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Pediatrics and Neonatology (2016) 57, 167e173

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REVIEW ARTICLE

Bird’s Eye View of a Neonatologist: Clinical


Approach to Emergency Neonatal Infection
Fu-Kuei Huang a,y, Hsiu-Lin Chen b,c,y, Peng-Hong Yang d,
Hung-Chih Lin a,e,*

a
Department of Pediatrics, China Medical University Children Hospital, Taichung, Taiwan
b
Department of Pediatrics of Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
c
Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung,
Taiwan
d
Department of Neonatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
e
School of Chinese Medicine, China Medical University, Taichung, Taiwan

Received Mar 18, 2014; received in revised form Apr 21, 2015; accepted Jun 1, 2015
Available online 23 October 2015

Keywords Though the incidence of neonatal infection in term and near-term infants is relatively low, inci-
neonatal sepsis; dence of infection in preterm very low birth weight infants is as high as 20e30% and may result in
antimicrobial neurodevelopmental impairment or mortality. Pediatricians should be familiar with recognition
therapy; and emergency management of life-threatening neonatal infections, such as congenital pneu-
sepsisi screen; monia, early onset sepsis, late onset sepsis, bacterial and fungal meningitis, disseminated
blood culture; neonatal herpes simplex virus (HSV), and HSV meningoencephalitis. For the pediatrician, it is
white blood cell logical to approach the management of these infections by time of onset, i.e., early versus late
count; onset of infection. Perinatal risk factors and simple laboratory tests, such as total white blood-
acute phase reactants cell count, immature/total ratio, and C-reactive protein are helpful in guiding the decision of an-
tibiotics therapy. Successful management of these critical infections depends upon early diag-
nosis and timely administration of adequate antibiotics. Empiric antibiotic therapy must cover
the most likely pathogens according to the risk factors of each individual neonate, and therapy
duration is dependent upon culture results, clinical course, and the microorganism. Future
research may focus on developing a practical neonatal sepsis score system based on risk factors
and common biomarkers, which are readily available at bedside to make early accurate decisions
and achieve better outcomes.
Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

* Corresponding author. China Medical University Children Hospital, Number 2 Yu-Der Road, Taichung, 404, Taiwan.
E-mail address: d0373@mail.cmuh.org.tw (H.-C. Lin).
y
These two authors contributed equally to authorship of this manuscript.

http://dx.doi.org/10.1016/j.pedneo.2015.06.004
1875-9572/Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
168 F.-K. Huang et al

in its diagnosis and management. Pneumonia caused by GBS


1. Introduction
or other pathogens is difficult to distinguish from respira-
tory distress syndrome in the preterm infant. The most
Although the incidence of neonatal infections in term and
common abnormality identified was dense bilateral alve-
near-term infants is relatively low, neonatal infections have
olar infiltrates with air bronchograms.4
a significant impact on medical resource utilization. The
incidence of health care-associated infections in preterm
very low birth weight (PVLBW) infants is as high as 20e30%.1 2.3. Management
Furthermore, infection of PVLBW infants can result in death
or neurodevelopmental impairment. Thus, pediatricians Successful treatment depends upon recognition of risk
must be aware of the possibility of sepsis or health care- factors. Treatments include prompt diagnosis with admin-
associated infections in any high-risk infants. istration of antibiotics and supportive therapy, including
Life-threatening neonatal infections include congenital surfactant replacement5 and nitric oxide inhalation for
pneumonia with the possibility of development into persistent PPHN. Although clinical trials regarding surfactant
pulmonary hypertension of the newborn (PPHN) and/or septic replacement for congenital pneumonias are limited, sur-
shock and even mortality; early onset sepsis (EOS) in neo- factant replacement may reduce mortality, especially for
nates, leading to high mortality rates and adverse neuro- PVLBW infants.6
developmental outcomes in preterm infants; late onset sepsis Ampicillin and gentamicin are commonly used to treat
(LOS) in neonates, resulting in moderate mortality rates and infants with congenital pneumonias. Since Gram-negative
adverse neurodevelopmental outcomes in preterm infants. bacilli rapidly develop resistance to cephalosporins, third-
Bacterial or fungal meningitis is related to adverse neuro- generation cephalosporins are not recommended routinely
developmental outcomes, and neonatal disseminated herpes for suspected pneumonia7 except when there is no
simplex virus (HSV) infection and HSV meningoencephalitis improvement after 24 hours of treatment or if S. pneumo-
can both cause high mortality and high morbidity rates. niae infection is highly suspected.8 Once a specific organ-
For the pediatrician, it is reasonable to approach the ism is identified, therapy is modified according to the
management of these infections by time onset, i.e., early susceptibility pattern.
versus late onset of sepsis, where EOS is defined as infec-
tion occurring within < 3 days usually presenting with
3. Early onset sepsis
pneumonia or sepsis.

3.1. Pathogenesis
2. Congenital pneumonia
EOS pathogenesis is the same as that of pneumonia. Or-
2.1. Pathogenesis ganisms responsible for EOS reside in the birth canal and
invade the amniotic cavity through the cervix. Given that
Congenital pneumonias result from intrauterine aspiration the signs and symptoms of sepsis are also subtle and
of infected amniotic fluid or aspiration of amniotic fluid nonspecific, identification of infants at risk is critical for
during the birth process. Pediatricians need to be aware emergency intervention.9 The neonate should be carefully
that congenital pneumonias sometimes progress to septic evaluated for the presence of risk factors, including the
shock and can be associated with persistent pulmonary following: intrapartum maternal temperature  38 C
hypertension. (100.4 F), chorioamnionitis, preterm infants at < 37-
Pneumonia is caused by many of the same pathogens weeks’ gestation, Apgar scores  6 at 5 minutes, evi-
associated with neonatal sepsis, including EOS and LOS. In dence of fetal distress, maternal GBS colonization, or
the area of antenatal chemoprophylaxis in developing membrane rupture of  18 hours.9 Heart-rate analysis
countries, the pathogens responsible for congenital pneu- might also help the early diagnosis of late onset neonatal
monia include Escherichia coli, group B streptococcus sepsis.10
(GBS), Staphylococcus aureus, Klebsiella spp, and Strep- Pneumonia is more common in EOS. If the classic signs of
tococcus pneumoniae.2 HSV is the most common viral agent respiratory distress, including tachypnea, dyspnea, grunt-
that causes pneumonia and has a very high mortality ing, and cyanosis present within the first 4e6 hours of life,
rate.2,3 According to the recommendations of the Centers pneumonia should be considered.
for Disease Control and Prevention (CDC), since 1996 early-
onset GBS infection has been reduced by more than 85% 3.2. Diagnostic approach
after GBS prophylaxis protocol in the USA.
However, some reports showed that there were more Low white blood cells (<5000/mL) (WBC), absolute neutro-
Escherichia coli infections in neonates or more ampicillin- phil count less than 1000/mL (ANC), or proportion of neu-
resistant organisms, although other reports did not have trophils that are immature greater than 0.6 have been
similar findings.4 highly associated with culture-proven early-onset disease.11
Sequential assessment of C-reactive protein (CRP) may
2.2. Diagnostic approach be helpful in guiding the duration of antibiotic therapy in
suspected neonatal bacterial infection,12 however, detailed
Any neonates who present with respiratory distress should physical examination with clinical symptoms is more
be evaluated for pneumonia, with chest X-ray most helpful important. Elevated procalcitonin (> 0.5 ng/mL) is equally
Emergency neonatal infection 169

effective as CRP in detecting bacterial infection.13 Serum In addition to bacteria, viruses and fungi also cause LOS.
calprotectin may be a promising marker of sepsis for pre- Candida infections have increased in frequency with ad-
term VLBW infants.14 Studies evaluating serum amyloid A vancements in the care of preterm extremely low birth
presented a variable positive predictive value (0.67 and weight (ELBW) infants. Factors that influence the severity
0.92), but with a high negative predictive value (0.97 and and type of neonatal Candida infections: gestational age <
1.00).15 Apart from expensive biomarkers for the diagnosis 32 weeks, Apgar score < 5 at 5 minutes, use of H2 blockers,
of neonatal sepsis, an objective scoring system according to shock, prior use of intralipids, parenteral nutrition days,
risk factors, clinical presentations, and simple tests might use of central-venous catheters, intubation, or prolonged
be more practical for neonatal intensive care units.16 hospital stays.21

3.3. Management 4.2. Diagnostic approach

Empiric antibiotic treatment is indicated whenever sepsis is The presentation symptoms and diagnostic approaches are
suspected based on clinical signs or in healthy-appearing similar to those for EOS, however, the clinical signs are
infants born to mothers with chorioamnionitis. Successful more subtle. Any change in vital signs, such as unexplained
treatment of EOS depends upon the gestational age, early tachycardia, hypo- or hyperthermia, apnea, and/or brady-
diagnosis and early intervention with appropriate antibi- cardia should be evaluated carefully. Changes in heart-rate
otics, and supportive intensive care. Severely ill PVLBW characteristics could constitute physiomarkers for LOS
infants frequently require respiratory and vasopressor detection.22
medical support as soon as possible in order to maintain Persistent hyperglycemia and thrombocytopenia are
adequate oxygenation and perfusion. Ampicillin and strongly associated with candidemia and, if present, a
gentamicin are still effective in treating most of the com- diagnosis of candidemia should be considered.23 Though
mon pathogens that cause EOS, GBS, and E. coli Rodwell et al24 developed the hematological scoring system
infections.17 (HSS) based on the findings of a peripheral blood smear,24
Cefotaxime may not be appropriate for the treatment of Makkar et al25 noted that the immature poly-
EOS as shown in retrospective data noting an increase in morphonuclear neutrophil (PMN) count was the most sen-
mortality rate (4.2% versus 1.9%).18 However, considering sitive and that the I:M PMN ratio was the most specific
that there is increasing resistance to Gram-negative or- indicator of sepsis. For sepsis and probable sepsis, the I:T
ganisms, the choice of antibiotics in neonatal sepsis should PMN ratio and immature PMN counts have highest sensi-
depend upon the prevalence of microorganism and antibi- tivity, whereas the I:T and I:M PMN ratios have highest
otic sensitivity in each unit.19 The duration of antibiotic specificity. HSS has much higher sensitivity, specificity,
therapy for culture-proven EOS depends upon the path- positive predictive value, and negative predictive value in
ogen. Usually, 10 days for Gram-positive and 14 days for preterm infants relative to term infants.25
Gram-negative microorganisms are adequate.19
In most cases, symptomatic infants with proven sepsis 4.3. Management
improve clinically within 48e72 hours. Empiric antibiotic
therapy can generally be discontinued in the infant after 48
Successful management of LOS depends upon early diag-
hours if blood culture is negative. In a critically ill infant
nosis with administration of appropriate antibiotics and
(with negative cultures), antibiotics should be continued
timely cardiopulmonary support. The choice of empiric
for 7 days.
antibiotics is dependent upon the most common pathogens
Outcomes of GBS neonatal sepsis after the introduction
causing LOS in the neonatal intensive care unit, and the
of intrapartum antibiotic prophylaxis and the routine use of
duration of therapy is dependent upon culture results,
empirical antibiotic therapy demonstrated an overall mor-
clinical course, and organism.
tality rate of between 5% and 10%, with mortality even
Empirical antibiotics treatment is often combination
lower in term infants with early onset disease ranging from
therapy with ampicillin and an aminoglycoside or vanco-
2% to 3%.20
mycin with third generation cephalosporin, according to
the most common current pathogen in each unit.26
4. Late onset sepsis In symptomatic preterm infants with a central-venous
catheter, the most common isolates are CoNS, with most
CoNS now resistant to oxacillin. In infants with necrotizing
4.1. Pathogenesis enterocolitis, the same antibiotic coverage may be used,
however, some clinicians add clindamycin or metronidazole
LOS is acquired principally by horizontal transmission from to cover anaerobic organisms. In systemic extended-
direct contact with care providers, catheters, or environ- spectrum beta-lactamase infections, meropenem is recom-
mental sources, and may occur as early as 3-days of age. mended, even without strong evidence of the efficacy or
Coagulase-negative staphylococci (CoNS) are the most toxicity for preterm infants.27 Many experts suggest treat-
common organisms associated with LOS. Other Gram- ment with a beta-lactam antimicrobial agent (beta-lactam or
positive organisms, including S. aureus, Enterococcus spp, beta-lactamase inhibitor) combined with an aminoglycoside
and GBS, and Gram-negative pathogens, including E. coli, for Enterobacter, Serratia, or Pseudomonas sepsis. Cefo-
Klebsiella, Pseudomonas, Enterobacter, and Serratia, were taxime is commonly reserved for the treatment of infants
the most frequent pathogens associated with LOS.1 with meningitis.
170 F.-K. Huang et al

Immunotherapeutic interventions, such as intravenous the initial manifestation of meningitis resulting from Gram-
immunoglobulin (Ig) infusion, IgM-enriched intravenous negative organisms.37
immunoglobulin, granulocyte and granulocyte-macrophage The decision to perform a lumbar puncture (L-P) in an
colony-stimulating factor administration, have been eval- infant with suspected sepsis is often difficult. We strongly
uated, but have not been shown to improve the outcome of suggest that L-P should be performed in any neonate with a
infants with sepsis.26 positive blood culture or with clinical and laboratory find-
Pentoxifylline, a synthetic theobromine derivative, is a ings strongly suggestive of sepsis.35e39 Additionally, thor-
nonsteroidal immunomodulating agent with unique hem- ough explanation to the family about the necessity of L-P is
orrheologic effects that has been used in a range of infec- important.
tious, vascular, and inflammatory conditions in adults and Initial cerebrospinal fluid (CSF) findings are usually suf-
children. The use of pentoxifylline to modulate inflamma- ficient to make the diagnosis of meningitis, however, the
tion in neonatal sepsis is controversial. A meta-analysis of range of normal values for CSF parameters varies according
four randomized controlled trials demonstrated that pen- to gestational age, chronological age, and birth weight. Cell
toxifylline therapy significantly decreased all-cause mor- counts and protein and glucose concentrations in CSF are
tality during hospital stays in infants with sepsis {typical highly variable in newborn infants both with and without
relative risk, 0.40 [95% confidence interval (CI), meningitis.
0.20e0.77]; typical risk difference, 0.15 (95% CI, WBC counts in CSF exceeding 21 cells/mL have a sensitivity
0.26e0.05); number needed to treat, 7 (95% CI, and specificity of w80% for predicting culture-proven men-
4e20)}.28 Subgroup analyses also revealed significant re- ingitis, however, neonatal meningitis can occasionally occur
ductions in mortality in preterm infants, infants with with normal CSF parameters.38 A CSF protein concentration
confirmed sepsis, and Gram-negative sepsis.28 However, > 150 mg/dL in preterm infants or > 100 mg/dL in term in-
these studies were conducted in underdeveloped or fants is consistent with bacterial meningitis.38 A CSF glucose
developing countries, therefore, the efficacy of pentox- concentration < 30 mg/dL (1.7 mmol/L) for term infants or <
ifylline therapy warrants further investigation in large 20 mg/dL (1.1 mmol/L) for preterm infants is consistent with
randomized clinical trials in developed countries. neonatal bacterial meningitis.39 Neonates for whom the L-P
In addition to its cytokine-suppressing effects, hydro- is traumatic should be treated presumptively for meningitis
cortisone improved myocardial contractility and stroke pending results of CSF cultures. Gram-stained smears pro-
volume, increased systemic vascular resistance, and vide important information regarding antibiotic selection,
enhanced urine output. Nonetheless, hydrocortisone has however, w20% of culture-confirmed bacterial meningitis
not been evaluated in prospective randomized clinical trials exhibit negative gram-stained smears. This is especially true
for the treatment of neonatal septic shock.29 for Listeria monocytogene, the third most common cause of
meningitis in newborns.

5. Bacterial meningitis
5.3. Management
5.1. Pathogenesis
Intensive care with effective control of intracranial hy-
st pertension, prevention of fluctuations in cerebral blood
Bacterial meningitis is more common in the 1 month than
flow, anticonvulsant therapy, maintenance of adequate
at any other time of life, and frequently occurs in infants
with EOS and LOS.30 Although the mortality rate for infant oxygenation, and prevention of hypoglycemia are crucial
meningitis has declined from w50% in the 1970s to 10e15% aspects of managing neonates with bacterial meningitis.
Empiric antimicrobial regimens are identical to those with
recently,31 the morbidity rate is relatively unchanged, with
a high prevalence of neurologic sequelae.32 for suspected EOS or LOS. However, in infants with sus-
In developed countries, GBS, E. coli, and other Gram- pected meningitis, cefotaxime is preferable to amino-
glycosides. In infants with a suspected shunt infection,
negative bacilli are the most common organisms causing
empiric therapy with vancomycin and gentamicin is
neonatal meningitis.30e33 A prospective surveillance dis-
closed that 72% of early sepsis or meningitis was caused by appropriate. Meropenem is recommended for treatment of
infections caused by most multidrug-resistant enteric or-
GBS and E. coli.33 However, Gram-positive organisms
ganisms. Although there are limited data documenting the
constitute a greater portion of the disease burden among
PVLBW infants.34 Neisseria meningitides is a rare form of optimal dose and toxicity of meropenem in neonates, a
meningitis in newborn infants.35 Additionally, in the dosage of 20e40 mg/kg every 8e12 hours is recommend.27
A 14-day course is sufficient for neonates with uncom-
developing world, the microbiology of bacterial meningitis
in neonates varies geographically.36 plicated GBS meningitis and for other Gram-positive or-
ganisms, while a 21-day course of therapy is required for
neonates with complicated GBS meningitis and Gram-
5.2. Diagnostic approach negative microorganisms. If ventriculitis, abscesses, or
multiple areas of infarction occur, 6e8 weeks of antibiotics
The clinical presentation of meningitis is highly variable. may be required. Administration of dexamethasone does
Some infants present with nonspecific signs of sepsis, while not significantly improve the mortality or morbidity of
other infants exhibit signs associated with the central meningitis.40
nervous system (CNS), such as irritability, lethargy, In the case of neonates with bacteremia and CSF findings
tremors, or seizures. It is suggested that seizures are often indicative of meningitis with negative CSF culture, we treat
Emergency neonatal infection 171

as if they have proven bacterial meningitis. For those who identifying high-risk neonates with a sepsis-like picture,
have CSF pleocytosis and negative blood cultures, we progressive pneumonitis, hepatitis, or meningoencephalitis
individualize the duration of antimicrobial therapy doses as methods for HSV screening and determination of early
for meningitis based on other parameters, such as CSF empiric antiviral therapy.46,48,49
glucose and protein concentrations. Definitive diagnosis of NHSV infection should be estab-
The L-P should be repeated at 24e48 hours after initi- lished through isolation of HSV in traditional monolayer cell
ation of antimicrobial therapy to document CSF steriliza- culture or enhanced cell-culture systems, detection of viral
tion.41 This is important because the first, delayed DNA using polymerase chain reaction (PCR) assays, and
sterilization of the CSF is associated with an increased risk detection of viral antigens using rapid direct immunofluo-
of developing neurologic sequelae and the second, persis- rescence assays or enzyme immunoassays (EIA). Negative
tent identification of organisms on a gram-stained smear HSV cultures, PCR, and rapid tests do not exclude NHSV,
may be an early indication of inadequacy of antimicrobial and the accuracy of EIA tests to diagnose NHSV infection is
therapy. The duration of antimicrobial therapy is often unknown. Shell-vial centrifugation fluorescent-foci cultures
determined by the first negative-CSF culture. The persis- and enzyme-linked virus-inducible systems are used in
tence of viable organisms more than 48 hours after initia- many clinical laboratories and provide rapid detection of
tion of antimicrobial therapy may be an indication of need HSV in clinical systems within 24e48 hours.50
for diagnostic neuroimaging, which can indicate a purulent Meningoencephalitis of NHSV usually occurs during the
focus (e.g., obstructive ventriculitis, multiple small-vessel first 6 weeks of life.51 Nearly 60e70% of infants with NHSV
thrombi) that may require additional intervention or pro- meningoencephalitis have skin vesicles at some point dur-
long the duration of antimicrobial therapy. ing the disease course,44 however, this may occur without
Cranial sonography is most helpful for assessing ven- skin involvement and with or without disseminated disease.
tricular size and the presence of intraventricular hemor- Intractable seizures, low-grade fever, irritability, and poor
rhage, ventriculitis, echogenic sulci, abnormal feeding are relatively specific for NHSV meningoencepha-
parenchymal echogenicities, and extracerebral fluid col- litis.52,53 CSF results may present as normal early in the
lections in the early course of infection. Magnetic reso- course of the illness, but will classically show mononuclear
nance imaging optimizes assessment of injury to white cell pleocytosis, normal or moderately low glucose con-
matter and formation of intracranial abscesses as centrations, and mild elevated protein concentrations. Red
compared to contrast-enhanced computerized tomography blood cells are not significantly associated with NHSV
scan.42 We believe that neuroimaging study 48e72 hours meningoencephalitis.46 Electroencephalogram results are
before the anticipated end of therapy provides the best often abnormal very early in the disease course and may
prognostic information. show focal or multifocal periodic epileptiform discharges.43
The detection of HSV DNA in the CSF of a neonate confirms
6. Herpes simplex virus infection the diagnosis of meningoencephalitis and is more sensitive
than viral culture. Nonetheless, the presence of blood or
high protein concentrations in the CSF may interfere with
6.1. Pathogenesis some PCR assays and produce false-negative results,54 and
> 90% of disseminated NHSV disease may have HSV DNA
Despite the advances in understanding how HSV is transmitted detected in CSF by PCR survey.43 Therefore, it is imperative
to the fetus and neonate, improved molecular methods to to include a CSF examination and HSV PCR for CSF in all
diagnose HSV, and better antiviral treatment strategies,43 neonates with suspected or proven NHSV infection. If initial
neonatal HSV infection remains a clinical challenge. CSF PCR is negative, yet HSV meningoencephalitis is
Most neonatal HSV (NHSV) infections (85%) are acquired strongly suspected, HSV PCR for CSF should be repeated
perinatally.44 Factors including maternal primary- or during the 1st week of illness.55
recurrent-HSV infection, maternal HSV-antibody status,
duration of ruptured membranes, use of fetal scalp moni-
tors, and vaginal delivery affect perinatal transmission.45 6.3. Management
Unfortunately, most NHSV disease occurs in mothers
without a history of HSV infection or other identifiable risk Given that early manifestations of NHSV are frequently
factors.46 Hematogenous spread might result in dissemi- nonspecific and prompt administration improves outcome,
nated disease in the neonate or retrograde spread from the many experts recommend empiric treatment with acyclovir
nasopharynx and olfactory nerves to the brain. in all neonates with aseptic meningitis or other signs and
symptoms of meningoencephalitis without an obvious bac-
6.2. Diagnostic approach terial cause.43,44,51,56 A comprehensive laboratory evalua-
tion for NHSV should be performed before initiation of
Disseminated NHSV infection has an 80% mortality rate if acyclovir therapy. These evaluations would include com-
untreated and often presents in the 1st week of life with plete blood count, liver transaminases, total and direct
nonspecific signs and symptoms, similar to neonatal bilirubin, ammonia (if clinically indicated), blood urea ni-
sepsis.46,47 More than 20% of neonates with disseminated trogen, creatinine, urinalysis, CSF cell count and differential
NHSV disease do not have vesicles,44 therefore, diagnosis of count, glucose, protein, and HSV-DNA PCR with viral culture
disseminated NHSV infection is often delayed due to wait- of the tracheal aspirate if the infant is intubated.43,51
ing for results of possible bacterial sepsis when the clinician Because the persistence of HSV DNA in the CSF is asso-
is not alert to HSV infection. Efforts should focus on ciated with poor outcomes,57 repeated spinal tap to obtain
172 F.-K. Huang et al

CSF HSV-DNA for PCR near the end of therapy is necessary 6. Herting E, Gefeller O, Land M, van Sonderen L, Harms K,
to make sure that HSV-DNA PCR is negative and that CSF Robertson B. Surfactant treatment of neonates with respira-
parameters have returned to normal.43,44,58 tory failure and group B streptococcal infection. Members of
Intravenous acyclovir (20 mg/kg/dose every 8 hours) the Collaborative European Multicenter Study Group. Pediat-
rics 2000;106:957e64.
may increase the dosage interval in patients < 34 weeks
7. Edwards MS. Antibacterial therapy in pregnancy and neonates.
postmenstrual age or in patients with significant hepatic or Clin Perinatol 1997;24:251e66.
renal failure. Treatment duration for localized infections is 8. Hoffman JA, Mason EO, Schutze GE, Tan TQ, Barson WJ,
14 days, however, for disseminated disease or CNS in- Givner LB, et al. Streptococcus pneumoniae infections in the
fections, duration of treatment would be 21 days. neonate. Pediatrics 2003;112:1095e102.
Recent evidence disclosed that suppressive therapy 9. Puopolo KM, Draper D, Wi S, Newman TB, Zupancic J,
might have favorable outcomes in CNS disease and reduce Lieberman E, et al. Estimating the probability of neonatal
cutaneous recurrences.57 Suppressive therapy with oral early-onset infection on the basis of maternal risk factors.
acyclovir (300 mg/m2 per dose, 3 times per day for 6 Pediatrics 2011;128:e1155e63.
months) immediately following parenteral treatment for all 10. Griffin MP, Moorman JR. Toward the early diagnosis of neonatal
sepsis and sepsis-like illness using novel heart rate analysis.
forms of neonatal HSV disease is highly suggested.43,52,58,59
Pediatrics 2001;107:97e104.
11. Newman TB, Puopolo KM, Wi S, Draper D, Escobar GJ. Inter-
7. Conclusion preting complete blood counts soon after birth in newborns at
risk for sepsis. Pediatrics 2010;126:903e9.
12. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-
Emergent infections, such as congenital pneumonia, EOS, reactive protein levels in the diagnosis of neonatal infection.
LOS, meningitis, and NHSV, still exhibit relatively high Pediatrics 1998;102:E41.
mortality rates and result in severe adverse neuro- 13. Maniaci V, Dauber A, Weiss S, Nylen E, Becker KL, Bachur R.
developmental outcomes, especially for PVLBW infants. Procalcitonin in young febrile infants for the detection of
Thus, the approach to treating these emergent infections is serious bacterial infections. Pediatrics 2008;122:701e10.
critical for the pediatrician. This review provides important 14. Terrin G, Passariello A, Manguso F, Salvia G, Rapacciuolo L,
clinical advice for pediatricians. Detailed physical exami- Messina F, et al. Serum calprotectin: an antimicrobial peptide
nations with observation of clinical symptoms are funda- as a new marker for the diagnosis of sepsis in very low birth
weight newborns. Clin Dev Immunol 2011;2011:291085.
mentally important. However, we believe a practical
15. Hedegaard SS, Wisborg K, Hvas AM. Diagnostic utility of bio-
neonatal sepsis scoring system based on risk factors and markers for neonatal sepsis - a systematic review. Infect Dis
common biomarkers is imperative to help pediatricians (Lond) 2015;47:117e24.
predict and diagnose these emergency neonatal infections 16. Yang YN, Tseng HI, Yang SN, Lu CC, Chen HL, Chen CJ. A
more accurately in order to achieve better neuro- strategy for reduction of antibiotic use in new patients
developmental outcomes. admitted to a neonatal intensive care unit. Pediatr Neonatol
2012;53:245e51.
17. Polin RA, Committee on Fetus and Newborn. Management of
Conflicts of interest neonates with suspected or proven early-onset bacterial
sepsis. Pediatrics 2012;129:1006e15.
The authors declare on conflicts of interest. 18. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of
ampicillin and cefotaxime, compared with ampicillin and
gentamicin, for neonates at risk for sepsis is associated with an
Acknowledgments increased risk of neonatal death. Pediatrics 2006;117:67e74.
19. Pickering LK, editor. American Academy of Pediatrics.
Red Book: 2009 Report of the Committee on Infectious Dis-
This study was supported by China Medical University Hos- eases. Elk Grove Village, IL: American Academy of Pediatrics;
pital (grant DMR99-053). We thank Professor Richard Polin 2009.
at the Morgan Presbyterian Stanley Children’s Hospital of 20. Remington JS, Klein JO, Wilson CB, Baker CJ. Group B strep-
New York, NY, USA for his generous and kind help in the tococcal infections. In: Infectious Diseases of the Fetus and
English editing. Newborn Infant. 7th ed. Philadelphia: Elsevier Saunders; 2011.
p. 419.
21. Saiman L, Ludington E, Pfaller M, Rangel-Frausto S, Wiblin RT,
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