REVIEW ARTICLE
Antimotility Agents for the Treatment of Clostridium
difficile Diarrhea and Colitis
Hoonmo L. Koo,1,2 Diana C. Koo,2 Daniel M. Musher,1,4 and Herbert L. DuPont1,2,3,5
1
Department of Medicine, Division of Infectious Diseases, Baylor College of Medicine, 2University of Texas–Houston School of Public Health,
University of Texas Medical School, 4Michael E. DeBakey Veterans Affairs Medical Center, and 5St. Luke’s Episcopal Hospital, Houston, Texas
3
(See the editorial commentary by Gerding on pages 606–8)
Antimotility agent use for the treatment of Clostridium difficile infection (CDI) is discouraged. We reviewed
the literature and unpublished postmarketing surveillance reports regarding antimotility treatment of CDI.
Twenty reports met inclusion criteria, describing 55 patients with CDI who were exposed to antimotility agents.
All studies were case reports or series, with the exception of 1 retrospective review. Nineteen patients (35%)
improved, with clinical resolution. Nine patients (16%) died, and 27 patients (49%) had unknown outcomes.
Seventeen patients (31%) with CDI developed colonic dilation; 5 of these patients with severe CDI died.
However, all patients who experienced complications or died were given antimotility agents alone initially,
without an appropriate antibiotic. Twenty-three patients who received metronidazole or vancomycin coadministered with the antimotility agent experienced no complications. Evidence supporting the hypothesis that
worsened outcomes are associated with antimotility therapy of CDI is lacking. Further study of the role of
antimotility agents in providing symptomatic relief and reducing environmental contamination with infectious
stool may be warranted.
Clostridium difficile infection (CDI) has emerged as a
prominent nosocomial disease. C. difficile is the most
common definable cause of hospital-acquired diarrhea
[1, 2]. The incidence of CDI continues to increase in
health care facilities in North America and Europe, despite improved measures in infection control and preventative strategies [1, 3–5]. Although ongoing clinical
trials are examining new potential treatment options
[5], currently recommended therapies for CDI are suboptimal. Reports from tertiary care hospitals suggest
that ∼25% of patients fail to respond to conventional
antibiotic treatment with metronidazole, and another
25% experience relapse within 2 months after apparent
successful treatment [6, 7]. The failure rate associated
with vancomycin is lower than that associated with
Received 19 June 2008; accepted 7 October 2008; electronically published 27
January 2009.
Reprints or correspondence: Dr. H. L. Koo, Baylor College of Medicine, One
Baylor Plaza, BCM 286, N1319, Houston, TX 77030 ([email protected]).
Clinical Infectious Diseases 2009; 48:598–605
2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4805-0012$15.00
DOI: 10.1086/596711
598 • CID 2009:48 (1 March) • Koo et al.
metronidazole [7, 8]; however, cure is by no means
uniform with this drug [8–12]. CDI is associated with
substantial morbidity and mortality [13–15].
Most cases of CDI occur in hospitalized patients.
Persons who are debilitated, malnourished, and bedridden are at especially increased risk of infection. A
vicious cycle may occur when diarrhea causes further
debilitation, increasing the morbidity associated with
infection and the likelihood of treatment failure or relapse. The use of antidiarrheal agents to provide symptomatic relief until specific antimicrobial treatment effects are experienced might thus benefit affected
patients. However, the use of antimotility agents for the
treatment of enterocolitis associated with invasive bacterial enteropathogens, such as Salmonella, Shigella, and
Campylobacter species, has been strongly discouraged
on the basis of results of animal studies and limited
observations in humans [16–19]. The manufacturer’s
instructions for loperamide, the most widely used antimotility drug, specifically proscribe its use for CDI
[20]. For these reasons, we sought to study the medical
literature to determine the basis for the recommen-
dation that loperamide or other antimotility drugs not be used
for CDI.
METHODS
Study identification. Articles relating to the use of antimotility agents in the treatment of C. difficile diarrhea and colitis
were identified through a comprehensive literature search using
PubMed, including articles published until 31 December 2007.
Key words used for the literature search were “Clostridium difficile,” “antimotility,” “loperamide,” “Imodium,” “diphenoxylate,” “Lomotil,” “opiate,” “opium,” “codeine,” “toxic megacolon,” and “diarrhea.” Reference lists from relevant studies
were carefully surveyed to find additional studies. A search of
the Cochrane Database of Systematic Reviews was also performed. Unpublished reports of toxic megacolon during treatment of CDI with loperamide were solicited from McNeil Consumer Healthcare, the manufacturer of this drug (Imodium).
Loperamide, an opiate receptor agonist, was originally developed by Janssen Pharmaceutica in 1969 and was later marketed
by McNeil Consumer Healthcare. As a result, unpublished adverse event reports were available for review since the first
licensure of this medication.
Study selection. Studies evaluating adverse effects associated with antimotility therapy for CDI were reviewed for the
following inclusion criteria: (1) inclusion of human subjects,
(2) inclusion of patients documented to have CDI or pseudomembranous colitis, and (3) inclusion of patients who received antimotility agents, such as loperamide, diphenoxylate,
and atropine, or opiates.
RESULTS
A total of 1100 articles were identified from the PubMed literature search with use of the key words and review of article
bibliographies (figure 1). The Cochrane Database of Systematic
Reviews yielded no additional articles. One thousand studies
were excluded because they did not meet the inclusion criteria.
The remaining potentially eligible 100 articles were reviewed.
Eighty-two of these reports were subsequently excluded. The
reasons for exclusion were failure to include patients with documented CDI (n p 55), lack of antimotility agent use (n p
23), no specification of the type of antidiarrheal agent used
(n p 1), general comments without providing data (n p 1),
redundant publication (n p 1), and no correlation between
antimotility medication use and CDI (n p 1). Six unpublished
reports were received from McNeil Consumer Healthcare. Four
of these reports had already been published in the medical
literature. As a result, 20 eligible reports were included in this
analysis (table 1). With the sole exception of 1 retrospective
review of hospital records, all of the other reports were individual case reports or case series reporting adverse events associated with antimotility drugs.
Figure. 1. Summary of the review process of the published literature
of antimotility therapy for Clostridium difficile infection (CDI).
A total of 55 patients were treated with an antimotility drug
for CDI. Thirty-two patients were described in case reports that
either were published or submitted to the drug company as
part of postmarketing surveillance. Twenty-three cases were
included as part of a review of the clinical experience at 1
institution by Wilcox et al. [36].
Overall, 19 (35%) of the 55 patients with CDI described
improvement and experienced clinical resolution. Nine patients
(16%) died, and 27 (49%) had unknown outcomes.
Seventeen (31%) of the 55 patients with CDI treated with
an antimotility agent clinically deteriorated and developed complications of toxic megacolon or colonic dilation (table 2). Five
of these 17 patients had underlying conditions associated with
immunosuppression, including advanced AIDS [34], pregnancy
(unpublished report), uncontrolled diabetes mellitus [23], and
cancer requiring chemotherapy [37, 38]. Six (40%) of the 15
patients with known outcomes of complicated colonic dilation
died, although 1 of the deaths may have been related to other
underlying infections and poorly controlled diabetes mellitus
[23]. One death may have been precipitated by performance
of a barium enema [24], which has also been associated with
Antimotility Agents and C. difficile Infection • CID 2009:48 (1 March) • 599
600
…
…
…
Patient 5
Patient 8
Patient 15
Case report
…
Patient 2
Hoogland et al. [30]
Case series
Patient 1
Boyd et al. [29]
Case series
…
Patient 4
Tedesco et al. [28]
Case series
Patient 1
Gibson et al. [27]
Case report
Case report
Axelrod et al. [26]
Case series
Tully et al. [24]
Wettach et al. [25]
Case series
Case series
Keeffe et al. [23]
Case report
Brown et al. [21]
Cohen et al. [22]
Study design
Study
1
2
2
8
5
5
5
5
5
1
1
1
1
1
1
No. of patients
who received
antimotility agents
Rectosigmoid tumor
Bronchitis
Hysterectomy
Chronic renal failure,
diabetes mellitus,
UTI, diverticulitis,
cellulitis, aneurysm
clipping, FUO
UTI
UTI, hip replacement
Metastatic breast
carcinoma
Rheumatoid arthritis,
right hemiparesis
Hip replacement
Blepharitis
Rhinoplasty
Pharyngitis
Diabetes mellitus,
Amputation of
lower extremity
Cellulitis
Otitis media
Comorbidities
DPO/A
DPO/A
None
Vancomycin
None
None
DPO/A
DPO/A
None
None
None
None
None
None
None
None
DPO/A
DPO/A
DPO/A
DPO/A
DPO/A
DPO/A
DPO/A
DPO/A
None
None
DPO/A
None
Antibiotic therapy
for CDI
DPO/A
DPO/A
Antimotility agent
Not applicable
timotility agent
14 Days after the an-
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Not applicable
Time of
antibiotic therapy
in relation to
antimotility therapy
Fever, confusion, renal failure, TM, septic shock
Fever, TM
Fever, dehydration, renal failure, TM, septic shock
Fever, confusion
Unknown
Fever, dehydration,
confusion
Unknown
Unknown
Fever, dysentery, TM
TM
Dehydration
Fever, ascites, TM,
septic shock, death
Fever, colonic dilation
Fever
Dehydration, urinary
retention, TM
Complication
Table 1. Studies included in this review of the use of antimotility agents for the treatment of Clostridium difficile infection (CDI).
Surgery required
Colostomy and loop
ileostomy
Subtotal colectomy
with ileostomy
Subtotal colectomy
with ileostomy
1 Patient required
ileostomy
Subtotal colectomy
with ileostomy
None
None
None
Procto-colectomy
Subtotal colectomy
with ileostomy
None
None
Subtotal colectomy
with ileostomy
None
None
Outcome
Death
Clinical resolution
Clinical resolution
Clinical resolution of
all patients
Clinical resolution
Incomplete recovery
at day 60 recorded
Death due to pulmonary embolism
Death due to
pneumonia
Death during surgery
Clinical resolution
Unknown
Death (sudden; following a barium
enema)
Death due to recurrent infections and
poorly controlled
DM
Clinical resolution
Clinical resolution
601
Case report
Case report
Burke et al. [32]
Walley et al. [33]
Case report
Report 2
Case report
Case report
Resnik et al. [37]
Kato et al. [38]
1
1
23
1
2
2
1
1
1
1
1
Laryngeal cancer
Metastatic ovarian
cancer receiving
chemotherapy
Unknown
None
Advanced AIDS
Advanced AIDS
Premature labor, uterine infection
None
Dental abscess
Congestive heart failure, renal insufficiency, resection of
lung nodule
UTI
Vancomycin
Vancomycin
Loperamide
Loperamide
Metronidazole or
Vancomycin
Metronidazole
Metronidazole
Vancomycin
Metronidazole
None
Codeine, Loperamide
Loperamide
Paregoric Tincture of
Opium
Loperamide
Loperamide
Loperamide
Metronidazole followed by Vancomycin
Metronidazole followed by Vancomycin
Codeine, Morphine
Loperamide
None
DPO/A
motility agent
11 Week after anti-
Unknown duration following loperamide
therapy
Coadministered
Unknown duration following loperamide
therapy
Unknown duration following antimotility
therapy
Unknown duration following loperamide
therapy
Followed initial course
of loperamide therapy
Not applicable
antimotility agent
Ascites, TM
None
None
Fever, vomiting,
sepsis
None
TM
None
Colectomy with ileostomy and
sigmoidostomy
Fever, TM, multiple
organ failure
None
Colectomy with ileostomy and
sigmoidostomy
Colectomy
None
Laparotomy, transverse colostomy
Colotomy
Subtotal colectomy
with ileostomy
Fever, TM, colonic
perforation, multiple
organ failure
TM
Dehydration, severe
colonic dilation
Fever, vomiting, dehydration, confusion,
TM, peritonitis
Nausea, vomiting,
TM, pneumo-peritoneum, peritonitis
∼8 Days after the antimotility agent
12 Weeks after the
Dehydration, colonic
dilation, ascites
Not applicable
Clinical resolution
Death
Unknown
Clinical resolution
Death
Death
Clinical resolution
Unknown
Clinical resolution
Clinical resolution
Unknown
a
Unpublished data.
NOTE. Antibiotic therapy included metronidazole, vancomycin, rifaximin, or nitazoxanide. DM, diabetes mellitus; DPO/A, diphenoxylate and atropine; FUO, fever of unknown origin; TM, toxic megacolon; UTI,
urinary tract infection.
Review of hospital
records
Wilcox et al. [36]
Case series
…
Patient 4
Snowden et al. [35]
Case series
Patient 3
Beaugerie et al. [34]
Case report
Report 1
McNeil Consumer
a
Healthcare
Case series
Schnitt et al. [31]
Table 2. Characteristics of and outcomes in 17 patients with
Clostridium difficile infection and toxic megacolon or colonic
dilation.
No. of patients, by outcome
Clinical
resolution
Death
Unknown
Total
Surgical intervention
9
6
6
5
2
1
Medical treatment
3
1
1
Variable
toxic megacolon in various intestinal disorders [39, 40]. For 5
patients, death occurred despite surgical intervention. Importantly, none of the patients who experienced complications of
CDI received appropriate antibiotics at the time of initiation
of the antimotility treatment. All patients who experienced
complications or death had received the antimotility drug
alone, although metronidazole or vancomycin was added later
in some cases. There were no significant differences in adverse
outcomes or clinical resolution when patients receiving loperamide were compared with those receiving a different antimotility agent (data not shown).
In contrast, all 23 patients reported by Wilcox et al. [36]
received metronidazole or vancomycin together with an antimotility agent as treatment for CDI. None of these patients
experienced complications of their infection. The investigators
concluded that they were unable to associate worsening outcome of CDI with treatment with antimotility agents, including
codeine phosphate or loperamide, despite acknowledging that
previous reports had recommended against the use of these
antidiarrheal drugs.
DISCUSSION
The use of antimotility agents for the treatment of enterocolitis
associated with invasive bacterial enteropathogens, such as Salmonella, Shigella, and Campylobacter species, has been strongly
discouraged for 13 decades. Studies of animal models in the
1960s suggested that intestinal motility served as a natural defense mechanism against enteric infections by promoting intestinal clearance of the infecting enteropathogens [16–18]. Shigella flexneri and Salmonella typhimurium caused serious
infection in guinea pigs when intestinal peristalsis was inhibited
by pharmaceutical agents, such as opiate alkaloids, or by mechanical obstruction secondary to intestinal ligation [17, 18].
Adult volunteers with experimental shigellosis demonstrated
prolonged febrile illness and persistent fecal shedding of the
infecting strain when treated with diphenoxylate hydrochloride
and atropine sulfate (Lomotil). Even when effective antibiotics
against S. flexneri were given, host recovery from clinical shigellosis appeared to be impaired when the antimotility medication was coadministered [19]. As a result of these studies, a
602 • CID 2009:48 (1 March) • Koo et al.
clinical dictum emerged, which recommended that antimotility
agents should be avoided for diarrheal disease caused by invasive or inflammatory pathogens, including Salmonella species, Shigella species, invasive Escherichia coli, and C. difficile,
to prevent potentiation of local bacterial proliferation, epithelial
penetration, and worsening of clinical outcome [19].
In a single prospective, blinded clinical study, Novak et al.
[41] demonstrated that diphenoxylate hydrochloride and atropine sulfate prolonged symptoms and increased the number
of loose stools in adult volunteers with lincomycin-associated
diarrhea. However, there have been no published clinical trials
evaluating the use of antimotility agents for the treatment of
antibiotic-associated diarrhea caused by an infectious agent
such as C. difficile. Over the years, there have been a number
of case reports describing adverse events, such as toxic megacolon, exacerbation of colitis, and systemic infection, associated
with the use of antimotility agents for CDI [21, 23, 24, 30, 38].
The pathogenesis of C. difficile disease is mediated by toxins
A and B. Although the role of toxin B is incompletely understood, it is believed that both toxins cause cellular necrosis and
death of the intestinal mucosal cells, increased intestinal permeability, and neutrophil infiltration of the lamina propria.
These toxic effects lead to marked intestinal injury and inflammation [42–44]. It has been suggested that decreased intestinal
peristalsis may allow for increased contact time between organisms such as C. difficile, toxins produced, and the mucosal
epithelium [41]. The belief that antimotility medications should
not be used for treatment of CDI has subsequently been reinforced by multiple reviews and expert opinions [45–49].
In more-recent studies, however, antimotility agents, such as
loperamide, have been to shown to be effective for the treatment
of diarrheal diseases, including travelers’ diarrhea, significantly
shortening the duration of the illness and the number of unformed stools passed [50–52]. Addition of loperamide to antibiotic therapy has consistently been shown to be effective in
treating travelers’ diarrhea, reducing the duration of diarrhea
when compared with antimicrobial therapy alone [53–55].
Combination of an antimotility agent such as loperamide with
a single antibiotic dose is sufficient to control gastroenteritis,
often within 24 h after therapy initiation [53, 54, 56].
The beneficial effects of loperamide use in conjunction with
active antimicrobials for travelers’ diarrhea are apparent even
when the causative pathogens have included enteroinvasive E.
coli, Shigella species, Salmonella species, or Campylobacter species [53, 56–58]. Similar results have been demonstrated in a
relatively large study in which hospitalized adult patients with
bacillary dysentery (n p 42 ) were treated with ciprofloxacin
and loperamide [59]. Prolongation or worsening of disease or
excretion of enteric pathogens was not seen. It should be noted,
however, that the studied patients with bacillary dysentery were
Thai residents who likely had some preexisting immunity to
invasive enteropathogens and were unlikely to suffer severe
dysenteric disease. Although limited, these studies suggest that
supplementation of antibiotics with loperamide, even for severe
travelers’ diarrhea with fever or dysentery, may facilitate clinical
resolution of symptoms [53, 56, 60]. These studies do not
support the belief that such supplementation contributes to an
adverse outcome.
The evidence supporting the concept that intestinal motility
is necessary to eradicate enteric pathogens, such as C. difficile,
and their toxins, compromising the safety of antimotility medication administration for CDI, appears to be conflicted and
limited. The purpose of this review was to examine the available
evidence that antimotility medication use for CDI complicates
the evolution of the disease. Our systematic review of the literature provided little support for the hypothesis that antimotility agents used to treat C. difficile diarrhea and colitis
worsen clinical illness by increasing local toxin effects secondary
to intestinal stasis and organism localization [38, 41]. Individual
case reports are subject to reporting bias, likely having been
written specifically to call attention to adverse effects of antimotility drugs in this disease. Furthermore, in every case in
which complications, such as toxic megacolon, were associated
with an antimotility drug, the treating physicians failed to treat
simultaneously with an appropriate antimicrobial agent directed against C. difficile. In contrast, the large retrospective
experience [36] reported from a single tertiary care hospital
may be regarded as relatively free of reporting bias. In this
study, the majority of patients were treated with an antimicrobial agent. Some patients also received an antimotility drug,
but no adverse effects were seen. C. difficile is a virulent pathogen that can cause severe disease manifesting as paralytic ileus,
toxic megacolon, colonic perforation, sepsis, and death [61–
64]. The complications ascribed to antimotility therapy for CDI
are difficult to differentiate from well-recognized complications
of untreated C. difficile diarrhea and colitis.
Limitations of this systematic review include exclusion of
articles that did not specifically correlate patient outcomes with
administration of antimotility drugs, but rather presented generalizations between antimotility use and patient responses
[65], exclusion of studies that did not specify the type of antidiarrheal agent used to treat CDI [39], and the potential omission of additional reports that may have been found with an
alternate search strategy. Complications of antimotility therapy
for CDI may be quite rare and unidentifiable with scientific
study of limited populations. However, we would anticipate
reporting of the association from postmarket surveillance to
the US Food and Drug Administration and to the manufacturer.
We think that our method of evaluating the literature was thorough, because our evaluation was supplemented by review of
the bibliographies of identified articles and the unpublished
reports from the pharmaceutical company, which holds the
license for the most commonly prescribed antidiarrheal agent.
Underreporting on this subject may have contributed to the
relative lack of studies found. Underreporting of the successful
use of antimotility drugs for treating CDI is even more likely
because of the current publication bias toward reporting complications or unexpected adverse events for established medications. It should be noted that the use of antimotility agents
for the treatment of CDI in pediatric patients was not studied,
and our results should not be extrapolated to children.
CDI is becoming an increasingly important problem worldwide. Better therapeutic strategies are needed to treat this common nosocomial infection. Caution has long been deemed necessary in administering antimotility medications to patients
with CDI, with the belief that their use may be associated with
increased risk for significant complications, including death.
However, these drugs, when combined with an active antimicrobial, may provide symptomatic relief to patients with C.
difficile disease in a safe and effective manner and may assist
in reducing the passage of infectious stools in the hospital environment. This systematic review emphasizes the need for
more rigorously controlled studies to help clarify and to provide
further insight regarding this issue, so that stronger evidencebased recommendations can be provided. We are currently conducting a randomized, double-blinded, placebo-controlled pilot study to test the hypothesis that loperamide therapy, in
conjunction with appropriate antibiotic therapy, shortens the
duration of CDI.
Acknowledgment
Potential conflicts of interest. All authors: no conflicts.
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