THE MEDICAL BULLETIN OF

SISLI ETFAL HOSPITAL

DOI: 10.14744/SEMB.2020.00236
Med Bull Sisli Etfal Hosp 2020;54(2):142–158

Review

Neonatal Sepsis
Ilkay Ozmeral Odabasi, Ali Bulbul
Department of Neonatology, Sariyer Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey

Abstract
Neonatal sepsis is associated with severe morbidity and mortality in the neonatal period. Clinical manifestations range from sub-
clinical infection to severe local or systemic infection. Neonatal sepsis is divided into three groups as early-onset neonatal sepsis,
late-onset neonatal sepsis and very late-onset neonatal sepsis according to the time of the onset. It was observed that the inci-
dence of early-onset neonatal sepsis decreased with intrapartum antibiotic treatment. However, the incidence of late-onset neo-
natal sepsis has increased with the increase in the survival rate of preterm and very low weight babies. The source of the causative
pathogen may be acquisition from the intrauterine origin but may also acquisition from maternal flora, hospital or community.
Prematurity, low birth weight, chorioamnionitis, premature prolonged rupture of membranes, resuscitation, low APGAR score,
inability to breastfeed, prolonged hospital stay and invasive procedures are among the risk factors. This article reviews current
information on the definition, classification, epidemiology, risk factors, pathogenesis, clinical symptoms, diagnostic methods and
treatment of neonatal sepsis.
Keywords: Early-onset; late onset; neonatal; sepsis; diagnosis; treatment.
Please cite this article as ”Ozmeral Odabasi İ, Bulbul A. Neonatal Sepsis. Med Bull Sisli Etfal Hosp 2020;54(2):142–158”.

N eonatal sepsis defines the systemic condition that

arises from the bacterial, viral or fungal origin, associ-
ated with hemodynamic changes and clinical findings and
diagnosed after the first seven days.[1, 2] Very late-onset
neonatal sepsis, on the other hand, describes sepsis cases
diagnosed in infants who are hospitalized in the neonatal
causing severe morbidity and mortality. Its incidence varies intensive care unit from the first 30 days of life until dis-
depending on the definition of the case and the popula- charge. Epidemiological studies related to neonatal sepsis
tion studied and is between 1 and 5 in 1000 live births. The since the early 1980s have shown a decrease in early-onset
clinical manifestations range from subclinical infection to neonatal sepsis cases, especially with Group B Streptococ-
severe focal or systemic disease. While the infectious agent cus (GBS), with the improvement of obstetric care and the
may arise from intrauterine or maternal flora, it may also
use of intrapartum antibiotic prophylaxis; while they show
be of the hospital or community origin. It is classified as
an increase in late-onset neonatal sepsis associated with
early-onset, late-onset and very late-onset neonatal sepsis
increased survival rates and long hospitalization times of
according to the time of onset of the findings. While early-
premature babies.[3, 4]
onset neonatal sepsis describes cases where clinical mani-
festations occur in the first three days of life (<72 hours),
Terminology
some researchers consider this limit as the first seven days
of life. In connection with this, late-onset neonatal sepsis Suspected sepsis: Regardless of whether there is a clinical
describes cases diagnosed on 4th-30th days of life or cases symptom or not, the presence of sepsis risk factors in the

Address for correspondence: Ilkay Ozmeral Odabasi, MD. Sariyer Hamidiye Etfal Egitim ve Arastirma Hastanesi, Neonatoloji Klinigi, Istanbul, Turkey
Phone: +90 506 336 30 26 E-mail: [email protected]
Submitted Date: December 05, 2019 Accepted Date: March 20, 2020 Available Online Date: June 12, 2020
©
Copyright 2020 by The Medical Bulletin of Sisli Etfal Hospital - Available online at www.sislietfaltip.org
OPEN ACCESS This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 143

baby or findings suggesting sepsis in follow-up.[5] score, resuscitation of the baby and the multiple pregnan-
Clinical sepsis: Clinical and laboratory findings are pres- cies increase the risk of early-onset sepsis, whereas invasive
ent, but the failure to show the causative microorganism.[5] procedures, such as frequent blood sampling, intubation,
mechanical ventilation, catheter/probe insertion, insuf-
Proven sepsis: Clinical and laboratory findings are pres-
ficient breastfeeding, long-term parenteral nutrition, low
ent, and demonstration of the pathogenic microorganism
stomach acid and surgical interventions especially increase
in cultures taken from the sterile field.[5]
the risk of late-onset sepsis.[5] Early neonatal sepsis risk fac-
Epidemiology Research shows that an average of 2.6 mil- tors in developing countries also include inadequate an-
lion newborns dies every year and three-quarters of these tenatal care, high rate of home birth, unsanitary birth and
deaths occur in the first week of life.[6, 7] In a study conduct- umbilical cord care practices, and late recognition of condi-
ed between 2000-2013, data of one hundred and ninety- tions that pose a risk of infection in the mother or baby.[14]
four countries were evaluated in which the causes of death
were investigated in the neonatal period, and the mortality Maternal Risk Factors
rate due to sepsis was found to be 15%. In this study, it was
Chorioamnionitis, premature rupture of membranes (>18
determined that 2.8 million babies died in the neonatal
hours), intrapartum maternal fever (>38 ºC), delivery earlier
period and 430.000 of these babies died due to sepsis and
than 37 weeks of gestation, maternal group B streptococcal
severe infections.[8] Neonatal sepsis ranks third among the
(GBS) colonization and other conditions that increase the
causes of neonatal death following prematurity and intra-
risk of GBS infection in the newborn (the mother's positive
partum-related complications.[9] In the late neonatal period vaginal-rectal GBS screening cultures in the late stages of
(7-27 days), the most common cause of death was sepsis, pregnancy, having a history of GBS-infected baby in a previ-
with a rate of 37.2%.[8] Neonatal death and sepsis frequency ous pregnancy, detection of GBS positive bacteriuria during
differ between populations. In their reports that Lawn et al. pregnancy, positive intrapartum nucleic acid amplification
presented epidemiological data, 99% of newborn deaths tests for GBS) increases the risk of early neonatal sepsis.[15, 16]
occurred in low- and middle-income countries and 1% in In the presence of early membrane rupture and chorioam-
high-income countries.[7] nionitis, the incidence of early-onset sepsis is 1-3%, i.e., the
The incidence of early-onset neonatal sepsis ranges from risk of early neonatal sepsis is increased 10-fold.[17] While
1 to 5 per 1000 live births. This incidence has been shown early-onset sepsis rate caused by Group B streptococci was
to decrease with intrapartum antibiotic therapy.[10, 11] How- 2 in 1000 live births and mortality was 50% in the 1960s,
ever, the incidence of late-onset neonatal sepsis increased today, antibiotic prophylaxis and early treatment reduced
with the increase in the survival rate of preterm and very morbidity and mortality rates.[18] However, GBS screening
low birth weight infants.[3] The incidence of late-onset neo- and intrapartum antibiotic prophylaxis do not eliminate
natal sepsis is reported to vary between 0.61% and 14.2% but decrease the risk of GBS infection. The effectiveness of
in hospitalized newborn babies.[2] When classified by birth prophylaxis was determined between 86-89%.[19] In a study
weight, the rate of early-onset neonatal sepsis in 1000 live where approximately 400.000 babies were evaluated in the
births was reported to be 0.57 in babies over 2500 grams, United States and the rate of early-onset sepsis was found
and 10.96 in babies with a birth weight of between 401- to be 0.98 per 1000 live births, mothers of 57% of babies
1500 grams.[12] The incidence of late-onset neonatal sepsis diagnosed with early neonatal sepsis were reported to
was reported as 51.2% in infants between 501-750 grams have GBS prophylaxis.[12] CDC (Centers for Disease Control
of birth weight, 15-25% in infants below 1500 grams and and Prevention) recommends GBS screening during 35,-
1.6% in infants above 2500 grams.[2] 37, gestational weeks and intrapartum prophylaxis in cases
with the indication in preventing early neonatal sepsis.[19]
Risk Factors The incidence of GBS carriers in a study that evaluated
500 women in Turkey in 2016 was discovered as 13.6%.[20]
Risk Factors Associated with the Newborn
In another study where a total of 150 pregnant women
The most important risk factor causing sepsis development were screened, the prevalence of GBS carriers in pregnant
in the neonatal period is premature birth and low birth women and frequency of colonization in newborns were
weight. Premature babies with low birth weight have a risk evaluated, approximately 32% of the pregnant women and
of developing sepsis three to ten times higher than full- 17.3% of the newborns were found to be colonized with
term babies with normal birth weight.[13] In addition, low GBS.[21] In another study conducted in our country, 500
levels of transplacental maternal IgG levels in preterm ba- pregnant women and newborn babies of these pregnant
bies are among the risk factors.[13] Fetal distress, low APGAR women were evaluated, and maternal and infant coloniza-
144 The Medical Bulletin of Sisli Etfal Hospital

tion rates were found as 9.2% and 1.6%, respectively, and coccus aureus (S. aureus), Klebsiella and CONS are less com-
vertical transition rate was determined as 15.2%.[22] mon. However, they are among the causative organisms for
early-onset neonatal sepsis factors.[23, 27] In emerging coun-
Pathophysiology and Causative tries, however, gram-negative bacteria (Klebsiella, Entero-
Microorganisms bacter, Acinetobacter, E. coli) are in the foreground.[28] Urea-
Causative microorganisms of early-onset neonatal sepsis plasma parvum and Ureaplasma urealyticum are the most
are generally vertically transmitted from the mother. Micro- common factors isolated from the placenta and amniotic
organisms in the mother's birth canal, cervix, vagina, and fluid in patients with histologically detected chorioamnio-
rectum are known to cause chorioamnionitis by crossing nitis; however, colonization of Ureaplasma strains in the re-
intact or ruptured membranes before or during labor.[23] spiratory system has been associated with bronchopulmo-
nary dysplasia in preterm infants.[12] In our country, when
Nevertheless, severe clinical findings and bacteremia find-
the different studies are examined, the most common fac-
ings starting from birth, especially in babies without rup-
tors are found as K. pneumoniae, S. aureus and CONS.[29–31]
ture in membranes and born by cesarean section, suggest
placental transmission.[24] Chorioamnionitis, which is one of Late-onset neonatal sepsis often shows horizontal trans-
the most important risk factors in early-onset neonatal sep- mission from individuals responsible for the care of the
sis, is defined as an acute inflammation of fetal membranes baby, from environmental or nosocomial sources. In the
and amniotic fluid. It often develops due to the microinva- case of vertical transmission, early colonization of the baby
sion of amniotic fluid as a result of prolonged rupture of occurs as an infection in the late period. Metabolic factors,
membranes. Fever, leukocytosis, foul-smelling or intense including hypoxia, acidosis, hypothermia, and hereditary
discharge, abdominal tenderness in the mother and fe- metabolic disorders (e.g., galactosemia), are likely to con-
tal tachycardia are among the clinical findings of chorio- tribute to the risk and severity of neonatal sepsis. These fac-
amnionitis. However, chorioamnionitis may also present tors are thought to disrupt the host's immune response.[32]
with a pathological laboratory finding without clinical When late-onset neonatal sepsis is analyzed, CONS takes
findings.[13] Pathogens that cause sepsis vary according to the first place as causative organisms in 53.7% -77.9% of
geographical differences and countries. The most com- cases in developed countries and 35.5% -47.4% of cases
mon pathogens in early-onset neonatal sepsis are GBS and in developing countries.[2, 4, 25, 33–35] In the United States, S.
Escherichia coli (E. coli) when coagulase-negative staphy- aureus, Candida spp., E. coli, Klebsiella spp., Enterobacter spp.
lococci (CONS) are excluded. Although some centers con- are listed as the most frequent factors, following CONS.
sider CONS growth as pathogens for disease, some centers The most frequently detected organisms in Australia are
consider this growth as contamination. In studies, cases CONS, S. aureus, Klebsiella spp., Pseudomonas spp., Candida
with the CONS positivity in a single culture were excluded spp., E. coli and Enterobacter spp., respectively. In the study
from the study,[12] while cases considered clinically signifi- by Aksoy et al. from Turkey, K. pneumoniae and S. aureus
cant in different studies were accepted as pathogens and were found to be the most common factors in late-onset
included in the study.[25] Stoll et al. defined the cases with neonatal sepsis.[30] In the study of Türkmen et al., S. epider-
CONS growth in blood culture in three groups. Patients midis was the most common agent and Candida was the
with CONS growth in two consecutive blood cultures taken second.[29] In a study by Özkan et al.[31] in preterm infants,
within two days, or with CONS growth in single blood cul- CONS was found to be the most common factor in late-on-
ture and C-reactive protein (CRP) elevation within two days set neonatal sepsis. In the study of Özdemir et al., S. aureus
after blood cultures were defined as a definitive infection. was the most common cause of late sepsis, followed by K.
Patients with CONS growth at blood culture while receiving pneumoniae and S. epidermidis, respectively.[36] CONS was
treatment with vancomycin, oxycycline or a semisynthetic the most frequent factor in the study of Bülbül et al.,[37] in
antistaphylococcal agent for at least five days were defined which they evaluated the nosocomial infections in the neo-
as suspected infection; cases with blood culture positivity natal intensive care unit, whereas MSSA and K. pneumonia
without accompanying CRP elevation or use of antibiotics were found in the second place.
were defined as contamination.[26] In data from the UK, GBS S. aureus infections are reported to be more frequent, espe-
was detected in 58% of early-onset sepsis cases and E.coli cially in patients with catheters. In a study conducted in the
in 18%.[25] These rates were found to be in the United States UK, where 117 sepsis episodes with S. aureus growth were
as 43% and 29%, respectively.[12] Listeria monocytogenes (L. evaluated, the central catheter was determined in 50% of
monocytogenes), Group A, C and G streptococci, Streptococ- the cases.[38] Especially in babies with long-term hospital-
cus pneumoniae (S. pneumoniae), Streptococcus viridans (S. ization due to prematurity, increased frequency of systemic
viridans), Haemophilus influenzae (H. influenzae), Staphylo- infections caused by Candida spp. is seen. Although there
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 145

is a difference between the institutions, Candida spp. is re- the sample are important. Minimum amount of blood re-
ported to be the third most frequent agent of late-onset quired for blood culture should be 0.5-1 ml. It is recom-
neonatal sepsis in babies weighing <1500 gr.[13] mended to take two different samples, preferably from
Herpes Simplex Virus (HSV), which is often presented with two different regions.[41] 90% of growth takes place within
late-onset neonatal sepsis is one of the most common fac- the first 48 hours.[42] While the growth of the microorgan-
tors when viral factors of neonatal sepsis are considered. Its ism in blood culture is diagnostic in the neonatal period,
frequency in the United States has been reported to be 1 in the failure to produce it does not exclude the diagnosis.
3200 births.[39] Despite the progress in diagnosis and treat- [23, 27]
No growth in culture may be related to insufficient
ment, it remains important concerning morbidity and mor- sample, mother's antibiotic use, antibiotic dose applied
tality. It has been reported that 85% of babies diagnosed before sampling, low amount of bacteria in the blood or
with disseminated HSV disease before antiviral treatment short term bacteremia.[5]
and 50% of those with central nervous system involvement After the area that the blood culture will be taken is
died before one year of age. Another viral factor in late-on- cleaned and prepared with an antibacterial solution,
set neonatal sepsis is enteroviruses. Enterovirus infections samples are taken from the arterial or venous route. Data
can present with nonspecific lethargy, poor nutrition, fever, on sterilization of intravenous catheter sites indicate that
restlessness, hypoperfusion, jaundice, meningoencephali- cleaning for 30 seconds or two consecutive cleansings is
tis, myocarditis and hepatitis.[40] The frequency of enterovi- superior to a single, short (5-10 seconds) disinfection.[43]
rus in the newborn period is not known exactly. Simultaneous blood culture using catheter and periphery
from patients with a central venous catheter is important
Diagnostic Methods
in distinguishing catheter-related bloodstream infec-
Clinical Findings in Neonatal Sepsis tions.[13] Results obtained with manual laboratory meth-
ods showed that 96% of cultures taken before antibiotic
Signs and symptoms are generally non-specific in neona- administration was positive at the end of 48th hour and
tal sepsis. Therefore, the differential diagnosis is important. 98% at 72nd hour.[44] However, laboratory automation has
While more than one organ or system findings may occur significantly reduced the time required to detect posi-
in early-onset neonatal sepsis, signs of infection in late and tive cultures.[45] In automated laboratory methods, 94% of
very late-onset neonatal sepsis may be multisystemic or fo-
cultures taken before antibiotic treatment were positive
cal (such as meningitis, pneumonia, omphalitis, osteomy-
within 24 hours (except for coagulase-negative Staphylo-
elitis, septic arthritis).[23] Neonatal sepsis can present with
coccus, Corynebacteria or yeast), and 97% were positive
groaning, contraction of the accessory muscles of respira-
within 36 hours.[46]
tion, nasal wing breathing, apnea, cyanosis, tachypnea in
the respiratory system; bradycardia/tachycardia, peripheral Cerebrospinal Fluid (CSF) Culture
circulatory disturbance, hypotension, prolonged capillary
refill time in the cardiovascular system; nutritional intol- The use of CSF culture in newborns with suspected sepsis
erance, difficulty sucking, vomiting, diarrhea, abdominal is controversial. Culture-proven bacterial meningitis occurs
distention, hepato-splenomegaly, jaundice in the diges- in about 0.25 per 1000 live births.[47, 48] Meningitis accom-
tive system; sclerema, cutis marmaratus, pustule, abscess, panies 20-25% of newborns with sepsis and 13% of early-
petechiae, purpura in the skin; and lethargy, hypotonicity, onset neonatal sepsis.[49–51] Although there is no consensus
sleepiness, weak or high-pitched crying, bulging fonta- on performing lumbar puncture in infants diagnosed with
nelle, irritability, convulsion, hypoactivity, body tempera- early neonatal sepsis, it should definitely be performed in
ture regulation problems and difficulty sucking in the cen- infants with blood culture positivity and clinically consid-
tral nervous system.[5, 13, 23, 27] ered meningitis.[23, 27, 47] Blood cultures cannot detect caus-
ative microorganisms in 15% to 50% of babies with bacteri-
Laboratory Methods al meningitis.[52, 53] Taking CSF culture before or just after the
administration of antibiotics may increase the likelihood of
Blood Culture bacteriological diagnosis.[47, 54, 55] However, antibiotherapy
The gold standard for the diagnosis of neonatal sepsis is should not be delayed to perform a lumbar puncture. On
the growth of pathogenic microorganisms in body fluids the other hand, although it is rare in asymptomatic term
(blood, urine, cerebrospinal fluid, pleural fluid, peritoneal babies, meningitis is still seen as a complication of neonatal
fluid, joint fluid) that are expected to be sterile. Therefore, sepsis, and there are sources suggesting lumbar puncture
the amount of the sample and the method of obtaining in the assessment of all sick newborns.[56]
146 The Medical Bulletin of Sisli Etfal Hospital

Urine Culture The sensitivity of the complete blood count samples taken
immediately after birth was found to be low in the evalua-
In infants diagnosed with early-onset neonatal sepsis, urine
tion of sepsis. Due to its weak positive and negative predic-
culture does not need to be evaluated as part of early-on-
tive value, the benefit of the use of complete blood count as
set neonatal sepsis since the amount of urine is limited and
a biomarker in neonatal sepsis has not been proven. How-
the rate of positivity in the urine culture is low, especially
ever, studies show that serial normal complete blood count
in the first 72 hours of life. Urinary tract infection assess-
measurements can be reliable in excluding sepsis.[61, 66, 67]
ment should be performed with the bladder catheter or
suprapubic bladder aspiration since there is a high risk of Another parameter used in sepsis assessment among com-
contamination in samples taken with urine bags.[27] Urine plete blood count is neutrophil count. The presence of neu-
culture in infants diagnosed with late-onset neonatal sep- tropenia is more valuable than neutrophilia, especially in
sis should be part of the evaluation of sepsis.[57] the first postnatal 48 hours in the diagnosis of sepsis.[60] It
should be noted that as the gestational age decreases, the
Tracheal Aspirate Culture lower limit of absolute neutrophil count decreases.[68, 69] In
addition, hypertension, maternal fever, asphyxia, meconi-
Tracheal aspirate culture may help diagnosis in babies who
um aspiration syndrome, mode of delivery, periventricular
are diagnosed with sepsis and need mechanical ventilation
hemorrhage, reticulocytosis, hemolytic disease and pneu-
due to respiratory failure; however, the risk of colonization
and contamination should be considered when evaluat- mothorax are known to affect the neutrophil count.[62]
ing the result.[27] It can be taken as a sample in patients In the evaluation of peripheral smear, vacuolization, Döhle
with ventilator-associated pneumonia or in cases whose bodies and toxic granulation are guiding in the diagnosis
amount and characteristics of secretion varies, but it should of bacterial sepsis.[27, 64, 70] The I/T ratio drops from 0.16 at
be known that its diagnostic value is low.[32] It is not recom- birth to 0.12 at 60 hours. I/T ratio of ≥0.2 is considered sig-
mended to take tracheal aspirate cultures in prolonged in- nificant in the diagnosis of sepsis.[68] However, I/T ratio may
tubation due to rapid colonization following intubation.[58] cause erroneous interpretation in cases, such as perinatal
asphyxia, maternal hypertension and long-term oxytocin
Superficial Swab Cultures induction.[15, 71] It should also be kept in mind that the tech-
Cultures obtained from superficial regions, such as the ax- nique of peripheral smear, the knowledge and experience
illa, umbilical cord, outer ear canal, nasopharynx and oro- of the investigator can affect the results.
gastric tubes, show poor correlation with pathogens isolat- Thrombocytopenia is a non-specific late finding of neo-
ed from sterile areas. Routine collection of superficial swab natal sepsis. It was found that the platelet count below
cultures is not recommended in neonatal sepsis, as it has 100000/mm3 for the first 10 days of the postnatal period
a low predictive value and can lead to erroneous assump- and below 150000/mm3 in later periods are associated with
tions in determining the factor.[59] sepsis.[72] In 50% of the cases with the bacterial infection,
platelet count was found to be below 100.000/mm3.[73] Ac-
Complete Blood Count Components and companying bacterial infections more frequently, throm-
Peripheral Smear bocytopenia is also seen in viral infections.[74, 75]
Many studies have been conducted on the diagnosis of
C-Reactive Protein (CRP)
neonatal sepsis, such as complete blood count, white blood
cell count (WBC), absolute neutrophil count and the ratio CRP, which is a pentameric structure, containing 187 amino
of immature neutrophil count to total neutrophil count acids and synthesized from hepatocytes, and an acute-
(I/T). The WBC upper limit is set at 30.000-40.000/mm3 in phase protein, is one of the most easily available and most
many sepsis screening protocols. However, it is noteworthy frequently used laboratory tests in the diagnosis of neona-
that leukocytosis was not detected in one-third of cases di- tal sepsis.[76, 77] Its synthesis is stimulated by cytokines, pri-
agnosed with sepsis.[27, 60, 61] Although the normal value of marily interleukin-6 (IL-6), IL-1 and tumor necrosis factor-α
WBC has a very wide range, it can be affected by the time (TNF-α). Its half-life is between 24-48 hours. The normal
and place of collection of the sample, the gestational week lower limit is considered as 1 mg/dL in the neonatal period.
of the baby, and factors other than sepsis.[27, 62–64] Among [78, 79]
It takes 10-12 hours for it to reach the measurable level
the factors other than sepsis that change the value of WBC in the serum, so its reliability is low in the early diagnosis
are conditions, such as preeclampsia, intraventricular hem- of neonatal sepsis. Serial CRP measurements have been
orrhage, perinatal asphyxia, meconium aspiration, pneu- shown to increase sensitivity in the diagnosis of sepsis 24
mothorax, convulsions and prolonged crying.[65] to 48 hours after the onset of symptoms.[80] Serial CRP mea-
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 147

surements are also used to evaluate the antibiotic response. Matrix-Assisted Laser Desorption Ionization-
[81]
Although CRP serum level rises mainly with infections, it Time of Flight Mass Spectrometry (MALDI-TOF)
may also rise due to non-infectious causes, such as prema-
ture rupture of the membranes, maternal fever, fetal dis- Matrix Assisted Laser Desorption Ionization-Time of Flight,
tress, difficult birth, and perinatal asphyxia. This causes low MALDI-TOF) started to take place among the new diag-
specificity of CRP for early neonatal sepsis.[23, 27, 64] nostic tests based on the identification of microorgan-
ism. MALDI-TOF is a mass spectrometer tool that allows
High Sensitivity-CRP (hs-CRP) rapid and accurate identification of the species within a
wide range of gram-negative and gram positive bacteria,
High Sensitivity CRP (hs-CRP) is more sensitive than con-
as soon as the organism is present in the culture.[93-95] It,
ventional CRP in the diagnosis of neonatal sepsis. While
therefore, allows organisms to be diagnosed earlier than
the normal lower value of conventional CRP is accepted as blood culture and targeted antibiotic therapy to start ear-
1 mg/dL, this value is 1 mg/L for hs-CRP.[82] In studies con- lier.[96] Its routine use is not yet common in the neonatal
ducted, infected newborns with high hs-CRP values were period.
reported to have a significant increase in hs-CRP compared
to non-infected newborns.[83] In another study, it was re- Molecular Methods
ported that there is no risk of infection when the hs-CRP
Nucleic acid analysis methods are important in recogniz-
value is detected as <0.5 mg/L, there is low infection risk
ing the morphological, metabolic or cytopathic features of
when the value is between 0.5–1 mg/L, moderate infection
microorganisms with no culture possibility or which grow
risk when between 1–3 mg/L, and there is a high risk of in-
slowly. Molecular technologies are being studied to enable
fection at values >3 mg/L.[84] As a result, more studies are
rapid identification of gram-negative and gram positive
needed to evaluate the role of hs-CRP in use as a neonatal
bacteria in the diagnosis of sepsis. Amplification of nucleic
sepsis marker.
acids can be done by methods, such as replication of the
Procalcitonin target nucleic acid (polymerase chain reaction), replication
of the nucleic acid probe (ligase chain reaction) or signal
Procalcitonin (PCT), which is the prohormone of calcitonin duplication (branched-probe DNA determination).[97] Poly-
and used as the acute-phase reactant protein, consists of merase chain reaction targets conserved regions of the 16S
116 amino acids. PCT is encoded by the Calc-1 gene and ribosomal RNA gene, which is common to all bacteria and
synthesized by macrophage and hepatocytes.[85] The PCT not found in organisms other than bacteria.[98] In the study
level rises rapidly 2-4 hours after exposure to bacterial en- conducted by Dutta et al.,[98] PCR analysis was performed
dotoxin, reaches a peak in 6-8 hours and remains high for before and after the initiation of antibiotherapy in clinically
24 hours.[86] The half-life of PCT is 24-30 hours. Due to its suspected sepsis cases; and the sensitivity, specificity, posi-
rapid rise from the onset of bacterial sepsis, it is considered tive and negative predictive values of PCR were found as
a better marker for early diagnosis of neonatal sepsis com- 96.2%, 96.3%, 87.7% and 98.8%, respectively. It was shown
pared to CRP. In healthy newborns, plasma PCT concentra- that the patients who had PCR positivity in the sample tak-
tions increase gradually after birth, reaching peak levels in en before antibiotherapy, continued their positivity at the
about 24 hours (in the range of 0.1-20 ng/mL), and then 12th hour after antibiotherapy, but that there was no PCR
falls to normal values below 0.5 ng/mL in 48-72 hours.[87] positivity at the 24th and 48th hours. This test, which may
Procalcitonin over 2-2.5 ng/ml after postnatal 72 hours be useful in early diagnosis, is not recommended for use in
should suggest infection.[88] patients whose antibiotic treatment is continued for more
Prematurity, intracranial hemorrhage, asphyxia, neonatal than 12 hours.[98]
hypoxemia, resuscitation, chorioamnionitis where neo- While it is advantageous that a small amount of sample is
natal infection does not develop, maternal GBS coloniza- sufficient and the test can be run in body fluids, such as
tion, prolonged membrane rupture, prenatal antibiotic surgical tissues and effusions, the disadvantages are the
use, surfactant administration, postpartum antibiotic use weakness of clinical correlation due to the inability to dis-
and very low birth weight may cause false positives. Thus, tinguish between active infection and past infection and
increases in the PCT level should be interpreted correctly. high probability of detecting contamination.[56] As a result,
[89-91]
It was concluded that PCT is a useful biomarker for comprehensive studies evaluating a larger number of cases
early diagnosis of newborn sepsis in critically ill patients for routine clinical use in newborns with suspected sepsis
in meta-analyses.[92] are required.
148 The Medical Bulletin of Sisli Etfal Hospital

Serum Amyloid A (SAA) to be high in early neonatal sepsis cases.[111, 112] Studies have
shown that IL-6 has better sensitivity and negative predic-
Serum Amyloid A (SAA) is an apolipoprotein synthesized
tive value compared to CRP when used as an early phase
by the liver, of whom the synthesis is controlled by IL-1, IL-6
biomarker.[70] Also, its combination with other sepsis mark-
and TNF-α.[99] It is secreted in response to injury or infection.
ers, such as TNF-a and CRP, has been shown to have higher
It is known to play a role in inflammation and stimulate the
sensitivity and negative predictive value in the diagnosis of
release of IL-8 from neutrophils. In a study comparing SAA,
early-onset neonatal sepsis.[113]
CRP, IL-6 and WBC in preterm infants with sepsis, it was re-
ported that mortality and SAA levels in newborn babies IL-8
were inversely proportional.[100] In another study, SAA levels
in septic babies were shown to be significantly higher at 0, IL-8 is a pro-inflammatory cytokine produced by monocyte,
24 and 48 hours, compared to SAA levels in non-septic ba- macrophage, fibroblast and endothelial cells. It is known to
bies. However, compared to CRP, SAA has been reported to be responsible for the activation and chemotaxis of neutro-
show a sharper and faster rise and also to return to normal phils.[114, 115] IL-8 guides both in the diagnosis and recogni-
faster.[101] As a result, SAA can be used as a useful marker in tion of the severity of neonatal sepsis. Its sensitivity was de-
early detection of neonatal sepsis if rapid and reliable kits tected as 80-91% and specificity as 76-100% in determining
neonatal sepsis.[70, 116] The combination of IL-8 with CRP as a
are used.
biomarker has been shown to have higher sensitivity and
Lipopolysaccharide Binding Protein (LBP): specificity in newborns considered suspicious sepsis and
The lipopolysaccharide-binding protein interacts with en- help reducing antibiotic use.[70] IL-8 level increases rapidly
dotoxins produced by Gram-negative bacteria species and within 2-4 hours from the start of an infection and then de-
transfers them to CD14 immune cells.[102, 103] LBP is produced creases within four hours. This makes IL-8 similar to IL-6, to
by hepatocytes, epithelium, muscle cells, and its level rises be used as only an early marker of infection.[117] As a result,
approximately 6-8 hours after the onset of acute infection. there are studies indicating that IL-8 may play a role in the
Another advantage of LBP, which has high sensitivity and diagnosis of neonatal sepsis, but more studies are needed
negative predictive value in the diagnosis of early-onset to provide strong evidence to support its use.
neonatal sepsis, is that it is less affected by physiological
changes and obstetric events that occur within the first two Tumor Necrosis Factor Alpha (TNF- α)
postnatal days.[104, 105] It is a proinflammatory cytokine produced by activated
phagocytes during systemic infection and inflammation.
Cytokines and Chemokines
It has pharmacokinetic properties similar to IL-6.[116] The
Cytokine levels change rapidly during the neonatal sepsis increase in TNF-α level is independent of the pregnancy
course. Cytokines, such as IL-6, IL-1b, SIL2R, IL-8 and TNF-a week of the newborn and postnatal age.[70] In studies com-
primarily increase in response to bacterial infections. This paring septic newborns and healthy newborns, TNF-α lev-
increase occurs before clinical symptoms or positive stan- els have been shown to be significantly higher in septic
dardized diagnostic tests.[56] Also, the levels of cytokines in cases.[118, 119] When combined with IL-6, it shows 60% sensi-
the newborn baby in the first few hours of life indicate the tivity and 100% specificity in the diagnosis of sepsis.[120] In
risk of infection.[106, 107] a meta-analysis study, TNF-α was found to show a moder-
ate accuracy both in the diagnosis of early-onset neonatal
Interleukin- 6 (IL-6) sepsis (sensitivity 66%, specificity 76%) and in the diagno-
Interleukin-6 stimulates the production of acute-phase re- sis of late-onset neonatal sepsis (sensitivity 68%, specificity
actants, such as CRP from the liver by releasing from B and T 89%).[121]
lymphocytes, monocytes, endothelial cells and fibroblasts
in the acute-phase of infections.[108, 109] The advantage of us- Other Chemokines
ing IL-6 as a marker of sepsis is that there is a rapid increase Chemokines that can be used with other inflammatory
in concentration just before the CRP level rises and imme- markers in the diagnosis of neonatal sepsis include mono-
diately after the onset of bacteremia. However, its half-life kines, RANKES, MCP-1 and IP-10.[122] While the use of che-
is being very short and its level is being normalized within mokine as a biomarker provides an advantage since it rises
24 hours after the start of antimicrobials appear to be dis- very early compared to CRP after the onset of infection;
advantages. Thus, IL-6 has a narrow window of opportuni- causes, such as decreased levels within approximately 24
ty.[110] IL-6 levels obtained from umbilical cord were found hours after the start of treatment, need of special tools for
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 149

the study of the test and difficulty to reach the test limit its neonatal sepsis.[127] Current studies have shown that CD11b
use.[107] However, more studies are needed for their wide- has good diagnostic accuracy as a biomarker for neonatal
spread and safe use. sepsis. However, the insufficiency and high cost of the cen-
ters where the examination can be carried out are among
Cell Surface Markers the factors limiting their routine use.
Cell surface markers can be determined by flow cytometry. Soluble CD163 (sCD 163) reduces the oxidative damage that
[64]
Studies are conducted on the use of cell surface anti- arises from hemolysis by clearing circulating free hemoglo-
gens as biomarkers, such as CD11b (100% specificity, 100% bin with the help of haptoglobin.[128] It binds to gram-neg-
sensitivity), CD64 (83% specificity and 82% sensitivity), ative and gram-positive bacteria, stimulating the synthesis
sCD163. CD64 is a high-affinity Fc receptor for immuno- of proinflammatory cytokines, such as TNF-α, IL-1b, IL-6
globulin G, of which its expression is increased in response and IL-10.[129] In a study comparing CRP, IL-6, IL-8, TNF-α and
to infection.[123] Its level increases ten-fold in activated neu- sCD163, it is concluded that sCD163 is the strongest predic-
trophils 4-6 hours after the onset of bacterial infection. Its tive marker for the differentiation of infected and uninfected
level decreases to normal within a few days after the infec- newborns before antibiotherapy is started.[130]
tion is suppressed.[124, 125] The combination of CD64 with
PCT, CRP and WBC has been shown to increase sensitivity Other Biomarkers
in the early diagnosis of sepsis.[126] Other biomarkers that draw attention in the diagnosis and
CD11b (Mac-1, CR3) is the α subunit of the b2-integrin ad- treatment of sepsis are suPAR, angiopoietins, pentraxin 3
hesion molecule and is expressed at low concentration in (PTX3), sTREM-1 and inter alpha inhibitory proteins (IaIp).
inactivated neutrophils. Its level rises five minutes after the [131-135]
However, further studies are needed to support their
onset of bacterial infection and it is thought to be a good routine use.
biomarker for early detection of neonatal sepsis.[70] In the
study of Weirich et al.,[124] CD11b was detected in all babies Diagnostic Algorithms
with proven sepsis, but not in newborns without sepsis. Early diagnosis of sepsis is difficult due to the absence of
In the diagnosis of neonatal infection, negative predictive specific symptoms and the suboptimal diagnostic value of
value, positive predictive value, sensitivity and specificity the laboratory findings. This causes high levels of empirical
of CD11b were detected as 100%, 99%, 96% and 100%, antimicrobial use. In the literature, sepsis scores were tried
respectively. Nupponen et al.[125] showed that CD11b has to be created with different combinations of inflammatory
100% sensitivity and specificity in the detection of neonatal response parameters, laboratory tests and physical exami-
sepsis in their studies comparing newborns with suspected nation findings. Töllner developed the first known new-
infections and healthy newborns. Adib et al. showed that born sepsis scoring system in 1982 to identify sepsis using
the sensitivity and negative predictive value of the combi- clinical and basic laboratory evaluations (Table 1).[136] The
nation of CD11b with CRP reached 100% in the diagnosis of Pediatric Committee (PDCO) of the European Medicines

Table 1. Töllner sepsis scoring system

Score 0 1 2 3

Change in skin color Absent Moderate Evident

Peripheral circulatory disorder Absent Impaired Evident
Hypotonia Absent Moderate Evident
Bradycardia Absent Present
Apnea Absent Present
Respiratory distress Absent Present
Hepatomegaly Absent >4cm
GIS finding Absent Present
Leukocyte count Normal Leukocytosis Leukopenia
Left shifting Absent Moderate Evident
Thrombocytopenia Absent Present
Metabolic acidosis Normal >7.2 <7.2

If the total score is below 5, it is normal, between 5-10 it is suspected, and above 10 points, it is considered as definite sepsis.
150 The Medical Bulletin of Sisli Etfal Hospital

Agency (EMA) proposed EMA sepsis criteria for standard- Empirical Treatment
ization of the definition of neonatal sepsis in 2010 (Table
Empirical treatment of early-onset bacterial infections
2).[137] However, the adequacy and reliability of the use of
should include ampicillin and an aminoglycoside antibiotic
a single scoring system in the diagnosis of sepsis have not
(usually gentamicin). Renal function tests should be evalu-
been proven yet.
ated at the beginning of treatment with gentamicin, and
Today, online early-onset neonatal sepsis calculators are serum gentamicin level should be checked in infants whose
also used to predict the possibility of early-onset neonatal antibiotherapy will be completed. If renal function tests are
sepsis and to guide decisions regarding initiation of anti- normal in babies whose treatment is completed after 48
biotherapy (https://neonatalsepsiscalculator.kaiserperma- hours, gentamicin level examination is not necessary.[23] The
nente.org). use of third and fourth generation cephalosporins should
only be added to the treatment in case of suspected gram-
Treatment negative meningitis.[13] The use of third-generation cepha-
Antimicrobial treatment of neonatal infections is divid- losporins and vancomycin has been associated with an
ed into two as the treatment of suspected (empirical) or increase in vancomycin-resistant enterococci and extended-
known (definitive) pathogens. Whether there is early or spectrum β-lactamase (ESBL)-producing gram-negative
late-onset of symptoms, and the infection is nosocomial bacteria (GNB).[138] Empirical use of third-generation cepha-
or community-acquired, affects antimicrobial selection. Al- losporins is not recommended, as it causes an increased risk
though it is important to take appropriate culture samples of invasive candidiasis in long-term administration as well as
before starting antibiotherapy, this should not delay start- resistance development.[139] Ampicillin and third-generation
ing treatment. cephalosporin regimen have been shown to be no more ef-

Table 2. EMA sepsis scoring system

Clinical Findings Laboratory Findings

Body temperature: Leukocyte count:

>38.5 ºC or <4.000/mm3 or >20.000/mm3
<36 ºC and/or temperature irregularities
Cardiovascular instability: Immature/total neutrophil ratio:
Bradycardia or tachycardia and/or ≥0.2
rhythm irregularity
Urine amount <1 ml/kg/hour
Hypotension
Impaired peripheral perfusion
Skin and subcutaneous lesions: Platelet Count:
Petechiae <100.000/mm3
Sclerema
Respiratory instability: CRP >15mg/L (1.5 mg/dL) or
Apnea or procalcitonin ≥2 ng/mL
Tachypnea or
Increased oxygen demand or
Increased need for ventilation support
Gastrointestinal: In blood sugar monitoring (at least twice):
Nutritional intolerance Hyperglycemia (>180 mg/dL or 10 mMol/L) or
Insufficient breastfeeding Hypoglycemia (<45 mg/dL or 2.5 mMol/L)
Abdominal distention
Non-specific: Metabolic acidosis:
Irritability Base deficit >10 mEq/L or
Lethargy Serum lactate >2 mMol/L
Hypotonia

Positivity in at least two of the clinical categories and at least two of the laboratory categories is considered
as clinical sepsis. It can be used up to postnatal 44 weeks.
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 151

fective than the combination of ampicillin and gentamicin. an antibiotic containing penicillin, and aminoglycoside can
[140]
Ampicillin + gentamicin is synergistic in the treatment be added to the treatment if the synergistic effect is docu-
of infections that arise from GBS and L. monocytogenes, but mented. Aminoglycoside therapy may be discontinued
cephalosporins are not effective against L. monocytogenes. when cultures result as sterile. Ampicillin-resistant entero-
Empirical treatment of late-onset neonatal sepsis usually in- coccal infections can be treated with vancomycin without
cludes vancomycin and an aminoglycoside antibiotic group, the addition of aminoglycosides. In S. aureus infections, van-
effective for coagulase-negative Staphylococci, S. aureus and comycin is used for treatment until the susceptibility profile
gram-negative organisms. However, as in early-onset sepsis, is concluded, while it is continued in patients with MRSA.
if gram-negative meningitis is suspected, the addition of If MSSA is detected, cefazolin can be used as an alterna-
third-generation cephalosporins should be considered.[139] tive treatment in conditions other than CNS infections and
Carbapenem group antibiotic use can be an option consid- endocarditis. Coagulase-negative staphylococcal infections
ering local resistance levels or if the patient has previously require treatment with vancomycin. Ampicillin (if sensitive)
used a third-generation cephalosporin antibiotic.[141] The use or an aminoglycoside is sufficient for the treatment of gram-
of piperacillin + tazobactam and ampicillin + sulbactam is negative enteric bacterial infections. However, if meningitis
gradually increasing in the treatment of infections that occur is suspected, third-generation or fourth-generation cepha-
during neonatal intensive care unit hospitalization; however, losporin (for example, cefotaxime, ceftazidime, or cefepime
penetration of tazobactam into the central nervous system
if Pseudomonas spp is the causative agent) or carbapenem
is unreliable and it should not be used to treat meningitis.
should be used. Carbepenem is the best option in the treat-
However, β-lactamase inhibitor sulbactam is known to reach
ment of Enterobacteriaceae strains that produce extended-
high concentrations in CSF when combined with ampicillin.
spectrum beta-lactamase (ESBL), while cefepime may also
[142]
Rapid and aggressive treatment should be initiated when
be considered. Infections that arise from Enterobacteriacaea
fungal infections, such as candidiasis, aspergillosis and zygo-
strains that produce carbapenemase are treated with colis-
mycosis, are suspected. Empirical antifungal therapy with
tin in addition to carbapenem, or high-dose tigecycline, or
amphotericin B deoxycholate can be considered in high-risk
a regimen containing aminoglycoside. It is appropriate to
babies with risk factors for invasive candidiasis.[13]
use clindamycin, ampicillin + sulbactam or metronidazole
Treatment should be continued for 7-10 days in the diagno-
in the treatment of anaerobic infections; if CNS involvement
sis of clinical sepsis. The clinical condition of the baby, labo-
is present, metronidazole is preferred. When fungal infec-
ratory examinations and response to the treatment are mon-
tions are evaluated, Amphotericin B deoxycholate is the first
itored. The improvement of clinical findings in the first 24-48
choice for the treatment of invasive candidiasis.[143] Flucon-
hours from the start of treatment, the normalization of CRP
azole can be used as an alternative therapy in the treatment
level, I/T ratio and white blood cell count in 48-72 hours in-
of patients with sensitive fungal infections and patients
dicates an appropriate response is received.[5] It is often diffi-
without prophylaxis given.[144] Liposomal amphotericin or
cult to determine an appropriate antibiotic treatment period
echinocandin (caspofungin or micafungin) can be used in
for suspected sepsis when cultures are negative. Standard
practice in babies who are fine and have no clinical or hema- the treatment of hepatic or splenic candidiasis. Antibiotics
tological evidence for infection is to stop antibiotherapy if and their frequently used doses in the neonatal period are
there is no culture growth after 48 hours.[139] summarized in Table 3.[145, 146]
The duration of treatment is determined by the site of in-
Pathogen-Oriented Treatment fection and the clinical response of the patient. Bacteremia
Once the pathogens have been identified, treatment should without infection focus is usually treated for 7-10 days. Al-
be reorganized according to the type and sensitivity. When though there are few randomized controlled studies on
looking at the treatment regimens, in babies with bactere- antibiotherapy periods in premature babies with very low
mia and sepsis that arise from GBS, gentamicin is often used birth weight, duration of antibiotherapy can be extended
in combination with ampicillin or penicillin, but there are until day 10-14 in infants younger than 32nd gestational
insufficient data to suggest that the aminoglycoside addi- weeks.[147] Gram-negative bacteremia treatment is also ex-
tion improves the result. However, it is common practice to tended until 10th-14th days. The duration of treatment in
use a combination of these two drugs in the first few days uncomplicated GBS meningitis is usually until day 10-14,
of treatment, and then continue treatment with just ampi- while the duration is extended in focal complications.[139]
cillin or penicillin.[24] Although ampicillin alone is sufficient In gram-negative bacterial meningitis, treatment is con-
in the treatment of L. monocytogenesis, aminoglycosides tinued for 21 days or for another two weeks after the first
show synergistic effects. Enterococci should be treated with negative CSF culture.[148]
152 The Medical Bulletin of Sisli Etfal Hospital

Table 3. Antibiotic doses

Antibiotic Administration Route Dosing
AMIKACIN IM, IV Gestational age <30 weeks:
PNA ≤14 days: 15 mg/kg/dose every 48 hours
PNA ≥15 days: 15 mg/kg/dose every 24 hours
Gestational age between 30-34 weeks:
PNA ≤60 days: 15 mg/kg/dose every 24 hours
Gestational age ≥35 weeks:
PNA ≤7 days: 15 mg/kg/dose every 24 hours
PNA ≥8 days: 17,5 mg/kg/dose every 24 hours
AMPICILLIN IM, IV Gestational age ≤34 weeks:
PNA ≤7 days: 50 mg/kg/dose every 12 hours
PNA 8-28 days: 75 mg/kg/dose every 12 hours
Gestational age >34 weeks:
PNA ≤28 days: 50 mg/kg/dose every 8 hours
Meningitis:
PNA ≤7 days (IV): 200- 300 mg/kg/days every 8 hours
PNA >7 days (IV): 300 mg/kg/days every 6 hours
CEFOTAXIME IM, IV Gestational age <32 weeks:
PNA <14 days: 50 mg/kg/dose every 12 hours
PNA 14-28 days: 50 mg/kg/dose every 8 hours
Gestational age ≥32 weeks:
PNA ≤7 days: 50 mg/kg/dose every 12 hours
PNA 8-28 days: 50 mg/kg/dose every 8 hours
MEROPENEM IV Birth weight ≤ 2 kg
PNA ≤14 days: 20 mg/kg/dose every 12 hours
PNA 15-28 days: 20 mg/kg/doz every 8 hours
PNA 29-60 days: 30mg/kg/dose every 8 hours
Birth weight > 2 kg
PNA ≤14 days: 20 mg/kg/dose every 8 hours
PNA 15-60 days: 30 mg/kg/dose every 8 hours
PIPERACILLIN - TAZOBACTAM IV Birth weight ≤ 2 kg
PNA ≤7 days: 100 mg/kg/dose every 8 hours
PNA 8-28 days: PMA ≤ 30 GH 100 mg/kg/dose every 8 hours
PMA >30 GH 80 mg/kg/ dose every 6 hours
PNA 29-60 days: 80mg / kg/dose every 6 hours
Birth weight > 2 kg
PNA ≤ 60 days: 80 mg / kg/dose every 6 hours
VANCOMYCIN IV Loading dose: 20mg/kg/dose
Gestational age <28 weeks:
Serum Creatinine <0.5 mg/dL 15 mg/kg/dose every 12 hours
Serum Creatinine 0.5-0.7 mg/dL 20 mg/kg/dose every 24 hours
Serum Creatinine 0.8- 1 mg/dL 15 mg/kg/dose every 24 hours
Serum Creatinine 1.1- 1.4 mg/dL 10 mg/kg/dose every 24 hours
Serum Creatinine >1.4 mg/dL 15 mg/kg/dose every 48 hours
Gestational age >28 weeks:
Serum Creatinine <0.7 mg/dL 15 mg/kg/dose every 12 hours
Serum Creatinine 0.7-0.9 mg/dL 20 mg/kg/dose every 24 hours
Serum Creatinine 1-1.2 mg/dL 15 mg/kg/dose every 24 hours
Serum Creatinine 1.3- 1.6 mg/dL 10 mg/kg/dose every 24 hours
Serum Creatinine >1.6 mg/dL 15 mg/kg/dose every 48 hours
TEICOPLANIN IV Loading dose: 16 mg/kg/dose
Maintenance dose: 8 mg/kg/dose every 24 hours
Ozmeral Odabasi et al., Neonatal Sepsis / doi: 10.14744/SEMB.2020.00236 153

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Disclosures
2006. MMWR Morb Mortal Wkly Rep 2009;58:109–12.
Peer-review: Externally peer-reviewed.
12. Stoll BJ, Hansen NI, Sánchez PJ, Faix RG, Poindexter BB, Van
Conflict of Interest: None declared. Meurs KP, et al; Eunice Kennedy Shriver National Institute of
Authorship Contributions: Concept – I.O.O., A.B.; Design – I.O.O., Child Health and Human Development Neonatal Research Net-
A.B.; Supervision – A.B.; Materials – I.O.O.; Data collection &/or work. Early onset neonatal sepsis: the burden of group B Strep-
processing – I.O.O.; Analysis and/or interpretation – A.B.; Litera- tococcal and E. coli disease continues. Pediatrics 2011;127:817–
ture search – I.O.O.; Writing – I.O.O.; Critical review – A.B.
26.
13. Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet
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