Journal of Infection (2014) 68, S24eS32

www.elsevierhealth.com/journals/jinf

Neonatal sepsis: Progress towards improved

outcomes
Andi L. Shane a,b,c,*, Barbara J. Stoll b,c,d

a
Division of Infectious Disease, Emory University School of Medicine, 2015 Uppergate Drive NE,
Atlanta, GA 30322, USA
b
Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive NE, Atlanta, GA
30322, USA
c
Childrens Healthcare of Atlanta, 2015 Uppergate Drive NE, Atlanta, GA 30322, USA

Accepted 20 September 2013

Available online 18 October 2013

KEYWORDS Summary Neonates are predisposed to infections during the perinatal period due to multiple
Neonatal sepsis; exposures and a relatively compromised immune system. The burden of disease attributed to
Burden; neonatal infections varies by geographic region and maternal and neonatal risk factors. World-
Management; wide, it is estimated that more than 1.4 million neonatal deaths annually are the consequence
Prevention of invasive infections. Risk factors for early-onset neonatal sepsis (EOS) include prematurity,
immunologic immaturity, maternal Group B streptococcal colonization, prolonged rupture of
membranes, and maternal intra-amniotic infection. Intrapartum antimicrobial prophylaxis
administered to GBS-colonized women has reduced the burden of disease associated with early
onset GBS invasive infections. Active surveillance has identified Gram-negative pathogens as
an emerging etiology of early-onset invasive infections. Late-onset neonatal sepsis (LOS)
attributable to Gram-positive organisms, including coagulase negative Staphylococci and
Staphylococcus aureus, is associated with increased morbidity and mortality among premature
infants. Invasive candidiasis is an emerging cause of late-onset sepsis, especially among infants
who receive broad spectrum antimicrobial agents. Prophylactic fluconazole administration to
very low birthweight (VLBW) neonates during the first 6 weeks of life reduces invasive candi-
diasis in neonatal intensive care units with high rates of fungal infection. Prevention of health-
care associated infections through antimicrobial stewardship, limited steroid use, early
enteral feeding, limited use of invasive devices and standardization of catheter care practices,
and meticulous hand hygiene are important and cost-effective strategies for reducing the
burden of late-onset neonatal sepsis.
2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Division of Infectious Disease, Emory University School of Medicine, 2015 Uppergate Drive NE, Atlanta, GA 30322,
USA. Tel.: 1 404 727 5642; fax: 1 404 727 9223.
E-mail addresses: ashane@emory.edu (A.L. Shane), barbara_stoll@oz.ped.emory.edu (B.J. Stoll).
d
Tel.: 1 404 727 2456; fax: 1 404 727 5737.

0163-4453/$36 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jinf.2013.09.011
Neonatal sepsis
Introduction
The perinatal period is hazardous with multiple opportu-
nities for exposures to virulent organisms. Potential sites of
exposure include the uterus, the birth canal, the neonatal
care unit, invasive procedures and devices, healthcare
providers, family and visitors, and the community. In
addition to these multiple sites of exposure and diverse
modes of infection transmission, neonates are relatively
immunocompromised. The impaired innate immune func-
tion of premature infants predisposes them to invasive
infections. Because the fetal immune response begins at
about 24 weeks of age and development occurs until term,
premature neonates do not benefit from complete immune
system development, making them more susceptible to
infection with organisms that term infants may be able to
suppress.1 Prolonged hospitalization, invasive procedures
and devices, lack of enteral feeding, and the utilization
of broad spectrum antibiotics, due to increased risk of in-
fections with multi-resistant pathogens, increase risk to
already vulnerable neonates.
The recognition of neonatal sepsis is complicated by
the frequent presence of non-infectious conditions that
resemble those of sepsis, especially in very low birthweight
(VLBW) preterm infants, and by the absence of optimal
diagnostic tests. While the laboratory identification of an
organism from a sterile site is optimal for definitive
diagnosis, it is not always possible to isolate a causative
pathogen. Invasive infections can also occur in seemingly
asymptomatic neonates. Therefore assessment of history
and risk factors in combination with diagnostic tests are
used to identify neonates who are more likely to be
infected.
Burden of disease and characterization
Worldwide, invasive neonatal infections are estimated to
cause approximately 36% of the estimated 4 million
neonatal deaths annually. Rates of infection vary by
geographic region, resource endowment, maternal and
infant risk factors. Early and late-onset neonatal sepsis is
differentiated by timing of symptom onset, virulence of the
infecting organism(s) and associated pathogenesis. Early-
onset sepsis (EOS) is defined by infection in the first week of
life. Many investigators, including those who participate in
the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD) Neonatal Network
and the Vermont Oxford Network, define EOS by the onset
of signs or symptoms and an associated positive culture at
or before 72 h of life. Late-onset sepsis (LOS) is character-
ized by the onset of symptoms consistent with sepsis at
greater than 72 h of life. These classifications of EOS and
LOS reflect the differing etiologies and proposed patho-
physiology of pathogens commonly associated with the
timing of onset of these conditions.
Early onset sepsis (EOS)
EOS remains a serious complication of the post-partum
period. Risk factors for EOS include prematurity and
S25
associated immunologic immaturity,2 maternal Group B
streptococcal (GBS) colonization, rupture of membranes
greater than 18 h, and maternal intra-amniotic infection.3,4
In the 1970s, Group B streptococci (GBS) emerged as the
leading cause of neonatal meningitis and bacteremia in
the United States. The association between maternal GBS
colonization and neonatal infection resulted in the devel-
opment of guidelines to administer intrapartum antimicro-
bials to GBS-colonized women in the United States to
reduce invasive GBS in the newborn. Widespread imple-
mentation of these guidelines has resulted in substantial
reduction in early-onset GBS disease. However, burden of
disease continue and GBS remains the most frequently iso-
lated EOS pathogen in the United States, particularly
among term infants.
Epidemiologic surveillance has noted the emergence of
Escherichia coli (E. coli) as an important pathogen associ-
ated with EOS, especially among VLBW infants. Increased
rates of severe disease and death with Gram-negative EOS
have been reported in some studies. To monitor changes
over time, it remains important to continue active surveil-
lance for rates of EOS and pathogens associated with
infection.
Burden of EOS
The burden of EOS in the United States, assessed by the
Centers for Disease Control and Prevention (CDC) through
their Active Bacterial Core Surveillance (ABCs) in 4 states
from 2005 to 2008 yielded an overall rate of EOS of 0.77 per
1000 live births and a case fatality rate of 10.9%. In the ABC
surveillance, GBS was responsible for 0.29 infections per
1000 live births with a case fatality rate of 7% and E. coli
was responsible for 0.19 infections per 1000 live births
with a case fatality rate of 25%.5 In comparison, the Na-
tional Institutes for Child Health and Development (NICHD)
Neonatal Research Network (NRN) assessed all live births
from 16 university neonatal care units from 2006 to 2009.
This evaluation resulted in an overall rate of EOS of 0.98
per 1000 live births with a case fatality rate of 16%; a
rate of GBS infections of 0.41 per 1000 live births and
case fatality rate of 9% and 0.28 E. coli infections per
1000 live births with a case fatality rate of 33%.6 In both
the CDC ABCs and NICHD NRN studies, rates of infection
and case fatality increased with decreasing gestational
age and birthweight. In both studies, the estimated burden
of EOS in the United States was approximately 3300 cases
and 400 deaths annually.
Group B streptococci (GBS)
The central challenge with the management of EOS GBS is
identifying the 2% of infants born to GBS colonized women
who will develop invasive disease (EOS, pneumonia, and/or
meningitis). One-half of infants born to GBS colonized
women will themselves be colonized.7,8 Of these, 98% will
be asymptomatic while 2% will have evidence of invasive
disease. Studies in the United States have elucidated a
number of risk factors for early onset (EO) GBS disease
including maternal GBS carriage, GBS bacteriuria, prematu-
rity, low birth weight, prolonged rupture of membranes
S26
(ROM) 18 h, intrapartum fever, young maternal age, Black
race, a previous infant with invasive GBS disease, and low
levels of anti-capsular antibody. A case-control study in
the United Kingdom (UK) found that maternal GBS carriage,
GBS bacteriuria, prolonged ROM, and intrapartum fever
were significantly associated with GBS EOS. Young maternal
age, Black race, and a previous infant with invasive disease
were not found to be risk factors for EO GBS; prematurity
and low levels of anti-capsular antibody were not evaluated
in the UK studies.9
Recommendations for intrapartum antibiotic prophylaxis
(IAP) in women who are colonized with GBS or have other
risk factors for EO GBS have been instrumental in reducing
the rates of EO GBS disease in the United States.10 Despite
the benefit of IAP, rates of uptake are limited by inade-
quate screening practices and missed opportunities to
administer IAP.6 The revised guidelines from the CDC pub-
lished in 2010 specify situations when IAP is indicated.
The most challenging situations are when GBS status at
the onset of labor is unknown. The guidelines advise that
if a woman delivers an infant at 37 weeks, has ROM
18 h, has an intrapartum temperature 38  C, or an intra-
partum nucleic acid amplification test detects GBS, then
IAP should be administered.10
Of note, not all countries have adopted policies for
universal GBS screening of pregnant women and provision
of intrapartum antibiotic prophylaxis to colonized women.
Multinational studies have demonstrated variability in
maternal recto-vaginal GBS colonization from 7 to 22%.
Several countries including the United States, Canada,
Australia, Spain, and Belgium experienced rates of EO
GBS of 1 in 1000 live births before the institution of IAP,
while other countries including England, Sweden, and
Finland reported lower baseline rates. Surveillance for EO
GBS in the United Kingdom (UK) revealed an incidence of
0.5 cases of EO GBS per 1000 live births and a case fatality
rate of 10.6%. In 2001, the burden of disease was estimated
at 376 cases with 39 deaths and in 2004 as 326 cases with 41
deaths.11,12 A recent meta-analysis of studies from all
World Health Organization (WHO) regions including 56
studies with incidence data, 29 with case fatality rates
(CFR), and 19 with serotyping, demonstrated a mean inci-
dence of EO GBS of 0.43 per 1000 live births and a CFR of
12.1%. The most common serotypes were 111 (49%), 1a
(23%), V (9%), 1b (7%), 11 (6%). Studies that reported any
use of IAP had a comparatively decreased incidence of EO
GBS of 0.23 per 1000 live births versus 0.75 per 1000 live
births when IAP was not reported.13
The US CDC recommends universal screening for recto-
vaginal colonization in pregnancy at 35e37 weeks gesta-
tion. Selective IAP is recommended for all colonized women
or for those with unknown colonization status at onset of
labor and risk factors including delivery <37 weeks, ROM
>18 h, intrapartum temperature 38  C or an intrapartum
rapid screen positive for GBS.10 In contrast, in the UK, ante-
natal GBS screening in pregnancy is not recommended by
the National Screening Committee, with the most recent
review in 2008e9 supporting this stance. In 2003, the Royal
College of Obstetricians and Gynaecologists recommended
a risk-based approach for identifying women who may
benefit from IAP for EO GBS prevention. Based on existing
evidence and expert consensus, a recent external review
A.L. Shane, B.J. Stoll
completed in July 2012 by the UK National Screening Com-
mittee recommended the continuation of risk-based ante-
natal GBS screening. The panel was unable to weigh the
benefits and harms of antenatal GBS screening, based on
an incidence of 0.5 per 1000 live births in the UK and a mor-
tality rate of 0.05 per 1000 live births. The panel estimated
that they would have to provide IAP to 210 women per 1000
pregnancies if universal screening were instituted. A
concern for antimicrobial resistance as a consequence of
universal screening provided additional evidence to the
panel to support risk-based screening and IAP.14 A July
2012 update to the 2003 guideline for the prevention of
EO GBS from the Royal College of Obstetricians and Gynae-
cologists continued to support the 2003 recommendations
for risk-based screening. The 2012 guidelines recommended
IAP for women with a history of an infant with invasive GBS
infection, GBS bacteriuria in the current pregnancy, a
vaginal swab positive for GBS in the current pregnancy, py-
rexia in labor and chorioamnionitis. For pyrexia and cho-
rioamnionitis, the panel recommended broad-spectrum
therapy that included coverage for GBS. IAP for GBS was
not felt to be necessary if the woman was delivering via a
caesarean section with intact membranes.15
Although randomized controlled trials have not been
conducted to compare the efficacy of a risk based versus a
screening based strategy to reduce vertical transmission of
GBS, international observational studies suggest that both
strategies reduce rates of invasive disease in the newborn.
Theoretically, universal screening would provide greater
protection by capturing women with unrecognized risk
factors and therefore may be more effective in preventing
EO GBS.
With increasing use of IAP, concerns have been raised
about an increase in non-GBS EOS and increasing antimi-
crobial resistance. Most population-based studies report
stable rates of EOS caused by non-GBS pathogens.16 Howev-
er, several studies have suggested that ampicillin-resistant
E. coli may be emerging, especially among VLBW
infants.17,18
The future of the prevention of perinatal GBS likely lies
in rapid testing to detect GBS colonization and to target at
risk women. A safe and effective vaccine would provide
protection against both EO and LO GBS and may be a more
suitable intervention in resource-poor settings where
screening and IAP may not be feasible. Maintenance of
surveillance systems to monitor rates of infection and
associated pathogens will be instrumental in optimizing
the allocation of resources.
Late onset sepsis (LOS)
Surveillance of neonates from 2006 to 2008 by the UK
NeonIN Surveillance Network demonstrated that Gram-
positive organisms comprised 70% of infections, Gram-
negative organisms 25% and fungi 5%. Of the Gram-
positive pathogens, CoNS was responsible for 42%, Staphy-
lococcus aureus for 10%, Enterococci for 9%, GBS for 5%,
with others contributing the remaining 4%. Of the Gram-
negative pathogens, E. coli contributed 8%, Klebsiella
spp. 5%, Enterobacter spp. 5% Pseudomonas spp. 3% and
other organisms responsible for 4%. Candida spp. were
Neonatal sepsis
responsible for all of the fungal infections.12 The majority
of bacterial isolates from blood cultures of neonates aged
2e28 days in England and Wales during the same time
period were Gram-positive (81%); CoNS (45%), Staphylo-
coccus aureus (13%), GBS (7%), non-pyogenic streptococci
(7%), and other (9%). Of the 19% of Gram-negative isolates,
Enterobacteriacae (9%) were most common followed by, E.
coli (7%), Pseudomonas spp. (2%), and other (1%).19 Surveil-
lance for this study included pathogens isolated from
neonates from 2 days of age, which may include presenta-
tions of EOS as well as LOS. In both of these studies, Gram-
positive organisms were isolated from septic neonates more
commonly than Gram-negative organisms. The later study
from England and Wales did not report the prevalence of
fungal isolates.
For over a decade, the NICHD Neonatal Research
Network, http://neonatal.rti.org has studied the epidemi-
ology of neonatal infections among thousands of VLBW ne-
onates. Gram-positive organisms are most commonly
associated with LOS among VLBW infants, although mortal-
ity is two to three times greater among infants with invasive
candidiasis and Gram-negative infections than in those with
Gram-positive infections.17,20,21 In the NRN cohort, 70% in-
fections were associated with Gram-positive organisms;
coagulase-negative staphylococci (CoNS) contributed 48%,
Gram-negative 18% and fungal 12%. In some evaluations,
more than one organism was isolated.17 The predominance
of Gram-positive organisms among VLBW infants was also
seen in a large study of community based NICUs over a 14
year period. Among 12,204 cases of LOS, Gram-positive or-
ganisms were most frequent.21 Several studies have noted
an increased risk of mortality among infants with LOS
compared to those who are uninfected.17,21,22
Coagulase negative staphyloccci (CoNS)
In a large retrospective cohort study conducted in 248
NICUs in the US from 1997 to 2009, 17,624 episodes of CoNS
sepsis were identified among 16,629 VLBW infants; most
episodes were classified as possible infections. Infants with
lower birth weights and gestational age (GA) were more
likely to have a CoNS isolated during an episode of sepsis. A
CoNS infection was characterized as isolation of the organ-
ism from 2 or more blood cultures, one blood culture and
one other sterile site, or one blood culture with a significant
infection. The number of central lines, clinical presentation
of lethargy, and gastric acid residuals, but not central line
duration was risk factors for a CoNS infection.23 As CoNS are
frequently isolated from neonates with clinical sepsis, it is
important to understand risk factors for their recovery and
strategies to decrease their prevalence.
Staphylococcus aureus
A retrospective evaluation of NICHD NRN sites from 2007 to
2009 identified 8444 VLBW neonates who survived greater
than 3 days. Among these infants, 316 (3.7%) had Staphylo-
coccus aureus (SA) bacteremia or meningitis; 88 infants had
methicillin-resistant Staphylococcus aureus (MRSA) infec-
tions, 228 infants had methicillin-susceptible Staphylo-
coccus aureus (MSSA) infections, and there were no
S27
coinfections. Almost all of the infants who had MRSA infec-
tions had manifestations after 7 days of age. Nine of twenty
participating centers had no cases of MRSA. Morbidities did
not differ between neonates with MRSA and MSSA infec-
tions. Although SA infections comprised only 1% of all cause
bacteremia and meningitis; mortality rates of neonates
with both MRSA and MSSA infections were high (26% and
24%, respectively) and comparable.24
Candidiasis
Although less frequent than Gram-positive or Gram-
negative infections, invasive infections with fungal organ-
isms, primarily Candida spp. result in substantial morbidity
and mortality, with a 13% mortality rate among a cohort
study of 128 US NICUs and 130,523 neonates.25e27 Overall,
between 1.5% and 2.5% of all BSI in VLBW neonates are esti-
mated to be due to fungal etiologies, the most common of
which are Candida albicans and C. parapsilosis.27,28 The
risk for fungal sepsis is increased by colonization acquired
vertically from maternal sources as well as horizontally
from the NICU environment. A positive correlation exists
between multiple sites of colonization and risk for invasive
candidiasis.25 Risk factors supporting the use of empiric
antifungal therapy in a neonate exhibiting signs and symp-
toms of sepsis include GA, exposure to third generation
cephalosporin antibiotics in the 7 days prior to symptom
onset, and thrombocytopenia.29 Invasive candidiasis
occurred in 137 of 1515 (9%) of neonates less than 1000 g
birthweight in a prospective observational cohort study
conducted in 19 NICHD NRN sites. Incidence of invasive
infection varied from 2 to 28% among the sites that enrolled
more than 50 neonates.30 Overall mortality in a cohort of
730 infants with invasive candidiasis from 192 US NICUs
enrolled between 1997 and 2003 was 19%.31 Among infants
weighing between 401 and 1000 g at birth born between
1993 and 2001, who had an invasive fungal infection, 31
(30%) had a head circumference less than the 10th percen-
tile at 18e22 months of corrected gestational age; a statis-
tically significant (p < 0.05) difference compared to
uninfected neonates and comparable to neonates with a
history of Gram-negative invasive infections.32
Prevention of candidiasis
Due to the burden and severity of disease associated with
neonatal candidiasis, prevention of colonization and inva-
sive infections would be beneficial. Oral nystatin and oral
and intravenous fluconazole have been evaluated in
several studies as prophylactic agents. Five international
evaluations have demonstrated reduced rates of coloniza-
tion, cessation of an outbreak33 and reduction in disease
incidence.34,35
Prophylactic administration of fluconazole during the
first six weeks of life reduces fungal colonization and
invasive fungal infection in extremely low birthweight
infantsdthose with birthweights <1000 g.36 In addition to
the individual benefit afforded by prophylaxis for VLBW ne-
onates, fluconazole prophylaxis may have a community
benefit by decreasing the overall fungal burden of a
NICU.28 A single center was able to decrease invasive candi-
diasis mortality, with fluconazole prophylaxis administered
S28
to high risk neonates.37 Results from over 14 trials at multi-
ple institutions with 3100 neonates suggests that flucona-
zole prophylaxis decreases colonization of the urine,
gastrointestinal tract, and integument, without promoting
the development of resistance and without adverse
effects.28,36e42 A meta-analysis published in 2009 of 5 trials
enrolling 656 neonates <1500 g demonstrated that 11 in-
fants needed to be treated to prevent 1 episode of invasive
candidiasis.43 Targeted therapy of 3 milligrams per kilogram
of intravenous fluconazole initiated before 48 h of life to
neonates <1000 g BW and continued for the duration of
intravenous access is a regimen that has been adopted by
some NICUs with high baseline rates of candidiasis.40 Of
note, enterally administered fluconazole does not appear
to provide protection against CVC associated candidiasis.28
Both the Infectious Diseases Society of America (IDSA) and
the American Academy of Pediatrics (AAP) support the
administration of prophylactic fluconazole to selected pre-
term infants.44,45 Based on an annual US preterm birth
cohort of w30,000 VLBW, it has been estimated that flucon-
azole prophylaxis could prevent w2000 to 3000 cases of
invasive candidiasis, w200 to 300 deaths, and the adverse
neurodevelopmental outcomes of invasive candidiasis in
w400 to 500 infants per year.28 Differing baseline rates of
fungal infections, practices related to CVC removal,
severity of illness, and practices related to the use of
broad-spectra antimicrobials make universal recommenda-
tions regarding prophylaxis challenging.
Additional strategies that have been proposed to
reduce the risk of invasive candidiasis include maternal
decolonization, through targeted therapy of women with
symptomatic vaginal candidiasis or empiric therapy for all
antepartum women.46 Neonatal practices that may reduce
the risks of invasive candidiasis include, limited use of
broad spectrum antimicrobials, use of an aminoglycoside
instead of a cephalosporin for empiric therapy when menin-
gitis or antimicrobial resistance is not suspected, limitation
of postnatal steroid use in VLBW infants, early enteral
feeding, and the establishment of the neonatal gut micro-
biome with human milk feeding.26,47
HAIs result in a notable burden of disease. In the United
States, four networks have recently been active in
describing LOS and HAI among VLBW and premature
neonates. The National Health Safety Network described
a range of central line associated blood stream infections
(BSIs) of 2.9 per 1000 catheter days among infants 750 g to
0.7 per 1000 catheter days for infants 2500 g birth-
weight.48 A national point prevalence survey conducted
by the Pediatric Prevention Network in 2001 demonstrated
that 11.4% of NICU patients had a HAI on the date of the sur-
vey.49 A study from the NICHD NRN conducted between
2006 and 2008 described a rate of LOS among infants
form 400 to 1500 g at birth of 24% and among infants of
22e28 weeks gestational age during the period from 2003
to 2007 of 36%.50 Risk factors for HAI included prematurity,
low birth weight, suboptimal hand hygiene, invasive proce-
dures, alteration of skin or mucous membrane barriers,
indwelling devices, parenteral nutrition with lipid emul-
sions, and exposures to broad spectrum antibiotics, ste-
roids, and histamine antagonists. Prolonged lengths of
stay and increased unit census were also identified as risk
factors for neonatal HAIs. Gram-negative bacilli comprised
A.L. Shane, B.J. Stoll
20% of LOS among VLBW neonates with a CFR of 36% and
fungi comprised 12% with a CFR of 32%; Gram-positive or-
ganisms accounted for 61% of the remaining isolates in
2002.20 A similar distribution of pathogens occurred in the
United Kingdom from 2006 to 2008 with Gram-negative or-
ganisms comprising 25% and fungi comprising 5% of isolates;
Gram-positive organisms comprised 64% of total isolates.12
Seventy-two percent of organisms isolated at between 2
and 28 days of age from neonates in England and Wales
from 2006 through 2008, were identified as Gram-positive
while 19% were classified as Gram-negative. No fungi
were reported from this series which likely included a
mixture of EOS and LOS organisms.
Other preventive strategies for neonatal sepsis
Because of the morbidity and mortality associated with
neonatal sepsis a number of adjunctive therapies have
been evaluated for treatment. Three small randomized
controlled trials (RCTs) comparing granulocyte transfusions
and placebo in 44 infants with neonatal sepsis did not
reduce mortality.51 Recombinant granulocyte colony stimu-
lating factor (G-CSF) and recombinant granulocyte-
macrophage stimulating factor (GM-CSF) have both been
shown to enhance the neutrophil function of leukocytes
removed from premature infants and evaluated in the lab-
oratory setting.52 A prospective, randomized case-control
study conducted over a 13 month period between 2009
and 2010 demonstrated that G-CSF administered to 60 neo-
nates with clinical sepsis resulted in decreased antibiotic
utilization and lengths of stay compared with 30 infants
who did not receive G-CSF.53 These studies suggest the po-
tential for enhancing immune response by supplementing
conventional therapies with G-CSF or GM-CSF. However,
there was no effect on mortality.54,55
An interest in the potential benefits of intravenous
immunoglobulin (IVIG) in the management of neonatal
sepsis stems from the potential of supplemental immuno-
globulin G to activate the immune response by augmenting
antibody dependent cytotoxicity, and improving neutrophil
function. The International Neonatal Immunology Study
Group (INIS Collaborative Group) demonstrated that ther-
apy with two infusions of polyvalent immunoglobulin G had
no effect on short and long term morbidity or mortality of
3493 septic infants receiving care at 113 hospitals in 9
countries.56 A Cochrane review of ten randomized or quasi-
randomized controlled trials of IVIG for treatment of sus-
pected bacterial or fungal infection in newborn infants
less than 28 days of age concluded that there is still insuf-
ficient evidence to support the administration of IVIG to
prevent mortality in infants with clinical or culture proven
sepsis.57 Mortality or major morbidity at 2 years of age was
compared in 3493 infants from 113 hospitals in 9 countries
who received directed or empiric antimicrobial therapy
and polyvalent immunoglobulin G immune globulin or a pla-
cebo. There were no significant differences in death, major
or minor disability at age 2 years, incidence of subsequent
sepsis episodes, and adverse events. These results did not
support a benefit of immune globulin therapy for neonates
with confirmed or suspected sepsis.56
Two RCTs using pentoxiphylline, an agent that improves
microcirculation and decreases tumor necrosis factor
Neonatal sepsis
(TNF)-alpha levels associated with sepsis, involving 140
neonates suggested potential improved survival among the
infants who had culture confirmed sepsis and who received
pentoxifylline.58 Additional large scale trials will be needed
to reproduce this potential benefit.
Antimicrobial utilization practices
Antimicrobial utilization practices in NICUs influence the
types of microorganisms responsible for neonatal sepsis and
their resistance patterns. The US Centers for Disease
Control and Prevention (CDC) has initiated a campaign to
prevent antimicrobial resistance in healthcare settings
http://www.cdc.gov/getsmart/healthcare/. This effort is
designed to increase clinician awareness and to improve
diagnosis and appropriate treatment of infection. The
campaign supports involving infectious disease and phar-
macy consultants, treating infections with an antimicrobial
with the narrowest spectra and discontinuing therapy when
adequate therapy has been administered. Prevention of in-
fections through optimizing infection control and enhanced
surveillance are additional components of the campaign.
Prevention of healthcare associated infections
(HAI)
Strategies to prevent hospital acquired late-onset infection
include improved hand hygiene, early human milk feeding,
meticulous skin care, limited use of invasive devices and
infrequent manipulation of devices when they are essential,
and uniform practices related to catheter insertion and care.
Environmental design that optimizes access to hygiene and
personal protective equipment as well as increased staffing
reduces opportunities for HAI. Ongoing surveillance is essen-
tial to monitor rates of infection and emerging pathogens to
optimally allocate resources. At our institution, we have
developed a campaign, One is Not Zero to draw attention to
infection control strategies. This campaign reinforces the
concept that even one hospital acquired infection is consid-
ered unacceptable; our aim is to have zero hospital acquired
infections. The success of the One is Not Zero philosophy
requires the support of providers, staff, and administrators.
Hand hygiene before and after contact with patients and
equipment is essential and compliance should be routinely
assessed. Standardization of processes related to central
venous and arterial catheter insertion and maintenance,
termed bundles, include the use of dedicated teams with
expertise related to the selection of optimal insertion sites,
the meticulous application of antisepsis, and the utilization
of maximal barrier precautions for insertion and manipula-
tion. Minimizing the numbers of ports, management of the
catheter insertion site, timely removal when access is no
longer needed and monitoring and reviewing local BSI data
regularly facilitates reductions in rates of HAIs.59,60 A legal
mandate passed in 2007 in New York state required surveil-
lance and reporting of central line associated BSIs in all inten-
sive care units. Participating hospitals joined the CDC
National Healthcare Safety Network to standardize surveil-
lance and reporting. In collaboration with the Quality
Improvement Network formed by representation from all of
S29
the 18 state-designated regional perinatal centers, these net-
works evaluated best practices and agreed to bundling of care
elements for insertion and maintenance of central catheters
and to utilize checklists to monitor adherence to the
bundle activities.60 A comparison of the pre- and post-
intervention period did not reveal that central catheter use
declined, however overall statewide catheter-associated
BSIs decreased 67% from 6.4 catheter-associated infections
per 1000 line days to 2.2 catheter-associated infections per
1000 line days (p < 0.005). With a change in definition of a
catheter associated BSI to a requirement for 2 or more iso-
lates of potential skin contaminants (for example coagulase
negative Staphylococci (CoNS), statewide rates decreased
40% from 3.5 catheter-associated infections per 1000 line
days to 2.1 catheter-associated infections per 1000 line
days (p < 0.005). Overall, there was no change in pathogen
distribution; CoNS remained the most commonly isolated
organism.
New strategies to prevent hospital associated
infections
Due to the burden of disease ensuing from hospital
associated infections, additional strategies including lacto-
ferrin and probiotic supplementation as well as anti-
staphylococcal monoclonal antibodies have been explored
as strategies to prevent nosocomial infections. While anti-
staphylococcal monoclonal antibodies have not proven to
be of benefit, preliminary data suggest that bovine lacto-
ferrin (BLF) supplementation alone and in combination with
probiotics may reduce LOS. A prospective, multicenter,
double-blind, randomized placebo-controlled trial in 11
tertiary care NICUs compared bovine lactoferrin alone or
in combination with the probiotic Lactobacillus rhamnosus
GG (LGG). Over a 9 month period during 2007e2008, 472
VLBW neonates received placebo, LGG and BLF, or BLF
only, daily from birth through 30 days of life or 45 days.
Compared with placebo, BLF supplementation with and
without LGG reduced the incidence of the first LOS episode
in VLBW neonates. Further studies of lactoferrin, with and
without probiotics, to reduce risk of neonatal sepsis are
indicated.61,62
Longer term risks of neonatal sepsis
Although rates and mortality as a consequence of neonatal
sepsis are declining in some settings, several studies sug-
gest that survivors or neonatal sepsis are at increased risk
for adverse neurodevelopmental sequelae. Brain imaging
reveals white matter injury (WMI) in survivors that may be
associated with neurodevelopmental delay. In a retrospec-
tive review of 133 neonates with GA <34 weeks, multiple
postnatal infections were noted to be associated with
progressive WMI. Thirteen percent of infants who had any
episode of sepsis had evidence of WMI compared with 4.7%
who did not have a documented episode of postnatal sepsis,
(odds ratio (OR) 3.2; 95% confidence interval (CI) 0.8e11.8).
Of infants who had multiple episodes of sepsis, 36.4% had
evidence of WMI by imaging compared with 5% of infants
with manifestations who had 1 or fewer episodes (OR 10.9;
95% CI 2.5e47.6).63 Infants with sepsis episodes not
S30
associated with necrotizing enterocolitis were significantly
more likely to have mild WMI (78%) than uninfected infants
(57%), p < 0.01.64 Among a cohort of 6093 VLBW infants,
those with a history of infection were significantly more
likely to develop cerebral palsy, to have lower scores on
Bayley scales of neurodevelopment, to have visual impair-
ment, and to experience poor growth.32 Of 320 VLBW in-
fants who developed invasive candidiasis, 73% had died or
had manifestations of neurodevelopmental impairment
when assessed at 18e22 months of age.26 Neurodevelop-
mental impairment, including cerebral palsy, was signifi-
cantly more likely in one quarter of 541 extremely
premature infants who had a neonatal infection than in
the neonates who did not experience an infection.65 Neuro-
developmental impairment was noted to be present during
long term follow up at school age entry among former VLBW
infants who experienced LOS.66 These studies underscore
the importance of neurodevelopmental follow-up of survi-
vors of neonatal sepsis, especially those who are preterm
and are of low birthweight.
Conclusions
Rates of early-onset sepsis, particularly due to GBS, have
declined, but the burden of disease remains significant due
to missed opportunities for prevention. In some settings,
rates of late-onset catheter associated bloodstream in-
fections have declined. However, late-onset hospital ac-
quired infections among premature and low birthweight
infants continue to be associated with substantial morbidity
and mortality, including long term neurodevelopmental
consequences. Strategies to prevent late-onset infections
require vigilance and attention to practices including hand
hygiene, early human milk supplementation, the use of
central line bundles, the limitation of indwelling devices,
and antibiotic stewardship. Additional prevention strate-
gies with potential benefit include immune modulators and
immunizations. Our greatest advances in improving out-
comes have been achieved through research; each patient
can be studied to contribute to evidence-based medicine
and improved care.
Conflict of interest
All authors, no pertinent conflicts of interest. A. Shane is
the recipient of a research grant from the Gerber Founda-
tion with funds provided to her institution.
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