Antibiotic Therapy and Early Onset Sepsis

Gustave Falciglia, Joseph R. Hageman, Michael Schreiber and Kenneth Alexander

Neoreviews 2012;13;e86
DOI: 10.1542/neo.13-2-e86

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Article infectious diseases

Antibiotic Therapy and Early Onset Sepsis

Gustave Falciglia, MD,* Educational Gaps
Joseph R. Hageman,
1. Evidence indicates that broadening empirical antibiotic coverage beyond ampicillin
MD,†,‡ Michael Schreiber,
and gentamicin for early onset sepsis (EOS) is both ineffective and potentially
MD,x Kenneth Alexander,
detrimental to the growing number of antibiotic resistant organisms.
MD, PhD║
2. An attempt should be made to clarify the inconsistent data suggesting that
intrapartum prophylaxis may be a contributing factor to the changing epidemiology
Author Disclosure and the antibiotic resistance of organisms implicated in EOS.
Drs Falciglia,
Hageman, Schreiber, Abstract
and Alexander have Early onset sepsis in the newborn infant continues to be an important clinical problem
for neonatologists everywhere in the world. Different routes of transmission, changes
disclosed no financial
in causative agents, and potential antibiotic resistance all influence the choice of anti-
relationships relevant
biotic therapy. Group B Streptococcus and Escherichia coli continue to be the major
to this article. This pathogens dictating antibiotic therapy in the United States. Ampicillin and gentamicin
commentary does not are the antibiotics used by most for empirical therapy; cephalosporins are used in cer-
contain a discussion of tain clinical situations. In this review, we address the reasons for these choices while
an unapproved/ highlighting clinically relevant aspects of the antibiotics commonly used in the treat-
ment of early onset sepsis in the newborn.
investigative use of
a commercial product/
device.
Objectives After completing this article, readers should be able to:

1. Recall the definition of EOS; distinguish it from late onset sepsis.

2. List common causative agents in all infants in EOS, including very low birth weight
(VLBW) infants.
3. Contrast the goals of empirical antibiotic therapy with definitive therapy.
4. Identify the risks associated with commonly used antibiotics in infants.

Introduction
Early onset sepsis (EOS) in the newborn infant continues to be a difficult clinical challenge
for neonatologists everywhere in the world. Multiple routes of transmission, change in caus-
ative agents, and potential antibiotic resistance contribute to the difficulty of this problem.
These factors influence the choice of antibiotic therapy. In this
review, we address the appropriate choice of antibiotic therapy
while highlighting clinically relevant aspects of the antibiotics
Abbreviations commonly used in the treatment of EOS in the newborn.
EOS: early onset sepsis
ESBL: extended spectrum b lactamase
GBS: group B Streptococcus
EOS: Definitions and Causative Agents
There is no single definition of EOS in the newborn; various
IAP: intrapartum antibiotic prophylaxis
definitions exist, each with subtle differences. EOS refers to
PBP: penicillin-binding protein
an infection of the blood stream or meninges proven by cul-
VLBW: very low birth weight
ture; EOS is usually acquired vertically from the mother and

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

†
Department of Pediatrics, NorthShore University HealthSystem, Evanston, IL.
‡
Professor Emeritus of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.
x
Department of Pediatrics and Professor of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL.
║
Division of Pediatric Infectious Disease and Professor of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL.

e86 NeoReviews Vol.13 No.2 February 2012

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 infectious diseases early onset sepsis

manifests shortly after birth as originally characterized by

McCracken. (1)(2) Philip (3) uses the terminology very
early onset disease for infections presenting in the first 24
hours after birth, early onset disease for infections between
1 and 7 days after birth, and late onset disease for infec-
tions after 7 days. Scandinavian investigators have used this
scheme because infection within the first 24 hours has
a higher mortality rate and rarely presents with meningitis.
The Centers for Disease Control and Prevention de-
fines EOS as a blood or cerebrospinal infection within
the first 6 days after birth proven by culture. (2) In very
low birth weight (VLBW) infants, EOS refers to infections
occurring within the first 3 days after birth; after the third
day after birth, infections tend to be nosocomial, acquired
horizontally. (2)(4)
The definitions are an attempt to describe the route of
transmission and, therefore, common flora associated
with each route. Although there are exceptions, these dis-
tinctions serve to aid the diagnosis (what is the likelihood Figure 1. Early onset sepsis in the United States.
of meningitis) and treatment (what antibiotics to use).
The causative organisms of EOS have been changing
for several decades in the United States. In the 1950s, the Haven Hospital, Bizzarro et al. (8) sought to determine
predominant organisms causing EOS were Staphylococcus if there was an increasing incidence of E coli EOS in VLBW
aureus and group A Streptococcus (S pyogenes). After the infants born during a period of no IAP (1979–1992),
introduction of antibiotics, gram-negative bacteria, especially compared with infants born during a period of risk-factor
Escherichia coli, became more common. (5) Since the late based IAP (1993–1996), and compared with infants
1970s, group B Streptococcus (S agalactiae; GBS), has re- born during a period of GBS screening-based IAP
mained the most common cause of EOS in infants, born (1997–2002). (8) Although there was a significant de-
term and preterm. (2) With decreasing gestational ages crease in gestational age and birth weight across these
of newborns and increasing rates of VLBW infants, there assessment periods, the final analysis controlled for the
is a dichotomy in bacterial culprits. GBS is the most com-
mon cause of EOS in term newborns, whereas E coli is
the most common cause of EOS in VLBW infants (Figs
1 and 2). (6)
The etiology of EOS in newborns in developing coun-
tries outside the United States differs from that of US-
born infants. In a combined review of EOS in Latin
America, the Caribbean, Asia, and Africa, the most com-
mon causes of EOS were Klebsiella spp, responsible for a
quarter of the cases in the first week after birth. The most
common gram-positive pathogen was S aureus (Fig 3). (7)
The authors suggest that some of the organisms responsi-
ble for EOS in the first week may be acquired horizontally
due to “lack of hygiene during and after delivery, poor
cord care, and unhygienic newborn care practices.” (7)

Effects of Intrapartum Antibiotic Prophylaxis

Complicating an understanding of bacterial epidemiol-
ogy in EOS is intrapartum antibiotic prophylaxis (IAP)
for GBS. Does IAP against GBS increase the incidence of Figure 2. Early onset sepsis among very low birth weight
gram-negative bacteria, especially E coli? At the Yale-New infants in the United States.

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infectious diseases early onset sepsis
Figure 3. Early onset sepsis in developing nations.
effect of these factors. The authors found that E coli EOS
increased with the advent of maternal GBS prophylaxis.
Similarly, data from the National Institute of Child Health
and Human Development (NICHD) revealed that the
incidence of E coli EOS in VLBW infants increased be-
tween the periods 1991–1993 and 1998 from 3.2 to
6.8 per 1000 VLBW births. (4)
Nevertheless, the NICHD later reported that there
was no significant increase in the incidence of E coli
EOS between 1998–2000 and 2002–2003. (6) Data
from Brigham and Women’s Hospital, and the Active
Bacterial Core Surveillance/Emerging Infections Pro-
gram Network also revealed no significant increase in
the incidence of E coli EOS. Instead, the authors found
only that the proportion of EOS attributable to E coli in-
creased, reflecting the success of GBS prophylaxis. (9)
(10) In Australia, no increased incidence in E coli was ob-
served in the 10-year period between 1992 and 2001.
(11) Interestingly, penicillin is the prophylactic antibiotic
of choice in Australia, and in the hospitals in the Boston
and Active Bacterial Core Surveillance study. (9)(10)(12)
Does IAP alter the resistance pattern of maternal bac-
teria? The NICHD reported ampicillin resistance was not
more likely among EOS infants whose mothers received
IAP compared with those who did not. (13) However,
Bizzarro et al. (8) noted that intrapartum ampicillin ex-
posure was an independent risk factor for EOS due to
ampicillin-resistant E coli, whereas there was no overall
increase in ampicillin resistant E coli. (8) Furthermore,
Towers and Briggs (14) demonstrated that mothers of
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infants with EOS from antibiotic resistant bacteria had
received IAP with the same antibiotic. Stoll and the
NICHD did not encounter ampicillin-resistant GBS.
(13) Puopolo and Eichenwald (9) recently concluded that
the incidence of EOS due to ampicillin-resistant bacteria
and ampicillin-resistant E coli remain stable.
Empirical Versus Definitive Therapy of EOS
Antibiotic coverage should initially be directed against
likely highly pathogenic bacteria (in the United States,
chiefly GBS and E coli). Ampicillin and gentamicin are
widely used empirical antibiotics because they target these
highly pathogenic bacteria until the infecting organism is
identified and antimicrobial susceptibilities are determined
(see Table). The use of ampicillin (or amoxicillin) and gen-
tamicin minimizes expense and causes minimal treatment-
related morbidity and mortality. (15) Three recent studies
from the NICHD, United Kingdom, and Israel revealed
that ampicillin and gentamicin remain appropriate empir-
ical therapy for suspected EOS. (13)(16)(17)
The temptation to broaden empirical therapy exists
and is most palpable on the rare occasion that ampicillin
and gentamicin were insufficient. Other antibiotics may
provide broader coverage; however, broader spectrum
antibiotics are associated with greater drug acquisition
costs, development of resistance, higher rates of funge-
mia, and increased toxicity (see Figs 4 and 5). Of these
complications, broad-spectrum antibiotic-induced fun-
gemia in neonates carries a particularly high mortality.
Ampicillin and Gentamicin, the Preferred
Empirical Antibiotic Regimen
Penicillins are bactericidal b-lactams that work by bind-
ing the penicillin-binding proteins (PBPs) and disrupting
bacterial cell wall synthesis. (18) Penicillin G is not effective
with gram-negative bacteria; however, aminopenicillins,
such as ampicillin and amoxicillin, have enhanced penetra-
tion through the outer membrane of gram-negative
Empirical Versus Definitive
Table.
Therapy
Empirical Definitive
Directed by Epidemiology Pathogen
Usage frequency Common Infrequent
Termination of A negative Eradication of
therapy culture pathogen
Tolerance of risk Low Dependent on
organism

Figure 4. Risk benefit uneven.
bacteria and enhanced binding to PBPs. Ampicillin is
a safe antibiotic with rare adverse effects that include
rash, urticaria, diarrhea, and liver function test eleva-
tions. (19) Two important mechanisms contribute to am-
picillin resistance. Bacteria can enzymatically inactivate the
b-lactam ring, or they can alter their PBPs. (18) In the
Figure 5. Risk benefit even.
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infectious diseases early onset sepsis
United States, 78% of E coli isolates are resistant to am-
picillin. (13)
Gentamicin and other aminoglycosides work by bind-
ing ribosomal RNA and inhibiting protein synthesis. (19)
Aminoglycosides also disrupt the bacterial cell membrane.
Aminoglycosides are highly polar, cationic molecules that
are attracted to the negatively charged lipopolysaccharide
molecule of gram-negative bacteria. (19) The polar nature
of aminoglycosides prevents efficient passage across the
blood-brain barrier. Ototoxicity and nephrotoxicity are
well known adverse effects of gentamicin therapy; how-
ever, the risk of toxicity can be mitigated with appropriate
drug dosing, avoidance of other nephrotoxic drugs, fre-
quent monitoring of renal function, and modification of
therapy under renal insufficiency. (20)
High-level aminoglycoside resistance occurs through
two mechanisms: ribosomal RNA mutation or modifica-
tion and inactivation of the aminoglycoside molecule.
(19) Bacteria can also decrease intracellular aminoglyco-
side concentrations by reducing aminoglycoside influx
and increasing aminoglycoside efflux or by sequestering
the aminoglycoside molecules resulting in decreased ef-
fective concentration. Despite these mechanisms of resis-
tance, gentamicin resistance remains quite low. In the
United States, only 4% of E coli isolates are gentamicin
resistant. Abroad, the rates are slightly higher, ranging
between 10% and 12%. (17)(21) Given the low rates of
gentamicin resistance in the United States, gentamicin
should remain part of empirical therapy for suspected
EOS. (7) Outside of the United States in developing
countries where Klebsiella can account for a quarter of
EOS, (7) gentamicin-resistance occurs in about 60% of
Klebsiella isolates. (21) As such, the role of gentamicin
for presumed EOS is more debatable. The use of an ad-
ditional antibiotic such as an additional aminoglycoside
should be dictated by local resistance patterns as well
as thoughtful antibiotic stewardship and outcomes data.
Concerns of Empirical Therapy
Additional antibiotics have been used for empirical ther-
apy of EOS. It is tempting to broaden initial coverage and
increase the spectrum of gram-negative coverage. How-
ever, such an attempt is not without risk.
Cephalosporins are b-lactam antibiotics that are mech-
anistically similar to penicillin but are not inactivated by
b-lactamases. (18) Although first generation cephalosporins
are used for methicillin-sensitive S aureus, the majority of
cephalosporins used in newborns are third generation.
(20) In addition to having enhanced gram-negative cov-
erage, third generation cephalosporins have excellent
central nervous system penetration. (18)(20)
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infectious diseases early onset sepsis
Nevertheless, third generation cephalosporins should
be used judiciously. Common adverse effects of third gen-
eration cephalosporins include intravenous site pain, phle-
bitis, fever, emesis, diarrhea, increased liver enzymes, and
cholelithiasis. Serious adverse effects include seizure, he-
molytic anemia, thrombocytopenia, and leukopenia. (20)
Ceftriaxone is not recommended for use in the first week
after birth, as ceftriaxone can displace bilirubin from albu-
min. (22) Furthermore, several cases of sudden calcium-
ceftriaxone precipitate in newborn lungs and kidneys
prompted the Food and Drug Administration to warn
against administration of ceftriaxone and calcium-containing
products within 48 hours of each other. (16)(23)
Cefotaxime and ampicillin are commonly used as a
substitute for ampicillin and gentamicin for the presump-
tive treatment of EOS. However, there appears to be an
increased risk of death with the use of ampicillin and cefo-
taxime. (24) This retrospective study looked at physician
rationale for the use of cefotaxime in lieu of gentamicin.
The authors found that clinicians frequently cited asphyxia
and suspected gram-negative sepsis as the most common
reasons for using cefotaxime. However, logistic regression
analysis could not exclude the use of ampicillin and cefo-
taxime as an important factor in the death of the newborns
in the study. Although Benjamin et al. (25) were careful
not to infer causation, third generation cephalosporin
use is probably a risk factor for invasive candidiasis.
Finally, rates of cephalosporin resistance are increasing.
(26) Cephalosporins are susceptible to degradation by
cephalosporinases (commonly seen in Enterobacter spp)
and by extended spectrum b-lactamases (ESBLs, com-
monly seen in Klebsiella spp). The former are located on
inducible chromosomal DNA, whereas the latter are lo-
cated on mobile plasmid DNA. (27) Unfortunately, in-
ducible resistance may not be detected by routine tests
for cephalosporin sensitivity.
Carbapenems are a newer class of antibiotics that also
target the PBPs. Carbapenems are not inactivated by ceph-
alosporinases or ESBLs. As such, carbapenems are an ideal
choice for definitive therapy of bacteria with cephalospor-
inase- or ESBL-mediated resistance. Carbapenems are also
ideal for polymicrobial infections. (27) Adverse effects of
carbapenems include thrombophlebitis and seizures. The
risk of seizure is lower with meropenem. This lower risk
of seizures is one of the reasons that meropenem is pre-
ferred to imipenem in newborns. (20)(27)
Carbapenems are potent inducers of cephalospori-
nases and select for ESBLs on plasmids. This would poten-
tially render later treatment with cephalosporins ineffective.
Much like cephalosporins, carbapenems destroy colonizing
flora, resulting in an increased risk of fungemia. (27)
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Criteria for Change
A regimen such as ampicillin and gentamicin should
remain the empirical therapy of choice for presumed
EOS until a correlation between antibiotic resistance
and treatment failure has been observed. At regular meet-
ings, neonatologists and microbiologists should continu-
ously evaluate their antibiotic choices for empirical EOS
therapy. The central question should be is there a corre-
lation between antibiotic resistance and treatment failure?
Decisions to modify antimicrobial regimens for EOS
should be driven by outcomes data, not solely resistance
patterns.
Based on current data, ampicillin and gentamicin
should remain the empirical antibiotic therapy of choice
for EOS. The combination of ampicillin and gentamicin
is effective against all strains for GBS and most strains of
E coli. Presumptive EOS therapy with ampicillin and gen-
tamicin is safe, inexpensive, and effective.
Finally, the best way to ensure that ampicillin and gen-
tamicin remain effective is responsible antibiotic steward-
ship. Cultures should be drawn before initiating empirical
therapy. Physicians should treat sepsis, not bacterial colo-
nization. (28) Finally, antibiotics should be discontinued
with negative cultures after 2 to 3 days of negative cultures
unless there is compelling clinical evidence against stop-
ping them.
American Board of Pediatrics Neonatal–Perinatal
Medicine Content Specifications
• Understand the treatment and
complications of sepsis.
• Know the infectious agents that cause
neonatal sepsis.
• For antibiotics used commonly in the
neonate, know indications for their use,
clinical effects, pharmacokinetics, side effects, and toxicity.
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infectious diseases early onset sepsis

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1. Early onset sepsis in the newborn refers to an infection of the bloodstream or the cerebrospinal fluid that is
proven by culture. Early onset sepsis typically manifests shortly after birth, is acquired vertically by spread from
mother to fetus, and carries a high risk of death. Of the following, according to the Centers for Disease Control
and Prevention, early onset sepsis is defined as infection that typically manifests after birth within the first
A. 0-24 hours
B. 0-72 hours
C. 0-6 days
D. 7-13 days
E. 14-20 days
2. A 12-hour-old term newborn has respiratory distress from suspected pneumonia. Maternal history is
significant for chorioamnionitis characterized by purulent amniotic fluid. You start antibiotic treatment
based on your knowledge about the microorganisms most likely to cause early onset sepsis in term neonates in
your nursery. Of the following, the most common microorganism responsible for early onset sepsis among term
neonates in the United States is
A. Enterococcus faecalis
B. Escherichia coli
C. Klebsiella pneumoniae
D. Staphylococcus aureus
E. Streptococcus agalactiae
3. A preterm neonate, who weighs 980g at birth at an estimated gestational age of 28 weeks, is suspected to have
early onset sepsis. Maternal history is significant for preterm prolonged rupture of membranes, which occurred
approximately 60 hours before birth of the infant by cesarean delivery. In choosing the antibiotics for
treatment, you review the profile of microorganisms likely to cause early onset sepsis in preterm neonates in
your nursery. Of the following, the most common microorganism responsible for early onset sepsis among
very-low-birthweight neonates in the United States is
A. Escherichia coli
B. Klebsiella pneumoniae
C. Pseudomonas aeruginosa
D. Staphylococcus aureus
E. Streptococcus agalactiae
4. The use of ampicillin and gentamicin as the initial empirical antibiotic combination is the current
recommendation for the treatment of early onset sepsis in neonates. Although other antibiotics may
provide broader antibacterial coverage, such treatment is of concern because of its side effects. Of the
following, the most significant adverse effect of broad spectrum antibiotics used as the initial empirical
combination in the treatment of suspected early onset sepsis in neonates is
A. Anaphylactic reactions
B. Development of bacterial resistance
C. Greater cost
D. High rate of fungemia
E. Increased toxicity

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 infectious diseases early onset sepsis

5. Cephalosporins are beta-lactam antibiotics that are mechanistically similar to penicillin but are not inactivated
by beta-lactamases. In addition to providing broader coverage, especially of gram-negative microorganisms,
cephalosporins have greater central nervous system penetration and therefore are more effective in the
treatment of meningitis. However, caution is warranted in the empirical use of cephalosporins for the
treatment of early onset sepsis in neonates because of their adverse effects. Of the following, the most serious
adverse effect of ceftriaxone, a third-generation cephalosporin, when used in the treatment of suspected early
onset sepsis in neonates is
A. Bilirubin toxicity
B. Cholelithiasis
C. Diarrhea
D. Hepatic dysfunction
E. Phlebitis

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 Antibiotic Therapy and Early Onset Sepsis
Gustave Falciglia, Joseph R. Hageman, Michael Schreiber and Kenneth Alexander
Neoreviews 2012;13;e86
DOI: 10.1542/neo.13-2-e86

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