Early-Onset_Neonatal_Sepsis.pdf

1
REVIEW PAPER REVIEW PAPER REVIEW PAPER
REVIJALNI RAD REVIJALNI RAD
UDK: 000.00-000.0/.0-000; 000.000/
Ser J Exp Clin Res 2019; 20 (1): 3-13
DOI: 10.2478/sjecr-2019-0041
Corresponding author:
Marija Jovicic
Institute of Neonatology
50 Kralja Milutina Street
11000 Belgrade, Serbia
Tel. +381641480036
e-mail: mexicomara@yahoo.com
Received/Primljen: 24.06.2019. Accepted/Prihvaćen: 31.07.2019.
ABSTRACT
Despite the great progress made in neonatal and perinatal
medicine over the last couple of decades, sepsis remains one of
the main causes of morbidity and mortality. Sepsis in pediatric
population was defined at the Pediatric Sepsis Consensus Confer-
ence in 2005. There is still no consensus on the definition of neo-
natal sepsis. Neonatal sepsis is a sepsis that occurs in the neonatal
period. According to the time of occurrence, neonatal sepsis can
be of early onset, when it occurs within the first 72 hours of birth
and results from vertical transmission, and of late onset, in which
the source of infection is found most often in the environment and
occurs after the third day of life. The most common causes of
early-onset sepsis are Group B Streptococcus (GBS) and E. coli.
Risk factors can be mother-related and newborn-related. Clinical
symptoms and signs of sepsis are quiteunspecific. Thedysfunction
of different organs may imitate sepsis. On the other hand, infec-
tious and non-infectious factors may exist simultaneously. The
start of the antimicrobial therapy in any newborn with suspected
sepsis should not be delayed. Pentoxifylline may have potential
benefits in preterm newborns with sepsis. The only proven inter-
vention that has been shown to reduce the risk of early-onset ne-
onatal sepsis is intrapartum intravenous antibiotic administration
to prevent GBS infection. It is still a great challenge to discon-
tinue antibiotic treatment in non-infected newborns as soon as
possible, because any extended antibiotic use may later be asso-
ciated with other pathological conditions.
Keywords: early onset neonatal sepsis, diagnostics, treatment
SAŽETAK
I pored velikog napretka u neonatologiji i perinatologiji u
toku poslednjih par decenija, sepsa ostaje i dalje jedan od glavnih
uzroka mortaliteta i morbiditeta. Sepsa u pedijatrijskoj populaciji
je definisana prvi put na Konsenzus Konferenciji pedijatara 2005.
godine. Međutim i dalje ne postoji konsenzus za definiciju neona-
talne sepse. Neonatalna sepsa je ona koja se javlja u neonatalnom
periodu. U odnosu na vreme javljanja, može biti rana neonatalna
sepsa, ukoliko se javi u prvih 72h od rođenja i rezultat je vertiklne
transmisije i kasna sepsa, kada je uzročnik najčešće iz okruženja
i javlja se nakon trećeg dana života. Najčešći uzročnici rane neo-
natalne sepse su Group B Streptococcus (GBS) i E. coli. Faktori
rizika za razvoj rane neonatalne sepse mogu biti od strane majke
ili od strane novorođenčeta. Klinički znaci i simptomi su dosta
nespecifični. Disfunkcija različitih organa može imitirati sepsu.
Sa druge strane infektivni i neinfektivni faktori mogu postojati
istovremeno. Započinjanje antimikrobne terapije kod svakog no-
vorođenčeta kod koga postoji sumnja na sespu ne sme da se
odlaže. Pentoksifilin može imati potencijalnu korist kod
prevremeno rođene novorođenčadi sa sepsom. Jedina dokazana
intervencija za koju je pokazano da smanjuje rizik od rane neona-
talne sespe je intrapartalna intravenska primena antibiotika kako
bi se sprečila GBS infekcija. I dalje ostaje veliki izazov prekinuti
sa terapijom kod neinficirane novorođenčadi što pre, jer bilo koja
produžena primena antibiotika je povezana sa drugim patološkim
stanjima.
Ključne reči: rana neonatalna sepsa, dijagnoza, terapija
EARLY-ONSET NEONATAL SEPSIS
Marija Jovicic1
, Marko Folic2,3
and Slobodan Jankovic2,3
1
Institute of Neonatology, Belgrade, Serbia
2
Clinical Pharmacology Department, Clinical Centrе Kragujevac, Kragujevac, Serbia
3
University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
RANA NEONATALNA SEPSA
Marija Jovičić1
, Marko Folić2,3
i Slobodan Janković2,3
1
Institut za neonatologiju, Beograd, Srbija
2
Služba za kliničku farmakologiju, Klinički centar Kragujevac, Kragujevac, Srbija
3
Univerzitet u Kragujevcu, Fakultet medicinskih nauka, Kragujevac, Srbija
Unauthentifiziert | Heruntergeladen 13.11.19 12:35 UTC

INTRODUCTION
Despite the great progress made in neonatal and perinatal
medicine over the last couple of decades, sepsis remains one
of the main causes of morbidity and mortality.
The term “σ´ ηψις” meaning to rot, to decompose, was
familiar and used even in the time before Hippocrates, and
sepsis was clearly defined for the first time at the end of the
20th
century. At the Consensus Conference in 1992, severe
sepsis was defined as sepsis with at least one organ dysfunc-
tion (1). This definition was confirmed at the 2001 Consensus
Conference (2). Sepsis in pediatric population was defined at
the Pediatric Sepsis Consensus Conference in 2005 (3). Sep-
sis can be diagnosed if a patient has a systemic inflammatory
response in the presence or as consequence of an infection. A
Systemic Inflammatory Response Syndrome (SIRS) exists if
at least 2 of the following 4 criteria are present (one of which
must include abnormal temperature or number of leuko-
cytes): rectal temperature higher than 38.5 °C or lower than
36 °C, tachycardia or bradycardia (median heart rate greater
than 2 SD above normal for the respective age in the absence
of external stimulus, medication or pain, or inexplicable per-
sistent heart rate elevation lasting between 0.5 and 4 hours,
or bradycardia in children under a year old below the 10th
percentile for the respective age in the absence of vagus stim-
ulation, beta blocker or congenital heart disease, or persistent
depression of the heart rate for at least 0.5 hour without any
other explanation), median respiratory rate above 2 standard
deviations compared to the normal value for the respective
age or mechanical ventilation (but not due to neuromuscular
weakness or general anesthesia) and the number of leuko-
cytes reduced or elevated compared to the normal values for
the respective age, or more than 10% of immature neutrophil
forms. Severe sepsis implies the existence of sepsis and one
of the following: dysfunction of the cardiovascular system or
acute respiratory distress syndrome or dysfunction of two or
more other organ systems (renal, neurologic, hematologic or
hepatic). Septic shock implies sepsis and the dysfunction of
the cardiovascular system that is defined when, in addition to
administering isotonic intravenous fluid in boluses (more
than 40 ml/kg during one hour), there is a drop in blood pres-
sure below 5 percentile for the respective age or systolic pres-
sure below 2SD for the respective age or need for vasoactive
drugs to maintain arterial pressure in the normal range (ad-
ministration of dopamine> 5ucg/kg/min or dobutamine, epi-
nephrine or norepinephrine at any dose), or two of the fol-
lowing: unexplained metabolic acidosis: base deficit >
5mEq/l, lactate value increase> 2 times above normal values,
oliguria (diuresis less than 0.5 ml/kg/h), prolonged capillary
refill time: > 5 sec, difference in body and peripheral temper-
ature greater than 3°C (3). The main difference between SIRS
in pediatric and adult population is that SIRS in the pediatric
population includes temperature or leukocyte abnormalities,
as tachycardia and tachypnea often occur also in other condi-
tions (3).
When measuring the temperature, it is necessary that the
measured temperature reflects the body temperature,
regardless of whether it is measured rectally, via the bladder
or through the central catheter. Tympanic or axillary temper-
ature measurements are not precise enough (3).
An infection occurring with the sepsis can be bacterial,
viral, fungal or caused by rickettsia (3).
While there is a consensus for the definition of pediatric
sepsis, such a consensus does not exist for neonatal sepsis.
Diagnostic tests are also missing that could predict the sever-
ity of the disease, as well as tests that would determine the
therapy.
Neonatal sepsis is a sepsis that occurs in the neonatal pe-
riod. According to the time of occurrence, neonatal sepsis can
be of early onset, when it occurs within the first 72 hours of
birth and results from vertical transmission, and of late onset,
in which the source of infection is found most often in the
environment and occurs after the third day of life. The differ-
ence between these two forms is also in the type of the mi-
croorganisms that are causing the infection, as well as in the
prognosis of the disease. According to some authors, early-
onset sepsis can also be defined as bacteremia or bacterial
meningitis that occurs within the first 72 hours of life in ne-
onates who are hospitalized in neonatal intensive care units
or within the first 7 days of life in term neonates (4).
Epidemiology
In the United States, the incidence of neonatal sepsis var-
ies from 1-4 infections per 1000 live births (5). In term neo-
nates of the male sex, there is a higher incidence of sepsis
than in term neonates of the female sex. This does not apply
to preterm neonates. The total rate of early-onset sepsis, with
a positive blood culture or fluid culture in the first 72 hours,
is 0.98 infections per 1000 live births, and is inversely pro-
portional to body weight (6).
Etiology
The most common causes of early-onset sepsis are Group
B Streptococcus (GBS) and E. coli (5). Most of the newborns
with GBS sepsis are term neonates, whereas 81% of those
with E. coli are preterm neonates (5). According to the data
from the US, the mortality rate is around 16% and is inversely
proportional to the gestational age (5). The risk of fatal out-
come is not significantly higher for those who had E. coli in-
fection compared to those with GBS infection, when adjusted
for age (5). Other rarer causes of early-onset sepsis include
methicillin-resistant Staphylococcus aureus (MRSA), Coag-
ulase-negative Staphylococcus (CNS), Streptococcus py-
ogenes, Neisseria gonorrhoeae, Enterococcus faecalis, Lis-
teria monocytogenes, atypical Haemophilus influenza and
other Gram-negative enteric bacteria, as well as Candida spp.
Current data show that there is a drop in the incidence of
early GBS disease due to intrapartum antibiotic administra-
tion. Intrapartum antibiotic administration reduced the inci-
dence of the GBS disease by at least 80%, but GBS still

remains one of the major causes of early-onset neonatal sep-
sis (6).
Group B Streptococcus (Streptococcus agalactiae) is a
facultative Gram-positive aerobic diplococcus with virulence
factors that include a polysaccharide capsule, residues of cap-
sular sialic acid, lipoteichoic acid and deacylated glycerol
teichoic acid (7, 8). Based on capsular polysaccharides, 10
types are described (Ia, Ib, II-IX). Type III is the predominant
cause of meningitis in early sepsis.
During pregnancy, GBS colonizes mucosa asymptomati-
cally. In the United States, the colonization rate is estimated
to be around 26% (9). Maternal colonization with GBS re-
sults in the colonization of newborns in 50% of the cases (4),
and newborns are colonized either intrapartum or by bacterial
translocation, even with intact membranes. Intrapartum anti-
biotic administration is believed to be able to prevent the oc-
currence of early-onset sepsis episodes in 85% of cases,
which can affect the increase in the incidence of neonatal sep-
sis caused by ampicillin-resistant E. coli (10).
E. coli is the second most common cause of early-onset
neonatal sepsis and accounts for 24% of all cases of early-
onset neonatal sepsis, and 81% occurs in preterm neonates
(11). If only preterm neonates with very low body weight
(VLBW) are considered, E. coli is the most common cause of
early-onset sepsis (12). The particularly important virulence
factor is the K1 capsular antigen associated with meningitis.
This is a polysialic acid that disturbs phagocytosis (13) and
is immunochemically difficult to distinguish from the capsu-
lar antigen of Neisseria meningitidis serogroup B. There is
higher mortality in newborns infected with this serotype with
a K1 capsular antigen (14) compared to those infected with
other E. coli strains.
Pathogenesis
The transmission from the mother to her infant occurs just
before or during childbirth. Microorganisms that lead to the
infection are those who colonize the maternal genitourinary
tract. The pathogen can penetrate when there is a rupture of
the fetal membranes or before delivery, leading to intra-am-
niotic infection (15). Thus, infections of the newborn can oc-
cur either in utero or intrapartum. Risk factors can be mother-
related and newborn-related. Mother-related risk factors are
the following: eating contaminated food, undergoing inva-
sive procedures during pregnancy such as cerclage and am-
niocentesis, premature rupture of the fetal membranes, fever,
vaginal colonization with GBS and GBS bacteriuria (16, 17).
Data about a previous child with GBS infection is also a risk
factor in subsequent pregnancies (18-20). Chorioamnionitis
that is defined as maternal fever, leukocytosis (Le in the
mother higher than 15000/mm3), maternal tachycardia, pain-
ful sensitivity of the uterus, unpleasant smell of the amniotic
fluid, fetal tachycardia at the time of delivery also represent
risk factors for early-onset neonatal sepsis. Mother-related
risk factors for the development of chorioamnionitis include
prolonged labor and the breaking of the amniotic sac,
multiple digital examinations, positioning of internal fetal
monitoring devices and meconium-stained amniotic fluid
(21). The risk of early-onset neonatal sepsis increases by 1%
if there is a rupture of the fetal membranes that lasts more
than 18h (22, 23). The risk of early-onset neonatal sepsis in
newborns of mothers with chorioamnionitis is estimated to
be 1-4% (23). The colonization of skin and mucosa by path-
ogens that cause chorioamnionitis can lead to an infection
immediately after birth when these barriers lose integrity, es-
pecially in preterm neonates.
Risk factors on the side of the newborn are: prematurity,
low birth weight, congenital anomalies, complicated birth or
instrument-assisted birth, low Apgar score (less than or equal
to 6 in the fifth minute (4)). In preterm newborns with low
birthweight there is 3 to 10 times higher incidence of infec-
tions than in term newborns with normal body weight (5).
Lower neonatal concentration of 25-hydroxyvitamin D is as-
sociated with a higher risk of early-onset sepsis (24).
Until recently, the immunological basis of sepsis was in-
terpreted as a bi-phase process with an initial hyperinflam-
matory phase followed by a subsequent anti-inflammatory
phase, which manifests itself as an immune function suppres-
sion (25). However, the latest studies have shown that pa-
tients can go cyclically through each phase several times dur-
ing a single sepsis episode (25).
The gestational and postnatal age are important factors
that influence the immune response during the critical period
of immune adaptation (26). The innate immunity of new-
borns is most often described as "impaired" or "immature".
To maintain tolerance to maternal antigens and to avoid the
inflammation-triggered premature delivery, the neonatal im-
mune response is mediated by Th2 and Th17 lymphocytes
(27). Such polarization and organization of the immune sys-
tem leads to vulnerability to invasive infections depending on
gestational age (25, 27). The reduced phagocytic activity me-
diated by a complement, the reduced absolute number of neu-
trophils and their reduced function, as well as the disturbed
function of professional antigen-presenting cells play a role
in the immune response in neonatal sepsis (25).
Systemic inflammation and high concentration of proin-
flammatory cytokines are associated with worse long-term
effects. Preterm neonates are particularly susceptible to in-
flammatory damage (28).
Clinical symptoms and signs of sepsis
Clinical symptoms and signs of sepsis are quite unspe-
cific. The exposure time, the amount of inoculum, the im-
mune status and virulence affect the clinical presentation. An
inflammatory response of non-infectious nature can imitate
neonatal sepsis. The initial symptoms may be individual (ap-
nea, tachypnoea or tachycardia). General symptoms include
the following: increased or decreased temperature, tempera-
ture instability, poor feeding, edema. Gastrointestinal signs
that can be seen during sepsis are the following: abdominal
distension, vomiting, diarrhea and hepatomegaly. As to the

respiratory system, apnea, dyspnea, tachypnea, grunting, cy-
anosis and nasal flaring may occur. Clinical signs of sepsis in
other organ systems include the following: oliguria, skin
paleness, tachycardia, hypotension, bradycardia, mottled
skin, irritability, lethargy, tremor, convulsions, hyporeflexia,
hypotonia, abnormal Moro reflex, irregular respiration, tense
fontanelle and changed crying sound. Jaundice, splenomeg-
aly, petechiae, purpura or prolonged bleeding may also oc-
cur.
It should be kept in mind that the dysfunction of different
organs may imitate sepsis. On the other hand, infectious and
non-infectious factors may exist simultaneously.
DIAGNOSTICS
Blood Culture
The traditional laboratory confirmation of neonatal sepsis
involves the isolation of the causative agent from the other-
wise sterile environment (blood, liquor, urine, pleural fluid,
peritoneal fluid, and synovial fluid). For all newborns with
suspected sepsis, a blood sample is required in an adequate
amount. Studies have shown that 1ml of blood is the mini-
mum quantity necessary for adequate sampling (23). Sche-
lonka et al. showed that 0.5ml, previously considered as an
adequate volume for sampling, is unreliable for bacteremia
with a small number of bacteria (4 CFU/ml or less) (29).
Blood culture taken from the arterial catheter immediately af-
ter its placing, as well as taking blood from the umbilical vein
immediately after birth using a double-clamped and ade-
quately prepared umbilical cord are acceptable alternatives
for blood taken from the peripheral vein (30, 31).
Urine culture, gastric aspirate, cultures from the skin
surface and tracheal aspirate
Urine culture should not be taken routinely as part of the
bacteriological analysis of early-onset sepsis (32), because
the bacteria in the urine are most commonly formed as a re-
sult of release from the kidneys during sepsis. The fetus con-
sumes 500 to 1000 ml of amniotic fluid every day. If there
are leukocytes in the amniotic fluid, they will be present in
the gastric aspirate at birth. These cells represent mother's re-
sponse to the inflammation and have a weak correlation with
neonatal sepsis, and Gram staining of gastric aspirate is not
recommended as a routine (33,34). Cultures obtained by tak-
ing a sample from the skin of the armpits, groins and the outer
ear have a poor positive predictive value. They are of little
importance in the evaluation of newborns at risk of develop-
ing early-onset neonatal sepsis (35,36). Tracheal aspirate cul-
tures may be of significance if they are taken immediately
after endotracheal intubation (37).
Lumbar Puncture
The decision on lumbar puncture in newborns with sus-
pected sepsis remains controversial. The risk of meningitis in
newborns that are at high risk, and which look good at birth
is small (38). On the other hand, in newborns with bactere-
mia, the incidence of meningitis can go up to 23% (39, 40).
It should be kept in mind that the blood culture can be nega-
tive for up to 38% of newborns with meningitis (41, 42).
Therefore, lumbar puncture should be performed in all new-
borns with a positive blood culture, as well as in those in
which the laboratory or clinical course speaks firmly for the
sepsis. Conditions when the lumbar puncture must be post-
poned involve a severely ill newborn, a tense fontanelle (until
high intracranial pressure is excluded), significant thrombo-
cytopenia, or the presence of a skin infection in the lumbosa-
cral part.
Findings in the cerebrospinal fluid that speak in favor of
meningitis are controversial. In some studies, the average
number of white cells was 10/mm3 (43-49). The number of
cells above 2 SD of the mean value was 20 cells/mm3 (45).
In Smith at al. the average number of white blood cells in
neonates born under 34 GN who had meningitis was reported
to be 110/mm3
(50). Newborns with Gram-negative menin-
gitis typically had a greater number of white blood cells than
those with Gram-positive meningitis (51).
The protein concentration in uninfected term neonates is
less than 100 mg/dl (43-49). Preterm neonates have a protein
concentration in the cerebrospinal fluid that is higher (150-
290 mg/dl) and varies inversely proportional to gestational
age (decreases with increasing gestational age). For normo-
glycemic newborns, the concentration of glucose in the cere-
brospinal fluid is like that of infants and children (70-80% of
the glucose concentration taken simultaneously from the
blood sample). Low glucose value in the cerebrospinal fluid
is a variable with the highest specificity for meningitis (50).
In numerous studies, different values of blood count were
analyzed - the absolute number of neutrophils, the absolute
number of bands, the ratio of immature and the total number
of neutrophils. Neutropenia is a better marker of sepsis and
has a better specificity than an increased number of neutro-
phils, as certain conditions in the mother (hypertension, as-
phyxiation, hemolytic diseases) reduce the neutrophil count
in newborns (52). The definition of neutropenia varies de-
pending on gestational age, mode of delivery (those delivered
via caesarean section have lower values than those naturally
born), the sample from which it is analyzed (they are lower
if arterial blood is analyzed) and altitude (those infants that
have been born at a higher altitude have a higher number of
neutrophils) (52-54). In late preterm and term neonates, the
definition of neutropenia implies the most common values
suggested by Manroe et al. (<1800/mm3
at birth and
<7800/mm3
at 12-14h) (52). In the study of Schmutz et al.
(53), lower limits of normal neutrophil values at birth were
3500/mm3
in newborns born with > 36 GN, 1000/mm3
in
those of 28-36 GN and 500/mm3 in those below 28 GN. The
top value appears 6-8h after birth. The lower limits are then
7500/mm3, 3500/mm3 and 1500/mm3
. It is important to note
that this study was done at an altitude of 4800 feet above sea

level, while the Manroe study was done at 500 feet above sea
level.
The absolute number of immature neutrophils follows a
similar pattern as the absolute number of neutrophils and the
peak is at about twelve hours of life. The number of immature
neutrophils is growing from a maximum of 1100 cells/mm3
at birth to 1500/mm3
after twelve hours (52). The I/T (imma-
ture and total forms) ratio has the best sensitivity and this ra-
tio is <0.22 in 96% of healthy preterm neonates born before
32 GN (55). Unlike the absolute number of neutrophils and
the absolute number of bands, the maximum normal I/T ratio
appears at birth (0.16) and decreases with an increase in post-
natal age to a minimum of 0.12 (52). In healthy term neo-
nates, the 90th
percentile for the I/T ratio is 0.27 (56).
The time for determining white blood cells is crucial (57).
Those values that are obtained 6-12h after birth will indicate
infection rather than those obtained immediately after birth,
because the number and ratio of mature and immature forms
requires an established inflammatory response. Optimal sam-
pling would then be 6-12h after birth (57).
Thrombocytes
Regardless of the lower levels of thrombocytes that can
occur in neonatal sepsis, they are non-specific, non-sensitive
and late indicators of sepsis (58).
Acute Phase Reactants
Many acute phase reactants were tested in newborns with
sepsis. Yet, only CRP and procalcitonin were tested in
enough studies (59, 60). CRP increases 6-8 h in the infective
episode and reaches its peak after 24 h. The determination of
the CRP value upon birth has low sensitivity. The sensitivity
increases dramatically if determined 6-12h after birth (23).
Benitz et al. showed that without taking CRP upon birth into
account, two determined values of CRP (first determined in
the period of 8-24 h after birth and the second 24h after the
first one) have a negative predictive value of 99.7% (61). The
10mg/l value was mostly used as a cutoff. The CRP increase
is a better predictor than the individual value.
Procalcitonin is a calcitonin pro-peptide produced mostly
by monocytes and hepatocytes. Procalcitonin values increase
2h after the beginning and reach their peak after 12h, while
normalizing after 2-3 days in healthy adults (62). The physi-
ological increase in procalcitonin exists in the first 24h after
birth. The increase also occurs in non-infective conditions
(e.g. RDS). Procalcitonin has a slightly better sensitivity than
CRP for the early detection of sepsis but is less specific (60).
Normal values for newborns older than 72h are <0,1ng/ml
(62).
Other biomarkers
Interleukin 6 (IL6), interleukin 8 (IL8), interferon
gamma (IFNγ), tumor necrosis factor α (TNFα), soluble in-
tercellular adhesion molecule (sICAM) and CD64 were also
tested as biomarkers for neonatal sepsis in different studies,
but none of them is used routinely (4).
THERAPY
Empirical therapy
The start of the therapy in any newborn with suspected
sepsis should not be delayed. Antimicrobial therapy should
be guided by the resistance pattern of bacterial isolates that
exist in a given intensive care unit. Initial antibiotic therapy
in early-onset sepsis should consist of the following: ampi-
cillin and aminoglycoside, with cephalosporins of the 3rd
or
4th
generation if there is a suspicion of meningitis caused by
Gram-negative bacteria (5). The therapy of sepsis caused by
Gram-negative bacteria that produce β-lactamases of a wide
spectrum should be with carbapenems (meropenem) (5).
Targeted therapy
Penicillin or ampicillin are effective against GBS. Ampi-
cillin is effective against Listeria monocytogenes. Entero-
cocci can be treated with a penicillin-containing antibiotic.
Infections with ampicillin-resistant enterococci should be
treated with vancomycin without the addition of aminogly-
coside (5).
For CNS, vancomycin is the selected therapy for a con-
firmed infection. Linezolid and daptomycin are alternative
therapies that are reserved for those cases when there is no
response to the therapy (5).
For Gram-negative enteric bacteria, the treatment of
choice is with ampicillin (if there is sensitivity) or gentami-
cin. But if there is a suspicion of meningitis or if meningitis
is confirmed, the treatment of choice is with the third or
fourth generation of cephalosporins or carbapenems (5). In-
vasive infections with enterobacteria that produce a wide
spectrum of β-lactamase (ESBL) are best treated with car-
bapenems. The treatment of infections caused by car-
bapenemase-producing enterobacteriaceae requires consult-
ing an infectious disease specialist (5).
Clindamycin, ampicillin-sulbactam or metronidazole are
used to treat anaerobic infections (5). Metronidazole is suita-
ble for anaerobic infections that affect CNS.
There is little evidence about the duration of the antibiotic
therapy. It is considered that 7 days of therapy is enough for
blood infections, 14 days for Gram-positive meningitis and
21 days for Gram-negative meningitis (5).
It should be borne in mind that newborns that are exposed
to antibiotics for a longer time period have a higher rate of
NEC and late-onset sepsis compared to those newborns who
are not exposed to antibiotics (63).

ADDITIONAL THERAPY
Immunoglobulins
Preterm newborns (before 32 GN) have a low level of
passively transmitted antibodies, and the synthesis of endog-
enous immunoglobulins does not start before 24 GN (64, 65).
The Cochrane Review from 2015 showed that the administra-
tion of immunoglobulins in diagnosed or probable neonatal
sepsis did not lead to a decrease in hospital mortality or to the
reduction of mortality and more significant damage in the 2nd
year of life in preterm newborns (66).
Glutamine
Endogenous glutamine is an essential amino acid that is
not sufficiently synthesized in metabolic stress conditions.
Glutamine supplementation improves the outcomes for criti-
cally ill adults (67). There is glutamine in mother’s milk, but
there is less of it in formulae. Despite its significant role in
metabolic stress, the significance of preventive administra-
tion of glutamine has not been confirmed (68).
Antioxidants: Selenium, Melatonin
Preterm neonates are at an increased risk of oxidative
stress and are potentially more exposed to reactive oxygen
compounds (69, 70). The Cochrane review from 2003
showed a significant reduction in sepsis episodes with the
prophylactic administration of selenium, but not a more sig-
nificant survival rate (71).
Melatonin has antioxidant, anti-inflammatory and apop-
totic properties that could improve the outcome in neonatal
sepsis (72). Studies have shown that there is a decrease in the
value of inflammatory markers and an improvement of the
clinical picture, but the benefit of using melatonin is still to
be confirmed (73).
Granulocyte and granulocyte-macrophage colony-stimu-
lating factor
Myeloid growth factors that include GM-CSF and G-CSF
stimulate the innate immune response and enhance myelo-
poiesis (74). The Cochrane Review from 2003 has not shown
a more significant survival rate on the 14th
day after starting
the therapy (75). There are currently no recommendations for
the prophylactic use of G-CFU or GM-CFU in newborns.
Preterm newborns with moderate (<1700 / ul) or severe
(<500 / ul) neutropenia and systemic infections might benefit
from the G-CFU or GM-CFU therapy (76). The optimal time
to administer and monitor G-CFU and GM-CFU levels
would be crucial for optimizing this therapy (25).
Granulocyte Transfusion
No difference has been established in the mortality of
those receiving granulocytes compared to the placebo group.
Due to insufficient evidence on safety and effectiveness, it is
not recommended for now (25).
Pentoxifylline
Pentoxifylline is a non-specific phosphodiesterase inhib-
itor with immunomodulatory capacity. It can have a potential
benefit in preterm newborns with sepsis and NEC. It sup-
presses to a greater extent the production of pro-inflamma-
tory, rather than anti-inflammatory cytokines (77, 78).
The meta-analysis of six randomized clinical trials has
shown that when used as an adjuvant therapy with antibiotics
in neonatal sepsis, it can reduce mortality (79). There were
no reported side effects.
FUTURE CONCEPT
Immunization of mothers
For now, there are recommendations for three types of
vaccines in pregnancy. These are the following: tetanus, in-
fluenza and pertussis vaccinations (80). Future studies are fo-
cused on designing vaccines against GBS, CMV and RSV.
Future concepts of additional therapy could include the
following: antimicrobial proteins and peptides (APPs), which
are primarily released by neutrophils, monocytes and macro-
phages, stimuli of innate immunity, stem cells, including
mesenchymal stromal cells (MSCs), which can potentially
modulate the immune response (25). Inflammasome inhibi-
tors are also being tested as a new group of compounds that
represent a promising therapy for various inflammatory con-
ditions, including inflammation due to the presence of micro-
organisms (25).
Antibiotics with Anti-Inflammatory Capacities
Some antimicrobial agents such as β-lactam antibiotics
may exacerbate inflammation by inducing lysis (81). Con-
trary to proinflammatory antibiotics, some antibiotics show
anti-inflammatory activity. Macrolides, rifampicin and tetra-
cycline exhibit anti-inflammatory and immunomodulatory
properties (82-84). Rifampicin and tetracycline are contrain-
dicated for use in newborns. The prophylactic use of azithro-
mycin significantly reduces BPD (85). In models conducted
on mice with sepsis, mortality was lower when a combination
of ampicillin with azithromycin was used instead of ampicil-
lin alone (86).
Prevention
The only proven intervention that has been shown to re-
duce the risk of early-onset neonatal sepsis is intrapartum in-
travenous antibiotic administration to prevent GBS infection
(87). Adequate prophylaxis is the use of penicillin, ampicillin
or cefazolin given ≥4 hours before birth (87). Erythromycin
is no longer recommended due to high resistance rates. In
those who have no severe form of allergy to penicillin,
cefazolin is the medicine of choice. In those with severe al-
lergic reactions to penicillin (anaphylaxis, angioedema,
choking), clindamycin is the medicine of choice, but only if

there is evidence of sensitivity. Otherwise, vancomycin is the
medicine of choice (87).
Intrapartum antibiotic administration is indicated in the
following situations (87):
1. Positive antenatal GBS cultures, except in women who
had a caesarian, without a membrane rupture
2. Unknown maternal status in gestation of less than 37,
rupture of fetal membranes longer than 18h or tempera-
ture higher than 38°C
3. GBS bacteriuria during the current pregnancy
4. Previous child with invasive GBS disease.
The highest risk for sepsis exists in mothers with chori-
oamnionitis and who are colonized with GBS and did not re-
ceive antibiotic therapy.
CONCLUSION
Early-onset neonatal sepsis, which occurs in the first 72h
of life, is still a significant cause of morbidity and mortality.
There is still no consensus on the definition of neonatal sep-
sis. Microorganisms that lead to infection are those that col-
onize the maternal genitourinary tract. Despite the prophy-
lactic use of antibiotics and the significant fall in the inci-
dence of the GBS disease, the most common cause of early-
onset sepsis is still Group B Streptococcus (GBS). The char-
acteristic organization of the immune system of newborns
triggers the sensitivity of this population to invasive infec-
tions, especially in preterm newborns. Clinical symptoms
and signs are quite unspecific. It should be borne in mind that
the inflammatory response of non-infectious nature may im-
itate neonatal sepsis.
The start of the therapy should not be delayed in any new-
born suspected of sepsis. Antimicrobial therapy should be
guided by the pattern of resistance to bacterial isolates that
exist in the given environment. Pentoxifylline may have po-
tential benefits in preterm newborns with sepsis. It should be
borne in mind that for the time being the only proven inter-
vention that has been shown to reduce the risk of early-onset
neonatal sepsis is intrapartum intravenous antibiotic admin-
istration. In the future, much is expected from other therapeu-
tic and preventive measures, such as the vaccination of moth-
ers. The difficult decision every clinician and neonatologist
must make is to identify those newborns who are at risk and
who are suspected of sepsis and immediately start the ther-
apy. This is especially difficult for preterm newborns because
other clinical conditions occurring in this population might
give a clinical picture of sepsis. On the other hand, it is still a
great challenge to discontinue antibiotic treatment in non-in-
fected newborns as soon as possible, because any extended
antibiotic use may later be associated with other pathological
conditions. If the adequate volume of blood is taken for blood
culture and if it is sterile and the inflammatory indicators in
serum measurement remain calm, the newborn is most likely
to have no sepsis and the antibiotic therapy should be discon-
tinued (it should be terminated after 48h in clinical situations
where the probability of sepsis incidence is small).
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