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Neoreviews. Author manuscript; available in PMC 2023 November 01.
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Published in final edited form as:

Neoreviews. 2022 November 01; 23(11): 738–755. doi:10.1542/neo.23-10-e738.

Updates in Late-Onset Sepsis: Risk Assessment, Therapy and

Outcomes
Sarah A. Coggins, MD1, Kirsten Glaser, MD2,*
1Division of Neonatology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
2Divisionof Neonatology, Department of Women’s and Children’s Health, University of Leipzig
Medical Center, Leipzig, Germany
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Abstract
Neonatal late-onset sepsis (LOS) continues to threaten morbidity and mortality within the neonatal
intensive care unit (NICU) and poses ongoing diagnostic and therapeutic challenges. Early
recognition of clinical signs, rapid evaluation, and prompt initiation of treatment are critical to
prevent life-threatening deterioration. Preterm infants – born at ever-decreasing gestational ages –
are at particularly high risk for life-long morbidities and death. This changing NICU population
necessitates continual reassessments of diagnostic and preventive measures and evidence-based
treatment for LOS. The clinical presentation of LOS is varied and nonspecific. Despite ongoing
research, identification of reliable, specific laboratory biomarkers facilitating early diagnosis is
lacking. These limitations drive an ongoing practice of liberal initiation of empiric antibiotics
among infants with suspected LOS. Subsequent promotion of multidrug-resistant microorganisms
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threatens the future of antimicrobial therapy and puts preterm and chronically ill infants at
even higher risk of nosocomial infection. Efforts to identify adjunctive therapies counteracting
sepsis-driven hyper-inflammation and sepsis-related functional immunosuppression are ongoing.
However, most approaches have either failed to improve LOS prognosis or are not yet ready for
clinical application. This article provides an overview of epidemiology, risk factors, diagnostic
tools, and treatment options of LOS in the context of increasing numbers of extremely preterm
infants. It addresses the question of whether LOS could be identified earlier and more precisely to
allow for earlier and more targeted therapy and discusses rational approaches to antibiotic therapy
to avoid over-use. Finally, this review elucidates the necessity of long-term follow-up of infants
with a history of LOS.

Evidence / Article Summary

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• Neonatal LOS is a life-threatening condition and a major cause of neonatal morbidity

and mortality worldwide.

*
Address correspondence to: Kirsten Glaser, Division of Neonatology, Department of Women’s and Children’s Health, University
of Leipzig Medical Center, Liebigstrasse 20a, 04103 Leipzig, Germany, Phone: +49-341-9720382, [Link]@[Link]-
[Link].
Conflict of Interest: The authors have no conflicts of interest to disclose.
Financial Disclosure: The authors have no financial relationships relevant to this article to disclose.
 Coggins and Glaser Page 2

• Preterm infants and chronically ill neonates are at highest risk, and VLBW infants
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account for up to 50% of LOS cases in high-income countries.

• Early recognition and prompt initiation of therapy are key to prevent life-threatening
deterioration.

• Antibiotic therapy includes initial empiric and organism-specific therapy. The choice
of empiric antibiotic agents should be based on the likely organism and patterns of
antibiotic susceptibility and resistance in the individual NICU setting. Duration should
be as short as possible and selection of antibiotic regimes as narrow as possible.

• Extended hygiene measures based on routine colonization screening of NICU patients

and CLABSI prevention efforts have been associated with reduced rates of LOS.

• Promotion of resistant microorganisms threatens the future of antimicrobial therapy.

High exposure rates to 3rd/4th generation cephalosporins, vancomycin, and meropenem
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likely reflect increasingly complex critically ill neonates and resistant organisms but
should also prompt antimicrobial stewardship efforts where feasible.

INTRODUCTION
Despite advances in overall neonatal care and implementation of quality improvement
measures, neonatal late-onset sepsis (LOS) remains a persistent threat in neonatal intensive
care units (NICUs). LOS disproportionately affects the most premature infants and is
associated with mortality and considerable morbidity among survivors.1–7 LOS recognition
and diagnosis remain challenging; LOS often presents with varied, nonspecific clinical
signs,8 and common laboratory biomarkers perform inconsistently in discriminating infected
from uninfected infants.9 10 This review focuses on current approaches to LOS risk
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assessment, diagnostic testing, antimicrobial management, and infection prevention. Finally,

we summarize survival outcomes and long-term morbidities associated with neonatal LOS
and highlight the need for neurodevelopmental follow-up of LOS survivors.

DEFINING LATE-ONSET SEPSIS

Sepsis is a life-threatening condition caused by systemic infections that prompt a cascade of
often fatal inflammatory immune responses. Neonatal sepsis is defined as sepsis presenting
in the first 28 days after birth.11 In view of distinct pathogenesis and pathogen epidemiology,
neonatologists discriminate early-onset sepsis (EOS) and LOS according to the timing of
infection onset.2 11 EOS is mostly defined as manifesting in the first 48–72 hours after
birth.1 11 12 In the preterm NICU population, sepsis may occur much later; thus, in research
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contexts, LOS encompasses sepsis presenting ≥72 hours after birth and through NICU
hospitalization.

Although there is general research consensus defining the timing of neonatal sepsis
subtypes, there is substantial heterogeneity in neonatal LOS definitions among observational
studies and major neonatal organizations, and there is no standard approach to diagnosing
LOS across NICUs.11–13 In variable combinations, the definition is based upon assessment
of microbiological cultures, clinical signs of infection, and adjunctive laboratory data.11 12

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Most definitions include a positive blood culture as the essential criterion, although culture
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collection requirements and procedures may vary widely. Clinical signs of sepsis are the
second major criterion. However, there is no consensus on key indicator signs among a
multitude of symptoms (Figure).11 In summary, “culture-proven sepsis” may be defined by
positive blood culture results, while the diagnosis of “culture-negative sepsis” or “clinical
sepsis” relies on variable clinical signs consistent with infection.11 “Septic shock” is
discriminated from sepsis when criteria for neonatal sepsis are met and blood pressure is
below the 5th percentile for age requiring hemodynamic stabilization with fluids or inotropic
agents.11

Heterogeneity in defining LOS hampers interpretation and comparability of clinical trials

and development of evidence-based guidelines for LOS diagnosis and management.13
There are ongoing attempts to establish a consensus definition of neonatal LOS, aiming
to identify neonatal-specific objective physiologic and laboratory characteristics that may
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allow more rapid recognition and initiation of therapy. Furthermore, this may facilitate more
standardized, comparable data collection worldwide that could contribute to diagnostic and
therapeutic innovations in LOS.11 12

EPIDEMIOLOGY, RISK FACTORS AND CAUSATIVE PATHOGENS

LOS is primarily attributed to nosocomial or horizontal pathogen acquisition, and exposures
to hospital or community environments. Pathogen exposure may occur due to contamination
or colonization of indwelling invasive medical devices, contact with care providers, and/or
other environmental sources and surfaces. Preterm birth and critical illness are major risk
factors for LOS given their associated needs for central catheters, mechanical ventilation,
prolonged parenteral nutrition, and surgical interventions.3 14 15 Predisposing factors
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further include maternal and perinatal risk factors, such as preeclampsia, chorioamnionitis,
and intrauterine growth restriction, as well as length of hospital stay and comorbidities
(Figure).1 3 4 15 16 The most immature infants experience the highest infectious burden;
LOS rates are reported at 1.6% in term neonates, compared to 12–50% among very preterm
and/or very low birth weight (VLBW) infants.1 2 4 6 LOS-associated mortality varies by
gestation and by organism, and may be as high as 35% in the most vulnerable, lowest-
gestation infants.6 14

Host response factors shape the inflammatory response to sepsis and contribute to the
severity of clinical presentation. Gestational age (GA)-specific patterns of immune function
place preterm infants at increased risk of infection, adverse or sustained inflammation, and
organ dysfunction.17–19 Moreover, microbial colonization and aberrations in microbiome
development are implicated in increased susceptibility to LOS.3 20 Specifically, prolonged
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empiric antibiotic therapy >4 days at birth is associated with 1.25 to 2.5-fold higher adjusted
odds of later LOS and combined LOS/death.21 The role of genetics remains unclear, and
LOS rates are not significantly different among infants born from singleton versus multiple
gestation pregnancies.14 Sex differences in immune function, infection development, and
potentially increased susceptibility to sepsis in male infants are poorly understood.22

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Ultimately, infection risk and clinical manifestation are driven by host factors (e.g., baseline
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organ dysfunction or immaturity), the pathogen type, and potential antimicrobial resistance
patterns. Causative pathogens vary widely across geographical regions and NICUs, and
infectious epidemiology may change over time within the same unit.4 5 Gram-positive
bacteria constitute the majority of pathogens isolated in high-income countries,1 6 14 23 while
gram-negative organisms are predominant in some low- and middle-income countries.5
Notably, >50% of gram-positive bacteremia among preterm infants is due to coagulase-
negative Staphylococci (CoNS),1 6 14 23 an organism considered to be a skin commensal in
term neonates. However, in preterm infants, CoNS may represent true pathogens causing
clinically significant infections.17 23 Ultimately, isolation of CoNS from blood cultures
necessitates discrimination between potential culture contamination and true bacteremia in
the individual patient and NICU setting.

Other important gram-positive bacteria implicated in LOS include S. aureus (isolated in

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4–18%), Enterococcus species (spp.) (3–16%) and Group B Streptococcus (1.8–8%), with
large variation among nationwide data reported by the US National Institute of Child
Health and Human Development (NICHD), the NeonIN surveillance network in England,
and the German Neonatal Network (GNN).1 2 4 6 24 Against the background of rising
numbers of multidrug-resistant organisms, methicillin-resistant S. aureus (MRSA) represents
an increasingly prevalent pathogen in gram-positive LOS, responsible for 11% of S. aureus
infections in the NeonIN surveillance cohort and 23% of S. aureus infections reported to the
Center for Disease Control’s National Nosocomial Infections Surveillance system.24 25 The
GNN and data from nationwide Australian and New Zealand cohorts still report a MRSA
prevalence of <1% of all pathogens isolated in VLBW infants with LOS (6% of S. aureus
infections in GNN infants).6 26 Other observational studies do not differentiate MRSA from
methicillin-sensitive S. aureus.1 2 4
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LOS caused by gram-negative pathogens is associated with higher illness severity,

significantly higher mortality, and higher likelihood of short- and long-term neonatal
morbidities.2 3 15 In nationwide cohorts in the United States, England, and Germany,
Escherichia (E.) coli (proportions range from 3 to 13%), Klebsiella spp. (4–5%),
Pseudomonas spp. (2–5%), Enterobacter spp. (2.5–21%), Serratia (0.8–2%), and
Acinetobacter (0.1–2%) account for the majority of cases of gram-negative LOS.1 2 4 6 24
In recent decades, a growing number of infections due to multidrug-resistant gram-
negative organisms (e.g., extended-spectrum beta-lactamase [ESBL]-producing bacteria)
have challenged antimicrobial therapy selection in LOS in high-risk NICU patients.5

Fungal organisms are isolated in about 3–10% of cases of neonatal LOS, with Candida
(C.) spp. (mainly C. albicans and C. parapsilosis) most frequently detected.2 4 6 Yeast
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infections have been associated with high mortality, and should be particularly considered
in LOS evaluation and empiric therapy in ill preterm and term neonates who demonstrate
clinical features possibly consistent with invasive fungal infections (e.g., rash, neutropenia/
thrombocytopenia, hyperglycemia).4 Finally, viral pathogens (e.g., parainfluenza, echo-,
entero-, coxsackie-, adeno-, rhino- and coronavirus) have been increasingly acknowledged
as causative agents of sepsis-like syndromes in preterm and term infants.27 28

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CLINICAL PRESENTATION
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The clinical presentation of LOS is nonspecific and varied, with respiratory signs,
lethargy, tachycardia, feeding intolerance, and temperature instability (fever or hypothermia)
commonly reported (Figure). The spectrum of illness severity ranges from moderate signs of
infection to critical illness with severe organ dysfunction and potential multiorgan failure.8
Secondary sites of infection that are most frequently associated with late-onset bacteremia
include pneumonia, urinary tract infections (UTIs), and skin and soft tissue infections, as
well as necrotizing enterocolitis. Translocation of pathogens colonizing the neonatal gut is a
major cause of neonatal sepsis, especially in very immature preterm infants and infants with
compromised intestinal integrity. In infants with clinically apparent necrotizing enterocolitis,
concurrent bloodstream infections (mostly of gram-negative origin) were detected in 40–
60% of cases.29 LOS is complicated by meningitis in approximately 5% of cases (in
which a lumbar puncture (LP) was performed).30 Clinically, sepsis cannot be distinguished
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from meningitis, since presentation is again nonspecific and includes apnea, lethargy, and
temperature instability, among other signs.

DIAGNOSIS
The ideal LOS biomarker would facilitate early diagnosis of culture-confirmed infections
with high positive and/or negative predictive value, generalizability across gestational and
postnatal age strata, and rapid turnaround time. However, this biomarker has not yet
been identified (Table 1). The complete blood count with differential has limitations in
both preterm and term LOS diagnosis. Complete blood count indices may be normal in
infected infants, and individual indices including white blood count, absolute neutrophil
count, immature-to-total (I:T) neutrophil ratio, and platelet count do not have sufficient
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sensitivity or specificity alone for reliable LOS diagnosis.31 C-reactive protein (CRP) is
an acute-phase reactant primarily produced in the liver with peak expression 36–48 hours
post-stimulation. CRP test characteristics in identification of culture-proven LOS in VLBW
infants are modest at best, with median sensitivity 62% and specificity 74%.32 Single CRP
measurements have limited diagnostic efficiency and cannot reliably identify nor exclude
infection in a symptomatic infant at the time of sepsis evaluation.32 However, three serial
CRP measurements obtained over days improve sensitivity to 98% and negative predictive
value to 99%.33 Thus, assessing CRP at the time of presentation is unlikely to assist in
clinical decision making, while repeated negative measurements may serve as a useful
adjunct in the decision to discontinue antibiotics.

Procalcitonin (PCT), like CRP, is an acute-phase reactant that is mostly synthesized in the
liver in response to interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha but appears
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to have faster kinetics with peak levels being detected 12–24 hours post-stimulation. Test
characteristics for PCT are variably reported, with median sensitivity 92% and median
specificity 80%.34 In summary, single CRP and/or PCT values obtained at the time of
LOS evaluation have limited diagnostic utility, as they do not reliably “rule-in” or “rule-
out” culture-confirmed infections. However, serial values trended over time may assist as
adjuncts in decision-making surrounding antibiotic discontinuation in the context of clinical
assessments and culture data.

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Multiple other biomarkers have been evaluated in LOS diagnosis. Proinflammatory

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cytokines (e.g., IL-6, IL-8, TNF-alpha) and cell surface markers (e.g., CD64, CD11b,
soluble CD14, HLA-DR) have moderate diagnostic efficiency,35–40 which increases with
serial measurements.10 However, these markers may not have available assays in hospital
laboratories, and they are not routinely used in most centers. In the future, machine learning
techniques may aid in constructing combined panels of biomarkers offering better diagnostic
efficiency than single biomarkers.

Positive blood cultures remain the “gold standard” for neonatal LOS diagnosis, given that
sensitivity for bacteremia detection may be as high as >98%.41 Improvements in laboratory
technology, including automated blood culture detection systems, have contributed to faster
time to organism detection and speciation. However, adequate blood culture volume is still
key for pathogen detection (Infobox).41 Most LOS evaluations, especially in preterm infants,
yield negative blood culture results;42 in a cohort of 99,796 VLBW infants with episodes of
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suspected LOS, only 8.9% of 164,744 blood cultures obtained were positive.14 This count
reflects the uncertainty facing clinicians: on one hand, LOS evaluations are initiated in the
face of clinical instability (which in the great majority of cases results from a non-infectious
etiology), though truly infected infants may also have “falsely negative” blood cultures if
there is low-level circulating bacteremia, insufficient blood culture volume, or antibiotic
administration prior to culture collection. Emerging molecular diagnostic adjuncts (e.g.,
reverse transcription - polymerase chain reaction [RT-PCR] of bacterial 16s ribosomal RNA)
amplify small amounts of genetic material of pathogens, with sensitivity and specificity
reported as high as 90% and 96%.9 However, these techniques are expensive, do not
differentiate between live and dead bacteria, and may lead to amplification of pathogenic
material unrelated to the clinical phenotype.
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Although urine cultures should be routinely obtained during LOS evaluations, inclusion is
variable and occurs in as few as 7% and up to 50% of LOS evaluations.43 44 UTIs were
reported in 8–11% of LOS evaluations in which a urine culture was sent, and tend to occur
more often in preterm infants with lower birth weight and higher postnatal age (reported
mean UTI diagnosis at 42 postnatal days).44 45 Variation in urine culture practices may stem
from lack of clinical suspicion for UTI, technical challenges in obtaining sterile cultures
(particularly in very immature infants or those with anatomic differences), and/or perceived
lack of patient stability to obtain a urine sample. Moreover, there is no consistent definition
of UTI applicable to NICU patients, cutoffs for urinalysis indices vary considerably, and
UTI may frequently occur in the absence of positive blood cultures. Urine specimens should
ideally be collected in a sterile fashion (via urethral catheterization or suprapubic tap),
as opposed to external bag collection which carries higher risks of contaminant pathogen
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growth. Antibiotic therapy prior to urine culture collection reduces the diagnostic efficiency
for UTIs, emphasizing the importance of urine sample collection at the time of sepsis
evaluation and prior to antibiotic exposure. 43 44

Inclusion of cerebrospinal fluid (CSF) diagnostics in LOS evaluation should be considered,

particularly among preterm infants and febrile neonates <28 days of age – since clinical
signs of meningitis are nonspecific and may overlap with other infectious processes.46 47
CSF cultures obtained prior to antibiotic administration are the “gold standard”. However, it

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is challenging to accurately estimate meningitis rates complicating LOS. LPs are often not
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performed as part of LOS evaluations, and those performed after antibiotic initiation may
reveal false-negative culture growth in CSF samples. Variations in rates of LP performance
could be attributable to several factors, including clinician awareness of the low estimated
prevalence of meningitis associated with LOS (~2–5%) and reluctance to perform LPs
(particularly in very small or clinically unstable infants).15 45 48 In a cohort of 2,989 VLBW
infants, only 24% of LOS evaluations included CSF cultures, with significant practice
variation (7–49% across 8 centers). Of those patients for whom CSF cultures were obtained,
only 2% were deemed to have meningitis.45 Of note, consistent evidence suggests that a
significant proportion of meningitis cases (30–70%) occur in the absence of bacteremia.45–47
Diagnostic adjuncts, particularly in infants with pre-treated cultures or uninterpretable CSF
indices, may include pathogen RT-PCR or cytokine profiling.49
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RISK ASSESSMENT
Improvements in LOS risk assessment strategies are needed for better discrimination among
heterogeneous NICU populations and earlier identification of evolving LOS. Due to a lack
of sensitivity and specificity, sepsis definitions based upon systemic inflammatory response
syndrome (SIRS) criteria have largely been abandoned in adult patients, with a shift to
metrics focused on infection-associated organ dysfunction that also have utility in predicting
sepsis-attributable morbidity and mortality.50 51 Revisions to pediatric sepsis definitions are
in progress and also appear to be shifting towards metrics focusing on organ dysfunction.52
The nSOFA (neonatal Sequential Organ Failure Assessment) is one proposed tool for
quantifying neonatal multi-organ dysfunction and associated mortality risk.53 It quantifies
respiratory, cardiovascular, and hematologic dysfunction using readily available clinical data
in the electronic medical record, and observational studies have demonstrated that changes
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in the nSOFA over time correlate with LOS-attributable and all-cause mortality in preterm
infants.53 54

Computer-based algorithms have attracted considerable interest as “early-warning systems”

for LOS diagnosis. Vital sign-based approaches include heart rate characteristic algorithms
to identify inflammation-induced periods of minimal heart rate variability, decelerations,
and/or tachycardia. Monitoring has been associated with reduced all-cause and sepsis-related
mortality in randomized controlled trials.55 Moreover, there is an evolution of predictive
bioinformatic approaches, such as machine learning modeling and artificial intelligence
methods. These aim at patient-level risk assessment based upon clinical data, including vital
signs, laboratory results, and clinical parameters (e.g., mechanical ventilation or vasopressor
support).56 Approaches are promising, though further evaluation of performance in sepsis
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recognition and assessment of outcomes are needed prior to clinical implementation.

“Omics”-based strategies for sepsis diagnosis (metabolomic, proteomics and genomic
approaches) are also being evaluated, but are not yet ready for clinical application.57

MANAGEMENT
Prompt initiation of antibiotic therapy is crucial. Additionally, hemodynamic stabilization
via volume resuscitation and/or vasopressor support may be required to counteract

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vasodilatation and capillary leakage and subsequent hypoperfusion and hypovolemia.

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Supportive care may also include supplemental oxygen and/or mechanical ventilation,
management of acid/base and electrolyte disturbances, and transfusion of blood products.
Aggressive supportive interventions are particularly required in infants with fulminant sepsis
and development of septic shock.

Antibiotic Treatment
Antibiotic therapy should be administered as quickly as possible once concern for LOS is
identified, and ideally after cultures have been obtained. Delayed antibiotic administration
for suspected LOS in a level IV NICU was independently associated with increased 14-day
mortality (47% increased risk of death for each additional 30-minute delay).58 While prompt
empiric antibiotic therapy is critical, the use of antibiotics for suspected LOS must be
balanced against potential risks (including drug toxicity, negative interference with healthy
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skin and gut microbiota, and antibiotic selection pressures).

There is no consensus upon the ideal empiric antibiotic regimen for LOS, and considerable
practice variation exists in antibiotic selection and treatment durations.26 59–61 Broad-
spectrum empiric antibiotics for LOS generally include two agents with complementary
spectra of activity. Beta-lactam agents (e.g., ampicillin, oxacillin, nafcillin) are commonly
utilized to provide gram-positive bacterial coverage.60 However, given high rates of LOS
due to CoNS (often resistant to beta-lactam antibiotics), vancomycin may be preferred
for initial gram-positive coverage. Additional patient factors that may influence decision-
making surrounding empiric vancomycin use include presence of indwelling central
catheters and known colonization with MRSA, as well as local resistance patterns.
Vancomycin use in the NICU is widespread: it was the sixth-most frequently prescribed
medication among NICU patients in a large US-based cohort – and after ampicillin and
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gentamicin, it was the third-most common antibiotic.62 However, due to associated risks
of acute kidney injury, vancomycin use requires renal function and drug level monitoring
to surveil for toxicity. Agents targeting gram-negative bacteria include aminoglycosides
(e.g., gentamicin), 3rd/4th generation cephalosporins (e.g., cefotaxime, cefepime) and
carbapenems (e.g., meropenem).63 64 Given its broad aerobic and anaerobic coverage,
piperacillin-tazobactam, a β-lactam antibiotic with β-lactamase inhibitor, is frequently used
in the context of presumed intra-abdominal sources of infection. Due to its poor central
nervous system (CNS) penetration, piperacillin-tazobactam is not recommended in cases of
clinical concern for meningitis. Instead, a 3rd/4th generation cephalosporin, or carbapenem,
is preferred for gram-negative CNS coverage.

Carbapenems are powerful β-lactam antibiotics with the broadest range of in-vitro
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activity against gram-positive and gram-negative bacteria (including ESBL-producing

Enterobacteriaceae) and are essential reserve antibiotics.64 Linezolid, fosfomycin, and
daptomycin are additional reserve antibiotics that may be used in multi-resistant gram-
positive infections. Ciprofloxacin and colistin have been used – despite concerns for adverse
effects – in neonatal infections with multi-resistant gram-negative bacteria.56 Use of these
antibiotics should be limited to definitive and antibiogram-guided therapy of infections with
a multidrug-resistant pathogen. They are not recommended as routine empiric therapy. We

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suggest that clinicians consider consultation with an infectious disease specialist in cases
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where the use of a “reserve” antibiotic might be indicated.

Major concerns exist about increasing numbers of multidrug-resistant bacteria among

NICU cohorts worldwide,60 65 driven by widespread use of vancomycin, 3rd/4th generation
cephalosporins and carbapenems.63 64 Empiric antibiotics are often inappropriately used, in
terms of unnecessarily broad spectra and prolonged durations of treatment in the setting
of negative cultures. In an evaluation of NICU antibiotic utilization as defined by the
Centers for Disease Control’s 12-Step Campaign to Prevent Antimicrobial Resistance, up to
25% of all antibiotic courses were considered inappropriate (39% were antibiotic regimens
inappropriately continued >72 hours’ duration, others related to inappropriate pathogen
targeting).65 Ultimately, local organism epidemiology, resistance patterns, and antibiotic
stewardship should guide individual regimens. Judicious and rational use is mandatory,
and antibiotic regimens should be narrowed as soon as organism speciation and antibiotic
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sensitivity data are available. Of note, quality improvement initiatives in settings with
low MRSA prevalence have demonstrated a reduction in vancomycin utilization (in favor
of anti-staphylococcal penicillins) and reduction in vancomycin-associated acute kidney
injury, without impacts on mortality.66 67 The duration of antibiotics for culture-proven
infections varies by organism and site. While bacteremia is usually treated with 10–14 days
of antibiotics (depending on organism), meningitis requires longer courses of 14–21 days,
especially in gram-negative meningitis.68 Empiric antibiotic durations to “rule-out” LOS
commonly range 48–72 hours, with discontinuation upon receipt of negative cultures. Given
that most blood culture growth occurs within 36 hours (with late culture growth largely
driven by CoNS), shorter empiric antibiotic durations may be adequate.69

Adjunctive Therapeutic Interventions

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There is an ongoing search for effective adjunctive therapies for neonatal sepsis – mainly
aiming at a beneficial modulation of both sepsis-driven hyper-inflammation and sepsis-
related functional immunosuppression.17–19 70 Sepsis is characterized by excessive induction
of pro-inflammatory and anti-inflammatory pathways, activation of the coagulation
cascade and complement system, sepsis-induced neutropenia and thrombocytopenia, and
biochemical imbalances resulting in an oxidant state associated with reduced plasma and
tissue levels of antioxidants (such as glutathione).70 Clinical and experimental data indicate
exaggerated and sustained pro-inflammatory but impaired counter-regulatory responses in
preterm infant sepsis, and impaired resolution of inflammation. Numerous therapeutic
interventions have been studied for potential utility in counteracting these mechanisms.
However, many of these approaches have either failed to affect the prognosis of LOS or are
not yet ready for clinical application (Table 2).60 70–89
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PREVENTION
Strategies focused on infection prevention are key to reduce LOS burden.90–92 Preventive
measures include hand hygiene, adherence to infection control protocols, implementation of
antimicrobial stewardship programs (ASPs), and care practices including early initiation of
enteral feeds and use of breast milk.91 93 Preventive immunomodulatory strategies aim at

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a beneficial modulation of skin and gut microbiome, inflammatory immune responses, and
oxidative stress (Table 2).70
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Hand Hygiene, Antiseptic Measures, and Colonization Screening

Hand hygiene remains one of the most effective measures to reduce infections associated
with care providers.94 Staff use of nonsterile gloves for patient contact may confer
additional protection – additive to hand hygiene. A randomized controlled trial demonstrated
reductions in late-onset infections among extremely preterm infants whose caregivers
used nonsterile gloves following hand hygiene, compared to hand hygiene alone.95 Strict
adherence to aseptic protocols prior to line and catheter insertion, in particular, is a key
preventive measure.96 Antiseptics, such as chlorhexidine gluconate provided in aqueous
and alcoholic forms (0.05% to 2%) and octenidine dihydrochloride, effectively reduce skin
colonization with pathogens in preterm and term neonates.97 However, national surveys
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reveal substantial variation in disinfection practices. In fact, there is no robust evidence

in favor of any specific skin disinfectant, and there is no consensus on whether alcoholic
or aqueous formulations should be preferred. In very immature preterm infants, there
are potential safety and toxicity issues to be taken into account, such as risk of thyroid
dysfunction associated with povidone-iodine use.97 Notably, 1% chlorhexidine gluconate
was found to be even more effective than 1% povidone-iodine in reducing blood culture
contamination rates in moderate preterm and term neonates.98 However, adverse skin
reactions to chlorhexidine have been reported in very immature preterm infants.97 Apart
from topical and systemic side effects, antiseptic regimens have the potential to promote
bacterial resistance. An observational study in two NICUs in the UK and Germany, using
chlorhexidine gluconate versus octenidine, demonstrated that long-term use of chlorhexidine
for skin antisepsis may select for chlorhexidine and octenidine tolerance among CoNS
isolates.99 Finally, there is no convincing evidence of any beneficial effect of full-body
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washing with antiseptics, such as chlorhexidine bathing, in preterm infants.100 Instead, there
are concerns about disturbance of skin pH and skin microbiome as well as disruption of
innate antimicrobial and immunological skin properties.100

In addition to antiseptic placement techniques, central line-associated bloodstream infection

(CLABSI) prevention quality improvement efforts stipulate a bundle of care measures,
including dressing change practices, reduction of daily central catheter accesses, and timely
central catheter removal, with the goal of preventing colonization of indwelling central
vascular catheters and systemic dissemination of pathogens. In a US-based initiative,
a 19% reduction in CLABSI rates was documented among a collaborative of tertiary
and quaternary NICUs following implementation of standardized CLABSI prevention
bundles.101 Implementation of weekly colonization screening of VLBW infants for high-risk
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or multidrug-resistant bacteria and subsequent individual extension of hygiene measures

has been associated with reduced sepsis rates.102 Routine use of prophylactic systemic
antibiotics for CLABSI prevention and routine vancomycin catheter locks, on the contrary,
are not recommended – for substantial risk of selection of resistant organisms and rather
high numbers needed to treat.103

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Antimicrobial Stewardship
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ASPs are collaborations between prescribing clinicians, infectious disease specialists, and
pharmacists, aiming at critical evaluation and reduction of antibiotic exposures. Examples
of ASP-guided interventions include guidance of empiric antibiotic selection and restrictions
on broad-spectrum antibiotic use as well as standardization of durations of antibiotic
treatment. Single-center reports of ASP implementation in NICUs have demonstrated
reductions in antibiotic initiation, improved narrow-spectrum antibiotic selection, and
improved rates of timely antibiotic discontinuation. However, programs have had variable
impact on overall antibiotic utilization.93 104

OUTCOMES
LOS contributes significantly to neonatal mortality and morbidity.1 3 5 7 Outcomes are
affected by etiology and causative pathogen, GA, underlying comorbidities, presence of
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organ dysfunction, and the cumulative number of infectious insults. Lower GA, higher
illness severity, and intra-abdominal, pulmonary, and CNS sites of primary infection are
associated with increased mortality in neonatal LOS.15 53

Mortality
Estimates of LOS-associated mortality vary based on the neonatal subpopulation of interest.
In a large NICHD Neonatal Research Network cohort study including >10,000 ELBW
infants, those with LOS experienced significantly higher all-cause mortality compared to
uninfected infants (24% vs. 18%).4 Among VLBW infants, all-cause mortality estimates
range from 4.2% of infants with LOS in the GNN,6 to 15% of infants in a large US
cohort from the Pediatrix database.14 LOS-related mortality further varies by organism class;
specifically, fungal and gram-negative sepsis is associated with higher mortality compared
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to gram-positive sepsis. Among a large US cohort of ELBW infants, sepsis-attributable

mortality occurred in 15% cases of gram-positive LOS, 20% of gram-negative LOS, and
31% of fungal LOS.4 In another large cohort study of >108,000 VLBW infants, organism-
specific mortality was highest in Pseudomonas LOS (occurring in 35% of all Pseudomonas
infections), followed by H. influenzae (33%), Candida (29%), and S. aureus (21%).14 In
4,094 VLBW infants with culture-proven sepsis in the German Neo-KISS surveillance
system, infection with Klebsiella spp. (HR 3.17; 95% CI 1.69–5.95), Enterobacter spp.
(hazard ratio (HR) 3.42; 95% CI 1.86–6.27), Escherichia coli (HR 3.32; 95% CI 1.84–6.00)
and Serratia spp. (HR 3.30; 95% CI 1.44–7.57) were associated with significantly higher
mortality risk compared to S. aureus.105 Of note, available epidemiologic data report CoNS-
related mortality in VLBW infants ranging from 1.6% to as high as 11.5%.23 106
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Morbidity
Neurodevelopmental impairment (NDI) is a major sequela of LOS.107–109 Central
nervous system (CNS) injury results from direct bacterial cytotoxicity, adverse systemic
inflammation (even without pathogen invasion into the CNS) and altered brain perfusion
in the setting of hemodynamic instability.108 110 Bacterial meningitis has potentially
devastating outcomes, and affected infants are at highest risk of poor neurocognitive
development – as high as 10-fold increase in risk of moderate or severe neurologic

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 Coggins and Glaser Page 12

disability at the age of 5 years (up to 15% of meningitis survivors).111 Moreover, white
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matter is particularly vulnerable to oligodendrocyte injury and aberrant maturation in the

face of inflammatory cascades, especially in preterm infants.109 110 In a US cohort of
>6,000 ELBW infants, adverse neurodevelopmental outcomes at 18–22 months corrected
age were identified in almost 50% of infants with a history of culture-confirmed sepsis.112
Compared to uninfected neonates, those with culture-proven sepsis had significantly higher
odds of NDI.112 Emerging literature is investigating the relationship between NDI and
“culture-negative” LOS syndromes. A Swiss cohort study of 541 infants born at 24–28
weeks’ GA identified that culture-proven sepsis, but not culture-negative “suspected sepsis”,
was associated with increased risks of NDI and CP, compared to uninfected infants.113 A
recent US study of >3,900 ELBW infants born at 22–26 weeks’ GA found infants with
culture-negative sepsis at increased risk of NDI.7 Increased risks of LOS-associated NDI
seem to persist into childhood. A French cohort study identified LOS as a significant risk
factor for CP at the age of 5 years (adjusted OR 1.7, 95% CI 1.1–2.6).114 Among children
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born <28 weeks’ GA, those with a history of LOS were at higher risk of NDI at the age
of 10 years compared to uninfected infants. NDI appeared to be largely manifested as
intellectual impairment, assessed as low IQ.107

Ultimately, adverse and/or sustained inflammatory immune responses in LOS are a

major contributor in the multifactorial pathogenesis of diseases of prematurity, and drive
organ injury and life-long morbidity, such as bronchopulmonary dysplasia.18 108 110 115
Finally, LOS has been associated with postnatal growth failure, potentially attributable to
inflammation and/or nutritional deficiencies in the setting of critical illness.112 116 In a
matched cohort study of ~700 VLBW infants born <32 weeks with sepsis (the majority of
which was LOS) growth failure manifested at least 3 weeks after LOS and persisted until
NICU discharge.116
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CONCLUSIONS AND OUTLOOK

LOS management and prevention pose ongoing challenges in current neonatal care,
particularly in the context of increasing populations of very immature preterm infants
and rising rates of multi-drug resistant organisms. Early recognition of infants with
suspected sepsis is critical to improve timeliness of therapy and optimize outcomes. Future
advancements in LOS care may focus on improving diagnostic accuracy via biomarker
discovery, incorporation of technology and/or computer-based algorithms for use in LOS
recognition, and quality improvement-based implementation of preventive measures. LOS-
driven adverse or sustained inflammation has been associated with increased neonatal
morbidity, including poor neurodevelopmental outcomes, particularly in preterm neonates.
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Ongoing efforts to better elucidate the unique features of early life immunity and adverse
inflammation may facilitate the development of targeted immunomodulatory therapies.
Finally, follow-up of neurocognitive and motor development into childhood and adolescence
is necessary to characterize enduring sequelae of infection. Ultimately, antimicrobial
stewardship is vital, and clinicians should critically evaluate prescribing practices to target
the narrowest effective antimicrobial regimens based on local antibiograms and sensitivity
patterns. Moreover, further research is needed to better define ideal empiric antibiotic

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 Coggins and Glaser Page 13

regimens, acknowledging center-specific variation in patient populations, care practices, and

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infection epidemiology.

Funding Source:
SAC is supported by NIH training grant T32HL007891.

Abbreviations
ASP antimicrobial stewardship program

CFU colony-forming units

CI confidence interval

CLABSI central line-associated bloodstream infections

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CNS central nervous system

CoNS coagulase negative Staphylococci

CRP C-reactive protein

CSF cerebrospinal fluid

ELBW extremely low birth weight

EOS early-onset sepsis

ESBL extended-spectrum beta lactamase

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GA gestational age

HR hazard ratio

IL-6 interleukin 6

LP lumbar puncture

LOS late-onset sepsis

MRSA Methicillin-resistant Staphylococcus aureus

NICU neonatal intensive care unit

NDI neurodevelopmental impairment

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OR odds ratio

nSOFA neonatal-specific sequential organ failure assessment

PCT procalcitonin

SIRS systemic inflammatory response syndrome

spp species

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 Coggins and Glaser Page 14

TNF-alpha tumor necrosis factor alpha

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UTI urinary tract infection

VLBW very low birth weight

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Infobox
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Best Practices for Blood Culture Collection & Volume Requirements

• Disinfection (May vary based on gestational age)
Topical disinfectants mainly include chlorhexidine gluconate and octenidine
dihydrochloride (povidone iodine is no longer recommended in neonates for
reason of potential systemic absorption and risk of hypothyroidism).97

1–2% chlorhexidine gluconate aqueous formulation with good efficacy;

alcohol component likely accounts for lower contamination than with 10%
povidone iodine.98

– Skin irritation due to chlorhexidine gluconate reported (ascribed to

alcohol component).
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Longer skin disinfection duration (>30 sec) has been reported more
efficacious than shorter durations (10 sec) in removing skin flora;97 allow
to dry.

Do not re-palpate phlebotomy site after disinfected

• Sites
Cultures should be obtained from a peripheral site (arterial or venous
puncture).

If a central catheter is present, consider concurrent central catheter sourced

blood culture.
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– Culture growth & differential time to positivity between peripheral

and central catheter culture may aid in CLABSI diagnosis.

– However, potential risks of central catheter contamination exist

• Blood volume 41

At least 1 mL recommended for blood culture

1 mL blood culture volume ≈ 63% probability of pathogen detection at 1

CFU/mL,

0.5 mL blood culture volume ≈ 39% probability at 1 CFU/mL

3 mL blood culture volume ≈ 95% probability at 1 CFU/mL,

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CFU: colony-forming units, CLABSI: central line-associated bloodstream infections

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Content Specifications:
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Understand the impact of neonatal late onset sepsis on neonatal morbidity and mortality
worldwide, particularly among extremely preterm neonates and chronically ill infants
(ABP Content 10.A.1)

Review the infectious epidemiology of neonatal late-onset sepsis and approaches to

antimicrobial therapy (ABP Content 10.A.1, 10.B.e, f)

Recognize the need for early sepsis recognition, rapid initiation of therapy, and the vital
importance of LOS prevention – largely relying upon hand hygiene and adherence to
infection control protocols (ABP Content 10.C.1,4,5).
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Practice Gap(s) or Education Gap(s):

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1. Neonatal late-onset sepsis (LOS) remains a significant cause of morbidity

and mortality in the NICU, particularly among extremely preterm and/or
chronically ill infants.

2. Early recognition and diagnosis of LOS is challenging due to often non-

specific presenting features and limited diagnostic efficiency of commonly
used biomarkers.

3. Advances in LOS prevention are needed and may primarily lie in quality-
improvement efforts in infection control.

4. Antimicrobial stewardship practices are vital to reduce antibiotic overuse and

emergence of antimicrobial resistance.
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Learning Objectives:
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After completing this article, readers should be able to

1. Recognize preventable and non-preventable risk factors for LOS in preterm

infants and chronically ill neonates.

2. Identify the need for continuous evaluation and critical judgment of

indwelling central lines, ongoing mechanical ventilation, and prolonged
parenteral nutrition, especially in high-risk infants.

3. Recognize existing limitations in early sepsis recognition and the vital role
of rapid initiation of empiric antibiotic therapy and supportive care whenever
LOS is suspected.

4. Understand the importance of judicious empiric antibiotic prescribing and

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duration of therapy – to avoid adverse effects for individual patients and to

reduce selection pressure promoting multi-drug resistant organisms across
NICUs and communities.
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Figure 1:
Etiology and Clinical Signs and Symptoms of Neonatal Late Onset Sepsis
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Table 1:

Diagnostic Characteristics of the Most-Studied Laboratory Adjuncts in LOS

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Biomarker Mechanism/Physiology Ref. Test Characteristics Notes

Complete Blood Cellular-based defense (31) WBC <5000/mm3: Sensitivity 7%, CBC indices often normal in infants
Count (CBC) meachnisms specificity 96% with culture-confirmed LOS
WBC >20,000/mm3: Sensitivity 23%,
specificity 80%
ANC <1000/mm3: Sensitivity 2%,
specificity 98%
I/T ratio >0.2: Sensitivity 54%,
specificity 62%
Platelet <50,000/mm3: Sensitivity 8%,
specificity 98%

C-reactive Acute phase reactant (34) Sensitivity (median, range): 85% (12 Peaks at 24–36 hours
protein (CRP) – 100%)
Produced in liver after Sensitivity and negative predictive
stimulation by IL-6, IL-1β, Specificity (median, range): 86% (41– value both improve with serial
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TNF-α 100%) measurements No consensus cut-off

value studied - range >1 – 111 mg/L
(32) Pooled sensitivity 62% (95% CI 50 –
72%), reported at median specificity
74%

Procalcitonin Acute phase reactant (34) Sensitivity (median, range): 92% (69 Peaks at 12–24 hours
(PCT) – 100%)
Largely produced in May have better diagnostic utility for
liver, similar cytokine Specificity (median, range); 80% (36 bacterial infections (vs viral infections)
stimulation as CRP. Down- – 92%) compared to CRP.
regulated by interferon-γ.
Response appears to be less affected
by postoperative inflammation,
compared to CRP No consensus cut-
off value studied: range >0.5 – 6.1
ng/mL
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Interleukin 6 Proinflammatory cytokine (35, Sensitivity range 78 – 94%, specificity Short measurement window: peaks at
(IL-6) 40) range 92 – 99% 2–3 hours, returns back to baseline
by 6–8 hours May have improved
diagnostic accuracy in combination
with CRP or PCT

Interleukin 8 Proinflammatory cytokine (37, Studies are widely variable: Similar to IL-6
(IL-8) 39) Sensitivity range 44 – 95%, specificity
range 89 – 100%

CD64 Neutrophil surface marker; (38) Sensitivity (95% CI): 79% (75 – May have better diagnostic accuracy
upregulated in setting of 82%), Specificity (95% CI): 71% (64 in term infants compared to preterm
bacterial infection – 74%) infants
Wide range of cutoff values (CD-64
index 2.19 – 46)

CD11b Leukocyte β2-integrin (36) Sensitivity range 72 – 100%, CD11b↑ not limited to infection-
surface protein, Specificity range 56 – 70% mediated inflammation
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expression↑ in
inflammation

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Table 2:

Adjunctive and Preventive Immunomodulatory Therapies Evaluated in LOS

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Intervention Mechanism Meta- Overall Results Recommendation

analyses/
RCTs

Adjunctive Therapies

Pentoxifylline Non-specific phosphodiesterase (79) Pentoxifylline used as adjunct No recommendation for

inhibitor with immunomodulatory to antibiotics decreased mortality routine use.
and anti-inflammatory properties. without adverse effects - however, Future studies needed.
overall quality low.

Immunoglobulins Low levels of immunoglobulins (74, 78) No effect on in-hospital mortality Routine administration
(IVIG) (Ig) in preterm infants and reduced and death/major disability at not recommended.
Ig levels in severe sepsis. 2y age in preterm infants with
suspected/proven LOS

Granulocyte Quantitative and qualitative (75) No significant difference in Not recommended due to
Transfusion deficits in neonatal granulocyte all-cause mortality. Pulmonary inconclusive evidence of
function have been described. complications. safety and efficacy.
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Granulocyte / Reversion of sepsis-induced (71) No survival advantage at 14 days Insufficient evidence

Granulocyte- neutropenia to promote of G-CSF / GM-CSF treatment. both for prophylactic
Macrophage Colony phagocytosis and granulocyte- One study: prophylactic GM-CSF administration and
Stimulating Factors driven mechanisms of resolution may protect against infection in treatment.
(G-CSF / GM-CSF) of inflammation. infants with neutropenia/high risk
of neutropenia.

Antioxidants Reduced blood levels of (72, 77, Routine selenium Not yet recommended.
(Selenium, Vitamin A, antioxidants in preterm infants and 80, 86) supplementation reduced number
Melatonin) increased risk of oxidative stress. of sepsis episodes.
Melatonin has additional anti- No effect on overall mortality or
inflammatory and anti-apoptotic major neonatal morbidities.
properties. Adjunctive Melatonin improved
condition.
No effect of routine Vitamin A.

Recombinant Role of rhAPC in modulating (76) Increased risk of bleeding and Neonates should NOT be
Activated Human coagulation and inflammation. higher mortality in trials in adults treated with rhAPC.
Protein C (rhAPC) and children.
Withdrawn from the market.

Antibiotics with Anti-inflammatory and (88) Promising results in adult sepsis. Research ongoing.
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Anti-inflammatory immunomodulatory properties of No existing trial in neonatal

Activity macrolide antibiotics by inhibition sepsis.
(Azithromycin) of IL-1 p response. Ongoing study on the effect of
early IV azithromycin as anti-
inflammatory therapy on survival
without BPD.

Preventive Strategies

Human Milk Contains antimicrobial proteins (73, 84) Many benefits of human milk. Human milk feeding,
and peptides and other beneficial Formula feeding might be esp. breast feeding,
components (lyzozymes, secretory associated with NEC|. However, highly recommended for
IgA, lactoferrin, growth existing studies provide many reasons.
factors, antioxidants, microbiota) inconclusive evidence that human
protecting against infection milk fe eding p revents infection
and contibuting to healthy and mortality.
microbiome.

Probiotics & Dysbiosis of skin and gut (83) Beneficial effect of probiotic AAP does not
Prebiotics microbiome has been associated supplementation on LOS risk. recommend routine and
with increased risk of infection. However, optimal composition universal use in preterm
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remains to be determined. infants (conflicting data

No evidence of efficacy of on safety, efficacy and
prebiotics. potential harm)

Lactoferrin Iron-binding protein, present (85, 87) Low quality/no evidence that Not recommended.
in high concentrations in routine routine enteral lactoferrin Future studies needed.
human milk. Wide range reduces the incidence of
of antimicrobial/ immuno- infection. No effect on mortality
or morbidity in preterm infants.

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Intervention Mechanism Meta- Overall Results Recommendation

analyses/
RCTs
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modulatory/anti-inflammatory
properties.

Glutamine Insufficiently synthesized in (82) No effect of preventive No evid ence for

conditions of metabolic sress. supplementation on mortality or supplementation apart
major neonatal morbidities. from clinical trials.

Zinc Vital trace element for growth, (89) Enteral zinc moderately No recommendation for
cell differentiation and immune decreased mortality, while no use.
function (oxidative stress↓ and effect on LOS incidence and Future studies needed.
pro-inflammatory↓) Low zinc common morbidities in preterm
stores in preterm infants. infants.

Future Therapies?

Inflammasome Specific blocking of pro- (70) Evidence from animal models. Research is ongoing.
Inhibitors (e.g., inflammatory IL-1 cytokine Promising results in adult
Anakinra, MCC950) cascades initiated by multiprotein inflammatory diseases.
complexes of the innate immune
system acknowledged as the
“inflammasome”.
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Antimicrobial Antimcrobial peptides and (81) Evidence of potential benefits in Research is ongoing.
Proteins & Peptides proteins released by innate pediatric sepsis.
(α-/β defensins, immune cells and mucosal
cathelicidins, surfaces contribute to mucosal
bactericidal/ immunity.
permeability-i Low levels in early life.
increasing protein
(BPI))
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