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12 Hearing Loss inNeonates Exposed toHerpes Simplex Virus
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Hearing Loss inNeonatal Sepsis
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andMeningitis
ÖzdenTürel, AyşeEnginArısoy,
andGailJ.Demmler-Harrison
13.1 Introduction
Neonatal sepsis and meningitis are worrisome infectious diseases that can lead to
serious consequences. Sepsis is dened as systemic signs of infection and isolation
of a pathogen from the bloodstream [1]. An infant with signs of infection without
culture conrmation from blood or other sterile sites is considered to have clinical
sepsis. Meningitis usually accompanies bacteremia and shares a common cause and
pathogenesis. Patients may have complications such as neuromotor and learning
disabilities, seizure disorders, visual problems, hearing loss (HL), and impaired
cognitive function. Here, the sequelae of neonatal sepsis and meningitis, emphasizing auditory problems, will be discussed.
13
Ö. Türel (*)
Division of Pediatric Infectious Diseases, Department of Pediatrics, Faculty of Medicine,
Bezmialem Vakif University, İstanbul, Türkiye
e-mail: barisbulent98@yahoo.com
A. E. Arısoy
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Kocaeli University,
Kocaeli, Türkiye
e-mail: arisoyengin@yahoo.com
G. J. Demmler-Harrison
Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, and
Infectious Disease Service, Texas Children’s Hospital, Houston, TX, USA
e-mail: gdemmler@bcm.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
A. E. Arısoy et al. (eds.), Hearing Loss in Congenital, Neonatal and Childhood
Infections, Comprehensive ENT, https://doi.org/10.1007/978-3-031-38495-0_13
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Ö. Türel et al.
13.2 Etiology
Neonatal sepsis may develop due to bacterial, viral, fungal, or protozoal infections.
Among neonates treated in the neonatal intensive care units (NICUs), 80% of conrmed infections are bacterial, causing receipt of antibiotics [2]. Bacterial pathogens, the most common causes of sepsis, differ according to the age of onset and
geographical areas. Early-onset sepsis (EOS) occurs in the rst 72h [3]. However,
some experts consider EOS acquired in the rst week of life. Streptococcus agalac-
tiae (group B Streptococcus [GBS]) and Escherichia coli are the most common
pathogens of EOS in high-income countries. Listeria monocytogenes is also a wellknown, relatively rare cause of EOS.In a recent multicenter study in the United
States, GBS (29.8%) was the most common gram-positive bacterial cause of EOS
[4]. Enterococcus and Streptococcus pyogenes (group A Streptococcus [GAS])
were detected in 5.5% and 3.8% of patients. Escherichia coli accounted for 35.3%
of infections, and an increased rate among the very-low-birth-weight (VLBW,
<1500g) infants was observed. Although data is scarce in low- and middle-income
countries, Klebsiella species, E. coli, and Staphylococcus aureus constitute almost
half of neonatal community-acquired infections [5]. Neonatal meningitis develops
most commonly by GBS and E. coli [6]. Streptococcus pneumonia, Neisseria men-
ingitidis, and non-typeable Haemophilus inuenzae may rarely be detected.
Bacterial pathogens encountered in neonatal late-onset sepsis (LOS) are mainly
coagulase-negative staphylococci (CONS), Klebsiella, Enterobacter, and other
gram-negative bacilli (GNB) such as Pseudomonas, Citrobacter, and Serratia spe-
cies in NICUs. Fifty percent of LOS cases in most countries are associated with
CONS [7].
Candida species is the third most common cause of LOS in VLBW infants [8].
Candida parapsilosis has emerged as a signicant cause of catheter-associated
infection in neonates [9]. Herpes simplex virus (HSV) infection may present as a
disseminated neonatal disease. Meningoencephalitis is seen in one-third of neonatal
HSV diseases [10]. Enteroviruses are among other viral causes of meningoencephalitis in neonates [11].
13.3 Microbiology
Group B streptococcus has major virulence factors, including capsular polysaccharide, pili, and C5a peptidase [8]. Capsular polysaccharide is effective in the prevention of phagocytosis. The pili enhance adherence of GBS to the host’s epithelial
cells and transepithelial migration, and C5a peptidase inhibits complement activation. Among ten capsular types, serotypes Ia, Ib, II, III, and V are the most prevalent
in invasive infections of infants [12].
The most crucial virulence factor of E. coli is the K1 capsular antigen [13]. This
antigen is immunologically similar to the capsular antigen of serogroup B N. men-
ingitidis. Strains of E. coli carrying the K1 antigen produce more severe illnesses,
including meningitis than those without the K1 antigen. Bacterial proteins such as
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ompA, ibeA, and ibeB are effective in endothelial invasion and promote penetration
of E. coli into host tissues.
Polysaccharide capsules, which prevent opsonization, phagocytosis, and bacterial lysis, are also responsible for the invasiveness of other bacteria, including
Enterobacter spp., Klebsiella spp., and Serratia spp. [14]. Citrobacter spp. and
Cronobacter sakazakii can cause meningitis and brain abscesses in neonates [15].
Listeria monocytogenes is a facultative anaerobic pathogen found in soil, feces,
and contaminated food and has an afnity to attacking the host’s monocytemacrophage system [8]. By listeriolysin, the bacterium escapes from the oxidative
stress of phagolysosomes and can replicate intracellularly. Lecithinase, phospholipase C, and Act A provide polymerization of actin and lysis of phagosomal membranes, which permit cell-to-cell transmission. The most commonly detected
L. monocytogenes serotypes are 1, 2, and 4, with serotype 4 being the most common
in neonatal meningitis [16].
Staphylococcus epidermidis, the leading species of CONS, is a common skin
colonizer. The ability to form biolms around implantable devices and catheters
makes S. epidermidis a signicant pathogen causing LOS [17]. Biolms protect
bacteria from the host immune system and inhibit antibiotic penetration. Preterm
and low-birth-weight (LBW, <2500g) infants have an increased risk of S. epidermi-
dis sepsis [7]. Other species, such as Staphylococcus haemolyticus, Staphylococcus
hominis, and Staphylococcus capitis, have also been reported in LOS. Staphylococcus
aureus is also responsible for healthcare-associated infections, especially in neo-
nates with vascular catheters [8].
Candida species can colonize the skin, gastrointestinal, and genitourinary tracts.
Both vertical and horizontal transmission can lead to invasive infection in neonates [18].
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13.4 Epidemiology
13.4.1 Incidence
During childhood, meningitis is most common in the rst month of life [19]. Fortyfour percent of all deaths under the age of 5years occur during the neonatal period,
and 26% is assumed to be due to sepsis [20]. Severe infections are the second cause
of neonatal deaths (35%) after birth asphyxia in low- and middle-income countries
[21]. In a neonatal unit in Kenya, among infants with suspected sepsis, 17.9% had
meningitis [22].
Early-onset sepsis has decreased by 80% following intrapartum antibiotic prophylaxis (IAP) in countries administered [23]. The incidence of EOS is 0.77 cases
per 1000 live births in the United States [24]. Limited data show communityacquired sepsis incidence as 21/100,000 person-years for infants under 2months to
1.571/100,000 live births in low- and middle-income countries [25]. Late-onset sepsis prevalence ranges from 14. 0 to 36.4% among infants with birth weight
401–1.500g [26].
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13.4.2 Risk Factors
Preterm birth, premature rupture of membranes, prolonged rupture of membranes
(>18 h), chorioamnionitis, and maternal GBS bacteriuria during pregnancy are
among the risk factors for EOS [27]. Complications during birth and fetal hypoxia
may also lead to infection. In a study, 70.8% of newborns with EOS had a premature
birth compared to 57.1% with LOS, and meningitis was more frequent in patients
with LOS (14%) than EOS (2%) [28]. Early-onset sepsis due to S. aureus has been
associated with invasive procedures antenatally [29].
Pregnant women are infected with L. monocytogenes by ingestion of contaminated food. The organism is transported to the mother’s liver and transplacentally
passed to the fetus [14]. The newborn may also be infected by swallowing the amniotic uid. Seventy percent of infected neonates are preterms due to insufcient
immunity to clear the organism.
Risk factors for LOS are prematurity, endotracheal intubation, catheter insertion,
failure in early enteral feeding, prolonged duration of antibiotic treatment, and
extended hospital stay [8]. Children with underlying respiratory and cardiovascular
diseases are also predisposed to infection. Eleven to 46% of VLBW infants have a
culture-proven infection during hospitalization [30]. In premature neonates, LOS
due to CONS may develop following gut translocation [31].
13.4.3 Morbidity andMortality
The mortality rate of neonatal sepsis depends on gestational age, and the causative
pathogen and varies widely (5–40%) [32]. Infants with VLBW and GNB sepsis
have the highest mortality rate [33]. Pseudomonas sepsis has a mortality rate of
52–78% compared to 10–25% for other GNB.In high-income countries, meningitis
mortality is 10–20%, and 20% of patients develop moderate to severe disabilities
[34]. In low- and middle-income countries, mortality is much higher (40–60%) [35,
36]. Meningitis mortality is increased in premature newborns [37]. Extremely low
cerebrospinal uid (CSF) glucose level (CSF/blood glucose <0.10) is another factor
increasing mortality in meningitis [38].
13.5 Bacteria andHost Interactions
13.5.1 Host andBacterial Factors
Neonates are vulnerable to infections due to the immaturity of the immunity system
[39]. Neutrophilic chemotaxis, T helper 1 (Th 1) cell levels, and complement reactions decrease. Neutrophil functions are decreased in preterm infants. In addition,
they have low concentrations of immunoglobulins (Igs), leading to increased susceptibility to invasive infections. The lectin pathway, an important component of
complement activation, is less expressed in neonates, especially preterms, than in
13 Hearing Loss inNeonatal Sepsis andMeningitis
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older infants [40]. Among 47 neonates with sepsis, the cord blood concentration of
H-colin and mannose-binding lectin were lower than control subjects [40].
Capsular polysaccharides in GBS, H. inuenzae type b (Hib), S. pneumonia, and
N. meningitidis are essential virulence factors [41]. The most common serotype
causing GBS meningitis is serotype III.The cell walls of GNB contain endotoxins,
and those of gram-positive cocci consist of peptidoglycan and teichoic acid. In case
of infection, they cause vascular endothelium damage and breakage of the blood–
brain barrier. As a result, vascular leak, thrombosis, cerebral edema, and cerebral
perfusion impairment may develop.
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13.5.2 Invasion andDisease Production
Early-onset sepsis may occur through the transplacental transmission of infectious
agents such as L. monocytogenes, Treponema pallidum, Mycobacterium tuberculo-
sis, cytomegalovirus (CMV), rubella virus, Toxoplasma gondii, or during labor in
case of colonization of the mother with pathogenic bacteria such as GBS, methicillinresistant S. aureus (MRSA), Pseudomonas, or Salmonella species. Chorioamnionitis
can induce preterm labor, a risk factor for both EOS and LOS [42].
Late infections are caused by environmental organism community-acquired or
healthcare-associated. Bacteria responsible for LOS and meningitis are usually
acquired after birth due to breakage of the—natural—skin and mucosal barriers
with the prolonged use of catheters and invasive procedures such as endotracheal
intubation. Contamination of healthcare personnel’s hands has been accused of
being the most common cause of postnatal infections among hospitalized infants
[43]. Prolonged use of antibiotics, H2 receptor blockers, or proton pump inhibitors
have also been associated with developing LOS [44, 45]. Meningitis can develop by
hematogenous spread via the choroid plexus or, less often, from the contiguous
spread of organisms in babies with open neural tube defects.
13.6 Clinical Manifestations
Clinical features of neonatal sepsis are nonspecic and can be similar to noninfectious problems. Patients may present with seizures, fever or hypothermia, respiratory
difculty, grunting, pallor, or cyanosis. Signs and symptoms of EOS usually appear
during the rst 24–48h and show a multisystemic pattern. In LOS, although many
systems can be affected, focal infections such as pneumonia, skin abscess, arthritis,
osteomyelitis, and meningitis can accompany sepsis [46]. Any changes in the baby’s
activity and feeding difculty should be regarded as clues for infection [27].
Listeria monocytogenes-infected babies usually have an embolic granulomatous
rash and hepatosplenomegaly. Meconium staining of amniotic uid, apnea on the
rst day or after 2weeks, hypoglycemia, and metabolic acidosis may be associated
with sepsis [47]. Bulging fontanelle has been reported in 30% and seizures in up to
50% of infants with meningitis [27].
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13.7 Diagnosis andLaboratory Findings
Blood culture is the gold standard and should always be taken before antibiotic therapy. The sensitivity of a single blood culture is 90% in diagnosing bacteremia [27].
The blood culture is considered positive for the etiologic agent if the isolated bacteria
is a known pathogen [2]. Time to positivity shows the level of bacteremia, and most
true positives occur within 48h [48]. Central line blood cultures should be taken with
simultaneously peripheral blood cultures. The sensitivity of C-reactive protein (CRP)
positivity (>1mg/dL) is high (50–90%) at the time of clinical signs [27]. Decreased
neutrophil count and increased immature to total leukocytes may indicate sepsis
[49]. A CSF examination should be performed in suspected sepsis since blood cul-
tures may be negative in 28–38% of neonates with bacterial meningitis [50].
13.8 Treatment
13.8.1 Empirical Treatment
Empirical antimicrobial therapy for EOS is recommended as ampicillin plus an
aminoglycoside. When cefotaxime was used instead of gentamicin during the rst
3 days after birth, an increased risk of death was observed [51]. Communityacquired LOS is treated with the same regimen. For meningitis, the combination of
ampicillin plus an aminoglycoside, mainly gentamicin, and an expanded-spectrum
cephalosporin is recommended [27]. Neonates with signs of staphylococcal infection, such as extensive skin pustules, abscesses, or omphalitis, are recommended to
receive cloxacillin rather than ampicillin [20]. Vancomycin is substituted with
ampicillin for LOS in neonates hospitalized since birth [27]. Ampicillin should be
added if GBS, enterococci, or Listeria infections are suspected [52]. If the NICU is
risky for multiresistant pathogens, meropenem may be used instead of cefotaxime.
Although multidrug-resistant gram-negative bacterial infections are uncommon in
NICUs in the United States, prevalence is increasing in older children [53].
Table 13.1 summarizes recommended empiric antibiotics and doses for neonatal
sepsis and meningitis [27, 52].
13.8.2 Specific Treatment
In neonates with suspected GBS meningitis, if a repeat lumbar puncture (LP) at
24–48h shows CSF sterilization, penicillin G or ampicillin monotherapy is given
for 14days [27]. Listeria monocytogenes meningitis is treated with ampicillin or
penicillin plus gentamicin [52]. If the patient is improved and CSF sterilization is
obtained, a 21-day course of therapy is completed with ampicillin. For meningitis
with methicillin-susceptible S. aureus (MSSA), nafcillin or oxacillin is preferred.
Vancomycin is recommended for treating MRSA meningitis, with a 14-day treatment duration [32].
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183
Table 13.1
Recommended empiric antibiotics and doses for sepsis and meningitis in neonates
Condition Antibiotic (Intravenous)
Early-onset
sepsis (EOS)
in term
Early-onset
sepsis (EOS)
in preterm
Ampicillin
plus
Gentamicin
Ampicillin
plus
Gentamicin
a
b
Meningitis Ampicillin
plus
Gentamicin
plus
An expanded-spectrum
cephalosporin
Late-onset
sepsis (LOS)
in terms
(communityacquired)
Late-onset
sepsis (LOS)
in preterm
(e.g., ceftazidime, cefepime, or
cefotaxime)
Ampicillin
plus
Gentamicin or
spectrum cephalosporin
(e.g., ceftazidime, cefepime, or
cefotaxime)
Vancomycin
plus
Gentamicin or amikacin
c
an expanded-
c
e
hospitalized
since birth
Late-onset
meningitis in
neonates
hospitalized
since birth
Vancomycin
plus
Gentamicin
plus
An expanded-spectrum
cephalosporin
(e.g., ceftazidime, cefepime, or
cefotaxime)
c
Dose (mg/kg/day)
Ampicillin
200–300,
divided q8h
Gentamicin
5, divided q12h
Ampicillin
300, divided
q6h
Gentamicin
7.5, divided
q8h
Dose and frequency change
according to gestational age
and birth weight
Serum levels of gentamicin are
required if therapy is given for
>72h, renal function is
abnormal or unstable, or birth
weight is <1500g
2
Ampicillin
300, divided
q6h
Gentamicin
Ceftazidime
50, divided
q8h
Same in
meningitis
Vancomycin
30–45,
divided q6h
or q8h
Amikacin
30, divided
Ampicillin
300, divided
q8h
Gentamicin
Ceftazidime
100–150,
divided q12h
Same in
meningitis
Vancomycin
20–30, divided
q8h or q12h
Amikacin
15–20, divided
q12h
q8h
Same in
meningitis and
LOS
Same in
meningitis
and LOS
Duration
(days)0–7days 8–28days
10
14–21
14–21
2
10–14
14–21
14–21
(continued)
d
d
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Table 13.1 (continued)
Condition Antibiotic (Intravenous)
LOS with
intestinal
source
suspected
Ampicillin,
gentamicin,plusclindamycin
or
Ampicillin,
gentamicin,plusmetronidazole
or
Piperacillin-
Dose (mg/kg/day)
Clindamycin
f
5–20, divided q6h or q8h
Metronidazole
Loading 15
g
Piperacillin-tazobactam
g
240–300mg piperacillin,
divided q6h or q8h
Duration
(days)0–7days 8–28days
10–14
tazobactamplusgentamicin
Adopted and modied from Refs. [27, 52]
a
Ampicillin dose for noncentral nervous system infections: 50mg/kg/dose every 8h for neonates
≤2kg and ≤34 weeks during the rst week of life; 75 mg/kg/dose every 12h between 8 and
28days of life
b
Gestational and postnatal ages for gentamicin dose:
<30weeks
≤14days
5mg/kg per dose intravenous (IV) every 48h (h)
>14days 5mg/kg per dose IV every 36h
30–35weeks
≤14days
5mg/kg per dose IV every 36h
>14days 5mg/kg per dose IV every 24h
≥35weeks ≤7days
4mg/kg per dose IV every 24h
>7days 5mg/kg per dose IV every 24h
c
Meningitis/sepsis caused by the community and hospital-acquired extended-spectrum betalactamase (ESBL) producing and multiple drug resistant (MDR) gram-negative organisms may be
seen in some newborns. If ESBL-producing or MDR gram-negative organisms are suspected, consider carbapenem, such as meropenem, until susceptibilities are known
d
Reassess at 14–21days end of treatment to see if prolonged therapy is indicated. In cases of ventriculitis and/or brain abscess development, extend treatment to 28–42days
e
Vancomycin initial loading dose: 20 mg/kg; subsequent dosing is based on gestational age and
serum creatinine level
f
Gestational age for clindamycin dose:
≤32weeks
5mg/kg/dose every 8h
>32–40weeks 7mg/kg/dose every 8h
>40weeks 9mg/kg/dose every 8h
g
Gestational age for metronidazole dose:
≤34weeks
7.5mg/kg/dose every 12h
>34–40weeks 7.5mg/kg/dose every 8h
>40weeks 7.5mg/kg/dose every 6h
or 10mg/kg/dose every 8h
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