BACTERIAL SEPSIS AND MENINGITIS - Nizet Laboratory at UCSD

IVIG on subsequent outcomes. The results revealed a
borderline significant reduction in mortality (relative risk
0.63, 95% confidence interval 0.40 to 1.00). In the studies
in which analysis was restricted to neonates with subsequently
proven systemic bacterial infection, a statistically
significant reduction of mortality was identified (relative
risk 0.55, 95% confidence interval 0.31 to 0.98). Based
on these preliminary encouraging data from diverse studies,
an ongoing, placebo-controlled multicenter trial in
low birth weight or ventilated neonates (INIS [International
Neonatal Immunotherapy Study]) is comparing
the adjunctive use of 10 mg/kg of IVIG versus placebo
at the time of suspected infection and 48 hours later; mortality
and major disability at 2 years are the major outcome
variables [662].
PROGNOSIS
Before the advent of antibiotics, almost all infants with
neonatal sepsis died [5]. Dunham [2] reported that physicians
used various treatments, including “erysipelas
serum” and transfusions, without altering the course of
the disease. The introduction of sulfonamides and penicillin
and later introduction of broad-spectrum antibiotics
such as chloramphenicol and streptomycin decreased the
mortality rate to about 60% [3,5]. During this period,
some infants undoubtedly died because of treatment with
high dosages of chloramphenicol, which can cause cardiovascular
collapse (i.e., gray baby syndrome).
The introduction of the aminoglycosides, first with
kanamycin in the early 1960s and gentamicin late in that
decade, vastly improved therapy for bacteremia caused by
gram-negative organisms, the leading cause of sepsis at that
time [6]. These therapies, together with an improved
understanding of neonatal physiology and advances in
life-support systems, combined to result in a steady
decrease in neonatal mortality in the United States [6] and
in Europe [257,258,286,663] during the period 1960-
1985. Mortality rates for sepsis, including infants of all
weights and gestational ages, decreased from 40% to 50%
in the 1960s [4,6,286,663] to 10% to 20% in the 1970s
and 1980s [6,10,258,447,663]. Population-based surveillance
of selected counties in the United States conducted
by the CDC from 1993-1998 reported 2196 cases of neonatal
sepsis caused by GBS, of which 92 (4%) were fatal [643].
The postnatal age at which infection occurs, previously
thought to be of prognostic significance, has become less
important within the past 2 decades. Fulminant sepsis,
with signs of illness present at birth or during the first
day of life, has a high mortality rate, ranging from 14%
to 20% [6,12,258,288] to 70% [664]. When infections
occurring during the first 24 hours of life, most of which
are caused by GBS, are excluded from the analysis, however,
the percentage of deaths resulting from early-onset
sepsis does not differ significantly from late-onset infection.*
Mortality from sepsis is higher for preterm than
for term infants in virtually all published studies, { but is
*References [6, 10, 85, 257, 258, 286, 447].
{ References [7, 10, 12, 18, 257, 258, 446, 447].
CHAPTER 6 Bacterial Sepsis and Meningitis
263
approximately the same for all major bacterial pathogens
(see Tables 6–4 and 6–5) [10,257].
In more recent surveys, the mortality rate for neonatal
meningitis has declined from 25% [10,24,665,666] to
10% to 15% [12,23,26,667,668]. This decrease represents
a significant improvement from prior years, when
studies reported a case-fatality rate of more than 30%
[21,431,648,649,669]. Mortality is greater among preterm
than term infants [12,23,26,670].
Significant sequelae develop in 17% to 60% of infants
who survive neonatal meningitis caused by gram-negative
enteric bacilli or GBS [23,665–668]. These sequelae
include mental and motor disabilities, convulsive disorders,
hydrocephalus, hearing loss, and abnormal speech
patterns. The most extensive experience with the longterm
observation of infants who had group B streptococcal
meningitis as neonates was reported by Edwards
and colleagues [670]. During the period 1974-1979,
61 patients were treated, and 21% died. Of the 38 survivors
who were available for evaluation at 3 years of age
or older, 29% had severe neurologic sequelae, 21% had
minor deficits, and 50% were functioning normally. Presenting
factors that were associated with death or severe
disability included comatose or semicomatose state,
decreased perfusion, total peripheral white blood cell
count less than 5000/mm 3 , absolute neutrophil count less
than 1000/mm 3 , and CSF protein level greater than
300 mg/dL.
A comparable study evaluating 35 newborns over 3 to
18 years showed more favorable outcomes with 60% of
survivors considered normal at the time of follow-up
compared with sibling controls, 15% with mild to moderate
neurologic residua, and 25% with major sequelae
[669]. Franco and coworkers [668] reported the results
of frequent and extensive neurologic, developmental,
and psychometric assessments on a cohort of 10 survivors
of group B streptococcal meningitis followed for 1 to 14
years. The investigators found that one child had severe
CNS damage; five children, including one with hydrocephalus,
had mild academic or behavioral problems;
and four children were normal.
The neurodevelopmental outcomes described for
infants with gram-negative bacillary meningitis are similar
to the outcomes reported for group B streptococcal meningitis.
Unhanand and colleagues [23] reported findings
from their 21-year experience with gram-negative meningitis
at two hospitals in Dallas, Texas. Of 72 patients less
than 28 days old at the onset of symptoms, there were 60
survivors, 43 of whom were followed and evaluated for at
least 6 months. Neurologic sequelae, occurring alone or
in combination, were described in 56% and included
hydrocephalus (approximately 30%), seizure disorder
(approximately 30%), developmental delay (approximately
30%), cerebral palsy (25%), and hearing loss
(15%). At follow-up, 44% of the survivors were developmentally
normal at follow-up. Among infants with gramnegative
bacillary meningitis, thrombocytopenia, CSF
white blood cell count greater than 2000/mm 3 , CSF protein
greater than 200 mg/dL, CSF glucose-to-blood glucose
ratio of less than 0.5, prolonged (>48 hours) positive
CSF cultures, and elevated endotoxin and interleukin-1
concentrations in CSF were indicators of a poor outcome