Antibiotic Therapy in Neonatal and Pediatric Septic Shock

Rajesh K. Aneja & Ruby Varughese-Aneja &

Carol G. Vetterly & Joseph A. Carcillo
Published online: 6 July 2011
# Springer Science+Business Media, LLC 2011
Abstract Severe sepsis accounts for nearly 4,500 deaths
(mortality rate 10%), and is responsible for nearly $2
billion annual healthcare expenditure in the United
States. Early and speedy treatment of critically ill septic
patients can halt or reduce the likelihood of physiologic
progression to multi-system organ failure. A cornerstone
of this therapeutic strategy is antibiotic administration. In
this review, we discuss the empirical treatment strategies
for the treatment of early and late neonatal sepsis, along
with pediatric sepsis. Furthermore, we discuss the
rationale that underlies the adoption of such treatment
strategies. The present article also discusses the emer-
gence of multi-drug organisms as the causative agents for
sepsis, i.e. methicillin-resistant Staphylococcus aureus
(MRSA), resistant enterococci and Klebsiella pneumoniae
carbapenemases (KPC).
Keywords Pediatric sepsis
.
Neonatal sepsis
.
Septic
shock
.
Antibiotics
.
Multi-drug resistant organisms
.
Antibiotic therapy
Introduction
The Need for Antibiotics
Sepsis continues to be an important global public health
challenge. Watson and colleagues [1, 2] analyzed hospital
discharge data (representing approximately one quarter of
the U.S. population), and reported that sepsis accounted for
nearly 4,500 deaths and nearly $2 billion annual healthcare
expenditure in the U.S. alone in 1995. The incidence of
sepsis was highest in infants (5.16 cases per 1,000
R. K. Aneja
:
J. A. Carcillo
Department of Critical Care Medicine,
University of Pittsburgh School of Medicine and Childrens
Hospital of Pittsburgh of UPMC,
Pittsburgh, PA 15224, USA
R. K. Aneja
:
J. A. Carcillo
Department of Pediatrics, University of Pittsburgh School of
Medicine and Childrens Hospital of Pittsburgh of UPMC,
Pittsburgh, PA 15224, USA
e-mail: carcilloja@upmc.edu
R. Varughese-Aneja
Division of Neonatology, The Western Pennsylvania Hospital,
4800 Friendship Avenue,
Pittsburgh, PA 15224, USA
e-mail: rvarughese@pol.net
C. G. Vetterly
Department of Pharmacy, University of Pittsburgh School of
Pharmacy and Childrens Hospital of Pittsburgh of UPMC,
Pittsburgh, PA 15224, USA
e-mail: carol.vetterly@chp.edu
R. K. Aneja (*)
Department of Critical Care Medicine, Childrens Hospital of
Pittsburgh of UPMC, Childrens Hospital Drive,
4401 Penn Ave,
Pittsburgh, PA 15224, USA
e-mail: anejar@upmc.edu
C. G. Vetterly
Department of Pharmacy, Childrens Hospital of Pittsburgh of
UPMC, Childrens Hospital Drive,
4401 Penn Ave,
Pittsburgh, PA 15224, USA
Curr Infect Dis Rep (2011) 13:433441
DOI 10.1007/s11908-011-0197-5
population per year) and lowest in older children (0.2 cases
per 1,000 population per year). Severe sepsis causes more
deaths in children compared to cancer. In a followup study
by the same author, the absolute mortality from sepsis has
decreased from 10.3% to 7.6% in the last decade. However,
the overall incidence of sepsis appears to have dramatically
increased in younger children (< 12 months of age) by
more than 50% [3, 4].
Since the seminal discovery of penicillin by Dr. Alexander
Fleming, administration of antibiotics has become a standard
of care in the treatment of septic children and adults.
Furthermore, the recently published American College of
Critical Care Medicine for Hemodynamic Support of Neo-
nates and Children with Septic Shock [5] recommend that,
after an initial evaluation of a critically ill septic pediatric
patient, antibiotic administration should be initiated within
the first hour. The decision to initiate antibiotics in a
critically ill child should be guided by the childs age,
history, comorbidities, presence of an intravascular catheter,
and local resistance patterns prevalent in the community.
Early and prompt administration of antibiotics to
critically ill patients can halt or reduce the likelihood of
physiologic progression to multi-system organ failure. This
article reviews the principles that guide antibiotic therapy in
neonatal and pediatric septic shock (Table 1). We also
review common antibiotic strategies used to treat critically
ill children that present with sepsis and septic shock.
Early Administration of Antibiotics: Does it Make
a Difference?
It is unlikely that a randomized control will ever test the
hypothesis that withholding antibiotics will be harmful to
septic patients. Therefore, we will have to be content with
the next level of evidence available. In a retrospective
study, Kumar et al. [6] reviewed the records of 2154 adult
septic shock patients (78.9% total) who received effective
antimicrobial therapy only after the onset of recurrent or
persistent hypotension and noted a strong relationship
between the delay in effective antimicrobial initiation and
in-hospital mortality. Almost 80% of the patients that
received antimicrobial therapy within the first hour of
documented hypotension survived, and each hour delay in
administration of antibiotic after the onset of hypotension
was associated with an average decrease in survival of
7.6% with every passing hour [6]. Gaieski et al. [7]
retrospectively analyzed severe sepsis and septic shock
patients treated with early goal directed therapy in the
Hospital of the University of Pennsylvania's emergency
department, and noted that mortality decreased by 13.5%
(25% versus 38.5%) when the time from triage to
appropriate antibiotic administration is <1 h.
Both these studies provide evidence that early adminis-
tration of appropriate antimicrobial therapy in severe sepsis
and septic shock is beneficial and potentially lifesaving.
Neonatal Septic Shock
Early-Onset Sepsis
The mortality associated with neonatal sepsis and septic
shock is staggering and accounts for more than a million
neonatal deaths each year [8]. The immunological immatu-
rity of the neonatal immune system creates a relative
immunodeficiency and predisposes the newborn to bacterial
infections. Some of these factors include a diminished
neutrophil storage pool, abnormal neutrophils and mono-
cyte chemotaxis, decreased cytokine and complement
production, and diminished levels of type-specific IgG,
secretory IgA, and IgM. In addition, the presence of
maternal risk factors e.g., premature or prolonged rupture
of membrane, premature labor, chorioamnionitis, aggra-
vates the predisposition of these infants to life threatening
severe infections. Knowing the presence or absence of these
risk factors is important to ascertain the need and duration
of antibiotic therapy in a sick neonate.
Prior to reviewing the treatment of neonatal septic shock,
it is important to understand the definitions used to define
early and late neonatal sepsis. There are many published
definitions of early-onset sepsis (EOS) but the widely
accepted definition is onset of symptoms within the first
few days of life (<72 h). Predictably, the organisms
Table 1 General principles guiding administration of antibiotics in pediatric and neonatal shock
1) Initial antibiotic coverage should be broad to cover possible pathogens for that age group
2) Early administration of antibiotics (with in the first hour of presentation) is recommended for critically ill septic pediatric patients
3) Culture results can be used to narrow or tailor antibiotic therapy after the first 48 72 h of therapy
4) Therapeutic drug monitoring aimed at ensuring adequate trough target levels should be performed where possible
5) Repeat cultures should be obtained to document proof of cure
6) Source control strategy should be implemented early
7) Complete course of antibiotics should be administered
434 Curr Infect Dis Rep (2011) 13:433441
associated with EOS are the same as those that are
prevalent in the maternal genital tract. The fetus or neonate
is exposed to the potentially pathogenic aerobic and
anaerobic bacteria either due to an amniotic infection, or
after membrane rupture when the infant passes through the
birth canal. A few days after aspiration of infected amniotic
fluid during the birth process, the neonate may manifest
with signs and symptoms of neonatal shock. Patients
diagnosed with EOS present with pneumonia or nonspecific
signs suggestive of sepsis. Meningitis as a manifestation of
EOS is rare.
Causative organisms that cause early-onset neonatal
sepsis include group B streptococcus (GBS), Escherichia
coli, Klebsiella spp., Enterobacter spp., and Listeria
monocytogenes. Muller-Pebody et al. [8] examined the
national laboratory surveillance data in England and Wales
between January 2006 and March 2008, and noted that a
third of the reported 1516 bacteremias (<48 h old defined as
early onset) were due to GBS. Other microbes included
coagulase-negative staphylococci (CONS; 22%), non-
pyogenic streptococci (9%), and E. coli (9%) [8]. The
presence of 22% Coagulase-negative staphylococcus
(CONS) was striking; it was unclear if these isolates were
contaminants or represent a true infection, as the registry
does not include reporting of clinical parameters [8]. We
discuss this study in the late-onset sepsis (LOS) section
again as the authors report almost half the isolates (45%) in
the LOS to be CONS.
Antibiotic Treatment of EOS
The empirical treatment of neonatal sepsis is a combination of
ampicillin and gentamicin as this therapy will cover almost all
of the organisms mentioned above [9]. A term neonate or a
late pre-term infant 7 days of age should be started on
ampicillin and gentamicin (Table 2). If the neonate is
clinically improving and it is anticipated that the antibiotic
course would be of a short duration, therapeutic monitoring
of serum gentamicin levels is not required in the setting of a
normal renal function [10]. However, if there is concern for
meningitis or prolonged treatment is required for a blood
culture positive sepsis/septic shock, then serum gentamicin
levels should be monitored.
The efficacy of this combination was recently tested in a
prospective multi-center surveillance study, in 12 English
neonatal units, using a web database [11]. Over a 3 year
period (January 2006 to December 2008), 125 episodes of
EOS were documented; 74% (93) were due to Gram-
positive organisms, 25% (31) to Gram-negative organisms.
GBS was the most frequent organism isolated. The majority
of organisms (95%) were susceptible to commonly used
empiric antibiotic combinations i.e., benzyl penicillin and
gentamicin or amoxicillin and cefotaxime for EOS.
Many neonatal ICUs use the antibiotic cefotaxime, as a
first-line agent, for treatment of neonatal sepsis. The use of
a third generation cephalosporin as a first line agent is
fraught with the development of resistant bacterial patho-
gens i.e., extendedspectrum -lactamase-producing bacte-
ria in neonatal intensive care units [1214]. As neonates
have minimal endogenous flora at the time of birth, these
neonates may be colonized with resistant pathogens. A
retrospective review examined the use of cefotaxime in
128,914 neonates and compared the cohort group treated
with ampicillin and cefotaxime to a group that received
ampicillin and gentamicin. Based on logistic modeling, the
authors demonstrated that neonates treated with ampicillin/
cefotaxime were more likely to die, and less likely to be
discharged to home or foster care as compared to neonates
treated with ampicillin/gentamicin [15]. Despite accounting
for several important confounding variables in this admin-
istrative database, the association of mortality with the use
of cefotaxime held strong. Does that mean we should stop
using cefotaxime to treat neonatal sepsis? Before we arrive
at this conclusion, this retrospective analysis of an
administrative data set needs to be evaluated further in a
prospective study.
CONS is the most frequent cause of neonatal LOS,
although recent data (as cited above) suggest that it is also
responsible for EOS. The reported incidence of CONS
varies from 2% to 20% [1619]. In these cases, Vancomy-
cin is the drug of choice and a set of repeat cultures prior to
initiation of antibiotics must be obtained to ensure that the
positive culture is not a contaminant. Persistent CONS
infection is defined as three or more consecutive positive
blood cultures, at least 48 h apart, during a single sepsis
episode [20]. Rifampin has been used as an adjunct therapy
in serious staphylococcal infections in combination with
other antibiotics such as penicillinase-resistant penicillins,
cephalosporins, vancomycin, and aminoglycosides [2123].
Late-Onset Sepsis
Similar to EOS, LOS is also defined based on the time when
symptoms start. Patients are diagnosed with LOS when the
onset of symptoms of sepsis is delayed beyond 72 h after birth;
the pathogens causing LOS are generally acquired from the
post-natal environment and classically present with septicemia,
pneumonia and/or meningitis. Certain risk factors also predis-
pose neonates to LOS: low birth weight, superficial infections
(pyoderma, umbilical sepsis), aspiration of feeds, disruption of
skin integrity, and central line access. A common source of
postnatal infections is transmission by the care taker i.e., hand
contamination of health care personnel, mother, and other
family members. Meningitis results from either the hematog-
enous dissemination or less commonly, a direct extension from
open neural tube defects or congenital sinus tracts.
Curr Infect Dis Rep (2011) 13:433441 435
Compared to EOS, a wider range of pathogens are
implicated in the accounts for LOS. In a 1-year longitudinal,
prospective surveillance study of systemic sepsis (septicemia
or meningitis) in Australian neonatal units, CONS was noted
to be the most common cause of LOS. The majority of these
episodes were in babies <1,000 g [24]. Gram-negative
bacillary infections occur less frequently than CONS, but
are associated with a higher mortality [25, 26]. In a decade
long prospective surveillance study, approximately 22%
(702/3113) episodes of LOS were from Gram-negative
bacilli and resulted in death of one-fifth of the infected
neonates. Remarkably, infection with Pseudomonas aerugi-
nosa sepsis was associated with a higher mortality (52.3%
versus 20%) [27]. Other organisms that cause morbidity and
mortality in LOS include Enterobacteriaceae, S. aureus and
methicillin-resistant S.aureus (MRSA).
Antibiotic Treatment of LOS
The empiric therapy for LOS in term or late preterm infants
admitted from the community after 7 days is a combination
of ampicillin and gentamicin (Table 2). If there is concern
for meningitis, then cefotaxime is administered every 8 h
instead of gentamicin. Once the child is stable, a lumbar
puncture should be performed. If there is history of
prolonged hospitalization or the child has a central venous
catheter, then vancomycin is preferable to ampicillin. In this
case, vancomycin and gentamicin/cefotaxime is preferable
empiric coverage. The switch to vancomycin provides
additional coverage for S. aureus and CONS. Once
sensitivities are determined, antibiotic course for MRSA
should be completed with nafcillin. Clindamycin is now
recommended for susceptible MRSA isolates in term
infants after resolution of bacteremia.
A detailed discussion addressing individual bacterial
infections is beyond the scope of this article; however some
common infections are being mentioned briefly. If GBS is
identified, antimicrobial therapy can be tapered to penicillin
G. Based on the antimicrobial sensitivity profile, if Gram-
negative bacilli are identified, a 10 to 14 day course of
cefotaxime is sufficient. Conversely, if the organism is
identified to be an extended-spectrum -lactamase produc-
ing organism, then treatment with meropenem is warranted.
Pediatric Sepsis
The burden of newborn and pediatric sepsis is increasing in
the U.S. As mentioned, the incidence of sepsis is highest in
infants as compared to older children (5.16 versus 0.20
Table 2 Ampicillin and gentamicin neonatal dosing guidelines
Post menstrual age (weeks) Postnatal age (days) Dose (mg/kg/dose) Interval (hours)
Ampicillin neonatal dosing guidelines
< =29 028 2550 12
meningitis and severe group B streptococcal sepsis: 100 12
>28 days 2550 8
meningitis and severe group B streptococcal sepsis: 100 8
3036 014 2550 12
meningitis and severe group B streptococcal sepsis: 100 12
> 14 2550 8
meningitis and severe group B streptococcal sepsis: 100 8
3744 07 2550 12
meningitis and severe group B streptococcal sepsis: 100 12
>7 2550 8
meningitis and severe group B streptococcal sepsis: 100 8
>=45 2550 6
meningitis and severe group B streptococcal sepsis: 100 6
Gentamicin neonatal dosing guidelines
<= 29 07 5 48
828 4 36
>=29 4 24
3034 07 4.5 36
>=8 4 24
>=35 4 24
436 Curr Infect Dis Rep (2011) 13:433441
cases per 1000 population). The mean age in the study was
4.7 years, and slightly more than half were male. Mortality
was higher in children who had underlying disease or
chronic conditions as compared to previously healthy
children (12.8% versus 7.8%). Examples of chronic
medical conditions in older children include seizure
disorders, cerebral palsy, and developmental abnormalities.
In contrast, younger children diagnosed with sepsis were
previously afflicted with respiratory and cardiovascular
diseases. The most common infecting organism was
Staphylococcus (17.5% overall) followed by Streptococcus,
Pseudomonas and Meningococcus.
In another retrospective study, medical records of children
(1 month to 21 years) admitted to the pediatric intensive care
unit from January 1998 to December 1999 with septic shock
were reviewed. A total of 96 episodes of septic shock in 80
patients were analyzed. Blood cultures were positive in half of
these cases. A single Gram-positive organism was isolated in
approximately two-thirds of the positive cultures, while 15%
of the patients had multiple organisms (Gram-positive and
Gram-negative organisms) [28]. The empirical antimicrobial
therapy for children who present with severe sepsis should
broadly cover bloodstream infections, pneumonia and intra-
abdominal infections. Therefore, antibiotics that cover both
Gram-positive and Gram-negative bacteria are needed for the
empirical treatment of critically ill patients with severe
sepsis. The choice of these antibiotics should be refined
based on the antimicrobial susceptibility of epidemiological
patterns of pathogens responsible for severe sepsis and
shock. The empirical antibiotics used at the authors
institution include vancomycin (15 mg/kg/dose Q 6H), and
piperacillin/tazobactum (<40 kg; 240300 mg [of piperacil-
lin component]/kg/day in divided doses Q 68H).
The patient cohort of todays intensive care unit (ICU) is
different compared to a decade ago. An increasing number of
the ICU patients are immunodeficient; many have undergone
multiple surgeries and need multiple invasive monitoring
devices. Most of these patients receive broad-spectrum anti-
biotics during their prolonged stay in the ICU. As a result,
these patients are at risk of infections with multi-drug resistant
isolates. These isolates were rare a decade ago, but are
increasingly being reported to cause morbidity and mortality.
Therefore, we would like to discuss three multi-drug
organisms that are increasingly responsible for morbidity
and mortality in the pediatric ICU. These include MRSA,
vancomycin resistant enterococci (VRE), and Klebsiella
pneumoniae carbapenemases (KPC).
MRSA
Historically, MRSA was recognized as a major cause of
morbidity and mortality related to hospital-acquired infec-
tions (HA-MRSA). However, the last decade has witnessed
the unprecedented increase in the incidence of MRSA as a
community-associated infection (CA-MRSA) [2931]. In
fact, CA-MRSA is the most common identifiable cause of
skin and soft-tissue infections in several metropolitan
emergency rooms across the U.S. [32]. The genotypic
characteristics that distinguish CA-MRSA strains from HA-
MRSA isolates include the architecture of the methicillin
resistance genetic elements, and the presence of Panton-
Valentine leukocidin (PVL) [33]. First described in 1930 by
Sir Philip Noel Panton and Francis Valentine, PVL is the
cytotoxin largely responsible for leukocyte destruction and
tissue necrosis [34]. The PVL is encoded on a prophage and
leads to the secretion of two proteins lukS-PVand lukF-PV
(together, the two components are referred to as lukSF-PV)
that synergistically work to form pores in the membrane of
host defense cells [35]. There are several other toxins that
contribute to the virulence of CA-MRSA, but due to space
limitations, are not being discussed here.
In the epidemiological study mentioned before, Staphy-
lococcus was isolated from 18% of cases overall and 26%
of all neonatal infections [4]. Among the staphylococcal
isolates, S. aureus accounted for approximately 20% of the
isolates. The most common invasive disease caused by CA-
MRSA is acute hematogenous osteomyelitis. Children with
underlying conditions are at risk of acquiring an invasive
infection compared to normal, healthy children (32% versus
5%; P<0.001) [36]. Furthermore, infections caused by
PVL-positive S. aureus are more severe than PVL-negative
S.aureus, and frequently associated with significant mor-
bidity and mortality. The PVL-positive S. aureus is more
likely to be associated with soft tissue infections, necrotiz-
ing pneumonia, sepsis, leukopenia, multi-organ failure, and
death [3740].
Treatment of MRSA
There are virtually no trials evaluating antimicrobial agents
for the treatment of invasive MRSA infections. Emergence
of a multidrug-resistant strains and limited availability of
antimicrobial agents active against MRSA further compli-
cate the treatment of invasive MRSA infections. The
definitive therapy of invasive infections caused by S.
aureus resistant to oxacillin or methicillin (minimum
inhibitory concentration [MIC] 4 mcg/mL) is vancomycin.
Trough vancomycin concentrations between 15 and
20 mcg/mL are recommended for critically ill patients with
serious MRSA infections [41]. The initial dose for
vancomycin is 15 mg/kg/dose Q6H for children with
normal renal function. If the treatment is directed toward
staphylococcal strains intermediately susceptible to vanco-
mycin, addition of other agents, i.e. gentamicin or rifampin,
is warranted. Serum trough levels are measured and
Curr Infect Dis Rep (2011) 13:433441 437
vancomycin doses are adjusted based on these levels. Once
the cultures are sterile, and the child is clinically improving,
vancomycin should be continued. The duration of therapy
for MRSA infection depends upon the site of infection, but
serious disseminated infections need to be treated for 4
6 weeks.
Depending upon the sensitivities and persistence of the
infection, other antibiotic therapies utilized for treatment of
MRSA infections include trimethoprim-sulfamethoxazole,
clindamycin [42], quinupristin-dalfopristin, and daptomy-
cin. Linezolid is an oxazolidinone antibiotic with bacterio-
static activity against S. aureus, and is being increasingly
used to treat sensitive strains of S. aureus [43]. In addition
to the well known side effect of Linezolid, i.e. reversible
myelosuppression, lactic acidosis is an additional side effect
that has gained prominence in the ICU setting [44]. The
mechanisms that underlie the generation of lactic acidosis
with the use of linezolid have still not been elucidated; a
possible mechanism that has been highlighted is linezolid-
induced mitochondrial toxicity. Discontinuation of linezolid
and supportive measures are used to treat these patients.
Resistant Enterococci
Thiercelin used the word enterocque in 1899 to describe
enterococci, Gram-positive cocci in pairs and short chains.
These catalase-negative, facultative anaerobes are now
recognized as an important cause of nosocomial infections.
Enterococci are normal habitants of the human bowel,
therefore, determining if it is a true pathogen can be
difficult. Enterococcus is frequently isolated from intra-
abdominal, pelvic infections and can cause urinary tract
infections, bacteremia, endocarditis, and meningitis. The
National Nosocomial Infections Surveillance (NNIS) Study
demonstrated a 12% increase in nosocomial infections in
the ICU related to vancomycin resistant Enterococci over a
5 year period (2003 versus1998) [45]. The majority of
invasive enterococcal infections are caused by Enterococ-
cus faecalis, and Enterococcus faecium.
Ampicillin has been the drug of choice to treat
enterococcal infections. The reasons for ampicillin
resistance in enterococci are production of -lactamase
or alterations in the expression or structure of penicillin-
binding protein. Penicillinase-production has been de-
scribed almost exclusively in E. faecalis and is largely
attributed to the acquisition of the -lactamase operon
[46]. Vancomycin resistance by enterococci has become a
serious problem in the management and control of these
infections. Resistance is mediated by the van family of
structurally similar, but genetically very distinct multigene
clusters; the most important are the vanA and vanB
clusters [47].
The pathogenesis of enterococcal infections has not been
clearly defined. It is thought that virulence factors are
responsible for the considerable morbidity and mortality
associated with VRE. Hemolysin/bacteriocin and aggrega-
tion substance are examples of the virulence factors that can
lyse of human erythrocytes, and promote clumping of the
bacteria resulting in adherence to tissue, respectively. Some
of the risk factors that are associated with acquiring VRE
include prolonged hospitalization and antibiotic use, mul-
tiple surgeries, immunocompromised state, and breakdown
of physical barriers.
Susceptible strains of enterococci should be treated with
ampicillin/penicillin. The isolate should also be screened
for -lactamase production and vancomycin should be used
in the setting of -lactam resistance. High serum concen-
trations of aminoglycosides act as synergistic agents for
treatment of enterococcal infections; therefore, isolates
should be tested for resistance to gentamicin. Aminoglyco-
sides are unlikely to be helpful if the strain is resistant to
high levels of gentamicin. Certain aminoglycosides i.e.
tobramycin or amikacin may not be helpful when used with
certain enterococcal species, i.e. E. faecium and E. faecalis,
as these strains are resistant to aminoglycosides. If there is
evidence of production of -lactamase, vancomycin can be
used to treat the Enterococci.
Treatment of VRE needs to be discussed on an
individual basis, and a broad set of recommendations is
not possible. The patient profile, resistance patterns, and
nature of the disease have to be considered to determine
the duration of therapy. The two agents that are
frequently used in the treatment of VRE are linezolid
and quinupristin/dalfopristin. Linezolid as described
above is a bacteriostatic, synthetic oxazolidinone antibi-
otic that inhibits bacterial protein synthesis. Furthermore,
it has a good oral bioavailability; therefore, both
intravenous and oral routes can be used to treat serious
infections. In a retrospective study, oral linezolid was
shown to be an effective alternative to intravenous
vancomycin for the treatment of Gram-positive bacterial
infections in a cohort of pediatric intensive care unit
patients [48]. Quinupristin-dalfopristin is a streptogramin
antibiotic and is approved by the FDA for the treatment of
VRE infections, i.e. E. faecium infections. It has poor
activity against E. faecalis due to species-specific ATP-
binding protein metabolic interactions, severe myalgias,
arthralgias, nausea, and hyperbilirubinemia.
In summary, multidrug-resistant enterococci are impor-
tant nosocomial pathogens and continue to be important
health hazards. The prolonged use of extended-spectrum
cephalosporins and drugs active against anaerobes predis-
pose a patient to VRE colonization and infection. Prompt
and aggressive treatment along with ICU-based prevention
strategies may help to decrease the incidence of VRE.
438 Curr Infect Dis Rep (2011) 13:433441
Carbapenemases
Currently, carbapenems are the drug of choice to treat
multidrug-resistant infections caused by Enterobacteria-
ceae bacteria (e.g., E. coli, Salmonella and Klebsiella)
producing extended-spectrum -lactamases (ESBLs).
Therefore, it is concerning that recent reports indicate the
emergence of carbapenem resistance in this class of
pathogens especially Klebsiella pneumoniae. The cause
for the resistance is multi-factorial. In addition to -
lactamases, that can hydrolyze carbapenem antibiotics,
overexpression of AmpC -lactamases (cephalosporinases
encoded on the chromomosomes of Enterobacteriaceae)
confers resistance to broad-spectrum cephalosporins.
Furthermore, these resistant organisms produce metallo-
carbapenemases or nonmetallo carbapenemases [49] that
in addition to all cephalosporins, can also hydrolyze
carbapenems [50]. Simply put, production of these
enzymes results in resistance to all penicillins, cephalo-
sporins, and carbapenems.
The KPC-producing Klebsiella are now a serious
problem that has been reported in North America and
several European nations. In an outbreak of KPC-producing
K. pneumonia, in an adult Greek ICU, the majority (62%)
of the strains were isolated from the respiratory tract, while
20% were recovered from the blood. Most of these patients
were admitted to the hospital frequently and required
prolonged administration of antibiotics and mechanical
ventilation. The mortality rate in this study was 22.2%,
which is in line with other reported adult data [51].
Similarly in an observational study, in two hospitals in
New York, isolates were examined for the presence of KPC-
type carbapenem-hydrolyzing -lactamases. Almost half
the isolates were ESBL-producing KPC, and only a small
percentage of these isolates (3.3%) carried the carbapenem-
hydrolyzing -lactamase KPC-2. Similar to the other study,
this study also reported high mortality rates (47%) in
bacteremic patients. Although there are no epidemiological
data about KPC in children, our institution has seen three
cases in the last year alone. It is likely that in the coming
decade, we will see an increased morbidity and mortality
associated with KPC-producing organism.
Infections associated with KPC are not specific to
anatomic locations or organs; instead, most of the infections
often occur in patients who have undergone multiple
procedures and have invasive devices for prolonged
duration [52]. A review of carbapenemases is beyond the
scope of this article, but the reader is referred to a recent
review published in the Pediatric Infectious Disease Journal
[53]. The optimal treatment of KPC-producing K.
pneumoniae remains uncertain, but proper in vitro suscep-
tibility testing and subsequent treatment is recommended.
Some reports suggest that continuous administration of
carbapenems is more effective than standard dosing in the
treatment of KPC K. pneumoniae, however one has to be
cautious while using carabapenems to treat KPC producing
organisms. Clinicians need to be aware of the importance of
laboratory screening for KPC producing K. pneumoniae
and treat with appropriate antibiotic strategies after consul-
tation with their infection disease specialist.
Conclusions
Sepsis remains a significant health problem and early
administration of appropriate antimicrobial therapy in
severe sepsis and septic shock is beneficial and potentially
lifesaving. CONS are a frequent cause of neonatal LOS,
and recent data suggest that it is also responsible for EOS.
Therefore, in addition to the usual empirical therapeutic
strategy, vancomycin should be added if CONS is identi-
fied. Multidrug-resistant bacteria continue to pose problems
in pediatric intensive care units. Sepsis associated with
emerging resistant microorganisms i.e., enterococci and
KPC, is difficult to treat and quite challenging. As the
understanding of these resistant microorganisms improves,
rational design of antibiotic strategies targeting these
organisms will improve outcome in sepsis.
Disclosure No potential conflicts of interest relevant to this article
were reported.
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