The fetal environment within the amniotic membranes is normally sterile until the
onset of labor and delivery. Once the membranes are ruptured, the infant may be at
risk for colonization of microorganisms from the maternal genital tract. Many of these
organisms do not cause infection in the mother, but may be detrimental to the infant.
Early-onset neonatal sepsis (sepsis that presents during the first 72 hours of life)
usually is caused by organisms acquired from the maternal genital tract. The most
common pathogens found in early-onset neonatal sepsis are group B streptococcus
(50%) and E. coli (20%). Other primary pathogens include Listeria monocytogenes,
Enterococcus, and other gram-negative bacilli (e.g., H. influenzae, Klebsiella
Late-onset sepsis (sepsis presenting after 3 days’ PNA) usually is caused by these
primary organisms or by nosocomial pathogens, such as coagulase-negative
staphylococci (CONS), particularly S. epidermidis, S. aureus, Pseudomonas species,
anaerobes, and Candida species.
84,86 The presence of IV catheters (umbilical or
central) and duration of parenteral hyperalimentation are major risk factors for
86,87 Other risk factors include prematurity, low birth weight,
prolonged hospital stay, prior antibiotic use, lipid emulsion, use of H2
invasive procedures, GI disease (including NEC), the presence of other indwelling
devices (e.g., ETTs, ventriculoperitoneal shunts), and nasal CPAP.
percent of late-onset sepsis in VLBW infants is caused by gram-positive organisms,
with CONS being the most common pathogen (68%); S. aureus, Enterococcus
species, and group B streptococcus account for the remainder.
continuation of antibiotic therapy, it is important to distinguish whether patient
isolates of CONS are the result of colonization of the catheters or IV tubing or
Neonatal sepsis may present with nonspecific or subtle signs, especially in VLBW
81 The most common signs are poor feeding, temperature instability, lethargy,
81,83 Other signs of neonatal sepsis include glucose instability (hypoglycemia
or hyperglycemia), tachycardia, dyspnea or cyanosis, tachypnea, diarrhea, vomiting,
feeding intolerance, abdominal distension, metabolic acidosis, and abnormal WBC.
Clinical signs and laboratory evidence of neonatal sepsis observed in J.E. include
tachycardia (HR, 190 beats/minute), hypothermia (temperature 35.8°C), leukopenia
/μL), neutropenia (absolute neutrophil count of 960/μL), a left shift
in the differential (i.e., an immature-to-total neutrophil ratio [I/T] of 0.38),
thrombocytopenia (platelets, 45,000/μL), and an elevated CRP (5 mg/dL).
Hypothermia is more common than fever in neonatal sepsis, especially in preterm
newborns. However, if fever is present, it is strongly associated with bacterial
infection. Neutropenia, especially with a left shift (as seen in J.E.), can be a sign of
WBC depletion from bone marrow owing to overwhelming sepsis. An elevated
WBC also can indicate a neonatal infection, but may be less specific. The I/T ratio,
defined as band forms plus any earlier cells divided by the total neutrophil count
(including early cells), has been shown to be useful in diagnosing neonatal sepsis. An
I/T ratio of less than 0.3 is normal.
82 CRP, an acute-phase reactant protein associated
with tissue injury in response to an inflammatory process, may also be included as
part of a sepsis workup. A CRP level of more than 1 mg/dL indicates inflammation
In infants with bacterial infection, serum CRP levels begin
to increase from 6 to 8 hours after the onset of the illness and peak after 2 to 3 days.
illness may aid in the determination of duration of empiric antibiotic therapy.
Empiric antibiotic therapy may be discontinued in infants with normal serial CRP
levels in the absence of any clinical signs suggestive of sepsis. However, elevated
CRP levels can be found in other clinical conditions such as viral infection, ischemic
tissue injuries, hemolysis, or chorioamnionitis. Procalcitonin, another acute-phase
reactant, rises more quickly than CRP in the presence of bacteria so it may be more
useful for early detection. However, there are also limitations to its routine use for
the evaluation of neonatal sepsis including nonspecificity (i.e., noninfectious
conditions can cause elevation of procalcitonin levels) and a lack of age-specific
89 Therefore, CRP and procalcitonin levels should be used with
caution as the sole diagnostic criteria for sepsis or bacteremia. Late signs of neonatal
infection include jaundice, hepatosplenomegaly, and petechiae.
posturing, or seizures indicate meningitis, although these CNS signs are not always
present when meningitis exists.
Bacterial meningitis should always be considered in infants with neonatal sepsis.
The major pathogens causing neonatal sepsis are also the primary pathogens that
83 The definitive diagnostic method for bacterial meningitis
is lumbar puncture. Lumbar puncture should be performed in infants with a positive
blood culture, abnormal neurologic signs, an elevated WBC or left shift, or the
presence of bacteria in the urine.
90 A lumbar puncture is not needed in neonates
receiving empiric antibiotics solely because of maternal risk factors.
important to note that a negative blood culture does not dictate the absence of
bacterial meningitis. Approximately 1 of every 4,000 live births has culture-proven
bacterial meningitis, and 15% to 50% of infants with bacterial meningitis may have a
89 The cerebrospinal fluid (CSF) should be tested with a Gram
stain, cell counts with differential, glucose and protein levels, and bacterial culture.
Normal CSF cell counts and protein concentrations are different for neonates
compared with older children and adults. For example, the CSF protein concentration
in a healthy neonate is about 2 to 3 times that of an adult and decreases with age;
preterm infants may have higher levels.
79 Neonatal CSF cell counts are also difficult
to interpret because values observed with meningitis may overlap with normal
neonatal values. The diagnosis of neonatal sepsis is confirmed by isolation of the
pathogen from blood, urine, CSF, or other body sites.
Treatment of Sepsis and Meningitis
CASE 105-5, QUESTION 2: What antibiotic regimen should be prescribed for J.E.?
Empiric treatment with appropriate IV antibiotics must be initiated immediately in
J.E. Significant morbidity or fatality would occur if antibiotics were withheld until a
diagnosis was confirmed by culture results (in 24–72 hours). This is especially true
in patients in whom meningitis is suspected. The initial empiric antibiotic treatment
of choice for early-onset neonatal sepsis and meningitis is ampicillin plus an
aminoglycoside (Tables 105-3, 105-4).
2,91–93 These antibiotics are used because they
(a) are bactericidal against the common neonatal pathogens; (b) penetrate into the
CNS; (c) are relatively safe; and (d) have proven clinical efficacy. If the culture is
positive for group B streptococcus, ampicillin should be replaced with high-dose
penicillin G because of its higher activity against group B streptococcus. If
meningitis is highly suspected, gentamicin may be replaced by a third-generation
cephalosporin (i.e., cefotaxime) owing to greater CSF penetration compared with
Gentamicin Dosing Guidelines for Neonates and Infants
Age Extended-Interval Dosing Regimen
PMA <32 weeks 4–5 mg/kg/dose every 36–48 hours
PMA 32–36 weeks 4–5 mg/kg/dose every 36 hours
PMA ≥37 weeks 4–5 mg/kg/dose every 24 hours
decreased peripheral perfusion).
Therefore, ampicillin 85 mg every 12 hours IV plus an aminoglycoside (e.g.,
gentamicin 4.2 mg every 48 hours IV) should be started in J.E. for suspected neonatal
sepsis and possible meningitis. Meningitic doses of ampicillin should be used in J.E.
until meningitis can be ruled out. Ampicillin is active against group B streptococci,
Enterococcus, Listeria, and some strains of E. coli. Aminoglycoside antibiotics (e.g.,
gentamicin or tobramycin) usually are active against gram-negative bacilli. In
addition, aminoglycosides may provide synergy with ampicillin against Listeria and
82 Selection of the specific aminoglycoside should be
determined by antibiotic resistance patterns within the neonatal ICU. Amikacin
should be reserved for gram-negative organisms resistant to gentamicin and
tobramycin. Aminoglycoside regimens need to be designed to achieve safe and
therapeutic serum concentrations (traditional dosing regimens: gentamicin and
tobramycin, peak 6–8 mcg/mL, trough <2 mcg/mL; amikacin peak 20–30 mcg/mL,
trough <10 mcg/mL) and to aim for a peak concentration that is more than 8 times
greater than the minimum inhibitory concentration (MIC) of the organism being
If extended-interval aminoglycoside dosing is used, peak gentamicin and
tobramycin serum concentrations of 10 to 12 mcg/mL and trough concentrations of
less than 1 mcg/mL may be reasonable, depending on the MIC.
Traditionally, aminoglycosides were administered to neonates in multiple daily
doses (e.g., gentamicin 2.5 mg/kg/dose 2 or 3 times a day). This dosing strategy
frequently resulted in peak serum concentrations below and trough concentrations
above the respective target ranges especially in preterm neonates. Evolution of the
understanding of developmental pharmacokinetics resulted in knowledge that
neonates have a larger volume of distribution for water-soluble drugs and a slower
renal elimination of aminoglycosides compared to infants, older children, and
95 Thus, many institutions now use higher mg/kg doses of aminoglycosides
(e.g., gentamicin 4–5 mg/kg) administered at prolonged dosing intervals (every 24,
36, or 48 hours; commonly determined by GA or PMA).
concluded that administering higher mg/kg aminoglycoside doses at prolonged
intervals to neonates was as effective as multiple daily doses without evidence of
increased toxicity. Serum peak and trough concentrations also were more likely to be
Antimicrobial Dosage Regimens for Neonates: Dosages and Intervals of
<1,200 g Weight 1,200–2,000 g Weight >2,000 g
Deoxycholate 1 every 24 1 every 24 1 every 24 1 every 24 1 every 24
bHigher dosage may be needed for meningitis.
cDoses listed are for treatment of group B streptococcal meningitis.
This dosing strategy (of giving higher mg/kg/doses at prolonged intervals) in
neonates is commonly referred to as extended-interval aminoglycoside dosing;
however, it should not be confused with the adult dosing method of the same name.
Extended-interval aminoglycoside dosing (also known in adults as once-daily dosing
or single-daily dosing) has been widely used in the adult population. Aminoglycoside
antibiotics display concentration-dependent killing of bacteria. Rationale for the use
of extended-interval aminoglycoside dosing include (a) enhancement of bacterial
killing by providing a higher peak serum concentration to MIC ratio, (b) provision of
a prolonged post-antibiotic effect, and (c) minimization of adaptive postexposure
microbial resistance by achieving a drug-free period at the end of the dosing
99 Key differences between this approach to aminoglycoside dosing in adults
and the use of higher mg/kg doses given at prolonged intervals to neonates include the
following: (a) Peak concentrations of ~20 to 25 mcg/mL are targeted in adults
compared to 8 to 12 mcg/mL in neonates, (b) a drug-free period occurs at the end of
the dosing interval in adults, while acceptably low, but measurable trough
concentrations are commonly observed in neonates, and (c) a standardized dosing
nomogram allows for interval adjustments based on a single serum concentration
(drawn 8–12 hours postdose) in adults; however, routine peak and trough
concentration monitoring is recommended for neonates.
In some nurseries, a third-generation cephalosporin (e.g., cefotaxime), instead of
an aminoglycoside, is added to ampicillin for initial empiric treatment of early-onset
neonatal sepsis and meningitis.
streptococci. Ceftriaxone should be avoided in neonates with hyperbilirubinemia
owing to bilirubin displacement from albumin-binding sites. Ceftriaxone has also
been associated with sludging in the gallbladder and cholestasis.
increase in serum free bilirubin concentrations and decrease in bilirubin elimination
can place the neonate at risk for kernicterus. In addition, calcium–ceftriaxone
precipitates have been found in the lungs and kidneys of neonates when ceftriaxone
was administered with calcium-containing solutions. Several fatalities have been
94 Hence, cefotaxime is the preferred cephalosporin
The third-generation cephalosporins have advantages over the aminoglycosides,
including better CNS penetration, the elimination of serum concentration
measurements, and less nephrotoxicity. However, these cephalosporins do not
significantly improve clinical or microbiologic end points compared with the
standard ampicillin and gentamicin regimen. In fact, overuse of cefotaxime during the
first few days of life has been associated with an increased risk of death compared
94 Furthermore, extensive use of the third-generation
species) and vancomycin resistance in enterococci. Also, prolonged treatment has
been associated with an increased risk of neonatal candidiasis.
rare cases of gentamicin resistance have been reported.
ampicillin and cefotaxime should be reserved for the following situations: (a)
neonatal ICUs in which aminoglycoside resistance to gram-negative enteric bacilli is
of concern, (b) neonatal ICUs in which serum concentrations of aminoglycosides
cannot be measured, and (c) specific neonates in whom aminoglycoside therapy
could be of concern (e.g., neonates with known renal failure).
Therapy for late-onset sepsis or meningitis is directed toward nosocomial
pathogens plus the primary pathogens of early-onset infection. Selection of initial
antibiotic therapy should consider the specific neonatal ICU’s nosocomial pathogen
and antibiotic resistance patterns, as well as the neonate’s risk factors, clinical
condition, and previous antibiotic therapy. CONS is now the most common pathogen
of late-onset neonatal nosocomial septicemia.
101 Because of the high incidence of
methicillin-resistant CONS, vancomycin has been used as the drug of choice for
empiric therapy for suspected late-onset neonatal sepsis. However, widespread use
of vancomycin has led to the emergence of vancomycin-resistant Enterococcus and S.
aureus. Therefore, the routine use of vancomycin as empiric therapy for nosocomial
neonatal sepsis should be discouraged. The highly selective use of vancomycin for
neonatal CONS septicemia results in low morbidity and mortality, while significantly
reducing vancomycin use. Guidelines for the selective use of vancomycin should be
tailored according to individual neonatal ICU’s nosocomial pathogens, susceptibility
patterns, and patient risk factors, clinical condition, and antibiotic history. Therefore,
if J.E. had a central venous catheter and presented with a late-onset sepsis, initial
antibiotic therapy should include an aminoglycoside (for gram-negative coverage)
plus either an antistaphylococcal penicillin (e.g., nafcillin, methicillin) or
vancomycin (for activity against S. aureus and S. epidermidis). Vancomycin is used
For systemic fungal infections, amphotericin B is considered the initial treatment
83 Because of the high incidence of Candida species colonization (up to
60%), with up to 20% progressing to invasive fungal infections in VLBW infants,
prophylactic fluconazole may be used to prevent Candida colonization and infection
Infants of 27 weeks’ gestational age or less and weighing less than
1,000 g benefited most from prophylactic fluconazole. Despite potential benefits,
routine use of prophylactic fluconazole is not recommended and should be reserved
for those units with a high incidence of fungal infections. Because uncommon
organisms are not suspected in J.E., the regimen of ampicillin 85 mg IV every 12
hours plus gentamicin 4.2 mg IV every 48 hours is appropriate.
Once a pathogen is isolated, the antimicrobial susceptibilities should be evaluated
and the drug therapy modified appropriately. Blood, CSF, or urine cultures should be
repeated to document bacterial sterilization after 24 to 48 hours of appropriate
therapy. J.E. should be evaluated carefully for the development of serious bacterial
complications such as meningitis, osteomyelitis, abscess formation, or endocarditis.
As long as there is no evidence of meningitis or other focal infection (e.g., abscess
formation), the duration of therapy for most systemic bacterial infections is 7 to 10
days (or approximately 5–7 days after significant clinical improvement). Antibiotic
therapy may need to be continued for 14 to 21 days if the neonate’s clinical response
is slow or if multiple organ systems are involved.
If cultures are negative at 48
hours and the infant does not have any clinical or laboratory signs of sepsis,
antibiotics can be discontinued. In neonates presenting with signs of severe infection
followed by improvement after initiation of antibiotics, therapy may be continued
If CSF cultures are positive, repeat CSF cultures should be obtained daily or every
other day in J.E. to document when the CSF becomes sterilized. The duration of
therapy for neonatal meningitis depends on the clinical response and duration of
positive CSF cultures after therapy is initiated. Appropriate antibiotics should be
continued for a minimum of 14 days after the CSF is sterilized. This is equivalent to a
duration of antibiotic therapy for a minimum of 21 days for gram-negative organisms
and at least 14 days for gram-positive pathogens.
81,83 As a general rule, it takes longer
to sterilize the CSF of neonates infected by gram-negative enteric bacilli (72 hours)
than those infected by gram-positive bacteria (36–48 hours).
What other tests and information are needed for S.Y. at this time?
Certain bacteria, viruses, and protozoa can cause fetal infections that may result in
fetal death, congenital anomalies, serious CNS sequelae, intrauterine growth
retardation, or preterm birth.
99 The primary organisms that cause these infections can
be remembered by the acronym, TORCH: toxoplasmosis; other (i.e., syphilis,
gonorrhea, hepatitis B, listeria); rubella; cytomegalovirus; and herpes simplex.
Because of the potential severity of these diseases, newborns who display any signs
of infection (e.g., irritability, fever, thrombocytopenia, hepatosplenomegaly) need to
be evaluated for these intrauterine and perinatally acquired infections. The diagnosis
of each of these infections should be considered separately. A complete infectious
disease workup should include specific antibody titer measurements or polymerase
chain reaction (PCR) to the suspected organisms rather than sending a single serum
sample for TORCH titer measurement.
Primary clinical manifestations and treatment for selected congenital infections are
2,84,103–106 The clinical signs of these infections may overlap, and
concurrent infection with two or more microorganisms is possible. The detection of
congenital infections often is difficult because many neonates are asymptomatic at
birth. Therefore, prenatal maternal screening and accurate evaluation of maternal
history for risk factors are very important. Other organisms that can cause
congenitally acquired infections include human immunodeficiency virus, human
parvovirus, varicella-zoster virus, and measles virus.
When congenital infections are suspected, appropriate diagnostic tests for each
suspected organism should be performed. Viral cultures of the urine, oropharynx,
nasopharynx, stool, and conjunctiva, and a complete maternal history along with the
results of recent maternal vaginal cultures also should be obtained.
of immunoglobulin M levels specific for each possible organism under consideration
are also recommended. S.Y. has signs of a congenital infection (respiratory distress,
skin rash, and conjunctivitis). Because of the nature of S.Y.’s skin rash (i.e.,
vesicular), infection with the herpes simplex virus (HSV) should be highly suspected.
Skin vesicles, conjunctiva, oropharynx, nasopharynx, rectum, urine, and CSF should
be cultured for HSV and other organisms known to cause congenital infections. Rapid
diagnostic testing using tissue scrapings from vesicles and fluorescein-conjugated
monoclonal HSV antibody can also be performed. Other appropriate tests for the
diagnosis and workup of suspected congenital infections should also be performed
(e.g., liver enzymes, prothrombin time, partial thromboplastin time,
electroencephalogram [EEG], computed tomography scan, or magnetic resonance
Selected Congenital and Perinatal Infections in the Neonate
Organism Primary Clinical Manifestations
Herpes simplex Cutaneous vesicles, keratoconjunctivitis, microcephaly, CNS
infection, hepatitis, pneumonitis, prematurity, respiratory distress,
sepsis, convulsion, chorioretinitis
Toxoplasmosis Chorioretinitis, ventriculomegaly, microcephaly, hydrocephaly,
intracranial calcifications, ascites, hepatosplenomegaly,
lymphadenopathy, jaundice, anemia, mental retardation
Early: Osteochondritis, periostitis, hepatosplenomegaly, skin rash
(maculopapular or vesiculobullous), rhinitis, meningitis, IUGR,
jaundice, hepatitis, anemia, thrombocytopenia, chorioretinitis
Late: Hutchinson triad (interstitial keratitis, VIII
Hutchinson teeth), mental retardation, hydrocephalus, saddle nose,
Hepatitis B Prematurity; usually asymptomatic; long-term effects include
chronic hepatitis, cirrhosis, liver failure, hepatocellular carcinoma
(maternal HbsAgpositive): HBIG and
Rubella Early: IUGR, retinopathy, hypotonia, hepatosplenomegaly,
thrombocytopenic purpura, bone lesions, cardiac effects
Late: Hearing loss, mental retardation, diabetes
Rare: Myocarditis, glaucoma, microcephaly, hepatitis, anemia
Cytomegalovirus Petechiae, hepatosplenomegaly, jaundice, prematurity, IUGR,
increased liver enzymes, hyperbilirubinemia, anemia,
thrombocytopenia, interstitial pneumonitis, microcephaly,
chorioretinitis, intracranial calcifications
Late: Hearing loss, mental retardation, learning and motor
abnormalities, visual disturbances
Ophthalmia neonatorum, scalp abscess, sepsis, arthritis,
aSee references 2 and 84 for dosing and recommended treatment duration.
intrauterine growth retardation.
Apnea in neonates is a life-threatening condition that occurs more frequently in
premature newborns and newborns of lower birth weights. Only 7% of infants of 34
to 35 weeks’ gestational age have apnea.
In contrast, the incidence of apnea has
been reported to be 78% in infants of 26 to 27 weeks’ gestational age and 84% in
infants with birth weights less than 1,000 g.
108 Although several definitions exist,
clinically significant apnea may be defined as cessation of breathing for at least 15
seconds, or less, if accompanied by bradycardia (HR <100 beats/minute), significant
107,109,110 Pallor or hypotonia also may occur.
In neonates, apnea may be caused by a severe underlying illness (e.g., infection,
metabolic disorders, intracranial pathology), drugs, or prematurity itself.
Appropriate patient history, physical examination, and laboratory tests must be
evaluated to rule out other causes of apnea before the diagnosis of apnea of
It is especially important to rule out sepsis before apnea
of prematurity is presumed. If an etiology other than prematurity is identified, therapy
would be directed toward that specific cause. For example, antibiotics are used to
treat neonatal sepsis with secondary apnea.
Apnea of prematurity is classified into three types: central, obstructive, and mixed.
Approximately 40% of apneic episodes are of central origin (i.e., no respiratory
effort), 10% are caused by obstruction, and 50% are attributable to both (i.e., mixed
109 Although these terms imply separate mechanisms, obstruction and airway
closure may be important in all three types (even “central”). Treatment of apnea of
prematurity includes the use of supplemental oxygen, gentle tactile stimulation,
environmental temperature control, methylxanthines, nasal CPAP, and positivepressure ventilation.
Methylxanthines, specifically caffeine and theophylline (or aminophylline), are
widely accepted as the initial pharmacologic approach for the treatment of idiopathic
107,109 These agents decrease apneic episodes via both central
and peripheral effects. Methylxanthines stimulate the medullary respiratory center
and increase receptor responsiveness to carbon dioxide. This results in an increase
in respiratory drive and minute ventilation. Central stimulatory effects may be
mediated by adenosine receptor blockade. Adenosine is a known inhibitor of
respiration, and both theophylline and caffeine competitively inhibit adenosine at the
107 Peripherally, methylxanthines increase diaphragmatic contractility,
decrease diaphragmatic fatigue, and improve respiratory muscle contraction. In
addition, methylxanthines increase catecholamine release and metabolic rate. This
may improve cardiac output and oxygenation, lessen hypoxic episodes, and decrease
Methylxanthine therapy generally is initiated for apnea of prematurity when apneic
episodes are frequent, prolonged for 20 seconds or greater, are accompanied by
significant bradycardia or cyanosis, or are not controlled by nonpharmacologic
means. S.M. has had prolonged apneas with bradycardia that have required
supplemental oxygenation. Initiation of a methylxanthine would be appropriate at this
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