOS is a necessary first step to design novel microbiota-based screening approaches that might lead to early interventions to prevent LOS in high risk infants. Using a case/control design nested in a cohort study of preterm infants, we analyzed stool samples that had been prospectively collected from ten preterm infants with LOS and from 18 matched controls. A 16S rRNA based approach was utilized to compare microbiota diversity and identify specific bacterial signatures that differed in their prevalence between cases and controls. Overall α-diversity (Chao1) was lower in cases two weeks before (p<0.05) but not one week before or at the time of diagnosis of LOS. Overall microbiota structure (Unifrac) appeared distinct in cases 2 weeks and 1 week before but not at diagnosis (p<0.05). Although we detected few operational taxonomic units (OTUs) unique or enriched in cases, we found many OTUs common in controls that were lacking in cases (p<0.01). Bifidobacteria counts were lower in cases at all time points. Our results support the hypothesis that a distortion in normal microbiota composition, and not an enrichment of potential pathogens, is associated with LOS in preterm infants.

Clinical signs to identify late-onset sepsis in preterm infants

Late-onset neonatal sepsis (LOS) in preterm infants is an important cause of morbidity and mortality in preterm infants. Since presenting symptoms may be non-specific and subtle, early and correct diagnosis is challenging. We aimed to develop a nomogram based on clinical signs, to assess the likelihood of LOS in preterms with suspected infection without the use of laboratory investigations. We performed a prospective cohort study in 142 preterm infants <34 weeks admitted to the neonatal intensive care unit with suspected infection. During 187 episodes, 21 clinical signs were assessed. LOS was defined as blood culture-proven and/or clinical sepsis, occurring after 3 days of age. Logistic regression was used to develop a nomogram to estimate the probability of LOS being present in individual patients. LOS was found in 48 % of 187 suspected episodes. Clinical signs associated with LOS were: increased respiratory support (odds ratio (OR) 3.6; 95 % confidence interval (CI) 1.9-7.1), capillary refill (OR 2.2; 95 %CI 1.1-4.5), grey skin (OR 2.7; 95 %CI 1.4-5.5) and central venous catheter (OR 4.6; 95 %CI 2.2-10.0) (area under the curve of the receiver operating characteristic curve 0.828; 95 %CI 0.764-0.892). Increased respiratory support, capillary refill, grey skin and central venous catheter are the most important clinical signs suggestive of LOS in preterms. Clinical signs that are too non-specific to be useful in excluding or diagnosing LOS were temperature instability, apnoea, tachycardia, dyspnoea, hyper- and hypothermia, feeding difficulties and irritability.

Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation

Staphylococcus epidermidis (SE) rarely causes infection in term infants but is a leading cause of late-onset sepsis in preterm infants. We hypothesized that the innate immune responses to SE in preterm infants are impaired in a gestational age (GA)-dependent manner. Cord and peripheral blood mononuclear cells (MNCs) were stimulated with SE bacteria, and a range of innate immune responses were assessed, including phagocytosis, intracellular killing, Toll-like receptor (TLR) pathway transcriptional activation, cytokine production, TLR2 and TLR4 expression, and cell signaling. Phagocytosis and intracellular killing of SE bacteria were similar in neonatal and adult monocytes. Cytokine gene expression and protein synthesis increased in a GA-dependent manner, which was confirmed at the single-cell level. These GA-related effects were not associated with differences in expression of TLR2 or TLR4, nor with downstream activation of nuclear factor-κB or mitogen-activated protein kinase pathways. The expression of TLRs, phagocytic capacity, and intracellular killing by monocytes develops early in fetal development, whereas the ability to mount a bacteria-induced cytokine response requires further maturation. The functional immaturity of monocyte activation pathways in the preterm infant may underpin their particular susceptibility to sepsis with commensal bacteria.

Histologic Chorioamnionitis Is Associated With Reduced Risk of Late-Onset Sepsis in Preterm Infants

Histologic chorioamnionitis (HCA) is implicated in the onset of preterm labor and delivery. Chorioamnionitis is a known risk factor for early-onset sepsis and may modulate postnatal immunity. Preterm infants are at greatly increased risk of late-onset sepsis (LOS), particularly with coagulase-negative staphylococci (CoNS), but the impact of HCA on the risk of LOS is unknown. Eight hundred thirty-eight preterm infants born at <30 weeks gestational age at a single tertiary center were included. Histologic examination of placenta and extraplacental membranes was performed, and clinical data were extracted from hospital databases. The influence of HCA on the incidence of early-onset sepsis and LOS was examined using logistic regression analysis and Cox proportional hazards regression. Mean gestational age was 26.9 ± 1.9 weeks, and mean birth weight was 936 ± 277 g. Two hundred and seventy-six (33%) of 838 infants developed LOS. The presence of fetal or maternal HCA, or maternal HCA and fetal HCA alone, was associated with a significantly decreased risk of LOS with any organism. Histologic chorioamnionitis correlated with a significantly decreased risk of CoNS LOS. HCA is associated with a significantly reduced risk of acquiring LOS, both with CoNS and other bacteria. Perinatal inflammation may enhance the functional maturation of the preterm immune system and provide protection against LOS in high-risk preterm infants.

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

Histologic Chorioamnionitis Is Associated With Reduced Risk of Late-Onset Sepsis in Preterm Infants

Histologic Chorioamnionitis Is Associated With Reduced Risk of Late-Onset Sepsis in Preterm Infants

Characteristics of Invasive Staphylococcus aureus in United Kingdom Neonatal Units

In industrialized countries, Staphylococcus aureus (SA) is a leading cause of late-onset neonatal sepsis. Culture-proven episodes were identified prospectively from neonatal units participating in the neonatal infection surveillance network. Demographic, risk factor, and outcome data were collected. Between 2004 and 2009, there were 117 episodes of SA infections (including 8 methicillin-resistant SA) in 116 infants from 13 units. The median gestational age and birth-weight were 27 weeks (90% ≤ 37 weeks, 85% ≤ 32 weeks) and 850 g (90% ≤ 2500 g), respectively. The overall incidence was 0.6 per 1000 live births and 23/1000 in infants <1500 g. Most episodes (94%) occurred more than 48 hours after birth (late onset). There were 7 early-onset episodes (< 48 hours) (median gestational age, 38.5 weeks), all due to methicillin-susceptible SA. At the time of culture, 67 of 95 (71%) infants were receiving respiratory support and 47 of 94 (50%) had a central line in situ. The majority of infants had nonspecific clinical features although evidence of focal infection (skin, soft tissue, bone, joint, or pneumonia) was ultimately seen in 41 of 91 (45%). There were 18 deaths, 4 (all late onset) directly due to methicillin-susceptible SA sepsis (4.4%). SA is the second most common pathogen causing late-onset neonatal infections in this neonatal network. Infants who weigh < 1500 g in intensive care settings are the most vulnerable group. Clinical signs are not sufficiently distinctive to allow targeted therapy, suggesting that an antistaphylococcal agent should be part of empiric therapy for late-onset sepsis in premature infants.

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

We aimed to reduce late-onset bacterial infections in infants born at 22 to 29 weeks' gestation by using collaborative quality-improvement methods to implement evidence-based catheter care. We hypothesized that these methods would result in a 50% reduction in nosocomial infection. We conducted an interrupted time-series study among 24 Ohio NICUs. The intervention began in September 2008 and continued through December 2009. Sites used the Institute for Healthcare Improvement Breakthrough Series quality-improvement model to facilitate implementation of evidence-based catheter care. Data were collected monthly for all catheter insertions and for at least 10 observations of indwelling catheter care. NICUs also submitted monthly data on catheter-days, patient-days, and episodes of infection. Data were analyzed by using statistical process control methods. During the intervention, NICUs submitted information on 1916 infants. Of the 242 infections reported, 69% were catheter associated. Compliance with catheter-insertion components was >90% by April 2009. Compliance with components of evidence-based indwelling catheter care reached 80.4% by December 2009. There was a significant reduction in the proportion of infants with at least 1 late-onset infection from a baseline of 18.2% to 14.3%. There was a 20% reduction in the incidence of late-onset infection after the intervention, but the magnitude was less than hypothesized, perhaps because compliance with components of evidence-based care of indwelling catheters remained <90%. Because nearly one-third of infections were not catheter associated, improvement may require attention to other aspects of care such as skin integrity and nutrition.

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

Genetics and late-onset septicemia in pre-term infants

Using a retrospective cohort of twins born from 1994 to 2009 in NICUs in New Haven and Farmington, Connecticut, sepsis concordance rates were compared between 170 monozygotic and 665 dizygotic twin pairs. With caveats of limitations outlined by the authors, the findings suggest that approximately one-half of the variation in incidence of late-onset sepsis in pre-term infants is due to genetic factors. These findings will influence future research and will need to be considered in analysis of causation and prevention of late-onset sepsis.

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

519 Predictive Value of Clinical Signs in Late-Onset Sepsis (LOS) in Preterm Neonates

Background: Accurate diagnosis of LOS in preterm neonates is a major challenge because clinical signs are aspecific leading to unnecessary antibiotic treatment. Aims: To determine the predictive value of clinical signs for identifying LOS in preterm infants. Methods: In all patients 2 seconds, dys/tachypnea, increasing oxygen-need, tachycardia, thermal instability, hyper/hypothermia, feeding difficulties, increasing apnoeic spells, lethargy and irritability) and 4 risk factors (gestational age (GA), weight, sex, central venous catheter (CVC), mechanical ventilation, postnatal age) were prospectively assessed. LOS was defined as bloodculture-proven sepsis occurring after 3 days of age. Results: LOS was diagnosed in 28% of 180 episodes of suspected infection, occurring in 142 neonates (mean GA 30+3 ±2+2 weeks). Only 3 signs were significantly associated with LOS: deterioration of respiratory condition (OR 3,2;95%CI 1,6-6,3), capillary refill >2 seconds (OR 2,9;95%CI 1,5- 5,7) and lethargy (OR 4,4;95%CI 2,2-8,7). Multiple regression resulted in a model with these 3 signs and the presence of a CVC (AUC 0,828; 95%CI 0,764-0,892, p< 0,001). In the absence of these 4 factors, LOS was found in 2,3% (1/43). In case of one or more of the 4 factors sensitivity was 98%, specificity 32%, positive LR 1,45 and negative LR 0,06. Conclusion: Deterioration of respiratory condition, capillary refill, lethargy and the presence of a CVC are the most important clinical signs in predicting LOS in preterm infants. In the absence of all these signs probably antibiotics can be safely withheld.

Risk factors and prevention of late-onset sepsis in premature infants

Late-onset sepsis in premature infants is a major cause of morbidity, mortality, and increased medical costs. Risk factors include low birth weight, low gestational age, previous antimicrobial exposure, poor hand hygiene, and central venous catheters. Methods studied to prevent late-onset sepsis include early feedings, immune globulin administration, prophylactic antimicrobial administration, and improved hand hygiene. In this review, we will outline the risk factors for development of late-onset sepsis and evidence supporting methods for prevention of late-onset sepsis in premature infants.

Seventy-Five Years of Neonatal Sepsis at Yale: 1928–2003

Yale-New Haven Hospital (Y-NHH) has maintained the longest running, single-center longitudinal database of neonatal sepsis, started in 1928. The objective of this study was to update this database with review of neonatal sepsis cases at Y-NHH to identify longitudinal trends in demographics, pathogens, and outcome. Records of infants with positive blood cultures obtained while they were inpatients in the NICU at Y-NHH from 1989 to 2003 were reviewed retrospectively. Records of infants who were < or =30 days of age, had positive blood cultures, and were hospitalized at Y-NHH outside the NICU from the same period were also reviewed, and all findings were compared with 60 years of preexisting data. A total of 862 organisms were identified in 755 episodes of sepsis from 647 infants. The percentage of cases of early-onset sepsis decreased and late-onset sepsis increased compared with the previous 10-year study period. A marked increase in cases as a result of commensal species was observed, particularly in preterm infants who had indwelling central vascular catheters, were receiving parenteral nutrition, and required prolonged mechanical ventilation. The overall percentage of sepsis caused by group B streptococcus and Escherichia coli decreased. No episodes of sepsis from Streptococcus pneumoniae or S pyogenes, common in the early years of the survey, were observed. The sepsis-related mortality rate steadily decreased, from 87% in 1928 to 3% in 2003. The demographics, pathogens, and outcome associated with neonatal sepsis continue to change. The increase in late-onset sepsis in preterm infants who required prolonged intensive care indicates that strategies to prevent infection are urgently needed for this population of infants.

Serum Amyloid A Protein Is a Useful Inflammatory Marker during Late-Onset Sepsis in Preterm Infants

Background: Few studies demonstrated that serum amyloid A (SAA), a non-specific acute-phase reactant, could be used as a reliable early marker for the diagnosis of late-onset sepsis (LOS). Objectives: To evaluate the diagnostic value and the dynamics of SAA levels during the course of LOS and to compare it to those of other inflammatory markers. Methods: Levels of SAA, C-reactive protein (CRP) and IL-6 together with clinical variables, biochemical parameters and cultures retrieved from all preterm infants suspected of LOS were checked at the first suspicion of sepsis and after 8, 24, 48 and 72 h. Results were compared to healthy, matched infants. Results: One hundred and sixteen infants were included in the study, 38 in the sepsis and 78 in the non-sepsis group. High levels of SAA were observed at sepsis onset, with a gradual decline thereafter, while CRP levels increased only at 24 h after sepsis onset. In the sepsis group, levels of SAA returned faster to baseline than CRP levels. Receiver-operating characteristic analysis values revealed that SAA at 10 µg/ml had the highest sensitivity at 0, 8 and 24 h after sepsis onset (95, 100 and 97%, respectively) and a negative predictive value (97, 100 and 98%, respectively). Conclusions: SAA is an accurate acute-phase protein during LOS in preterm infants. Quick and reliable SAA kits can make this marker a useful tool in LOS in preterm infants.