Neonatal sepsis is an
important cause of morbidity and mortality of newborns and a major cause of
prolonged hospitalization, especially in preterm infants and neonates with very
low birth weight [1]. The incidence of neonatal sepsis in high-income countries
is estimated between 1 and 12 per 1000 live births [2]. Whereas the incidence
in low and middle-income countries is higher, with about 62.5 % neonatal
emergencies being attributed to sepsis in some settings [3]. Mortality rates up
to 70% have been observed in some low- and middle-income countries, making the
pathology not only an old issue, but an important and persistent concern in
pediatrics and public health at large [4]. Frequently reported risk factors
include low birth weight (<2500grams) and preterm, febrile illness in the
mother within 2 weeks prior to delivery, Foul smelling and/or meconium stained
amniotic fluid, prolonged rupture of membranes (>24 hours), repetitive
vaginal examinations during labor, prolonged and difficult delivery with instrumentation,
as well as difficult resuscitation [5]. The source of infection may also be
nosocomial or community acquired through admission in the Neonatal Intensive
Care Unit (NICU), poor hygiene, poor umbilical cord care, bottle feeding,
invasive procedure, superficial infection, prelacteal feeding, ventilation, and
aspiration of feeds [6]. The most frequently involved pathogens in bacterial
neonatal sepsis of term and preterm infants are the Group B streptococcus (GBS)
and Escherichia coli, which account for approximately 70% of sepsis. Group B
streptococcus (GBS) is the most common etiologic agent, while Escherichia coli
is the most common cause of mortality [7]. Other bacteria involved are
Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus species.
Gram-negative enteric bacilli such as Enterobacter species, Haemophilus and
Listeria monocytogenes [8]. Similarities of the pathogenic bacterial ecologies
and hence the treatment for sepsis in infants within the first three months of
life has led to an extrapolated definition of neonatal sepsis, beyond the
neonatal period [9]. Because of its severity and incidence, there have
gradually been a focalization on bacterial sepsis, and less for others, with
non-bacterial pathogens rarely discussed. Nevertheless, viral infections,
including herpes simplex virus (HSV), enteroviruses, and parechoviruses, may
also be responsible for neonatal sepsis and need to be differentiated from
other causative agents [10]. Some viruses such as rubella virus, cytomegalovirus
may equally be involved in congenital infections, with an onset which is
earlier before the neonatal period, while seasonal viruses including influenza
virus, respiratory syncytial virus (RSV), adenoviruses, rhinoviruses, and
rotaviruses may sometimes be implicated in neonatal sepsis as well [11]. On the
other hand, very few fungal pathogens apart from Candida species are
responsible for sepsis in neonates [12]. Most pathogens responsible for
neonatal sepsis are colonizers of the maternal urogenital tract from which they
may ascend through the vagina and the cervix to infect the chorion, the amnios
(chorioamnionitis) and placenta, contaminating the amniotic fluid. This is
favored by prematurely and prolonged ruptured membranes occurring before the
start of labor. Due to this phenomenon, the infant may be infected in utero, or
on its passage through the birth canal during delivery. Moreover, hematogenic
contamination from an infected mother through the placenta is also possible,
just as environmental and community borne neonatal infections [13]. The
pathophysiology of sepsis in neonates may be explained as an immunological
response mainly from the innate and less from the adaptive immune system,
occurring as a result of the penetration of a pathogen into the bloodstream,
creating a septic state [14]. This induces a systemic inflammatory response
which is more or less responsible for the signs, symptoms and biological
manifestations observed (SIRS). Maternal transfer of IgG via the placenta is
proportional to gestational age and makes preterm infants more vulnerable. IgA,
IgG, cytokines and antibacterial peptides are low as well in term neonates and
only rises with continuous breastfeeding, meanwhile the full functionality of
the spleen is acquired with time as the neonate develops [15]. Due to the
immaturity of the immune system in neonates, the progression of bacteremia is
rapid and clinical manifestations may be subtle, in which case sepsis may
evolve towards severe sepsis and eventually septic shock [16]. The clinical
manifestations of neonatal sepsis are diverse and mainly depend on gestational
age and the severity of the infection. They may occur as early as within the
first 24 h of life [17]. Unexpectedly, Fever could be rare and hypothermia
considerably common. Some general symptoms include lethargy, poor activity,
poor feeding and hypothermia, while anuria and acidosis seems nonspecific.
Common respiratory symptoms are apnea, tachypnea, grunting, nasal flaring, and
intercostal retractions [18]. Digestive symptoms such as abdominal cramps
(wriggling or squirming), vomiting, diarrhea, hematemesis and melena need to be
investigated, while abdominal distension, hepatomegaly and splenomegaly are
important signs. Cardiac signs such as cyanosis, desaturation, bradycardia,
poor perfusion, reduced capillary refill, and hypotension may occur as well
[19]. Convulsion, neurologic deficits and irritability are frequent symptoms,
whereas attenuated reflexes, hypotonia, and bulging fontanelle are common
neurological signs to look for. Rash, petechiae, purpura, and jaundice are the
main reported cutaneous signs. It is important to recall that subtle changes in
respiratory status, temperature instability, or feeding problems can be the
first signs of a life-threatening infection in a neonate [20]. Therefore,
considering the non-specificity of the semiology of neonatal sepsis, all
symptomatic neonates should be suspected of neonatal sepsis until it is proven
otherwise. Although novel diagnostic tools from biomarkers to molecular
diagnosis such as acute phase reactants (C-reactive protein, ferritin,
lactoferrin, neopterin, procalcitonin, serum amyloid A), cytokines (tumor
necrosis factor-alpha, Interleukins), Leucocyte surface markers, endotoxin and
Polymerase chain reaction offer substantial promises for detecting neonatal
sepsis, the paraclinical diagnosis for neonatal sepsis has historically relied
on full blood count, urinalysis, cerebrospinal fluid analysis and blood culture
which is the gold standard. However, a combination of anamnestic information,
physical examination and laboratory findings appears to be indispensable and
more reliable [21]. Primary prevention of neonatal sepsis is by optimal
prenatal follow-up including vaccinations. Intrapartum chemoprophylaxis with penicillin
for mothers with prenatal GBS-positive cultures or unknown GBS status is a
recommended preventive therapy as well [22]. Best obstetrical practices,
effective newborn care and neonatal immunization is also a necessity, while
caesarean delivery may sometimes be indicated in case of active genital tract
infection such as Herpes Simplex Virus [23]. Good hygiene and dietetic
practices is encouraged. Mothers’ education to recognize danger signs which may
enable prompt diagnosis and management is necessary and has a key role in the
prevention of microbial dissemination in neonates. The early diagnosis of
neonatal sepsis, just as the choice of antibiotics for an infant with suspected
sepsis depends upon the predominant pathogen and antibiotic sensitivity pattern
of a given region. However, a broad spectrum antibiotherapy is often
recommended, especially in developing countries, and the treatment is usually
started before a definitive causative agent is identified [24]. The
antibiotherapy consists of a penicillin, usually ampicillin, which targets GBS
plus an aminoglycoside such as gentamicin for synergistic effect. A third
generation cephalosporin such as cefotaxim (with the advantage of not inducing
jaundice) covering the gram negative bacteria is often combined, especially
when meningitis is suspected. In case of
community acquired neonatal sepsis, cloxacillin targeting staphylococcus aureus
may be used in replacement of ampicillin. Because of the continuous emergence
of bacterial resistance, combinations like ceftazidim/amikacin,
imipenem/amikacin, and ciprofloxacin are respectively used as 2nd, 3rd and 4th
line drugs in some settings. Supportive
care is important as well and can’t be dissociated from the overall management
of neonatal sepsis [25].