Clinical Infectious Diseases

Major Article

Risk Factors Associated With Carbapenemase-Producing

Carbapenem-Resistant Enterobacteriaceae Positive
Cultures in a Cohort of US Veterans
Geneva M. Wilson,1 Katie J. Suda,2,3 Margaret A. Fitzpatrick,1,4 Brian Bartle,1 Christopher D. Pfeiffer,5,6 Makoto Jones,7,8 Michael A. Rubin,9,10
Eli Perencevich,9,10 Martin Evans,11 and Charlesnika T. Evans1,12; the QUERI CARRIAGE Program
1
Center of Innovation for Complex Chronic Healthcare (CINCCH), Hines Jr Veterans Affairs Hospital, Hines, Illinois, USA, 2Center for Health Equity Research and Promotion, VA Pittsburgh Heath
Care System, Pittsburgh, Pennsylvania, USA, 3University of Pittsburgh School of Medicine, Department of Medicine, Pittsburgh, Pennsylvania, USA, 4Department of Medicine, Division of Infectious
Diseases, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA, 5Department of Veterans Affairs, Portland VA Healthcare System, Portland, Oregon, USA, 6Department of
Medicine, Division of Infectious Diseases, Oregon Health Science University, Portland, Oregon, USA, 7Department of Veterans Affairs, VA Salt Lake City Healthcare System, Salt Lake City, Utah,

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USA, 8Department of Medicine, Division of Epidemiology, University of Utah, Salt Lake City, Utah, USA, 9Department of Veterans Affairs, Center for Access & Delivery Research and Evaluation,
Iowa City VA Health Care System, Iowa City, Iowa, USA, 10Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA, 11Department of Veterans Affairs,
Lexington VA Medical Center, Lexington, Kentucky, USA, 12Department of Preventive Medicine, Center for Health Services and Outcomes Research, Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA

Background.  Carbapenem-resistant Enterobacteriaceae (CRE) cause approximately 13 100 infections, with an 8% mortality rate
in the United States annually. Carbapenemase-producing CRE (CP-CRE) a subset of CRE infections infections have much higher
mortality rates (40%–50%). There has been little research on characteristics unique to CP-CRE. The goal of the current study was to
assess differences between US veterans with non-CP-CRE and those with CP-CRE cultures.
Methods.  A retrospective cohort of veterans with CRE cultures from 2013–2018 and their demographic, medical, and facility
level covariates were collected. Clustered multiple logistic regression models were used to assess independent factors associated with
CP-CRE.
Results.  The study included 3096 unique patients with cultures positive for either non-CP-CRE or CP-CRE. Being African
American (odds ratio, 1.44 [95% confidence interval, 1.15–1.80]), diagnosis in 2017 (3.11 [2.13–4.54]) or 2018 (3.93 [2.64–5.84]),
congestive heart failure (1.35 [1.11–1.64]), and gastroesophageal reflux disease (1.39 [1.03–1.87]) were associated with CP-CRE cul-
tures. There was no known antibiotic exposure in the previous year for 752 patients (24.3% of the included patients). Those with no
known antibiotic exposure had increased frequency of prolonged proton pump inhibitor use (17.3%) compared to those with known
antibiotic exposure (5.6%).
Discussion.  Among a cohort of patients with CRE, African Americans, patients with congestive heart failure, and those with
gastroesophageal reflux disease had greater odds of having a CP-CRE culture. Roughly 1 in 4 patients with CP-CRE had no known
antibiotic exposure in the year before their positive culture.
Keywords.  antimicrobial resistance; CRE; epidemiology.

Carbapenem-resistant Enterobacteriaceae (CRE) have been
identified as an urgent antibiotic-resistant threat by the Centers
for Disease Control and Prevention [1]. Infections caused by
CRE are difficult to treat due to the limited number of antibi-
otic options available. In 2017, the Centers for Disease Control
and Prevention reported 13  100 hospital-based CRE cases in
the United States and 1100 estimated deaths (8.4% mortality
rate) [1]. The geographic distribution of CRE in the continental
United States is highly variable, with incidence rates ranging
from 0.82 cases per 100 000 persons (Oregon) to 4.80 cases per
Received 19 January 2021; editorial decision 21 April 2021; published online 11 May 2021.
Correspondence: G. M.  Wilson, 5000 S Fifth Ave, (151H) Bldg 1, D304, Hines, IL 60141
(geneva.wilson2@va.gov).
Clinical Infectious Diseases®  2021;73(8):1370–8
Published by Oxford University Press for the Infectious Diseases Society of America 2021. This
work is written by (a) US Government employee(s) and is in the public domain in the US.
DOI: 10.1093/cid/ciab415
100 000 persons (Maryland) [2, 3]. Previous exposure to anti-
biotics, particularly carbapenems, is a significant risk factor for
CRE. A  pooled analysis of 25 studies found carbapenems to
have the strongest association with CRE infection of all antibi-
otic classes explored (pooled odds ratio [OR], 4.71 [95% con-
fidence interval (CI), 3.54–6.26]) [4]. Other major risk factors
for CRE infection include mechanical ventilation, intensive care
unit admission, use of an indwelling medical device, chronic
comorbid conditions, such as obesity or lung disease, and use of
gastric acid–suppressing medications [4–8].
Carbapenemase-producing CRE (CP-CRE) are a subset of
CRE that are resistant to β-lactam antibiotics via the produc-
tion of carbapenemase enzymes [3, 9]. Compared with CRE,
CP-CRE infections are more concerning because they have
higher mortality rates and a greater degree of antimicrobial re-
sistance than non-CP-CRE infections [9]. According to a 2017
report from the Centers for Disease Control and Prevention’s

1370 • cid 2021:73 (15 October) • Wilson et al

Antibiotic Resistance Laboratory Network on isolates across
the United States, CP-CRE are estimated to account for approx-
imately 33% of all CRE infections [10] and are associated with
mortality rates between 40% and 50% [11, 12].
Predictors that can distinguish non-CP-CRE versus CP-CRE
may guide more rapid and accurate detection and treatment of
individuals with either, yet discriminating predictors remain
largely unexplored. A  single study comparing CP-CRE and
non-CP-CRE bloodstream infections found that patients with
CP-CRE bacteremia were more likely to have a history of me-
chanical ventilation and nursing home residence compared to
non-CP-CRE patients [13]. The goal of the current analysis was
to assess risk factors associated with positive CP-CRE cultures
at all body sites among a large cohort of US veterans with posi-
tive CRE cultures from 2013 to 2018.
METHODS
Study Design and Setting
A retrospective cohort was conducted of Department of
Veterans Affairs (VA) patients with a positive CRE culture
from any body site between 1 January 2013 and 31 December
2018. Patients from 127 VA medical centers (VAMCs) across
the United States and territories (Puerto Rico) were included.
This study was deemed quality improvement research by the
VA, and thus institutional review board approval was not
required.
Microbiologic Cultures and CRE Identification
All study data were collected using the VA’s electronic
data repository, the Corporate Data Warehouse. Bacterial
species identification and antibiotic susceptibility testing
was performed by each VAMC’s clinical laboratory ac-
cording to local protocol and entered into the electronic
medical record, from which Corporate Data Warehouse
data sets are derived. Microbiologic cultures that met def-
initions for CRE defined by VA over the time frame were
included. CRE were defined as Escherichia coli, Klebsiella
spp., or Enterobacter spp. isolates that were (1) resistant
to imipenem, meropenem, or doripenem [14, 15] and/or
(2) resistant to ertapenem plus any tested third-generation
cephalosporins [15, 16]; isolates resistant to ertapenem
alone were excluded. Laboratory tests used to confirm
carbapenemase production included the modified Hodge
test, the Carba-NP test, the carbapenem inactivation
method, matrix-assisted laser desorption/ionization–time
of flight, and polymerase chain reaction tests, such as the
Carba-R test.
Cultures negative for carbapenemase production are hence-
forth referred to as non-CP-CRE. Cultures that were positive for
carbapenemase production were defined as CP-CRE. Cultures
that did not undergo carbapenemase testing were classified as
non-CP-CRE.
CP-CRE–Associated Factors in Veterans  •  cid 2021:73 (15 October) • 1371
Patient and Facility Characteristics
Demographic variables, including age, race, sex, patient care
setting at time of culture, and year of culture, were collected. All
comorbid conditions needed to calculate the Charlson comor-
bidity index were included [17, 18]. Because there is evidence
that individuals with spinal cord injuries and disorders, chronic
gastrointestinal illnesses, and history of solid organ and stem
cell transplantation may be at increased risk of colonization and
infection with multidrug-resistant gram-negative organisms,
including CRE [19–25], information on the presence of these
conditions was collected.
Culture specimens were defined as urine, respiratory (sputum,
bronchial lavage, tracheal aspirate, and lower respiratory tract
fluids), blood, or other (wound, skin/soft tissue, bone/joint).
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A positive blood culture was classified as a true infection, whereas
nonsterile sites such as urine could not be classified as infection
or colonization using our electronic data. Therefore, a subanalysis
of patients with bloodstream infection was conducted. The fa-
cility complexity level and geographic region where the culture
was collected were recorded; facilities ranked 1a are the most
complex, followed by those ranked 1b, 1c, 2, and 3.
Statistical Analysis
Unadjusted analyses were conducted using χ 2 and Fisher exact
tests for categorical variables and Wilcoxon rank sum test for
continuous variables to determine associations with CP-CRE
positivity. Variables significant at a P < .05 and those biolog-
ically relevant to CRE were included in the adjusted analysis.
A sensitivity analysis of the 2017 and 2018 data was done, be-
cause there were higher rates of CP-CRE testing in those years
than in the earlier years of the cohort. Generalized estimating
equation models were fit to assess the association between dem-
ographic, medical, and facility level characteristics and CP-CRE
positivity. Models were run using binomial distribution and
logit link clustering data at the patient level and accounting for
the inclusion of persons with multiple cultures over the study
time period. ORs and 95% CIs were reported to show associ-
ations. All statistical analyses were completed using SAS 9.4
software (SAS Institute).
RESULTS
From 2013 to 2018, 5778 qualifying CRE isolates were identified
in 3096 patients. Overall, patients were mostly white (74.1%),
>65 years old (74.8%), and male (95.1%) and received diagnoses
at a 1a–1c high-complexity VA facility (91.2%). One-third of
cultures, or 1905 (32.9%), were tested for a carbapenemase.
Of those, 1603 (84.1%) were CP-CRE. Figure 1 shows that al-
though the number of CRE cultures decreased over time, the
percentage of cultures tested for carbapenemase production
increased (from 25.6% in 2013 to 59.5% in 2018), leading to
an apparent increase in the number of CP-CRE cultures (from
23.3% in 2013 to 46.3% in 2018).

Figure 1.  Testing for and detection of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) cultures over time.
In the unadjusted analysis (Table 1), when compared with
those with non-CP-CRE cultures, patients with confirmed
CP-CRE cultures were more frequently African American
(27.2% vs 20.6%, respectively; P < .001) and residents of long-
term care facilities (18.0% vs 11.3%; P < .001). Blood cultures
represented a higher percentage of CP-CRE compared with
non-CP-CRE cultures (10.5% vs 7.5%; P = .003). Klebsiella spp.
Represented 82.1% of the CP-CRE cultures, compared with
62.7% of the non-CP-CRE cultures (P < .001). There was no dif-
ference in the duration of days of antibiotic and proton pump
inhibitor (PPI) exposure in the year before the culture date be-
tween CP-CRE and non-CP-CRE cultures (P = .22 and P = .73,
respectively).
The presence of the following comorbid conditions were
significantly associated with CP-CRE cultures: myocardial in-
farction, congestive heart failure (CHF), peptic ulcer disease,
diabetes with chronic complications, renal disease, peripheral
vascular disease, paralysis (including spinal cord injuries as well
as other disorders), multiple sclerosis, and gastroesophageal re-
flux disease (GERD) (Table 1). Individuals with CP-CRE cul-
tures had significantly higher Charlson scores (mean [standard
deviation], 5.7 [2.93]) than those with non-CP-CRE cultures
(mean 4.73 [2.99]; P < .001). CP-CRE cultures were also as-
sociated with significantly more days in the hospital over the
previous year, compared with non-CP-CRE cultures (median
[interquartile range], 29 [5–77] vs 18 [0–58] days; P < .001).
CP-CRE cultures varied by facility complexity. Geographically,
most CP-CRE cultures came from the South (33.5%), Northeast
(25.3%), or outside the continental United States (23.6%,) while
most of the non-CP-CRE cultures were from outside the conti-
nental United States (29.3%) or the South (27.9%).
The final multivariable model was adjusted for the following
covariates: race, admission type, bacterial species, CHF, chronic
gastrointestinal illness, GERD, facility complexity, facility re-
gion, and year of culture. In the multivariable cluster adjusted
1372 • cid 2021:73 (15 October) • Wilson et al
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analysis, having a culture in the year 2017 (OR, 3.11 [95% CI,
2.13–4.54]) or 2018 (3.93 [2.64–5.84]), being African American
(1.44 [1.15– 1.80]), having GERD (1.39 [1.03–1.87])), and
having CHF (1.35 [1.11–1.64]) were independently associated
with increased odds of a positive CP-CRE culture. CP-CRE was
less often associated with a level 3 complexity facility (OR, 0.15
[95% CI, .07–.33]), facility location in the Midwest (0.41 [.29–
.57]), an outpatient (vs inpatient) culture location (0.76 [.64–
.88]), or Enterobacter (0.45 [.36–.56]) or E. coli (0.28 [.20–.40])
spp. culture vs Klebsiella spp. culture (Figure 2). The Charlson
comorbidity index did not remain significant in the adjusted
analysis and was removed so that individual significant co-
morbid conditions could be reported.
Because significantly more cultures were tested for CP-CRE
in the later years of the cohort, a sensitivity analysis including
only 2017 and 2018 data was performed to determine whether
there were any differences in factors associated with having a
CP-CRE culture compared with the larger cohort. There were
no major differences between the results of the sensitivity anal-
ysis and the main analysis. Effect sizes were similar, though
some variables were no longer significant owing to smaller
sample sizes, resulting in wider CIs.
Almost one-quarter of patients (752; 24.3%) had no
documented antibiotic exposure in the prior year (Table 2).
There was no difference in the rate of CP-CRE detection
between those with and without antibiotic exposure (26.5%
vs 27.9%). Patients with no antibiotic use in the previous
year had lower rates of several chronic comorbid condi-
tions (Table 2) and a higher percentage of prolonged proton
pump inhibitor use in the prior year than those with anti-
biotic exposure (27.8% vs 5.6%, respectively). Although no
regional differences were identified, patients without anti-
biotic exposure were less often treated at a complex 1a–1c
facility than those with such exposure (89.9% vs 93.9%,
respectively).
Table 1.  Demographic, Medical, and Facility Characteristics by Table 1.  Continued
Positivity for Carbapenemase-Producing Carbapenem-Resistant
Enterobacteriaceae Cultures, No. (%)a

CP-CRE CRE P
Cultures, No. (%)a Characteristic (n = 1603) (n = 4175) Value

CP-CRE CRE P   Solid organ transplantation 28 (1.7) 74 (1.8) .95

Characteristic (n = 1603) (n = 4175) Value   Stem cell transplantation 1 (0.1) 14 (0.3) .07

Age, y   CCI, mean (SD) 5.47 (2.93) 4.73 (2.99) <.001

 18–49 4 (2.5) 132 (3.2) .57 Facility complexity

 50–64 301 (18.4) 7 (18.9)  1a–1c 1534 (95.8) 3853 (92.3) <.001

 ≥65 1214 (76.0) 3119 (74.7)  2 63 (3.9) 154 (3.7)

 Missing 47 (2.9) 137 (3.3)  3 6 (0.4) 168 (4.0)

Male sex 1541 (96.1) 4001 (95.8) .61 Facility region

Race  South 537 (33.5) 1171 (28.1) <.001

  White non-Latin 729 (45.5) 1949 (46.7) <.001  Midwest 122 (7.3) 566 (13.6)

  African American 436 (27.2) 861 (20.6)  West 160 (10.0) 461(11.0)

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 Latin 423 (26.4) 1310 (31.4)  Northeast 405 (25.3) 755 (18.1)

 Otherb 15 (0.9) 55 (1.3)   Outside continental US 379 (23.6) 1222 (29.3)

Care setting Abbreviations: CCI, Charlson comorbidity index; CHF, congestive heart failure; CP-CRE,
carbapenemase-producing carbapenem-resistant Enterobacteriaceae; CRE, carbapenem-
 Inpatient 777 (48.7) 1944 (46.5) <.001 resistant Enterobacteriaceae; GERD, gastroesophageal reflux disease; GI, gastrointestinal;
 Outpatient 536 (33.3) 1761 (42.3) ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; PPI, proton pump in-
hibitor; SCI/D, spinal cord injuries and disorders; SD, standard deviation; US, United States.
  Long-term care 290 (18.0) 470 (11.3)
a
Data represent no. (%) of cultures, unless otherwise specified.
ICU admissionc 27 (1.7) 49 (1.2) .13 b
d
“Other” includes Asian, Native American, and Pacific Islander. 
LOS in previous year, median (IQR), d 29 (5–77) 18 (0–58) <.001 c
Seventy-six cultures from 60 unique patients were collected during an ICU admission.
Specimen type d
A total of 4399 cultures were obtained from 2199 unique patients with inpatient admis-
 Urine 972 (60.6) 2601 (62.3) .003 sions in the year before the culture.
e
 Respiratory 213 (13.2) 558 (13.4) “Other” specimen types included skin and soft-tissue, abscess fluid, and bone samples.
 Blood 168 (10.5) 313 (7.5)
 Othere 250 (15.6) 703 (16.8)
Bacterial organism The findings of the multivariable adjusted subgroup analysis
  Klebsiella spp. 1322 (82.1) 2610 (62.5) <.001 of 481 blood cultures from 310 unique patients were almost
  Enterobacter spp. 210 (13.1) 1045 (25.0) identical to the findings of the overall cohort (Table 3). The only
  Escherichia coli 71 (4.4) 520 (12.5) differences were that having multiple sclerosis (OR, 1.52 [95%
Duration of PPI use in prior year, d
CI, 1.07–2.15]) was associated with CP-CRE positive blood cul-
 0 393 (24.5) 1120 (26.9) .20
 1–30 261 (16.3) 631 (15.2)
tures, as opposed to CHF and GERD, which were significant in
 31–60 123 (7.6) 281 (6.8) the overall cohort. In addition, though being African American
 61–90 81 (5.1) 239 (5.7) was significant in the unadjusted analysis, it was not associated
 >91 745 (46.5) 1904 (45.5) with CP-CRE positivity in the blood culture subanalysis.
Duration of antibiotic use in prior year, d
 0 271 (16.8) 746 (17.9) .70 DISCUSSION
 1–30 797 (50.0) 2096 (50.1)
 31–60 305 (18.9) 730 (17.5) In a cohort of 5778 CRE-positive cultures collected at VAMCs
 61–90 86 (5.2) 225 (5.4) between 2013 and 2018, we found that 27.7 % were CP-CRE
 >91 144 (9.0) 378 99.1) positive, a CP-CRE prevalence significantly lower than that
Comorbid conditions reported in the literature [10]. However, this finding was
 SCI/D 259 (16.1) 598 (14.3) .08
likely significantly affected by the low rate of CP-CRE testing
  Chronic GI illness 791 (49.2) 1942 (46.6) .054
 GERD 522 (32.5) 1182 (28.3) .002
in this cohort (32.9%). A  sensitivity analysis of the 2017
  Myocardial infarction 169 (10.6) 279 (6.7) <.001 and 2018 years of the cohort, which had higher testing rates
 CHF 575 (36.0) 1133 (27.1) <.001 (46.7% and 59.5%, respectively), yielded similar results to the
  Rheumatologic disease 38 (2.4) 67 (1.6) .051 main analysis presented in this article. In addition, a second
  Peptic ulcer disease 89 (5.5) 154 (3.7) .002
sensitivity analysis was done for individuals with only 1 versus
  Mild diabetes 826 (51.3) 2143 (51.4) .89
>1 culture during the study period, but this also yielded sim-
  Complicated diabetes 534 (33.3) 1165 (27.9) <.001
  Renal disease 1004 (62.8) 2247 (53.8) <.001
ilar results to the main analysis presented. The majority of
  Peripheral vascular disease 489 (30.4) 1023 (24.5) <.001 non-CP-CRE and CP-CRE cultures were Klebsiella spp., con-
 Paralysis 421 (26.3) 820 (19.7) <.001 sistent with previous literature showing that Klebsiella spp.
  Multiple sclerosis 45 (2.8) 47 (1.1) <.001 represent a high proportion of CRE cases [26, 27]. Our re-
 Cancer 476 (29.7) 1137 (27.2) .06
sults were also consistent with prior literature showing that

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Figure 2.  Cluster-adjusted multivariable analysis. The following were used as reference categories: white, for racial/ethnic groups; inpatient care, for outpatient and long-
term care; Klebsiella spp., for Enterobacter spp. and Escherichia coli; level 1 complexity facilities, for levels 2 and 3 facilities; the South, for other regions; and 2013, for later
years. Abbreviations: CHF, congestive heart failure; GERD, gastroesophageal reflux disease; GI, gastrointestinal; US, United States.

most CP-CRE cultures originate in an inpatient setting and in
higher-complexity facilities [3, 11, 28].
Other correlates associated with having a CP-CRE versus a
non-CP-CRE culture were having CHF and GERD and being
African American. The association between CP-CRE and co-
morbid conditions is supported by previous literature that has
shown an increased number of comorbid conditions associated
with an increased risk of CRE infection [2, 29]. An interesting
finding in our study that was not identified in previous litera-
ture is the association between race and CP-CRE [29, 30]. Our
study found that African Americans had a 44% increased odds of
CP-CRE positivity compared, with non-Latin whites. While this
link has not been well established for CRE, previous literature has
shown a link between race and increased risk of other multidrug-
resistant infections, such as methicillin-resistant Staphylococcus
aureus and vancomycin-resistant Enterococcus [31–33].
The risk of CRE infection is known to be linked to general
poor health, indicated by a greater number of chronic comorbid
conditions [3, 5, 34]. Race/ethnicity is correlated with lower
socioeconomic status in the United States which also serves to
increase the likelihood of less access to healthcare and poorer
general health [35, 36]. In addition, some studies have found
differences in antibiotic use by race and sex [37, 38], which
could in turn influence CP-CRE risk. However, no such inter-
action was identified in the current study. Further research is
needed to explore the social determinants of health that may
affect these findings.
Previous antibiotic use is an established risk factor for CRE
colonization and infection [11, 29, 39]. However, in our analysis
we found that nearly 25% of patients had no history of docu-
mented antibiotic use in the previous year. This finding may be
due to some misclassification and receipt of antibiotics outside
the VA system not captured by VA data. However, although there
was no difference between CP-CRE– and CRE-positive cultures
by antibiotic exposure, we did find several key differences be-
tween these groups of individuals. Patients without antibiotic
exposure in the previous year were more likely to be white, had
significantly lower rates of all major comorbid conditions, and

1374 • cid 2021:73 (15 October) • Wilson et al

Table 2.  Demographic and Medical Characteristics by Exposure to Further research should investigate the risk of PPI exposure
Antibiotics in the Previous Year
on CRE colonization in the absence of antibiotics. A  meta-
analysis of 5 studies found that the odds of CRE colonization
Cultures, No. (%)a
was doubled in patients with a history of gastric acid suppressor
≥1 Antibiotic Day use (pooled OR, 2.04 [95% CI, 1.34–3.10]) [8]. These findings
No Antibiotics in Pre- in Previous Year P
Characteristic vious Year (n = 1017) (n = 4761) Value suggest that there is a group of patients with positive CRE cul-
CP-CRE 271 (26.6) 1332 (27.9) .39 tures who do not have the traditional risk factors for coloniza-
Race tion/infection. We were not able to identify a medical comorbid
  White non-Latin 499 (49.1) 2179 (45.8) .01 condition that was related to CRE positivity in these patients;
  African American 188 (18.5) 1109 (23.3) more work needs to be done to determine the risk factors for
 Latin 316 (31.1) 1417 (29.8)
CRE in this group.
 Other 14 (1.4) 56 (1.2)
Male sex 951 (93.5) 4591 (96.4) <.001
In our subanalysis of blood cultures, having multiple sclerosis
Duration of PPI use , d was the only patient factor associated with CP-CRE positivity in
 0 460 (45.2) 1053 (22.1) <.001 the adjusted analysis. Race and long-term care residency were

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 1–30 174 (17.1) 718 (15.1) significant in the unadjusted analysis but did not reach signif-
 31–60 62 (6.1) 342 (7.2) icance in the adjusted analysis, possibly owing to sample size.
 61–90 38 (3.7) 282 (5.9)
A previous analysis compared patients with CP-CRE and CRE
 >91 283 (27.8) 266 (5.6)
Comorbid conditions
bacteremia and found that the 14-day mortality was 4 times
 SCI/D 85 (8.4) 772 (16.2) <.001 greater in those with CP-CRE bacteremia as compared to CRE
  Chronic GI illness 328 (32.3) 2405 (50.5) <.001 bacteremia [30].
 GERD 176 (17.3) 1528 (32.1) <.001 The current analysis included a large cohort of >3000 indi-
  Myocardial infarction 44 (4.3) 404 (8.5) <.001
viduals with CRE cultures and allowed for an in-depth anal-
 CHF 206 (20.3) 1502 (31.5) <.001
ysis of factors associated with CP-CRE culture positivity.
  Peptic ulcer disease 26 (2.6 ) 217 (4.6) .004
  Mild diabetes 392 (38.5) 2577 (54.1) <.001 Comparisons between CP-CRE and non-CP-CRE cultures are
  Complicated diabetes 220 (21.6) 1479 (31.1) <.001 underevaluated, and this study adds to that body of literature.
  Renal disease 437 (43.0) 2814 (59.1) <.001 Furthermore, the inclusion of multiple years of data allows for
  Peripheral vascular 164 (16.1) 1348 (28.3) <.001 the analysis of changes in CP-CRE versus non-CP-CRE over
disease
 Paralysis 120 (11.8) 1121 (23.5) <.001
time. This analysis had several limitations. This study included
  Multiple sclerosis 7 (0.7) 85 (1.8) .01 only VAMCs, which may limit its generalizability owing in part
Organ transplantation 7 (0.7) 95 (2.0) .004 to the predominantly male population. The electronic-only, ret-
Stem cell transplantation 0 (0.0) 15 (0.3) .07 rospective nature of the study did not allow us to capture other
CCI, mean (SD) 3.40 (2.77) 5.26 (2.94) <.001 meaningful clinical information, such as if nonblood cultures
LOS in previous year, me- 3 (0–28) 26 (4–71) <.001
dian (IQR), d
indicated colonization versus true infection.
Facility complexity In addition, only 32.9% of the included cultures were tested
 1a–1c 915 (89.9) 4,472 (93.9) <.001 for CP-CRE; therefore, the CP-CRE detection rates are un-
 2 42 (4.1) 175 (3.7) derrepresented and some of the CRE cultures may have been
  3 60 (5.9) 144 (2.4)
misclassified. This may have led to an underestimation of the
Facility region
associations we identified. However, a sensitivity analysis of the
 South 282 (27.7) 1426 (29.9) .07
 Midwest 133 (12.9) 557 (11.7) years with the highest reported testing percentages did not yield
 West 116 (11.4) 505 (10.6) different results than the overall analysis, strengthening the im-
 Northeast 181 (17.8) 979 (20.6) pression that true patterns were detected in this study. Finally,
  Outside continental US 307 (30.2) 1294 (27.2) because the study was conducted in the VA system, all cultures
Abbreviations: CCI, Charlson comorbidity index; CHF, congestive heart failure;
were defined according to VA CRE definitions, which exclude
CP-CRE, carbapenemase-producing carbapenem-resistant Enterobacteriaceae; GERD,
gastroesophageal reflux disease; GI, gastrointestinal; IQR, interquartile range; LOS, length cultures resistant to ertapenem alone. This could have led to
of stay; PPI, proton pump inhibitor; SCI/D, spinal cord injuries and disorders; SD, standard
deviation; US, United States. inappropriate exclusion of some CP-CRE cultures that express
a
Data represent no. (%) of cultures, unless otherwise specified. weak carbapenemases, such as OXA-48–like enzymes.
In conclusion, in this analysis we explored the difference
had significantly fewer inpatient days in the previous year than between CP-CRE and non-CP-CRE cultures in a cohort of
those with antibiotic exposure history. veterans between 2013 and 2018. Being African American,
Prior PPI exposure for >90 days was also significantly higher receiving a diagnosis in 2017 or 2018, and having CHF or
among patients without an antibiotic exposure than among GERD were all associated with an increased risk of CP-CRE.
those with antibiotic exposure (17.3% vs 5.6%, respectively). More than 90 days of PPI exposure was more frequent among

CP-CRE–Associated Factors in Veterans  •  cid 2021:73 (15 October) • 1375

Table 3.  Adjusted and Unadjusted Analysis of Bloodstream Infections Subanalysis

Unadjusted Analysis Adjusted Analysis

a
Cultures, No. (%)

Characteristic CP-CRE (n = 168) CRE (n = 313) P Value OR (95% CI) P Value

Age, y Not included …

 18–49 11 (6.6) 10 (3.2) .08 …
 50–64 49 (29.2) 71 (22.7) …
 ≥65 98 (58.3) 216 (69.0) …
 Missing 10 (5.9) 16 (5.1) …
Race
 White 71 (42.3) 110 (35.1) .002 Reference
  African American 49 (29.2) 68 (21.7) 1.12 (.96–1.31) .16
 Latin 44 (26.2) 133 (42.5) 0.97 (.79–1.18) .80
 Other 4 (2.4) 2 (0.6) 1.15 (.89–2.35) .14

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Male sex 147 (87.5) 301 (96.2) <.003 1.12 (.96–1.38) .36
Care setting
 Inpatient 91 (54.2) 199 (63.6) .01 Reference …
 Outpatient 40 (23.8) 77 (24.6) 0.95 (.84–1.07) .45
  Long-term care 37 (22.0) 37 (11.8) 1.07 (.88–1.28) .48
ICU admission 2 (1.2) 12 (3.8) .10 Not included …
Bacterial organism
  Klebsiella spp. 141 (83.9) 226 (72.2) .002 Reference …
  Enterobacter spp. 25 (14.9) 63 (20.1) 0.89 (.78–1.02) .09
  Escherichia colib 2 (1.2) 24 (7.7) 0.76 (.66–.87) <.001
Duration of PPI use, d Not included …
 0 25 (14.9) 49 (15.7) .74 …
 1–30 32 (19.0) 57 (18.2) …
 31–60 14 (8.3) 16 (5.1) …
 61–90 9 (5.4) 25 (8.0) …
 >91 88 (52.4) 163 (52.1) …
Duration of antibiotic use, d Not included …
 0 24 (14.3) 55 (17.6) .61 …
 1–30 86 (51.2) 170 (54.3) …
 31–60 25 (14.9) 37 (11.8) …
 61–90 10 (6.0) 17 (5.4) …
 >91 23 (13.7) 37 (11.8) …
Comorbid conditions
 SCI/D 23 (13.7) 35 (11.2) .42 Not included …
  Chronic GI illness 96 (57.1) 170 (54.3) .55 Not included …
 GERD 68 (40.5) 100 (31.9) .06 Not included …
  MI in previous year 20 (11.9) 23 (7.3) .10 Not included …
 CHF 55 (32.7) 101 (32.3) .92 Not included …
  Peptic ulcer disease 15 (8.9) 20 (6.4) .31 Not included …
 Cancer 39 (23.2) 109 (34.8) .008 0.95 (.85–1.05) .31
  Mild diabetes 86 (51.2) 185 (59.1) .10 Not included …
  Complicated diabetes 53 (31.5) 82 (26.2) .21 Not included …
  Renal disease 103 (61.3) 189 (60.4) .84 Not included …
  Peripheral vascular disease 52 (31.0) 78 (24.9) .16 Not included …
 Paralysis 56 (33.3) 42 (13.4) <.001 1.14 (.96–1.36) .13
  Multiple sclerosisb 20 (11.9) 5 (1.6) <.001 1.52 (1.07–2.15) .02
  Organ transplantation 4 (2.4) 7 92.2) .92 Not included …
  Stem cell transplantation 1 (0.6) 10 (3.2) .07 Not included …
  CCI, mean (SD) 5.44 (2.98) 5.17 (2.85) .56 Not included …
  LOS in previous year median (IQR), d 47.5 (8–99.5) 31 (7–87) .28 Not included …
Facility complexity Not included …
 1a–1c 164 (97.6) 303 (96.8) .32 …
 2 4 (2.4) 6 (1.9) …
 3 0 (0.0) 4 (1.3) …

1376 • cid 2021:73 (15 October) • Wilson et al

Table 3.  Continued

Unadjusted Analysis Adjusted Analysis

Cultures, No. (%)a

Characteristic CP-CRE (n = 168) CRE (n = 313) P Value OR (95% CI) P Value

Facility region
 South 72 (42.9) 91 (29.1) <.001 Reference …
 Midwestb 10 (6.0) 31 (9.9) 0.81 (.66–.99) .046
 West 8 (4.8) 25 (8.0) 0.91 (.73–1.15) .45
 Northeast 37 (22.0) 41 (13.1) 1.06 (.87–1.28) .54
  Outside Continental US 41 (24.4) 125 (39.9) 0.79 (.70–1.06) .16
Year
 2013 29 (17.3) 59 (18.8) <.001 Reference …
 2014 38 (22.6) 82 (26.2) 0.99 (.8–1.14) .88
 2015 16 (9.5) 65 (20.8) 1.03 (.87–1.20) .75

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 2016 24 (14.3) 56 (17.9) 1.07 (.90–1.28) .42
 2017b 30 (17.9) 30 (9.6) 1.31 (1.07–1.60) .008
 2018b 31 (18.5) 21 (6.7) 1.51 (1.24–1.84) <.001
Abbreviations: CCI, Charlson comorbidity index; CHF, congestive heart failure; CI, confidence interval; CP-CRE, carbapenemase-producing carbapenem-resistant Enterobacteriaceae; CRE,
carbapenem-resistant Enterobacteriaceae; GERD, gastroesophageal reflux disease; GI, gastrointestinal; ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; MI, myocardial
infarction; OR, odds ratio; PPI, proton pump inhibitor; SD, standard deviation; US, United States.
a
Data represent no. (%) of cultures, unless otherwise specified.
b
Significant at P < .05.

those without previous antibiotic exposure. More work should
be done to determine the patient risk factors correlated with
CP-CRE versus non-CP-CRE cultures.
Notes
Disclaimer. The views expressed in this article are those of the authors
and do not necessarily reflect the position or policy of the Department of
Veterans Affairs or the US government.
Financial support. This work was supported by the Department of
Veterans Affairs, Veterans Health Administration, Office of Research
and Development, Health Services Research and Development (Quality
Enhancement Research Initiative QUE 15–269 and Research Career
Scientist Award RCS 20–192).
Potential conflicts of interest. C. D. P. reports grants as primary site in-
vestigator for a Clostridium difficile vaccine trial from Pfizer, outside the
submitted work. C. T. E. reports personal fees from BioK+, outside the sub-
mitted work. All other authors report no potential 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
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