M A J O R A R T I C L E
Intestinal Domination and the Risk of
Bacteremia in Patients Undergoing Allogeneic
Hematopoietic Stem Cell Transplantation
Ying Taur,1,2Joao B. Xavier,2,3Lauren Lipuma,2Carles Ubeda,5Jenna Goldberg,4Asia Gobourne,2Yeon Joo Lee,1
Krista A. Dubin,2Nicholas D. Socci,3Agnes Viale,6Miguel-Angel Perales,4Robert R. Jenq,4Marcel R. M. van den
Brink,4,5and Eric G. Pamer1,2,5
1Infectious Disease Service, Department of Medicine,2Lucille Castori Center for Microbes, Inflammation and Cancer,3Computational Biology Center,
and4Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, and5Immunology Program, and6Genomics
Core Laboratory, Sloan-Kettering Institute, New York, New York
(allo-HSCT). It is unclear whether changes in the intestinal microbiota during allo-HSCT contribute to the devel-
opment of bacteremia. We examined the microbiota of patients undergoing allo-HSCT, and correlated microbial
shifts with the risk of bacteremia.
Methods.Fecal specimens were collected longitudinally from 94 patients undergoing allo-HSCT, from before
transplant until 35 days after transplant. The intestinal microbiota was characterized by 454 pyrosequencing of the
V1-V3 region of bacterial 16S ribosomal RNA genes. Microbial diversity was estimated by grouping sequences
into operational taxonomic units and calculating the Shannon diversity index. Phylogenetic classification was ob-
tained using the Ribosomal Database Project classifier. Associations of the microbiota with clinical predictors and
outcomes were evaluated.
Results.During allo-HSCT, patients developed reduced diversity, with marked shifts in bacterial populations
inhabiting the gut. Intestinal domination, defined as occupation of at least 30% of the microbiota by a single
predominating bacterial taxon, occurred frequently. Commonly encountered dominating organisms included En-
terococcus, Streptococcus, and various Proteobacteria. Enterococcal domination was increased 3-fold by metronida-
zole administration, whereas domination by Proteobacteria was reduced 10-fold by fluoroquinolone
administration. As a predictor of outcomes, enterococcal domination increased the risk of Vancomycin-resistant
Enterococcus bacteremia 9-fold, and proteobacterial domination increased the risk of gram-negative rod bactere-
Conclusions.During allo-HSCT, the diversity and stability of the intestinal flora are disrupted, resulting in
domination by bacteria associated with subsequent bacteremia. Assessment of fecal microbiota identifies patients
at highest risk for bloodstream infection during allo-HCST.
Bacteremia is a frequent complication of allogeneic hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation
(allo-HSCT) is a potentially curative treatment for a
range of malignant and nonmalignant disorders. Pre-
transplant conditioning transiently ablates circulating
granulocytes and monocytes and markedly increases
susceptibility to disseminated infections [1, 2]. Mucosal
barrier injury is also a complication of allo-HSCT and
enables commensal microbes to invade underlying
tissues and the bloodstream . As a result, systemic
bacterial infections are frequent during the early trans-
plant period [4–6]. Vancomycin-resistant Enterococcus
(VRE), viridians-group Streptococcus, and aerobic
gram-negative bacteria are the most common causes
of bloodstream infection following allo-HSCT [5–8].
Why some patients develop bacteremia while others
do not is unclear.
Received 16 February 2012; accepted 30 May 2012; electronically published 20
Correspondence: Ying Taur, MD, MPH, Memorial Sloan-Kettering Cancer
Center, 1275 York Avenue, Box 9, New York, NY 10065 (firstname.lastname@example.org).
Clinical Infectious Diseases2012;55(7):905–14
© The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
Intestinal Domination and Bacteremia • CID 2012:55 (1 October) • 905
The complex microbial populations colonizing the human in-
testine provide resistance to infection. The intestinal microbiota
also serves as a sanctuary for highly antibiotic-resistant bac-
teria .Prior studies using in vitro culture methods have char-
acterized microbial populations inhabiting the intestine ;
more recently, massively parallel pyrosequencing of bacterial
16S ribosomal RNA (rRNA) encoding genes has provided new
insights into the composition and complexity of the intestinal
microbiota by identifying bacterial taxons that are not readily
cultivated in vitro [11–14].These approaches have demonstrated
the compositional changes and resilience of the intestinal mi-
crobiota of healthy individuals after antibiotic treatment .
Studies with mice demonstrated dramatic changes in the micro-
biota of the ileum and cecum following antibiotic treatment,
and dramatic expansion of antibiotic-resistant microbes such as
vancomycin-resistant Enterococcus (VRE) .Intestinal expan-
sion of VRE following antibiotic treatment is also seen in
humans, with episodes of VRE domination in patients undergo-
ing allo-HSCT preceding the development of VRE bacteremia
in 2 patients .
Because the effect of allo-HSCT conditioning, prolonged
neutropenia, and antibiotic administration on the gastrointes-
tinal tract microbiota is unknown, we characterized the fecal
microbiota of patients undergoing transplant at multiple time
points using 454 pyrosequencing of 16S rRNA genes. (Data
deposition: 454 pyrosequencing reads have been deposited in
the National Center for Biotechnology Information Sequence
Study Patients and Specimen Collection
Subjects consisted of adult patients undergoing allo-HSCT at
Memorial Sloan-Kettering Cancer Center (MSKCC), from 4
September 2009 to 4 August 2011. Fecal specimens were collect-
ed longitudinally from each patient during their transplant hos-
pitalization. For each patient, serial specimen collection began at
the start of pre-transplant conditioning (up to 15 days before
stem cell infusion) and continued until 35 days after transplant
or at hospital discharge, whichever occurred sooner. Because of
the expected variability among patients in the timing and fre-
quency of bowel movement patterns, subjects were excluded
from the study if they did not provide at least 1 pre-transplant
specimen and at least 2 specimens between transplant and 35
days after transplant. The study protocol was approved by the
MSKCC institutional review board; informed consent was ob-
tained from all subjects prior to specimen collection.
For each fecal specimen, DNA was extracted and purified, and
the V1-V3 region of the 16S rRNA gene was amplified by
means of polymerase chain reaction (PCR) using modified
universal bacterial primers. Purified PCR products were se-
quenced on a 454 GS FLX Titanium platform. Sequence data
were compiled and processed using Mothur, version 1.20 .
Sequence data were screened and filtered for quality , then
aligned to the full-length 16S rRNA gene, using as template the
SILVA reference alignment . Sequences were grouped into
operational taxonomic units of 97% similarity.
Microbial diversity was estimated by calculating the
Shannon diversity index , along with other diversity mea-
sures for comparison. Phylogenetic classification to genus level
was performed for each 16S sequence using the Ribosomal
Database Program naive Bayesian classification scheme .
To assess the presence of VRE, specimens with ≥2% entero-
coccal sequences were screened for the presence of the vanco-
mycin resistance gene vanA (see Supplementary Methods for
We evaluated trends in microbial diversity over time using
moving average filtering. Curvewise 95% confidence intervals
and P values were calculated using bootstrap resampling
within each subject.
Phylogenetic classification was used to describe the intesti-
nal composition of each subject over the course of transplant.
Hierarchical clustering of the specimens was performed ,
based on genus-level phylogeny. Microbial state transitions
between consecutive specimens were characterized using
Circos plots . The diversity trends and hierarchical cluster-
ing analyses were performed using Matlab, version 7.12.
Next we determined whether clinical variables were predic-
tive of changes in microbial composition, and in turn,
whether the microbial composition was predictive of clinical
outcomes. In our prior findings , we observed that some
allo-HSCT patients experienced shifts in intestinal composi-
tion from a diverse microbiota to one that was largely occu-
pied by a single taxon. We referred to this phenomenon as
intestinal domination and defined it as having occurred if a
single bacterial genus comprised >30% of sequences and was
the most abundant taxon.
First, we examined intestinal domination as a microbial end-
point of interest, using Cox proportional hazards regression.
The following clinical variables were assessed as univariate pre-
dictors of domination: age, sex, underlying diagnosis (leukemia
vs other), receipt of prior antibiotics (within 14 days prior to
start of the observation period), conditioning regimen intensity
(myeloablative or reduced intensity vs non-myeloablative ),
whether stem cells were ex vivo T-cell depleted , stem cell
source (peripheral blood donor vs umbilical cord blood), first
onset of fever during the observation period, and antibiotic ad-
ministration (vancomycin, metronidazole, fluoroquinolones,
906 • CID 2012:55 (1 October) • Taur et al
and beta-lactams). Fever and antibiotic administration were
analyzed as time-varying variables, in order to avoid time-de-
pendent bias. Next, we again examined intestinal domination,
this time as predictor of clinical outcomes. Domination was
analyzed as a time-varying predictor of bloodstream infection
with either VRE or aerobic gram-negative bacilli. In order to
avoid problems with monotone likelihood for parameter
estimate calculations, we employed a penalized maximum
likelihood for all Cox hazard calculations . These analyses
were performed using R, version 2.15.
During the study period, fecal specimens were obtained from
113 patients during their transplant hospitalization. Nineteen
patients provided insufficient specimens, leaving 94 subjects
for analysis. No exclusion was due to early death. Time of dis-
charge following allo-HSCT ranged from 13 to 95 days after
transplant (median, 21 days). Clinical characteristics of the 94
patients are listed in Table 1. Most patients engrafted within
14 days after transplant. All patients received antibiotics
during the study period; in particular, vancomycin and beta-
lactam antibiotics were administered to most patients. Blood-
stream infection was detected in 22 (23.4%) patients. Of these,
9 were due to VRE and 10 were due to gram-negative bacteria
Specimen Collection and Bacterial Sequences Obtained
A total of 439 fecal specimens were collected, with 3–8 speci-
mens per patient. From these specimens, a total of 1838 205
high-quality 16S rRNA-encoding sequences were identified.
The mean number of sequences obtained per specimen was
4187 (range, 852–9862).
Table 1. Characteristics of Patients and Transplant Course
No. (%) of
Prior antibiotics (within 14 days before study
Stem cell source
Time to engraftment, daysa,b
Table 1 continued.
No. (%) of
Gram-negative bacilli, aerobic
aEngraftment was defined as an absolute neutrophil count of >500 cells/µL
for 3 consecutive days.
bAssessed during inpatient allogeneic hematopoietic stem cell trans-
plantation hospitalization, from 15 days before transplant to 35 days after
cAntibiotic variables are not mutually exclusive and do not sum to 100%.
dBeta-lactams include cephalosporins, beta-lactam–beta-lactamase combi-
nations, and carbapenems.
ePositive bacteremia values not meeting standard Centers for Disease
Control and Prevention definitions of a laboratory-confirmed bloodstream
infection (eg, a single positive blood culture for coagulase-negative
Staphylococcus)  were excluded.
Intestinal Domination and Bacteremia • CID 2012:55 (1 October) • 907
Loss of Microbial Diversity Following Allo-HSCT
There was considerable variation among Shannon diversity
index values (Figure 1). During the pre-transplant period, the
average Shannon diversity index ranged approximately 3–4,
similar to values observed for healthy volunteers in both our
prior observations (not shown) and previous reports .
However, over the course of allo-HSCT, the mean diversity
index decreased to approximately 2 and remained low until
the end of our observation period. Similar decreases were ob-
served with other measures of microbial diversity (Supplemen-
tary Figure 1). By subgroup, patients with leukemia and those
receiving either metronidazole or beta-lactam antibiotics expe-
rienced comparatively greater decreases in Shannon diversity
index (Supplementary Figure 2).
Development of Intestinal Domination
The microbial composition for 12 selected patients over time,
with concurrent episodes of bacteremia and administration of
antibiotics, is shown in Figure 2A. In some patients, the mi-
crobiota remained relatively diverse, experiencing only mild
fluctuations in composition. In these patients, the genus
Blautia was frequently an abundant inhabitant and appeared
to be associated with diminished antibiotic administration.
However, other patients demonstrated marked changes in
composition, with transitions from a relatively diverse micro-
biota to a simpler one with fewer members. In many instances,
the microbial composition became dominated by a single bac-
terial taxon. Enterococcus was the most frequent dominating
genus, occurring in 38 (40.4%) patients. Of these patients,
most (92%) had detectable expression of the vanA gene, sug-
gesting the presence of VRE. Streptococcus was the next most
frequent dominating genus, observed in 35 (37.2%) patients.
Domination by phylum Proteobacteria, which includes Enter-
obacteriaceae and other aerobic gram-negative bacteria, was
observed in 12 (12.8%) patients. Domination by these bacteria
occurred at various times relative to transplant (Figure 2B).
The composition of all 94 patients is provided (Supplementary
Hierarchical clustering of the phylogenetic composition of
all 439 specimens demonstrated that specimens can be catego-
rized into specific states of either biodiversity or domination
by specific taxa (Figure 3A), with biodiverse specimens being
more common during the pre-transplant period. Circos plots
demonstrated a large number of state-to-state transitions
(Figure 3B–E). Although most pre-transplant specimens
remained biodiverse, transitions to states of domination
were most prevalent between the pre-transplant specimen and
the first post-transplant specimen and intermediate between
sequential post-transplant specimens.
Clinical Factors Associated With Development of Intestinal
Clinical predictors of intestinal domination with Enterococcus,
Streptococcus, and Proteobacteria are shown in Table 2. Age,
sex, conditioning regimen intensity, and stem cell source were
not associated with intestinal domination by the 3 organisms
evaluated. An underlying diagnosis of leukemia was associated
with a higher risk of domination by Enterococcus.
Antibiotics, given at various time points for various indica-
tions (eg, prophylaxis or empiric/directed treatment) were
associated with subsequent enterococcal domination. Metroni-
dazole was associated with a 3-fold increase in risk of entero-
coccal domination. Metronidazole was given for various
reasons, including treatment for Clostridium difficile infection
quantified by the Shannon diversity index, was calculated for each fecal specimen of each patient and plotted over day of transplant (circles). A diversity
trend (solid black line; 95% confidence intervals shown in gray) was constructed using moving average filtering.
Changes in microbial diversity within the intestinal tract during allogeneic hematopoietic stem cell transplantation. Microbial diversity,
908 • CID 2012:55 (1 October) • Taur et al
selected patients, plotted over day of transplant. Each stacked bar represents the microbial composition of a single fecal specimen, based on taxonomic
classification. Shading between specimens are provided for interpolation and visualization of changes in relative abundances. Concurrent antibiotic
administration (vancomycin, fluoroquinolones, metronidazole, and beta-lactams) and detected bacteremias are shown for each patient. Patients in the
first row generally maintained diversity with few changes in composition; patients in the second row developed intestinal domination by Enterococcus;
patients in the third row developed intestinal domination by Streptococcus; and patients in the fourth row developed domination with Proteobacteria.
Note that patient 58 in the top row maintained diversity but developed Enterococcus domination shortly after metronidazole administration. (Plots of all
94 patients can be found in Supplementary Figure 3.) B, Kaplan-Meier plot of intestinal domination as a survival event. Crosshairs represent censored
observations. Intestinal domination by Enterococcus, Streptococcus, and Proteobacteria was common and occurred at various times throughout the
Characterization of the intestinal microbiota during allogeneic hematopoietic stem cell transplantation. A, Genus-level taxonomy of 12
Intestinal Domination and Bacteremia • CID 2012:55 (1 October) • 909
classification. There was wide variation in phylogenetic composition; some specimens showed a relatively biodiverse membership, whereas others were
largely dominated by a single bacterial taxon. B, Circos plots representing microbiota state transitions between consecutive specimens within the
observation period. Subplots of transitions during specific transplant periods are shown in C–E. C, Pre-transplant transitions revealing that patients in
the “biodiverse microbiota” state tend to remain in that state; resilience of the “biodiverse” state, measured as the percentage of consecutive speci-
mens that remain in that state, is 77%. D, Resilience of “biodiverse” state decreasing to 35% during the intra-transplant period (consecutive specimens
straddling the day of stem cell infusion). E, Post-transplant transitions with the “biodiverse” state resilience staying low at 48%.
Microbiota states and their transitions. A, Hierarchical clustering of all fecal specimens according to microbiota state based on phylogenetic
910 • CID 2012:55 (1 October) • Taur et al
(14 of 30 metronidazole recipients). Vancomycin, fluoroquin-
olone, and beta-lactam administration did not increase the
risk of domination. Fluoroquinolone administration was asso-
ciated with a 10-fold decreased risk of intestinal domination
Association of Intestinal Domination With Bacteremia
Analysis of intestinal domination as predictor of bloodstream
infection is shown in Table 3. Patients with enterococcal dom-
ination had a 9-fold increased risk of VRE bacteremia, and
intestinal domination by Proteobacteria increased the risk of
bacteremia with aerobic gram-negative bacilli 5-fold. In the
time leading up to bloodstream infection, enterococcal domi-
nation with detectable vanA was observed in 8 of 9 patients
with VRE bacteremia, and proteobacterial domination was ob-
served in 2 of 10 patients with gram-negative bacteremia. In
total, 11 of the 22 patients with bacteremia demonstrated pre-
ceding intestinal domination by a corresponding organism;
the median time between domination and bacteremia in these
patients was 7 days.
Patients undergoing allo-HSCT are subjected to chemothera-
py, radiation, and antibiotics within a short time frame. In
this study we observed extreme shifts in the intestinal micro-
biota during transplant. In many instances, domination by a
single bacterial taxon occurred. These perturbations correlated
Table 2.Clinical Predictors of Intestinal Domination
Predictor HR (95% CI)P HR (95% CI)P HR (95% CI)P
Underlying diagnosis (leukemia vs other)
Prior antibiotics (14 days)a
Conditioning regimen (myeloablative or
reduced intensity vs non-myeloablative)
T-cell depleted graft
Stem cell source (cord vs other)
Abbreviations: CI, confidence interval; HR, hazard ratio.
aDefined as administration of any antibacterial drug within 14 days prior to observation period.
bAnalyzed as a time-varying predictor.
cFluoroquinolones consist of ciprofloxacin and levofloxacin.
dBeta-lactams include cephalosporins, beta-lactam–beta-lactamase combinations, and carbapenems.
Table 3.Association of Intestinal Domination With Bacteremiaa
VRE BacteremiaGram-negative Bacteremia
HR (95% CI)PHR (95% CI)P
Abbreviations: CI, confidence interval; HR, hazard ratio; VRE, Vancomycin-resistant Enterococcus.
aBacteremia for each organism was defined as at least one positive blood culture within the study period.
bIntestinal domination was analyzed as a time-varying predictor.
Intestinal Domination and Bacteremia • CID 2012:55 (1 October) • 911
with subsequent development of a corresponding bloodstream
infection with either VRE or gram-negative bacteria.
The intestinal microbiota is engaged in a complex relation-
ship with the mucosal epithelium. Intestinal epithelial cells,
underlying immune tissues, and the microbiota establish a
state of equilibrium that optimizes resistance to infection and
facilitates the absorption of nutrients . Allo-HSCT dis-
rupts this equilibrium, resulting in dramatic compositional
the bloodstream. Radiation and chemotherapy-mediated de-
struction of gut epithelial stem cells, inhibition of microbial
populations by antibiotic administration, and suspension of
innate immune defenses each affect intestinal environment
and host-microbe interactions.
during allo-HSCT hospitalization, perhaps due in part to con-
tinued antibiotic pressure. Other studies of the intestinal
microbiota have shown the resilience of bacterial populations
following antibiotic therapy [12, 27], and experimental studies
in mice demonstrate that decreased diversity increases sus-
ceptibility to dense colonization by VRE . Although the
benefits of diversity remain unproven, strategies to reintroduce
complex microbial populations into the gut following allo-
HSCT may be of benefit.
How the complex microbiota prevents domination by rogue
bacterial species such as VRE or Enterobacteriaceae remains
unclear. Antibiotic administration results in expansion of En-
terobacteriaceae and enterococci in the gut and increases sus-
ceptibility to infection by these organisms. The suppression of
newly introduced bacteria by the intestinal microbiota is re-
ferred to as colonization resistance [28–30]. Although com-
mensal microbes may outcompete VRE by depleting nutrients
or occupying spatial niches, other mechanisms such as pro-
duction of inhibitory short-chain fatty acids may play a more
important role [31, 32].
In this and our previous studies , bloodstream infections
during allo-HSCT are frequently preceded by intestinal domi-
nation by the same organism. In this study, two-thirds of pa-
domination during the course of transplant. Interestingly, vi-
ridians-group streptococci and VRE were historically the most
frequently encountered bloodstream infections in allo-HSCT
patients during the pre-engraftment period [4–8]. Prior to
2002, viridans streptococci were an important cause of bacter-
emia at our center, with significant morbidity [4, 6]. Prophy-
lactic vancomycin administration during transplant has
virtually eliminated viridans-group Streptococcus bacteremia in
our center . Because streptococcal domination remained
common in this study, vancomycin prophylaxis may have
served to prevent bloodstream invasion but not intestinal
In contrast to Streptococcus domination, enterococcal domi-
nation was highly associated with VRE bacteremia. Prior
studies of allo-HSCT patients have demonstrated associations
between VRE colonization and the development of VRE bac-
teremia [7, 8, 33], leading many centers to routinely test for
VRE colonization by means of rectal swab cultures prior to
transplant. Compared with routine surveillance culture find-
ings, enterococcal domination was detected in a greater per-
centage of subjects (40% vs 21%, respectively), and we
identified more patients with VRE bacteremia (8 of 9 instead
of 6). It is possible that bacteremia occurred with greater fre-
quency than was documented, because blood cultures were
largely obtained in the setting of fever or other evidence of
septicemia. Indeed, a study involving surveillance blood cul-
tures of steroid-treated allo-HSCT patients revealed bacteremia
in more than one-third of patients .
Our finding that metronidazole administration is strongly
associated with the development of Enterococcus domination
is consistent with prior studies demonstrating that antibiotics
with anaerobic activity promote VRE colonization [35, 36] and
supports the notion that anaerobic bacteria contribute to colo-
nization resistance [30, 31]. Because vanA was present in most
cases of enterococcal domination, and because most cases of
enterococcal bloodstream infections were vancomycin resis-
tant, we presume antibiotic resistance contributes to microbial
shifts within the microbiota; however, indirect effects of anti-
biotic treatment resulting from interdependencies of bacterial
taxa in the gut are likely important as well . The Shannon
diversity index was also lower in recipients of metronidazole,
presumably reflecting our observed association with entero-
coccal domination. However, beta-lactam recipients also lost
diversity but were not associated with enterococcal domi-
nation. Although this disparity may reflect the ability of
beta-lactams to inhibit enterococcal growth in the intestine, an
alternative explanation is that beta-lactams were administered
later during the course of transplant, as empiric therapy for
fever in the setting of neutropenia, and thus were largely un-
evaluated in the Cox model as a preceding risk factor for
We found that fluoroquinolones protected against proteobac-
terial domination, which in turn protected against gram-nega-
tive bloodstream infections. This finding supports prior studies
of fluoroquinolone prophylaxis in neutropenic patients [38, 39]
and provides insight into the mechanism of protection. The
routine practice of fluoroquinolone prophylaxis in neutropenia
has been controversial, in part due to concerns about resistance
or disturbance of the microbiota. Other studies show fluoro-
quinolones having effects of varying duration in healthy
humans [12, 37]. In those subjects, there were no clinically
apparent consequences resulting from these microbial distur-
bances. Whether fluoroquinolone prophylaxis in patients
912 • CID 2012:55 (1 October) • Taur et al
undergoing allo-HSCT has any deleterious consequences
Patients with leukemia were more likely to develop entero-
coccal domination than those with other underlying diseases.
The reason for this association is unclear but is likely multifac-
torial, including greater pre-transplant exposure to antibiotics,
more intense conditioning prior to transplant, and/or greater
exposure to VRE in conjunction with prior treatment for leu-
kemia. However, our analysis did not identify associations
between these factors and enterococcal domination.
Our study has several limitations. Specimens were collected
with variable frequency of approximately 1 week apart. Thus,
our microbiologic data could be viewed as interval-censored
since we do know the state of the microbiota between succes-
sive specimens. At times we observed rapid transitions, and
thus there may have been transient microbial states which
were not captured. For example, episodes of domination,
perhaps preceding some episodes of bloodstream infection,
may have occurred but went undetected. To obviate this, we
used a cutoff definition of 30% for intestinal domination, even
though in many instances the relative abundance was much
higher. We chose this cutoff primarily on the basis of resultant
grouping of microbial states in our hierarchical cluster analy-
sis, but this cutoff likely enhanced the identification of domi-
nation states, given the frequency of collection. The number of
16S sequences obtained per specimen was lower than that of
some other studies . Thus, the depth of coverage may have
been insufficient to determine whether certain infrequent bac-
terial taxons were present. Since we focused on dominating
(ie, highly abundant) microbes, we expect that our results
would be unaffected by deeper sequencing. Furthermore,
Good’s coverage was ≥98% in >96% of specimens in this study.
Although our studies are limited to allo-HSCT patients at
one medical center, we suspect similar microbiota shifts are
also occurring at other centers, and for that matter in other
populations of patients who might be at risk for bloodstream
infections due to neutropenia, such as those receiving cytotoxic
chemotherapy for hematologic malignancies. Based on evidence
from prior studies, it is also likely that disturbances of the
microbiota are implicated in the pathogenesis of other compli-
cations of allo-HSCT, such as such as graft-versus-host disease
of the gut and C. difficile associated diarrhea [40–43]. Further
study is needed in order to fully grasp the clinical implications
of microbial derangements in these patient populations.
Our study demonstrates that intestinal domination in a
subset of allo-HSCT patients precedes bloodstream infection
by a median of 7 days, suggesting that determination of the
fecal microbiota composition can identify patients at highest
risk for bacteremia. This longitudinal study provides an
example of how analysis of the intestinal microbiota can
have relevance in clinical disease. Although current deep
sequencing platforms for the analysis of the microbiota
require substantial time for specimen preparation, amplifica-
tion, sequencing, and analysis, it is likely that these platforms
will evolve in the near future to provide microbiota analyses
within a clinically meaningful period. With this progress, mi-
crobiota analyses such as that presented in our study will in-
creasingly guide the treatment of pertinent populations such
as allo-HSCT recipients.
Supplementary materials are available at Clinical Infectious Diseases online
(http://cid.oxfordjournals.org). Supplementary materials consist of data
provided by the author that are published to benefit the reader. The
posted materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or messages
regarding errors should be addressed to the author.
tutes of Health (grants 1K23 AI095398-01 to Y. T., DP2OD008440 to
J. B. X., and 1RO1 AI42135 to E. G. P.), the Lucille Castori Center for
Microbes, Inflammation, and Cancer, and the Tow Foundation.
Potential conflicts of interest.
All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
This study was supported by the National Insti-
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