Article

infectious diseases

Future Directions in the Evaluation and

Management of Neonatal Sepsis
Micah Bhatti, MD, PhD,*
Alison Chu, MD,* Joseph

R. Hageman, MD,

Michael Schreiber, MD,*

Kenneth Alexander, MD,
PhD*

Author Disclosure
Drs Bhatti, Chu,
Hageman, Schreiber,
and Alexander have
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.

Abstract
Although sepsis is one of the important etiologies of illness in hospitalized infants, it is
often difcult to determine if an infant is truly infected and, moreover, how to treat
these infections. To address the rst issue, researchers have begun to examine techniques to shorten the amount of time it takes to culture and identify organisms. On
the clinical side, the development of biomarkers may help physicians to better identify
infants who are likely ill from infection versus those infants who are unstable from
other processes. The ability to distinguish between these cohorts will help to curtail
excessive use of empirical antibiotics. Even if infants are determined to truly have infection on the basis of a positive culture, it is becoming more challenging to appropriately treat causative organisms, as multidrug resistance becomes more prevalent.
Furthermore, it becomes more important to evaluate strategies to prevent these infections before they occur.

Objectives

After completing this article, readers should be able to:

1. Understand new developments in serum biomarker research.

2. Recognize the steps in identifying infectious organisms and how current research into
new laboratory techniques may be able to expedite this process.
3. Understand the uses and limitations of less well-known antimicrobial agents in
treating multidrug-resistant infections.
4. Understand the importance of hand hygiene and careful central catheter use in
preventing neonatal infection.
5. Become familiar with recent research on the utility of nutrition, including early
enteral feeding, human milk, and lactoferrin, in the prevention of infection.

Introduction
One of the most challenging aspects of neonatal sepsis is determining if an infant who is
clinically unstable is truly infected. To improve our ability to accurately detect sepsis, research has been conducted assessing the use of various biomarkers. In addition, advancements in medical microbiology have led to faster detection
of pathogens in blood samples. Another challenge to the
management of critically ill infants is the emergence of
Abbreviations
multidrug-resistant (MDR) organisms that will require neoCLABSI: central lineassociated bloodstream infections
natologists to use unfamiliar antibiotics with well-known toxCRP:
C-reactive protein
icities. In the wake of MDR organisms and limited antibiotics,
EOS:
early onset sepsis
hospitals have implemented rigorous prevention programs.
GBS:
group B streptococcal
We will review advances in the prevention and diagnosis of
HRC:
heart rate characteristics
neonatal sepsis and the treatment of MDR infections.
LOS:
MDR:
PCR:
PCT:
WC-MS:

late onset sepsis

multidrug-resistant
polymerase chain reaction
procalcitonin
whole-cell mass spectrophotometry

Advances in Sepsis Detection

Clinical sepsis is dened as a whole-body inammatory state
(systemic inammatory response syndrome) and the presence of a known or suspected infection. (1) This seemingly

*Pritzker School of Medicine, University of Chicago, Chicago, IL.

Department of Pediatrics, NorthShore University Health System, Evanston, IL, and Professor Emeritus of Pediatrics, Feinberg
School of Medicine, Northwestern University, Chicago, IL.

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infectious diseases future of neonatal sepsis

straightforward denition poses two major challenges.

First, although many clinicians almost automatically ascribe neonatal systemic inammatory response syndrome
to infection, the causes of this syndrome are myriad
and include many noninfectious processes. Second, the
sensitivity of blood cultures for identifying pathogenic
bacteria may be lower in neonates than in adults because
of previous antibiotic treatment, small specimen volumes, and low-grade bacteremia. (2)(3) Complicating matters, it can take up to 48 hours to detect an organism on
the basis of blood culture by using current methods (4)
and then an additional 24 to 48 hours before the identity and antibiotic sensitivities are known. During this
time, empirical antibiotics are administered.
To improve the diagnosis of neonatal sepsis, new technologies are being introduced in clinical laboratories that
will reduce the time required to identify a potential pathogen. In addition, various biomarkers and heart rate characteristics (HRC) monitoring are being assessed to determine
whether it is possible to rapidly identify infected neonates.

HRC Monitoring
Research into cardiac electrical patterns has revealed that
reduced variability and transient decelerations in heart
rate may be early indicators of clinical instability and are
hypothesized to be mediated by the cholinergic antiinammatory pathway. (5) The HRC index is a statistically derived interpretation of the beat-to-beat variation
in a patient. (6) A low index indicates normal variation,
but as normal variation is lost, the index rises, as does the
risk of clinical deterioration. A recent randomized controlled trial of >3,000 very low birth weight infants revealed that the use of HRC monitoring signicantly
decreased the 30-day mortality rate after a septic-like
event without a signicant increase in antibiotic days.
(5) The mechanism by which mortality is decreased in
the monitored cohort remains unclear. In a separate study,
neonates with culture-proven sepsis had a statistically
higher HRC during the 24 hours leading up to the septic
episode compared with healthy controls. (6) However,
neonates with culture-negative, septic-like events had a
statistically similar rise in HRC. Therefore, HRC is able
to serve as an early warning of impending clinical instability, and additional research is needed to determine if
it can differentiate between true sepsis versus a culturenegative, septic-like event.

Serum Biomarkers
Although a positive blood culture remains the standard
for diagnosing neonatal sepsis, many investigators have
assessed measuring the host response as an adjunct to

culture-based diagnosis. The goal of serum biomarker

research is to identify a means by which an infected
child can be identied rapidly, before the onset of lifethreatening symptoms. A good diagnostic host marker
for sepsis with a high negative predictive value would
reduce the inappropriate use of antibiotics, health care
costs, and lengths of hospital stays. (7) An ideal biomarker should be elevated early in the course of infection and stay elevated for a sufcient period to provide
opportunity for sampling. The biomarker should have
well-dened values to differentiate infected from noninfected infants, with a very high sensitivity and negative
predictive value. (8) It also is helpful if its values reect
the progression of disease and response to therapy. (8)
Several serum biomarkers have been evaluated as potential indicators of neonatal sepsis.
C-reactive protein (CRP), the most commonly used
biomarker, is synthesized within 6 hours of exposure
to an infectious process and usually becomes abnormal
within 24 hours. (7) Because CRP takes up to 24 hours
after the onset of an infection to become abnormal, it has
little utility in assisting in the early detection of sepsis. CRP
is also limited in that other processes in addition to infection
can result in elevation, including trauma and ischemia. (7)
It does have a high specicity, between 93% and 100%;
thus, a normal CRP in a septic-appearing neonate is unlikely
to be ill because of an infectious process. Levels generally
remain elevated until the infection is controlled; therefore,
CRP can serve as a marker of successful treatment.
Procalcitonin (PCT) is a 116amino acid peptide
precursor to calcitonin that rises in response to most
infections and some inammatory processes. (9) The
increase of PCT in sepsis seems to correlate with the
severity and mortality of disease, and increases in PCT occur more rapidly than increases in CRP. (10) A metaanalysis of 22 studies found that PCT was more accurate
in the diagnosis of late onset sepsis (LOS) than CRP. (9)
A separate meta-analysis included 29 studies and found
a pooled sensitivity and specicity of 81% and 79%, respectively. (11) In the neonate, PCT is increased during
the rst 2 days of life and is theorized to be secondary to
peripartum proinammatory changes, making it less diagnostic during this time period. (12) Levels can also be
elevated in infants with noninfectious processes, such as respiratory distress syndrome, hemodynamic failure, and
perinatal asphyxia, as well as postresuscitation. (10)
Other immunologic markers are being studied for
their utility in the detection of neonatal sepsis. Proinammatory cytokines such as interleukin-6 and interleukin-8
were initially thought to be excellent markers for detecting infection, but the very short half-life of circulating

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infectious diseases future of neonatal sepsis

cytokines signicantly increased the rate of false-negative

results. (8)(12) Increased levels of circulating calprotectin, a major product of innate immune cells, were shown
to have higher sensitivity and specicity (89% and 96%,
respectively) for LOS sepsis than CRP, and, in one cohort
of very low birth weight infants, levels were not inuenced by postnatal age. (13) Advances in ow cytometery
have allowed the investigation of cell surface antigens as
potential markers. A study found CD64 expression to be
signicantly increased in infants with culture-proven sepsis compared with those with culture-negative sepsis or
healthy controls, with a sensitivity of 88.6% and a negative
predictive value of 94%. (14)
Despite thorough investigation into many other proteins and small molecules, no single biomarker has been
perfect for detecting neonatal sepsis. Therefore, investigators have tried combining markers in an effort to boost
their sensitivity and specicity. (8)(15) A study combining four different markerssoluble intercellular adhesion
molecule 1, CRP, soluble E-selectin, and serum amyloid
Awas able to generate a sensitivity of 90% and a negative predictive value of 91.3%. (16) Another study using
a proteomic approach found that combining proapolipoprotein C-II and a des-arginine variant of serum amyloid
A was effective in identifying sepsis, with a negative predictive value of 100% in their cohort. (17) Thus, the next
phase in the early detection of neonatal sepsis will be the
development of a panel of readily measurable markers
that will assist in determining which infants are at increased risk for impending sepsis.
Although the study of biomarkers may assist in the
early detection of sepsis, virtually all of the biomarkers
studied to date are nonspecic indicators of infection
and inammation. They are incapable of providing information about the etiology of the infection, and therefore the microbiology laboratory remains necessary to
identify the pathogen.

Molecular Microbiology
Isolation of a bacterial pathogen from blood requires
growth of the organism in liquid media, subculture of
the organism on solid media, and identication of the
organism according to its characteristic appearance,
growth properties, metabolism of various substrates, and
expression of certain surface proteins. (5)(18) The entire process can take up to 4 days before the identity
and sensitivities of a bacterium can be reported to the
clinical care team. To reduce the time required to identify
a pathogen, there is a shift toward identifying bacteria
on the basis of genotypic analysis. The two most promising methods are whole-cell mass spectrophotometry

(WC-MS) and amplication and sequencing of 16S ribosomal nucleic acid. (19)(20)
In WC-MS, bacterial cells undergo ionization that
generates a unique protein spectral ngerprint. The protein spectral ngerprint allows bacterial identication by
using a spectral database of known bacteria. (21) WC-MS
can determine the identity of an organism in <10 minutes, reducing the time from sample collection to pathogen identication to 3 days. Current devices can resolve
the species and genus of >90% of bacterial isolates, a rate
that is superior to traditional biochemical approaches.
(22) The recent development of automated whole-cell
mass spectrophotometers will make this technology accessible to most clinical laboratories in the near future.
(18) Ongoing research is being conducted to determine
if WC-MS may be used to identify bacteria in samples
taken directly from positive blood culture bottles, which
would bypass the need for subculturing and reduce bacterial identication time to 2 days. (23)
Nucleic acid amplication and sequencing of 16S ribosomal nucleic acid is now considered the gold standard
for identifying bacteria, although routine use has been
limited by expense and time. (20) Several approaches
are being used to bring 16S ribosomal nucleic acid detection into the clinical laboratory. The most advantageous
is broad-range polymerase chain reaction (PCR), which
utilizes amplication by using nonspecic 16S ribosomal
DNA primers on DNA extracted directly from blood or
spinal uid without previous culturing. (2) Detection of
a pathogen by using broad-range PCR takes <8 hours
and requires <500 mL of sample. (19) The PCR product
can be sequenced or probed to determine the identity of
the pathogen. Therefore, in <24 hours, a physician would
know whether a patient is bacteremic, and if so, with what
pathogen. Implementation of 16S PCR in the detection of
neonatal sepsis has been shown to decrease inappropriate
use of antibiotics. (24) In recent studies, the sensitivity of
broad-range PCR varied widely, from 41% to 100%. (19)
More reliable methods for DNA extraction and the development of automated systems are necessary before this
technique is ready for the clinical laboratory. (2)

Treating MDR Infections

Many clinicians are now nding that their infant patients
are infected with antibiotic-resistant nosocomial pathogens
such as vancomycin-resistant Enterococcus, carbapenemaseproducing Enterobacteriaceae, Pseudomonas aeruginosa,
and Acinetobacter baumannii. (25) Described here are
several antibiotic agents, not routinely used in the NICU,
that are capable of treating infections caused by resistant
organisms. As with older antibiotics, the emergence of
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infectious diseases future of neonatal sepsis

microbial resistance to these newer antibiotics is inevitable and has, in many cases, already occurred. Thus, continued judicious use of antibiotics is necessary to maintain
the usefulness of these new antimicrobials.

Gram-Positive Infections
Gram-positive organisms are the most commonly isolated
organism in the laboratory evaluation of LOS. Unfortunately, antimicrobial resistance among Gram-positive organisms is now common. Recent studies have reported
the use of linezolid and daptomycin in children and neonates for treatment of infections caused by Gram-positive
organisms resistant to b-lactams and vancomycin.
Linezolid is an oxazolidinone antimicrobial that was
licensed by the US Food and Drug Administration for
use in pediatrics in 2002. The drugs antimicrobial effect
is mediated through disruption of bacterial protein synthesis induced by linezolid binding to ribosomal RNA.
(26) Although linezolid is bacteriostatic against all Staphylococcal and Enterococcal species, it has been successfully
used to treat neonatal methicillin-resistant Staphylococcal
and vancomycin-resistant Enterococcus infections. (26) A
subset analysis of 63 neonatal patients included in a pediatric Phase III study compared the use of linezolid with
vancomycin in the treatment of resistant Gram-positive
infections and revealed equal cure rates and lower adverse events in the linezolid group. (27) Linezolid has
good penetration into the skin and lungs and is approved for the treatment of pediatric skin and soft-tissue
infections and nosocomial pneumonias. Linezolid is not
recommended as a rst-line drug in the treatment of
endocarditis or catheter-related infections because it is
bacteriostatic and has been associated with high adverse
events in adult patients with catheter-related infections.
However, linezolid has been used successfully to treat
pediatric bloodstream infections and endocarditis caused
by vancomycin-resistant organisms. (28) Adverse effects
of linezolid treatment are seen more commonly in therapy courses lasting >2 weeks and include reversible myelosuppression and lactic acidosis. During treatment with
linezolid, patients should have their serum lactate and
blood cell counts checked periodically. Currently, resistance to linezolid is rare; however, outbreaks of linezolid-resistant organisms have been reported. (29)
Daptomycin is a cyclic lipopeptide antimicrobial derived from Streptomyces roseosporus and is bactericidal
against resistant Gram-positive organisms. The mechanism of action is poorly understood, but daptomycin is
theorized to form pores in the cell membranes of Grampositive organisms. (30) Although daptomycin has had
great success in treating adult bloodstream infections

and endocarditis, it is not currently approved by the US

Food and Drug Administration for use in pediatric patients. (31) A small number of reports describe the successful off-label use of daptomycin for the treatment
of resistant infections that occurred in neonates while
receiving vancomycin therapy. (31)(32) Daptomycin is inactivated by pulmonary surfactant, rendering it ineffective
in treating pulmonary infections. Until appropriate pharmacokinetic studies are performed in the pediatric population, daptomycin should be used only as a second-line drug
for treatment of neonatal vancomycin-resistant infections,
including bloodstream infections and endocarditis.

Gram-Negative Infections
In neonates with LOS in the United States and other developed countries, Gram-negative organisms are isolated
less frequently than Gram-positive organisms. However,
in some developing nations, Gram-negative organisms
are more common in both early onset sepsis (EOS) and
LOS. (33) Unfortunately, the global epidemic of antibiotic
resistance has created a major problem in treating Gramnegative sepsis everywhere. (34) Therefore, the evaluation
of antimicrobial agents effective against Gram-negative
organisms not previously used in the pediatric population
has become critically important. Here we review the use of
ciprooxacin and colistin in neonates.
Ciprooxacin is a uoroquinolone that inhibits bacterial DNA topoisomerases. (35) Ciprooxacin is bactericidal against most Gram-negative organisms, including
P aeruginosa. The use of uoroquinolones in pediatrics
has been limited by reports of increased musculoskeletal
adverse events in young animals. (36) A recently published
systematic review suggests that there is increased risk of
arthropathy in ciprooxacin-treated pediatric patients,
but that this risk is relatively low and that the arthropathy
is reversible. (36) Despite concerns over possible adverse
effects, ciprooxacin has been approved by the US Food
and Drug Administration for the treatment of complicated urinary tract infections in children. It has been
used off-label in many countries with good outcomes
in the treatment of various Gram-negative infections.
(35) A systematic review of ve cohort studies evaluated
the use of ciprooxacin for the treatment of neonatal sepsis caused by antibiotic-resistant Gram-negative organisms.
(37) Two of the ve cohorts assessed clinical response,
with one showing a signicantly higher survival rate in
the ciprooxacin-treated group versus treatment with ampicillin, gentamicin, and/or cefotaxime. The other cohort
reported equal survival rates between the ciprooxacintreated group and the control group. None of the ve cohorts reported any major adverse events associated with

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infectious diseases future of neonatal sepsis

the use of ciprooxacin. Two signicant limitations to the

use of ciprooxacin in neonates are the paucity of pharmacokinetic data in the neonatal population and the very
high doses of ciprooxacin needed to successfully treat infections caused by Acinetobacter and Pseudomonas organisms. (37) Resistance to uoroquinolones has been well
documented and may be increasing in certain parts of
the world. (34) In an effort to minimize resistance,
the use of ciprooxacin should be restricted to infections
caused by resistant organisms.
Colistin is a polymyxin initially discovered in 1947,
and it functions as a detergent, dissolving the cellular
membranes of Gram-negative organisms. (38) Systemic
polymyxins fell into disuse in the early 1980s in favor of
less toxic aminoglycosides and broad-spectrum b-lactams.
However, with the continued emergence of MDR organisms, polymyxins have again found use as the only antibiotic left to treat some Gram-negative infections. In a
retrospective study of neonates with MDR Gram-negative
infections susceptible to only colistin, 12 neonates were
bacteremic; two had concomitant meningitis. (39) Of
the colistin-treated cohort, two-thirds of the patients
survived, including one with meningitis. Two infants
developed renal impairment, the main toxicity associated with colistin use, but both infants had multiorgan
dysfunction before starting colistin therapy. In view
of the situations requiring its use, which are often
desperate, the rate of colistin-related nephrotoxicity
is tolerable; however, regular monitoring of patients
renal function during colistin therapy is recommended.
(38) Colistin dosing guidelines have not been well established in the neonatal population. Finally, although
rare, resistance to colistin has emerged, leaving patients
mortally infected by organisms resistant to all commercially available antibiotics. (40)
It should be emphasized that none of the antibiotics
discussed here are superior for treatment of infections
sensitive to older, more commonly used antibiotics. The
use of these newer antibiotics should remain restricted to
the denitive therapy of infections caused by resistant organisms. None of these drugs should be used for empirical
therapy. The recommended doses of antibiotics mentioned
here and in the two previous articles are listed in Table 1.

the safe use and early removal of intravascular catheters.

Other potentially promising interventions for prevention
of LOS are being studied, including the concept of bundles, early enteral feeding, nutritional supplements, and
maternal vaccination.

Reducing Central-LineAssociated Bloodstream

Infections

Prevention of LOS

Although there is an abundance of research evaluating

complex and expensive methods for prevention of neonatal sepsis, there are several simple, low-cost strategies that
are highly effective. First and foremost is good hand hygiene. (41) Despite being a well-studied and established
means for preventing and controlling transmission of
infectious organisms, hand hygiene is poorly instituted,
and the rates of hand hygiene protocol adherence by
care providers are often well below 50%. Nonetheless,
improved compliance with hand hygiene protocols can
be achieved through a multimodal approach.
A bundle is a group of specic, evidence-based practices that, when performed together, result in improved
patient outcomes. (42) The bundle concept has been
applied successfully to reduce central lineassociated
bloodstream infections (CLABSI). A study in the NICU
setting revealed that the use of an insertion and maintenance bundle, including improved hand hygiene, use of
good sterile technique during placement (sterile gown,
sterile gloves, surgical mask and hat, and thorough skin
disinfection), aseptic technique when accessing the catheter, and daily inspection of central catheters reduced
CLABSI by 67%.
The use of antimicrobial prophylaxis remains a highly
controversial method for preventing CLABSI. A Cochrane
review assessing the use of a prophylactic systemic antibiotic found that almost 10 infants need to be given preventative antibiotics to avoid one case of infection. (43)
Given the toxicities associated with broad-spectrum antibiotics and the potential for resistant organisms, antimicrobial prophylaxis is not recommended. Similarly,
although there are some data supporting the use of vancomycin catheter locks for prevention of CLABSI, (44)
the risk of selection of vancomycin-resistant organisms
is substantial. Further studies need to be conducted before vancomycin line locks can be used outside of a controlled clinical trial. (45)

Although research involving the prevention of EOS has

largely been limited to the use of intrapartum prophylaxis, there is a myriad of proposed interventions for
the prevention of LOS. Of these many proposed preventive interventions, the only established effective means
for decreasing the rate of LOS are hand hygiene and

Altered bacterial colonization of the gut in premature infants as a consequence of delayed enteral feeding, antibiotic exposure, and immature gut barrier function may
impair the development of innate and adaptive immunity.

Nutrition and Nutritional Supplements

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infectious diseases future of neonatal sepsis

Table 1.

Dosing of Antimicrobial Agents

Agent

Dosing

Amphotericin B (conventional)
Ampicillin

1 mg/kg per dose q24h

50 mg/kg per dose
<7 d
2 kg: ql2h
2 kg: q8h
GBS meningitis: 300 mg/kg per d divided q8h
>7 d
<1.2 kg: q12h
1.2L2 kg: q8h
>2 kg: q6h
GBS meningitis: 300 mg/kg per d divided q6h
25 mg/m2 per dose q24h
50 mg/kg per dose
<7 d, <2 kg: q12h
<7 d, 2 kg: q8h
>7 d
<1.2 kg: q12h
1.2L2 kg: q8h
>2 kg: q6h
10 mg/kg per dose q12ha
2.55 mg/kg per d (expressed as colistin base) divided q6hq12h
Limited data regarding neonatal dosingb
12 mg/kg per dose q24h
2.5L3.5 mg/kg per dose q8hq24h based on postnatal age, weight, and
serum concentrations (varies according to institution)
10 mg/kg per dose
GA 34 wk
PNA <7 d: q12h
PNA 7 d: q8h
GA 35 wk: q8h
GA 30 wk: 20 mg/kg per dose q12h
GA >30 wk
PNA 07 d: 20 mg/kg per dose q12h
PNA >7 d: 20L40 mg/kg per dose q8h
1015 mg/kg per dose q6hq24h based on postnatal age, weight, and
serum concentrations (varies by institution)

Caspofungin
Cefotaxime

Ciprofloxacin
Colistimethate
Daptomycin
Fluconazole
Gentamicin
Linezolid

Meropenem

Vancomycin

Dosing regimens from Lexicomp online (http://online.lexi.com/). Only agents mentioned in the articles of this series are included. GA, gestational age;
PNA, postnatal age.
a
Higher doses may be necessary to treat organisms such as Pseudomonas and Acinetobacter. (37)
b
Use of 10 to 15 mg/kg q24h has been reported. (31)

Based on this hypothesis, research has been conducted to

determine if early enteral feedings with human milk may be
protective against sepsis in the neonate. Although early enteral feeding may have benet, there is concern that early
enteral feeding also increases the risk of necrotizing enterocolitis. In a few retrospective studies, there was an inverse
relationship between risk of nosocomial infection and the
initiation of feeding, without increased risk for necrotizing
enterocolitis. (46)(47) Human milk, which contains lactose, nucleotides, oligosaccharides, and lactoferrin, has
been shown to be protective against a variety of infections
in the newborn. (48) Lactoferrin, a glycoprotein found in

human milk, has antimicrobial, anti-inammatory, and immunomodulatory properties. A statistically signicant decrease in the rates of sepsis was seen in infants randomized
to receive lactoferrin supplementation (4.6%) versus those
receiving placebo (17.3%, p<0.001). (49)
Because poor bacterial gut colonization secondary to
prematurity and antibiotic exposure may increase the risk
of infection, therapeutic colonization of the neonatal gut
with probiotic organisms may help to prevent LOS.
However, studies using different combinations of Lactobacillus species, Bidobacterium species, and Streptococcus
thermophilius have been inconclusive. (50)

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infectious diseases future of neonatal sepsis

Maternal Group B Streptococcal Vaccination

Another potential mechanism for prevention of EOS and
LOS is the use of vaccines. Initial investigations into the
development of group B streptococcal (GBS) vaccines
have been promising. The vaccines target conserved surface antigenic proteins, such as the Sip protein located
on the cell surface or immunogenic proteins from GBS
pili. If a protective immune response is achieved, it would
inhibit GBS adhesion to host tissue and prevent transepithelial migration. Although not yet commercially available, several vaccines are close to being released and
will hopefully prove to be efcacious in decreasing the
rates of EOS and LOS caused by GBS. (51)

Conclusions
The diagnosis of neonatal sepsis continues to be a major
clinical challenge. In an effort to improve outcomes of
infected infants, research is being conducted to improve
our ability to detect sepsis sooner and identify organisms
more quickly. The use of biomarkers and the HRC index
will hopefully provide additional tools for neonatologists
to recognize and treat potentially infected infants. New
technology being introduced into the microbiology laboratory will be able to conrm the presence of a pathogen
by using faster and more reliable methods. Another important challenge in neonatal sepsis is the increasing rates of
antimicrobial resistance, requiring the use of unfamiliar antimicrobial agents to treat MDR organisms. Initial studies
of newer antibiotics are promising, but larger studies are
needed to better evaluate these agents and provide better
neonatal pharmacokinetic data. Lastly, because novel
treatment agents will only take us so far, more research
is needed to determine how to prevent these infections.
ACKNOWLEDGMENTS The authors thank Elisabeth
Mouw, PharmD, for her assistance with dosing recommendations for antimicrobial agents presented in Table 1.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications

Know the clinical manifestations,
laboratory features, and differential
diagnosis of neonatal sepsis.
Know the effective techniques for control
of nosocomial infection in the nursery,
neonatal intensive care unit, and
obstetrical unit.
Know the pathogenesis and prevention of transmission of
infections with multidrug-resistant bacteria.

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Future Directions in the Evaluation and Management of Neonatal Sepsis

Micah Bhatti, Alison Chu, Joseph R. Hageman, Michael Schreiber and Kenneth
Alexander
Neoreviews 2012;13;e103
DOI: 10.1542/neo.13-2-e103

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