Burden of Clostridium difficile Infection in the United States
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 372;9 nejm.org fe
uary 26, XXXXXXXXXX
original article
Burden of Clostridium difficile Infection
in the United States
Fernanda C. Lessa, M.D., M.P.H., Yi Mu, Ph.D., Wendy M. Bamberg, M.D.,
Zintars G. Beldavs, M.S., Ghinwa K. Dumyati, M.D., John R. Dunn, D.V.M., Ph.D.,
Monica M. Farley, M.D., Stacy M. Holzbauer, D.V.M., M.P.H., James I. Meek, M.P.H.,
Erin C. Phipps, D.V.M., M.P.H., Lucy E. Wilson, M.D., Lisa G. Winston, M.D.,
Jessica A. Cohen, M.P.H., Brandi M. Limbago, Ph.D., Scott K. Fridkin, M.D.,
Dale N. Gerding, M.D., and L. Clifford McDonald, M.D.
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Lessa at the Centers for Disease Con-
trol and Prevention, 1600 Clifton Rd., MS
C-25, Atlanta, GA 30333, or at flessa@
cdc.gov.
N Engl J Med 2015;372:825-34.
DOI: XXXXXXXXXX/NEJMoa1408913
Copyright © 2015 Massachusetts Medical Society.
A BS TR AC T
Background
The magnitude and scope of Clostridium difficile infection in the United States con-
tinue to evolve.
Methods
In 2011, we performed active population- and laboratory-based surveillance across
10 geographic areas in the United States to identify cases of C. difficile infection
(stool specimens positive for C. difficile on either toxin or molecular assay in resi-
dents ≥1 year of age). Cases were classified as community-associated or health
care–associated. In a sample of cases of C. difficile infection, specimens were cul-
tured and isolates underwent molecular typing. We used regression models to cal-
culate estimates of national incidence and total number of infections, first recur-
ences, and deaths within 30 days after the diagnosis of C. difficile infection.
Results
A total of 15,461 cases of C. difficile infection were identified in the 10 geographic
areas; 65.8% were health care–associated, but only 24.2% had onset during hospi-
talization. After adjustment for predictors of disease incidence, the estimated num-
er of incident C. difficile infections in the United States was 453,000 (95% confi-
dence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher
among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95%
CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16
to XXXXXXXXXXThe estimated number of first recu
ences of C. difficile infection was 83,000
(95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95%
CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1
(NAP1) strain was more prevalent among health care–associated infections than
among community-associated infections (30.7% vs. 18.8%, P<0.001)
Conclusions
C. difficile was responsible for almost half a million infections and was associated
with approximately 29,000 deaths in XXXXXXXXXXFunded by the Centers for Disease Con-
trol and Prevention.)
The New England Journal of Medicine
Downloaded from nejm.org on October 6, 2015. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 372;9 nejm.org fe
uary 26, XXXXXXXXXX
Changes in the epidemiology of Clos-tridium difficile infections have occu
ed since the emergence of the North Ameri-
can pulsed-field gel electrophoresis type 1 (NAP1)
strain, which has been responsible for geograph-
ically dispersed hospital-associated out
eaks.1-3
In the United States, hospitalizations for C. diffi-
cile infection among nonpregnant adults doubled
from 2000 through 2010 and were projected to
continue to increase in 2011 and 2012, especially
as laboratories transition to more sensitive C. dif-
ficile assays, such as the nucleic acid amplifica-
tion test (NAAT).4-6 On the basis of data from
U.S. death certificates, C. difficile infection is the
leading cause of gastroenteritis-associated death
and was estimated to cause 14,000 deaths in
2007.7 C. difficile has become the most common
cause of health care–associated infections in U.S.
hospitals, and the excess health care costs relat-
ed to C. difficile infection are estimated to be as
much as $4.8 billion for acute care facilities
alone.8-10 In addition, C. difficile infection has
een increasingly reported outside of acute care
facilities, including in community and nursing
homes settings, where infection may be diag-
nosed and treated without hospitalization.11-13
As the epidemiology of C. difficile changes, both
in health care and community settings, it is im-
portant to understand the magnitude and scope
of this infection in the United States to help
guide priorities for prevention.
In 2009, the Centers for Disease Control and
Prevention (CDC) started active population- and
laboratory-based surveillance for C. difficile infec-
tion at 7 U.S. sites. This surveillance was ex-
panded to 10 sites in 2011 to provide better na-
tional estimates of disease burden, incidence,
ecu
ence, and mortality by capturing data
across the spectrum of health care delivery and
community settings.
Me thods
Surveillance Population and Case Definition
C. difficile surveillance is a component of the
CDC’s Emerging Infections Program (EIP). In 2011,
C. difficile surveillance was conducted at 10 EIP
sites across 34 counties (total population, approx-
imately 11.2 million) for the entire calendar year.
Surveillance catchment areas included California
(1 u
an county; population, 812,826), Colorado
(5 u
an counties; population, 2,488,410), Connect-
icut (1 u
an county; population, 861,113), Georgia
(8 u
an counties; population, 3,753,452), Mary-
land (3 rural and 8 u
an counties; population,
835,893), Minnesota (2 rural and 2 u
an coun-
ties; population, 248,079), New Mexico (1 u
an
county; population, 670,968), New York (1 u
an
county; population, 745,625), Oregon (1 rural coun-
ty; population, 66,299), and Tennessee (1 u
an
county; population, 635,475).
The surveillance methods have been described
previously.14,15 Briefly, surveillance staff at each
EIP site identified all positive C. difficile test re-
sults from 88 inpatient and 33 outpatient labo-
atories serving residents in surveillance areas in
2011. A case of C. difficile infection was defined
as a positive result on a C. difficile toxin or mo-
lecular assay of a stool specimen obtained from
a surveillance-area resident at least 1 year of age
who had not had a positive assay in the previous
8 weeks (i.e., incident infection). This surveil-
lance was approved by the institutional review
oards at the CDC and at the participating EIP
sites.
Data Collection
We performed an initial medical-record review to
collect data on demographic characteristics, the
location of stool collections, and health care expo-
sures on all cases of C. difficile infection in 8 of the
10 EIP sites. In 2 EIP sites with the largest surveil-
lance populations (Georgia and Colorado), we per-
formed an initial medical-record review on a ran-
dom sample of cases, as described previously.15
On the basis of the initial medical review, a
case was classified as community-associated if
the C. difficile–positive specimen was collected on
an outpatient basis or within 3 days after hospi-
tal admission and the patient had no document-
ed overnight stay in a health care facility during
the previous 12 weeks. All other cases were
classified as health care–associated and further
categorized into three mutually exclusive groups:
community onset associated with a health care
facility, hospital onset, or nursing home onset
(Table S1 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org).
All cases that were classified as either commu-
nity-associated or community-onset health care–
associated underwent full medical-record review
to collect information on coexisting medical
conditions, medication exposures, first laboratory-
confirmed recu
ences (i.e., positive specimen
The New England Journal of Medicine
Downloaded from nejm.org on October 6, 2015. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Clostridium difficile Infection in the United States
n engl j med 372;9 nejm.org fe
uary 26, XXXXXXXXXX
within 2 to 8 weeks after the last positive test),
and death within 30 days after diagnosis of
C. difficile infection. In addition, we reviewed a
sample consisting of 10% of cases with an onset
in a nursing home or hospital.
A convenience sample of clinical laboratories
across the EIP sites (37 laboratories) submitted
all C. difficile–positive stool specimens from cases
with full medical-record review for culture.16
Recovered isolates underwent pulsed-field gel
electrophoresis (PFGE). PFGE patterns were ana-
lyzed with the use of BioNumerics software,
version 5.10 (Applied Maths) and grouped into
pulsed-field types with the use of Dice coeffi-
cient analysis and UPGMA (unweighted pair
group method with arithmetic mean) clustering.
An 80% similarity threshold was used to assign
North American PFGE (NAP) types.17 Isolates
also underwent polymerase-chain-reaction (PCR)
assay to detect the presence of tcdA, tcdB, and
inary toxin (cdtA and ctdB) genes and a subset
of the most common NAP types underwent PCR
ibotyping.18
Between November 2011 and January 2012,
all laboratories serving the surveillance popula-
tion were surveyed to assess the type of C. difficile
diagnostic tests that were used during XXXXXXXXXX
Laboratory surveys were used to estimate the
proportion of cases in the surveillance areas that
were identified by means of NAAT.
Statistical Analysis
Data were analyzed with the use of SAS software,
version 9.3 (SAS Institute). In cases of C. difficile
infection in