Annals of Internal Medicine
Narrative Review: The New Epidemic of Clostridium difficile–
Associated Enteric Disease
John G. Bartlett, MD
Antibiotic-associated diarrhea and colitis were well established soon
been more frequent, more severe, more refractory to standard
after antibiotics became available. Early work implicated Staphylo-
therapy, and more likely to relapse. This pattern is widly distributed
, but in 1978 Clostridium difficile
became the estab-
in the United States, Canada, and Europe and is now attributed to
lished pathogen in the vast majority of cases. In the first 5 years
a new strain of C. difficile
designated BI, NAP1, or ribotype 027
(1978 through 1983), the most common cause was clindamycin,
(which are synonymous terms). This strain appears more virulent,
the standard diagnostic test was the cytotoxin assay, and standard
possibly because of production of large amounts of toxins, and
management was to withdraw the implicated antibiotic and treat
fluoroquinolones are now major inducing agents along with ceph-
with oral vancomycin. Most patients responded well, but 25%
alosporins, which presumably reflects newly acquired in vitro resis-
relapsed when vancomycin was withdrawn. During the next 20
tance and escalating rates of use. The recent experience does not
years (1983 through 2003), the most commonly implicated antibi-
change principles of management of the individual patient, but it
otics were the cephalosporins, which reflected the rates of use; the
does serve to emphasize the need for better diagnostics, early
enzyme immunoassay replaced the cytotoxin assay because of
recognition, improved methods to manage severe disease and re-
speed of results and technical ease of performance; and metroni-
lapsing disease, and greater attention to infection control and an-
dazole replaced vancomycin as standard treatment, and principles
of containment hospitals became infection control and antibiotic
Ann Intern Med.
control. During the recent past (2003 to 2006), C. difficile
For author affiliation, see end of text.
iarrhea and colitis due to Clostridium difficile
are well- ical significance, and is resistant to fluoroquinolones in
recognized and extensively studied iatrogenic compli-
vitro. Successful management of patients with this strain
cations of antibiotic use and have been for nearly 30 years.
requires early detection of infection, rapid treatment, and
Important risks for infection include hospitalization, ad-
implementation of infection control, sometimes including
vanced age, gastrointestinal surgery or gastrointestinal pro-
cedures, and antibiotic exposure. The most common in-
was identified as the major cause
ducing agents have been clindamycin or broad-spectrum
of antibiotic-associated diarrhea and the nearly exclusive
cephalosporins, but nearly all agents with an antibacterial
cause of pseudomembranous colitis in 1978. Subsequent
spectrum may be responsible. The cytotoxin assay that
work in the following 2 years defined the clinical features,
originally led to the detection of C. difficile
in 1978 re-
methods of laboratory diagnosis, epidemiology, principles
mains the most sensitive diagnostic test, but the enzyme
of infection control, and treatment of C. difficile
immunoassay is now used by most laboratories because of
disease. Clostridium difficile
infection is an important and
ease of processing, cost, and speed of results. Standard
frequent iatrogenic complication, but it has been relatively
treatment of C. difficile
infection includes withdrawal of
easy to manage, with the exception of occasional institu-
the inducing agent and use of oral metronidazole or oral
tional outbreaks and a nagging problem of relapsing disease
vancomycin; metronidazole is preferred in guidelines, but
following treatment. However, during the past 5 years, an
vancomycin is probably more effective, especially in seri-
unanticipated increase in infection has been recognized,
ously ill patients. The major complications of treatment are
particularly in some locations where C. difficile
failure to respond, primarily because of advanced disease
disease has become more frequent, more serious, and more
with ileus, and relapse or reinfection after treatment is dis-
refractory to standard therapy. It now seems that this
continued. Prevention principles include hospital infection
change is explained by a unique strain of C. difficile
has unusual virulence factors, which may account for in-
Against this background, there is a new epidemic of C.
creased severity, and fluoroquinolone resistance, which
infection that is occurring more frequently and ismore serious and more refractory to therapy. Evidence ofthe severity of the infection includes high rates of toxic
megacolon, leukemoid reactions, severe hypoalbuminemia,
requirement for colectomy, shock, and death. These com-
Key Summary Points . . . . . . . . . . . . . . . . . . . . . . . 759
plications are most common in elderly patients, and theinducing agents are often fluoroquinolones and cephalo-
sporins. Analysis of outbreaks in North America implicates
a unique strain of C. difficile
that produces large amounts
of toxin in vitro, produces a binary toxin of uncertain clin-
2006 American College of Physicians
–Associated Colitis Review
Key Summary Points
Almost all studies include the 3 major risks for infec-
is the most common identifiable bac-
tion with C. difficile
: antibiotic exposure, advanced age,
terial cause of diarrhea in the United States.
and hospitalization (6 – 8). With regard to antibiotic expo-sure, any antimicrobial agent with an antibacterial spec-
Tissue culture assay is the best diagnostic test to detect
trum can be the cause, but there is a hierarchical list of
the cytotoxin; enzyme immunoassay is the test used in
agents that has been subject to change. Clindamycin fol-
most hospitals, but it has a sensitivity of only about 75%.
lowed by ampicillin or amoxicillin played prominent rolesin the 1970s, but these were largely supplanted by cepha-
A new epidemic strain of C. difficile
has emerged that
losporins in the 1980s (9, 10). Researchers from Sweden
causes more frequent and more serious disease.
showed that advanced age was a risk in population-basedanalyses indicating that the rate per 100 000 persons older
Features of severe disease include ileus, toxic megacolon,
than 65 years of age was 20 times higher than that in
pseudomembrane formation, leukemoid reactions, hyperal-
persons younger than 20 years of age (11). The risk asso-
buminemia, requirement for colectomy, sepsis, and death.
ciated with hospitalization and chronic care facilities is at-tributed to high rates of C. difficile
Risk factors are use of antibiotics (especially broad-spec-
have shown a 20% to 40% rate of colonization in hospi-
trum cephalosporins and fluoroquinolones), advanced age,
talized adults compared with 2% to 3% in healthy adults
hospitalization, and gastrointestinal surgery or gastrointes-
(12, 13), reflecting widespread contamination of hospital
environments, especially in areas associated with infection(6, 7, 14, 15). Gastrointestinal surgery and gastrointestinal
Oral vancomycin is the preferred treatment for seriously ill
Infection control and antibiotic control are important pre-
Clinical disease and C. difficile
toxin are present almost
exclusively in patients with recent antibiotic exposure (6, 7,12, 16), with rare exceptions (17, 18). A recent reportimplicates gastric acid–suppressive agents as a risk for dis-ease (19), but this has not been consistently observed (20).
Clinical expression of infection almost always includes di-
may account for increased frequency. These recent obser-
arrhea, but severity of this and constitutional symptoms
vations have resulted in renewed interest in an “old patho-
(6 – 8, 16, 17) varies widely. Common findings in patients
gen.” This review updates the status of C. difficile
with infection include colitis with cramps, fever, fecal leu-
ated enteric disease and its management in light of these
kocytes, and inflammation on colonic biopsy. Pseudomem-
branous colitis represents an advanced stage of disease, andalthough considered “nonspecific,” it is nearly diagnostic ofC. difficile
infection (17). The disease is almost always re-stricted to the colon (21). Clostridium difficile
INITIAL STUDIES (1974 TO 2003)
is a protein-losing enteropathy that is often associated with
Antibiotic-associated enterocolitis was generally attrib-
hypoalbuminemia and sometimes with anasarca (3). Most
uted to Staphylococcus aureus
in the first 25 years of the
patients have leukocytosis, and this infection is now recog-
antibiotic era (1, 2). In 1974, Tedesco and colleagues (3)
nized as a prominent cause of leukemoid reactions (22).
reported results of a prospective study of 200 patients given
clindamycin who underwent endoscopy after reporting di-
The standard test for infection is detection of C. diffi-
arrhea. In this study, 41 (20.5%) patients had diarrhea and
toxin in stool. The initial report in 1978 (5) used the
20 (10%) had pseudomembranous colitis (3). Despite the
tissue culture assay, and no subsequent test has proven
ease of recovering S. aureus
in stool, tests to detect the
superior in terms of sensitivity or specificity (23–25). The
organism yielded negative results. This led our group and
main limitations of the test are the 24 to 48 hours required
others to pursue an alternative putative agent by using the
for results, work intensity, and cost (25). Most laboratories
hamster model (4) for correlations with observations in
now use enzyme immunoassay to detect toxin A or toxins
patients. Clostridium difficile
was reported as the agent of
A and B, but several studies show that these are only about
antibiotic-associated pseudomembranous colitis in 1978 (5).
75% sensitive compared with tissue culture assays (23–25)
During the ensuing 25 years, researchers established
so that repeated tests or empirical treatment may be re-
essential data documenting associated risks, clinical fea-
quired (26). Alternative methods of detection include de-
tures, diagnosis, and management of C. difficile
tection of C. difficile
by culture, by polymerase chain reac-
diarrhea that became widely accepted.
tion testing, or by analysis for the “common antigen” of C.
21 November 2006 Annals of Internal Medicine Volume 145 • Number 10 759
Review Clostridium difficile
Some laboratories use 1 of these last methods to screen
Table. Treatment Recommendations for Clostridium
stool samples, with subsequent testing for the cytotoxin in
samples with positive results (25, 28).
Discontinue implicated antimicrobial agent or agents
Standard recommendations of the Society for Health-
Institute supportive care: hydration and electrolyte replacement, if
care Epidemiology of America for infection control include
Avoid antiperistaltics, including narcotics and loperamide
the following: patient isolation in a single room, preferably
with a bathroom; contact precautions; room cleansing with
Oral vancomycin, 125–250 mg 4 times daily for 10 d
a 1:10 dilution of bleach; avoidance of rectal thermome-
Advantages: ideal pharmacologic profile; unbeaten in clinical trials;
only FDA-approved treatment; in vitro activity vs. all strains
ters; and soap and water for handwashing rather than al-
Disadvantages: high relapse or reinfection rate; promotion of
cohol-based hand hygiene (14). Alcohol-based hand clean-
acquisition of vancomycin-resistant Enterococcus faecalis
ing is considered inferior because clostridia spores survive
Oral metronidazole, 250 mg 4 times daily or 500 mg 3 times daily for
alcohol. This is important because health care workers can
transmit C. difficile
via their hands. Antibiotic control of
Advantages: comparable to vancomycin in most clinical trials;
preferred according to IDSA, CDC, and SHEA guidelines; low
clindamycin or cephalosporins has sometimes been neces-
sary during epidemics (29, 30). Attempts to prevent infec-
Disadvantages: poor pharmacologic profile; in vitro resistance for
some strains; high relapse or reinfection rate; less effective than
tion with prophylactic metronidazole or oral vancomycin
may actually increase the rate of C. difficile
Infection control: Nosocomial cases
Single room with bathroom; barrier precautions; hand hygiene with soap
Recommendations for treatment are supportive care,
and water; avoidance of rectal thermometers; terminal roomcleaning with 1:10 household bleach
withdrawal of the implicated antibiotic, and avoidance of
Consider antibiotic restrictions based on epidemiologic associations if C.
unnecessary use of drugs with antiperistaltic activity (Ta-
). When continued antibiotic treatment is necessary, it
is best to use agents with a low probability of causing C.
Inability to take medications by mouth: IV metronidazole† (500 mg 4
–associated disease, such as urinary antiseptics, tetra-
times daily) and vancomycin (500 mg every 6 h by retentionenema or nasogastric tube)
cyclines, narrow-spectrum betalactams, macrolides, sulfon-
Delayed response and critical illness: consider IVIG (400 mg/kg of body
amides, aminoglycosides, vancomycin, metronidazole, and
weight)† or surgical consultation for possible colectomy,
trimethoprim–sulfamethoxazole (32). It is not clear
especially if leukemoid reaction (leukocyte count Ͼ 20 ϫ 109cells/L), renal failure, septic shock, or any combination of these
whether mild cases require antibiotic treatment against C.
(33). When symptoms are at least moderately se-
vere or persistent despite withdrawal of the implicated anti-
Withdraw inducing agentSubstitute agent or agents unlikely to cause C. difficile
microbial agent, the usual options are oral vancomycin or
diarrhea, avoiding clindamycin, broad-spectrum cephalosporins,
oral metronidazole (6 – 8, 14, 16, 34). Oral vancomycin is
the only drug approved by the U.S. Food and Drug Ad-
Repeat treatment with metronidazole or vancomycin using standard
ministration for C. difficile
enteric infection. It has ideal
pharmacologic properties for treating a pathogen that is
Oral vancomycin in tapering or pulse dosing (125 mg every other day
completely restricted to the colonic lumen because the
Biotherapy: Oral lactobacilli, such as Lactinex (Becton–Dickinson, San
drug is not absorbed and is found at levels in the colonic
Diego, California) (1 g 4 times daily), or Lactobacillus
lumen that are more than 100 times higher than the high-
twice daily for 4–6 wk), or Saccharomyces boulardii
est minimum inhibitory concentration reported (31, 35, 36).
250-mg capsules twice daily for 4–6 wk)
Metronidazole is the preferred treatment agent in
Anion exchange resin: oral cholestyramine (4-g packet 3 times daily)†Fecal transplant (30–50 g fresh stool from healthy donor in normal
guidelines from the Society for Healthcare Epidemiology
saline delivered by enema or nasogastric tube)
of America, Infectious Diseases Society of America (IDSA),
and the U.S. Centers for Disease Control and Prevention
Combinations of above, but do not give vancomycin concurrently with
lactobacilli (vancomycin is active against lactobacilli) or
(16), presumably because of its low cost and because of the
possibly erroneous conclusion that vancomycin promotes
fecal colonization with vancomycin-resistant enterococci
* CDC ϭ U.S. Centers for Disease Control and Prevention; CFU ϭ colony-
more than metronidazole does (37). The pharmacologic
forming unit; FDA ϭ U.S. Food and Drug Administration; IDSA ϭ Infectious
properties of metronidazole are poor for treating a patho-
Diseases Society of America; IV ϭ intravenous; IVIG ϭ intravenous immunoglob-
ulin; SHEA ϭ Society for Healthcare Epidemiology of America.
gen in the colonic lumen because its absorption is nearly
complete and at detectable levels in stool only in the pres-ence of diarrhea (31, 35, 36) and because some strains of
(25, 27, 28). An inherent problem with detection
are resistant to metronidazole in vitro (38).
of the organism rather than the toxin is that 10% to 30%
Comparative trials of vancomycin versus metronidazole
of hospitalized patients are colonized without disease (13).
have shown that the drugs are equivalent (39, 40), but
21 November 2006 Annals of Internal Medicine Volume 145 • Number 10
–Associated Colitis Review
there is some evidence that oral vancomycin is preferred in
THE NEW EPIDEMIC OF CLOSTRIDIUM DIFFICILE
seriously ill patients because of relatively high failure rates
of metronidazole in recent reports (41), poor response to
Investigators from Que´bec, Canada, noted an increase
metronidazole when antibiotics for the initial condition
in the frequency and severity of C. difficile
need to be continued (42), and a slower clinical response
arrhea in the early 2000s (20, 63– 65). A review of 1771
compared with oral vancomycin treatment (43).
case-patients from 1991 through 2003 in Sherbrooke,
The expected response to treatment is rapid deferves-
Que´bec, showed that the incidence of C. difficile
cence in patients who are febrile and resolution of diarrhea
disease per 100 000 people increased 4-fold for the entire
over 4 to 6 days (44). In my experience (45) with 189
region and 10-fold for persons older than 65 years of age.
patients with C. difficile
enteric infection, including 100
Among those admitted to the hospital in the region, the
with endoscopic evidence of pseudomembranous colitis,
incidence increased from 3 to 12 per 1000 persons in 1991
96% responded to oral vancomycin. For patients who are
to 2002 to 25 to 43 per 1000 persons in 2003 to 2004
seriously ill and cannot take oral medications, it is recom-
(63). Furthermore, the disease seemed to be more serious
mended that vancomycin be delivered by nasogastric tube
and refractory to therapy, as indicated by increased rates oftoxic megacolon, disease requiring colectomy, associated
or by enema (46). This may be augmented with intra-
shock, or death (20, 63, 66). Indeed, the attributable mor-
venous metronidazole, but evidence of efficacy of intra-
tality rate was an astonishing 16.7% (66). Five variables
venous metronidazole treatment is poor (47). Another op-
were associated with these complications: age older than 65
tion, based on previous studies showing a correlation
years, acquisition of infection at a hospital, peripheral leu-
between clinical expression and serum levels of IgG anti-
kocyte count higher than 20 ϫ 109 cells/L, renal failure,
body versus C. difficile
(48), is intravenous immunoglobu-
and immunosuppression (66). The implication is that the
lin (49, 50). Results using intravenous immunoglobulin in
disease was more frequent, more severe, more refractory to
acutely ill patients are variable and anecdotal (49, 50).
therapy, and subject to high rates of relapse (63– 68).
Some patients with advanced disease, especially those with
While these developments were occurring in Canada,
ileus or toxic megacolon, require colectomy. However, the
McDonald and colleagues (68, 69) at the Centers for Dis-
frequency of patients with advanced disease was only 0.4%
ease Control and Prevention noted reports of increasing
at The Johns Hopkins Hospital in the early 1990s (51).
frequency and severity of C. difficile
from U.S. physicians,
Patients with serious disease who do not respond to stan-
including 8 hospital outbreaks in 6 states (68, 69). An
dard therapy should be considered for colectomy (51–53).
analysis of the International Classification of Diseases,
The mortality rate in reports of 94 patients who had co-
Ninth Revision (ICD-9) coding in the United States
lectomy for C. difficile
–associated colitis was 45% (51–53).
showed an increase 82 000 cases in 1996 to 178 000 in
The major complication of antibiotic treatment of C.
2003 (69). There were also other reports of C. difficile
infection has been relapse, which is seen in about
causing more disease and more serious disease in the
20% of patients treated with metronidazole or vancomycin
United States (70, 71) and in other areas of the world (72).
(39, 40, 45). The clinical features of relapse are highly
Thus, this seemed to be an experience that was widespread
characteristic: The patient reports a recurrence of symp-
toms identical to those of the initial illness, usually within
1 week but up to 6 to 8 weeks after vancomycin or met-
Clinical features of the epidemic disease are similar to
ronidazole is withdrawn (45, 54). These patients usually
the historical experience but more severe. Prominent com-
respond well to retreatment, but some have additional re-
plications include toxic megacolon, leukemoid reactions,
lapses and a small portion have repeated relapses necessi-
septic shock, requirement for colectomy, and death (20,
tating several courses of antibiotics (45, 54, 55). Relapse is
62–71). The newly implicated class of antibiotics was fluo-
caused by the initial strain of C. difficile
, but nearly half of
roquinolones for most of the recent outbreaks, although
patients experiencing relapse may be infected with new
cephalosporins still accounted for a substantial portion (20,
strains of C. difficile
(56). These observations illustrate the
paradox that oral vancomycin and metronidazole both
cause and cure antibiotic-associated diarrhea. The postu-
This epidemic, with a large increase of patients with
lated cause of recurrence is failure to mount an immune
infection, many experiencing severe complications, raised
response as indicated by low serum levels of IgG versus
the possibility of a new strain of C. difficile
that had unique
toxin A (50, 57). Several methods are used to treat relaps-
properties accounting for enhanced virulence. This suspi-
ing disease, including biotherapy or probiotics (such as
cion was confirmed by analysis of epidemic strains from
and Lactobacillus rhamnosus
Que´bec and 8 U.S. sites. Results of the analysis showed a
(58 – 61), stool implants (62), immunotherapy (intra-
highly characteristic strain, designated BI/NAP1, that has
venous immunoglobulin) (48, 49), and tapering or pulse
been rare historically and is responsible for the majority of
these outbreaks (20, 68, 73). This strain has several appel-
21 November 2006 Annals of Internal Medicine Volume 145 • Number 10 761
Review Clostridium difficile
lations, according to the biological property tested: NAP1
not standard in most laboratories. Nevertheless, a pathogen
by pulsed-field gel electrophoresis, BI on restriction-endo-
should be suspected if there is an increase in the occurrence
nuclease analysis, toxinotype III, and ribotype 027 on
of infection and more severe associated disease as indicated
polymerase chain reaction. With regard to unique features,
by high rates of serious complications, including toxic
5 factors have been found in nearly all strains that may
megacolon, leukemoid reactions, requirement for colec-
contribute to the clinical observations.
tomy, shock, or death. Fastidious attention to infection
The first of the 5 factors are toxins A and B, which are
control is required because infection with this strain may
the classic toxins associated with C. difficile
be a major nosocomial complication, especially in elderly
ease. Most strains of C. difficile
produce both toxins, but
patients. Outbreaks may require restriction of antibiotic
the epidemic strain has been shown to produce substan-
use with attention to antibiotics implicated in the epi-
tially more toxins A and B in vitro (73). The second factor
demic, which now include fluoroquinolones, clindamycin,
is toxinotype III. Toxinotyping is based on analysis of the
and cephalosporins. Traditional treatment, including oral
region of the C. difficile
genome known as the pathogenic-
metronidazole or oral vancomycin, is recommended. These
ity locus (PaLoc) that includes genes that encode for toxin
drugs seem to be similar in clinical trials, but many author-
) and toxin B (tcdB
) and the neighboring regulatory
ities now prefer oral vancomycin for more serious disease
genes. All BI/NAP1 strains are toxinotype III, but more
and for patients who do not respond rapidly to metroni-
than 80% of other strains are toxinotype 0 (68, 73). The
third factor is the deletion of tcdC
, which is an 18 base-pairsequence in the pathogenicity locus (PaLoc) responsible for
From John Hopkins University School of Medicine, Baltimore, Mary-
downregulation of toxin production (68, 74). The fourth
factor is binary toxin, an iota-like toxin similar to that
Potential Financial Conflicts of Interest: Consultancies:
Dr. Bartlett is on
produced by Clostridium perfringens
type E (75). The bi-
the HIV advisory boards of Abbott, Bristol-Myers Squibb, and Glaxo-
nary toxin is present in the epidemic strain, but its role in
the pathogenesis of C. difficile
–associated disease is unclear.
It causes fluid accumulation in rabbit ileal loops, but C.
Requests for Single Reprints:
John G. Bartlett, MD, Department of
strains that possess binary toxin without toxins A
Medicine, Johns Hopkins University School of Medicine, 1830 Monu-
and B fail to cause disease in hamsters (76). The final factor
ment Street, 437, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
is resistance in vitro to fluoroquinolones, which is infre-quently observed in strains collected before 2001 and maybe an important factor in the increased frequency of disease
rather than contributing to its virulence (20, 66, 68, 77).
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21 November 2006 Annals of Internal Medicine Volume 145 • Number 10
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Robert Hitchins – Book Review 3 July 2011 THE EMPEROR’S NEW DRUGS: EXPLODING THE ANTIDEPRESSANT MYTH Irving Kirsch is Professor of Psychology at Hull in the UK and Emeritus Professor atConnecticut in the USA. His published research into placebos is highly regarded. Before training in psychology, he played strings in Aretha Franklin’s backing band,which is sufficient to get my R-E-