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Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6

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Gut bacteria and late-onset neonatal bloodstream infections in

preterm infants
Phillip I. Tarr a, *, Barbara B. Warner b
Division of Gastroenterology, Hepatology, and Nutrition, Pathobiology Research Unit, Department of Pediatrics, Washington University School of Medicine,
St Louis, MO, USA
Fetal Center, Division of Newborn Medicine, Washington University School of Medicine, St Louis, MO, USA

s u m m a r y
Keywords: Late-onset neonatal bloodstream infections remain challenges in neonatology. Hand hygiene, line care,
Late-onset neonatal bloodstream infections and judicious use of indwelling lines are welcome interventions, but might not reduce the incidence of
Gram-negative bacteria
late-onset neonatal bloodstream infections from bacteria originating in the gut. Accumulating data
Gram-positive bacteria
Gut microbes
suggest that many pathogens causing late-onset neonatal bloodstream infections are of gut origin,
including Gram-positive cocci. In addition to the host-canonical paradigm (i.e., all bacteria have equal
risk of invasion and bloodstream infections are functions of variable infant susceptibility), we should now
consider bacteria-canonical paradigms, whereby late-onset neonatal bloodstream infection is a function
of colonization with a specific subset of bacteria with exceptional invasive potential. In either event, we
can no longer be content to reactively approach late-onset neonatal bloodstream infections; instead we
need to reduce the occurrences of these infections by broadening our scope of effort beyond line care,
and determine the pre-invasive habitat of these pathogens.
© 2016 Published by Elsevier Ltd.

1. Introduction cerebral palsy, independent of intracranial structural abnormalities

[7]. Neonatal infections are also associated with lower Bayley Scale
Late-onset neonatal bloodstream infections in preterm infants of Infant Development II scores, worse psychomotor development,
are illnesses (i) in which a credible pathogen is recovered from the abnormal vision, and lesser occipital frontal circumferences, among
blood, and (ii) that occur after the first 72 h of age [1e5]. The Gram- those infants who survive their episode of late-onset neonatal
negative bacilli, Gram-positive cocci, and fungi that represent the bloodstream infections and who are discharged to home [3].
majority of infections have differing pre-invasion habitats in the Our understanding of late-onset neonatal bloodstream
body, control strategies, treatments, and prognoses when they infections is severely limited by their unpredictable onset in infants
cause extraintestinal infections. at risk. In this review, we emphasize data from human cohorts, and
Infants who have had culture-proven late-onset neonatal cite animal data only if they might illuminate human biology
bloodstream infections have higher mortality than those who have relevant to late-onset neonatal bloodstream infections.
not had these infections [1,6]. Late-onset neonatal bloodstream
infections in very low birth weight infants bestow independent
risks to long-term child development, in addition to the well- 2. Prospects for preventing late-onset neonatal bloodstream
recognized risks bestowed by brain injury, bronchopulmonary infections beyond line care and hand hygiene
dysplasia, and retinopathy of prematurity [2]. Indeed, it has been
calculated that a single late-onset neonatal bloodstream infection Lessons can be learned from attempts to control early-onset
in a preterm infant approximately quadruples the likelihood of (occurring <72 h after birth) infection with Streptococcus aga-
lactiae (Group B streptococcus (GBS)). Screening for maternal
colonization with GBS, and the treatment of mothers and their
newborns with parenteral antibiotics (usually b-lactam agents),
* Corresponding author. Address: Department of Pediatrics, Washington
University School of Medicine, Campus Box 8208, 660 S. Euclid, St Louis, MO 63110,
have reduced the incidence of early-onset bloodstream infections
USA. Tel.: þ1 314 286 2848. with GBS [8,9]. In contrast, the incidence of late-onset neonatal
E-mail address: (P.I. Tarr). bloodstream infections caused by GBS is increasing [10,11], and can
1744-165X/© 2016 Published by Elsevier Ltd.

Please cite this article in press as: Tarr PI, Warner BB, Gut bacteria and late-onset neonatal bloodstream infections in preterm infants, Seminars
in Fetal & Neonatal Medicine (2016),
2 P.I. Tarr, B.B. Warner / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6

exceed the incidence of early-onset GBS bloodstream infections Box 1

[12]. It is logical, therefore, to extend successful strategies to reduce Host-canonical vs bacteria-canonical paradigms for late-onset
early-onset GBS infections to late-onset neonatal bloodstream in- neonatal bloodstream infections.
fections, caused by GBS as well as by other pathogens. However, it is
important to note that prevention strategies focused on early-onset
GBS rely on one critical assumption: the mother at risk, by virtue of Host-canonical risk for late-onset neonatal bloodstream
gut or birth canal colonization with GBS, may be identified. Once infections
this risk is identified, it can be managed (perinatal and usually There are major inter-individual variations in host risk.
parenteral antibiotics). We do not yet know if this strategy can be There are minor variations in bacterial populations to which
extended to late-onset neonatal bloodstream infections, but data the hosts are exposed, at least at taxonomic levels of genus
are emerging that might inform the discussion. and higher. Therefore, specific host risks ordain late-onset
Late-onset neonatal bloodstream infections are generally caused neonatal bloodstream infections in infants exposed to a
by species whose members are well represented in the gut and set of bacteria with similar pathogenic potential.
elsewhere in and on the body in health. There are, therefore, two
Observations in support of a host-canonical paradigm for
distinct paradigms for the pathobiology that underlies the occur-
late-onset neonatal bloodstream infections:
rence of a late-onset neonatal bloodstream infection (Box 1). The
first paradigm, and one that is highly ingrained among
1 Line care checklists and protocols, and augmented hand
neonatologists, assumes that risk for a late-onset neonatal blood-
hygiene reduce late-onset neonatal bloodstream infec-
stream infection is a function of specific host factors that increase
tion incidence. This is a host-specific intervention.
susceptibility. Such variably at-risk hosts are then exposed to a
2 Children “age-out” of a period of high risk for late-onset
population of microbes that have constant pathogenic potential. In
neonatal bloodstream infections. This suggests matura-
this “host-canonical” situation, invasion of the bloodstream is
tion of a host-defense process.
considered to be driven by physical breaches in the integrity of the
mucosa or the integument, or by impaired or poorly developed
innate or acquired host defense mechanisms. According to this first Bacteria-canonical risk for late-onset neonatal bloodstream
model, late-onset neonatal bloodstream infections would be best infections
prevented by attention to host biology (though recognizing that
There are inter-individual variations in host risk, but most
beyond line care and hand hygiene, protection interventions are
differences are based on gestational age and illness
not well validated). The second paradigm assumes that among
severity. Hence, among infants of the same gestational age,
preterm infants, there is a fairly constant level of impairment of
day of life, and with a similar set of general co-morbidities,
host defense against bacteria that can invade the bloodstream. In
there is a fairly consistent inter-child risk from mucosal and
this “bacteria-canonical” situation, late-onset neonatal blood-
integumentary barrier defects, and from poorly developed
stream infections result when a specific member (i.e., a species,
immune systems. However, there may be major variations
serotype, pathotype, or clade) of a genus that is widely found in or
in bacterial populations that hosts encounter. If a preterm
on infants in the healthy state, colonizes a host and then invades
infant is colonized with an organism with highly virulent
the bloodstream, because that specific member has exceptional
potential, even though it might belong to a taxon that is
invasive potential.
often regarded as “commensal” or harmless, bloodstream
It is quite plausible that all very preterm infants are at high risk
infections occur. In this scenario, the specific organism or-
for late-onset neonatal bloodstream infections, by virtue of their
dains most of the risk.
poorly developed immune systems, increased gut permeability,
and the near-universal use of indwelling lines (at least tempo- Observations in support of a bacteria-canonical paradigm
rarily), and that this risk is further stratified according to gesta- for late-onset neonatal bloodstream infections:
tional age at birth, day of life, and certain co-morbidities. Such a
non-dissimilar high risk background would tend to support the 1 The number of taxa that inhabit the gut is large, whereas
bacteria-canonical paradigm, within defined subgroups (e.g., the number of species that cause late-onset neonatal
gestational age at birth, age, etc.). That is to say, late-onset neonatal bloodstream infections (and, indeed, bloodstream in-
bloodstream infections occur only if a rare member of a common fections at all ages) is much more circumscribed. This
bacterial taxon colonizes the infant and if that colonizer has path- demonstrates, at least at the species level, variant path-
ogenic potential. Additional data support this concept. For example, ogenic potential.
even though there are many genera of bacteria in and on the bodies 2 Considerable molecular epidemiologic data suggest that
of preterm infants, the number of identified genera in blood cul- species causing many episodes of late-onset neonatal
tures is highly circumscribed. Specifically, Gram-negative bacilli bloodstream infections, namely E. coli and Group B
(largely Escherichia coli, Klebsiella, Serratia, Enterobacter, and Pseu- streptococcus, belong to phylogenetic subsets that are
domonas spp.), GBS, enterococci, Staphylococcus aureus, and associated with extra-intestinal pathogenicity.
coagulase-negative Staphylococci account for almost all late-onset 3 One technique to interdict outbreaks of late-onset
neonatal bloodstream infections [14,15]. Interestingly, with few neonatal bloodstream infections is to isolate infected in-
modifications, these pathogens account for the bulk of bloodstream fants, even though the pathogens in question may belong
infections at all ages, and in diverse settings, even though they are to organisms that, at a genus and species level, are
not the most prevalent members of the gut bacterial communities. frequently found in the gut.
If the bacterial canonical paradigm explains even a subset of 4 Bacteria that invaded the bloodstream of patients in the
late-onset neonatal bloodstream infections, it would be logical that study by Carl et al. [13] were rarely found in “overlap” or
by reducing the rate, duration, and consequences of colonization by random controls. The inferred relative risk for invasion by
highly virulent bacteria, there will be great benefit to very low birth these specific organisms is high.
weight infants. If the host-canonical paradigm is more appropriate,

Please cite this article in press as: Tarr PI, Warner BB, Gut bacteria and late-onset neonatal bloodstream infections in preterm infants, Seminars
in Fetal & Neonatal Medicine (2016),
P.I. Tarr, B.B. Warner / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6 3

there are some tools to achieve the goal of reducing the incidence of were associated with microbial gut predominance of Enter-
late-onset neonatal bloodstream infections, but most such at- obacteriaceae. They also identified in many subjects a concordance
tempts to prevent these infections focus on central line care and between antibacterial resistance of the bloodstream isolate and
hand hygiene [16e18]. The only intervention to prevent blood- that of bacteria from the stool prior to culture, but did not report
stream infections caused by organisms that do not dwell on the more specific characterization of the pathogens and the stool
skin is isolation of children during apparent outbreaks. However, isolates.
the vast majority of late-onset neonatal bloodstream infections do Our personal view of the origin of late-onset neonatal
not occur in nosocomial clusters, at least not those that are bloodstream infections has been influenced by Carl et al. [13].
recognized in real-time, and isolation is an intervention that This paper precisely established identity between specific bac-
actually endorses the concept of the bacteria-canonical paradigm. teria in the stool and subsequent invasion of the blood by these
Whereas it is not surprising that Gram-negative bacteria that strains. Specifically, in a cohort of 217 preterm infants in a single
reside in the gut cause Gram-negative bacterial bloodstream in- neonatal intensive care unit, 11 children whose bloodstream in-
fections, there has been remarkably little emphasis in the field of fections were caused by E. coli, Serratia marcescens, Klebsiella
neonatology on the threat posed by this biomass. However, accu- pneumoniae, and methicillin-resistant Staphylococcus aureus
mulating data now compel us to consider the infant gut as a critical (MRSA) also had sufficient stool prior to the event that was stored
habitat of organisms that subsequently invade the bloodstream of and available for microbiologic study. Of these 11 cases, seven
their hosts. These data build on two complementary contributions excreted a cognate pathogen (E. coli, S. marcescens, and GBS)
from the internal medicine literature. First, resistance patterns of before clinical deterioration was apparent, and the culture was
colonizing bacteria in the gut may be used to tailor and optimize obtained. Isogenicity between stool and blood isolates was
empiric antibiotics during clinical deterioration, a strategy established by whole pathogen sequencing, which offers a
employed mostly in intensive care units [19e21]. Second, selective considerable degree of confidence that the gut and the blood-
bowel decontamination, a practice more common in Europe than in stream isolate were of the same origin. Asymptomatic carriers of
the USA and most frequently used in adult intensive care settings, is isogenic GBS and S. marcescens were also identified in time- and
effective at reducing mortality and nosocomial infections including physical-proximity to cases, but, overall, excretion of these
bloodstream infections [22]. Parenthetically, selective bowel particular agents was rare. Hence, there appear to be
decontamination does not favor the emergence of antibiotic- microclusters of colonization within the neonatal intensive care
resistant pathogens in these settings [23,24]. unit (NICU) of infants' gut with pathogens that can invade the
blood. Such a finding is in accordance with data from a large
3. The gut as the pre-invasion habitat/reservoir of bacterial German network [30] suggesting that microclusters of late-
bloodstream invaders onset neonatal bloodstream infections occur, but that they are
often not identified as outbreaks in real-time.
Several observations support the concept that the gut is the A summary of studies that have attempted to match bacteria in
reservoir of Gram-negative pathogens before late-onset neonatal the blood with bacteria in the stool before the late-onset neonatal
bloodstream infections are clinically apparent. Though it is bloodstream infection episode occurred is provided in Table 1.
intuitive that increased gut permeability would permit the extra- Most studies of the role of the gut as the habitat/reservoir for
intestinal dissemination (translocation) of bacteria harbored by pathogens that subsequently cause late-onset neonatal blood-
this organ, it was not until Graham et al. demonstrated that, stream infections exclude Gram-positive bacteria. However, MRSA
among 20 episodes of bloodstream infections in 15 infants [33,34] and methicillin-susceptible S. aureus [35] are found in the
caused by Gram-negative bacilli, 19 of the bloodstream isolates gut [36] and stool has been recommended as an optimal specimen
could be paired to bacteria in stool samples that had been ob- for their surveillance [37,38] in preterm infants. Coagulase-negative
tained before the episode of sepsis. Putative identity was Staphylococci, which are bona fide pathogens in preterm infants
assigned according to identical pulsed-field gel electrophoresis [6,14,39], also have a gastrointestinal reservoir [40]. Staphylococcus
(PFGE) patterns [25]. PFGE is a macrogenomic microbial finger- as a genus is well represented in the stools of preterm infants,
printing technique that differentiates isolates within the same especially in the first week of life [41], an observation that also
species. Antibiotic susceptibility (to gentamicin) was similarly demonstrates that the gut harbors Gram-positive bacteria with
concordant between the bloodstream and fecal surveillance particular ability to invade the bloodstream, even though such or-
isolates. In a subsequent study, this group demonstrated that 58 ganisms are generally considered to colonize the skin. Finally, the
of 59 episodes of Gram-negative bacillary bloodstream infections origins of GBS that cause late-onset neonatal bloodstream in-
were caused by bacteria that could be matched to organisms of fections remain enigmatic. Intra-institutional outbreaks of late-
the same genus and species, based on concordant gentamicin onset GBS bloodstream infections are rare [42e44], suggesting
susceptibility/resistance profiles [26]. that the bloodstream isolate is probably acquired by infants during
With the recent explosion of interest in the gut microbiome, birth. However, Carl et al. [13] found fecal excretion of GBS by in-
attempts have been made to determine if there exists an identifi- fants who subsequently developed a late-onset neonatal blood-
able community of bacteria that predispose to late-onset neonatal stream infection with an isogenic GBS, after an earlier-in-life
bloodstream infections. In general, these studies have suggested interval in which GBS was not recoverable from the stool, and, on
potentially different microbial populations prior to the onset of occasion, the same GBS colonized infants in the vicinity of the cases.
sepsis, with risks including low microbial diversity [27]. Taft et al. These data now prompt us to reconsider in-neonatal intensive care
[28] identified a paucity of actinobacteria in early life and under- unit (NICU) acquisition of the pathogen, and the infant gut as the
representation of Pseudomonades in samples just before late-onset pre-invasive habitat.
sepsis, but no highly compelling concordance between blood- Interestingly, many of these studies identified prior antibiotic
stream isolate and fecal sequences at the level of species. Shaw et al. use (though variably defined) as a risk factor for bloodstream
[29] identified overrepresentation of fecal aerobic bacteria and infection. No doubt sicker children in general receive more antibi-
facultative anaerobes compared to infants who did not have otics and are more prone to late-onset neonatal bloodstream in-
bloodstream infections. Gram-negative bloodstream infections fections. However, animal data [45] support the role of antibiotics

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Table 1
Studies attempting to link bloodstream infections to pre-infection gut bacteria.

Study Technology applied Findings Comments

Almuneef et al. [31] Antibiogram and bacterial identification Two of three E. coli bloodstream infections Simultaneous carriage by
of individual isolates from stool were matched to fecal isolates by infants without bloodstream infection
non-sequence typing methodology of similar organisms as those causing
(antibiograms). bloodstream infections was demonstrated.
Graham et al. [25] Prior to bloodstream infection, infants' stool There was considerable concordance Sole focus was on Gram-negative bacteria
isolates were saved and these organisms were between the bloodstream isolates
compared (antibiograms, species) to the and bacteria in stool prior to the infection
subsequent bloodstream isolate from these infants
Smith et al. [26] Prospective stool culture-based isolates Isolates from the surveillance Associations between fecal carriage and
were saved and compared to subsequent culture obtained a mean of six bloodstream isolation were not as strong
bloodstream isolates by gentamicin days before the episode were highly for gentamicin-susceptible Gram-negative
susceptibility profiling predictive of gentamicin-resistant pathogens
subsequent infections (100% sensitivity,
98% specificity, 94% positive predictive value)
Stewart et al. [32] 454 pyrosequencing and denaturing Five infants developed late-onset neonatal No attempt to recover bloodstream
gradient gel electrophoresis analysis of bloodstream infections, and two of these isolate from stool
stools prior to the development of late-onset had NEC. In one child there was an
neonatal bloodstream infection apparent match between fecal
carriage of coagulase-negative staphylococci
and subsequent bloodstream infection.
Taft et al. [28] 16S rRNA gene sequencing of stool prior to Bacteria were compared at the genus and Many episodes were associated with
the development of late-onset neonatal species level based on sequence data from prior fecal excretion, but the degree
bloodstream infection, supplemented by stool the stool and compared to the specific of comparison is limited because the
shotgun sequencing isolate from the blood fecal analysis was not based on isolated
pathogen sequencing
Carl et al. [13] Stools stored culture-based recovery of cognate Isogenicity was demonstrated between These organisms were
pathogen in stools collected prior to the bloodstream and pre-bloodstream quite rare in two different control groups.
onset of episodes of late-onset neonatal infection isolates of pathogens in Colonization was demonstrated for variable
bloodstream infections in pre-term infants. 7 of 11 intensively studied children. intervals prior to clinical deterioration.
Antibiograms and other phenotypes, and whole GBS unexpectedly was harbored in the gut.
genome sequencing, were used to confirm or
refute identity between blood and fecal isolates.
Shaw et al. [29] 16S rRNA gene sequencing from fecal DNA. Staphylococci in stool preceded staphylococcal Bloodstream infections are preceded by
Some samples underwent bacterial bloodstream infection. Antibiograms overrepresentation of taxa in the gut that
isolation attempts. of blood and fecal isolates were concordant. are plausibly related to that event,
including staphylococcal colonization.

in promoting bacterial translocation through the colon wall to purity of probiotic formulations and the risk of serious neonatal
extra-intestinal sites, so a direct causal association cannot be systemic infections from probiotics [49,50], we cannot endorse
excluded. this intervention to prevent late-onset neonatal bloodstream
4. Probiotics to prevent late-onset neonatal bloodstream
infections 5. The future

Probiotics offer a possible intervention to prevent late-onset Worldwide, neonatologists approach late-onset neonatal
neonatal bloodstream infections, especially those of gut origin. bloodstream infections in a reactive “rule out sepsis” mode. It is
Two recent meta-analyses have addressed the efficacy of pro- critical that neonatologists remain vigilant and respond to the
biotics in preventing late-onset neonatal bloodstream infections. earliest signs of bloodstream infections in all preterm infants, as
Zhang et al. [46] proposed that probiotics might prevent blood- these are not normal hosts. However, in many cases, the specific
stream infections in low birthweight infants, but no effect was pathogens that subsequently invade the bloodstream may be found
seen in children weighing <1000 g at birth. Rao et al. also in the stool prior to clinical signs of systemic infection. Moreover,
concluded that probiotics had a preventive effect [47] and like- accumulating data suggest that colonization with specific blood-
wise found that infants in a subgroup analysis (those born at <28 stream invaders appears to be relatively rare among infants at risk.
weeks' gestation and/or weighing <1000 g at birth) did not Hence, such colonization might be an ultimate biomarker of soon-
benefit from this intervention. Late-onset neonatal bloodstream to-be-apparent sepsis.
infections were an outcome in the large probiotic study recently Ideally, colonization with bacteria with enhanced capability of
reported by Costeloe et al. [48]. This study failed to demonstrate invading the host would be avoided altogether in NICUs, but a sec-
any benefit of Bifidobacterium breve BBG-001 in preventing late- ondary goal should be the prevention of systemic dissemination
onset neonatal bloodstream infections. As with all meta- among the colonized. If further studies confirm these findings, then it
analyses of studies of probiotics, conclusions are necessarily will be appropriate to consider bacteria-canonical approaches to
limited by the various probiotics chosen in these interventions, prevent late-onset neonatal bloodstream infections. Specifically, all
differing dosage regimens and durations, and single versus preterm infants will be considered to be at similar risk according to
combination probiotics. In view of continuing concerns about their degree of prematurity, and risk reduction will be focused on the

Please cite this article in press as: Tarr PI, Warner BB, Gut bacteria and late-onset neonatal bloodstream infections in preterm infants, Seminars
in Fetal & Neonatal Medicine (2016),
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events that lead to acquisition or invasion of the bloodstream of the Conflict of interest statement
subset of infants harbouring a bacterium, generally in the gut, with
exceptional pathogenic potential. Such bacteria-canonical ap- None declared.
proaches will quite likely involve microbial monitoring of the hosts,
and require more extensive knowledge of the genomics of neonatal
Funding sources
pathogens than exists now, so as to decide appropriate taxonomic
targets at the level of species, serotype, pathotype, or clade, as
This work was supported by NIH Grants UH3AI083265,
appropriate, on a pathogen-by-pathogen basis within a genus.
P30DK052574 (for the Biobank Core) and the Children's Discovery
Possible risk mitigation strategies among infants colonized by an
Institute of Washington University and the St Louis Children's
organism with exceptional pathogenic potential might include at-
tempts to alter the gut microbial community by diet or probiotics,
implementation of selective bowel decontamination, administration
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in Fetal & Neonatal Medicine (2016),
6 P.I. Tarr, B.B. Warner / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e6

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Please cite this article in press as: Tarr PI, Warner BB, Gut bacteria and late-onset neonatal bloodstream infections in preterm infants, Seminars
in Fetal & Neonatal Medicine (2016),