Antimotility Agents for the Treatment of Clostridium difficile Diarrhea and Colitis

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1 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. DuPont 1,2,3,5 1 Department of Medicine, Division of Infectious Diseases, Baylor College of Medicine, 2 University of Texas Houston School of Public Health, 3 University of Texas Medical School, 4 Michael E. DeBakey Veterans Affairs Medical Center, and 5 St. Luke s Episcopal Hospital, Houston, Texas (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 We reviewed the literature and unpublished postmarketing surveillance reports regarding antimotility treatment of CDI.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 Reprints or correspondence: Dr. H. L. Koo, Baylor College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX (koo@bcm.tmc.edu). Clinical Infectious Diseases 2009; 48: by the Infectious Diseases Society of America. All rights reserved /2009/ $15.00 DOI: / 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- 598 CID 2009:48 (1 March) Koo et al.

2 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 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

3 Table 1. Studies included in this review of the use of antimotility agents for the treatment of Clostridium difficile infection (CDI). Study Study design No. of patients who received antimotility agents Comorbidities Antimotility agent Antibiotic therapy for CDI Time of antibiotic therapy in relation to antimotility therapy Complication Surgery required Outcome Brown et al. [21] Case report 1 Otitis media DPO/A None Not applicable Dehydration, urinary retention, TM None Clinical resolution Cohen et al. [22] Case series 1 Cellulitis DPO/A None Not applicable Fever None Clinical resolution Keeffe et al. [23] Case series 1 Diabetes mellitus, Amputation of lower extremity DPO/A None Not applicable Fever, colonic dilation Subtotal colectomy Tully et al. [24] Case series 1 Pharyngitis DPO/A None Not applicable Fever, ascites, TM, septic shock, death Death due to recurrent infections and poorly controlled DM None Death (sudden; following a barium enema) Wettach et al. [25] Case report 1 Rhinoplasty DPO/A None Not applicable Dehydration None Unknown Axelrod et al. [26] Case report 1 Blepharitis DPO/A None Not applicable TM Subtotal colectomy Clinical resolution Gibson et al. [27] Patient 1 Case series 5 Hip replacement DPO/A None Not applicable Fever, dysentery, TM Procto-colectomy Death during surgery Patient 4 5 Rheumatoid arthritis, right hemiparesis Patient 5 5 Metastatic breast carcinoma DPO/A None Not applicable Unknown None Death due to pneumonia DPO/A None Not applicable Unknown None Death due to pulmonary embolism Patient 8 5 UTI, hip replacement DPO/A None Not applicable Fever, dehydration, confusion Patient 15 5 UTI DPO/A None Not applicable Unknown Subtotal colectomy Tedesco et al. [28] Case series 8 Chronic renal failure, diabetes mellitus, UTI, diverticulitis, cellulitis, aneurysm clipping, FUO Boyd et al. [29] DPO/A None Not applicable Fever, confusion 1 Patient required ileostomy Patient 1 Case series 2 Hysterectomy DPO/A None Not applicable Fever, dehydration, renal failure, TM, septic shock Patient 2 2 Bronchitis DPO/A Vancomycin 14 Days after the antimotility agent Hoogland et al. [30] Case report 1 Rectosigmoid tumor DPO/A None Not applicable Fever, confusion, renal failure, TM, septic shock None Incomplete recovery at day 60 recorded Subtotal colectomy Fever, TM Subtotal colectomy Colostomy and loop ileostomy Clinical resolution Clinical resolution of all patients Clinical resolution Clinical resolution Death 600

4 Schnitt et al. [31] Case series 1 UTI DPO/A None Not applicable Dehydration, colonic dilation, ascites Burke et al. [32] Case report 1 Congestive heart failure, renal insufficiency, resection of lung nodule Codeine, Morphine Metronidazole followed by Vancomycin Walley et al. [33] Case report 1 Dental abscess Loperamide Metronidazole followed by Vancomycin McNeil Consumer Healthcare a 8 Days after the antimotility agent 12 Weeks after the antimotility agent Nausea, vomiting, TM, pneumo-peritoneum, peritonitis Fever, vomiting, dehydration, confusion, TM, peritonitis Subtotal colectomy Unknown Colotomy Clinical resolution Laparotomy, transverse colostomy Clinical resolution Report 1 Case report 1 None Loperamide None Not applicable Dehydration, severe colonic dilation Report 2 Case report 1 Premature labor, uterine infection Beaugerie et al. [34] Loperamide Metronidazole Followed initial course of loperamide therapy Patient 3 Case series 2 Advanced AIDS Loperamide Vancomycin Unknown duration following loperamide therapy Patient 4 2 Advanced AIDS Paregoric Tincture of Opium Metronidazole Unknown duration following antimotility therapy Snowden et al. [35] Case series 1 None Loperamide Metronidazole Unknown duration following loperamide therapy Wilcox et al. [36] Review of hospital records Resnik et al. [37] Case report 1 Metastatic ovarian cancer receiving chemotherapy 23 Unknown Codeine, Loperamide Metronidazole or Vancomycin Loperamide Vancomycin Unknown duration following loperamide therapy Kato et al. [38] Case report 1 Laryngeal cancer Loperamide Vancomycin 11 Week after antimotility agent None Unknown TM Colectomy Clinical resolution Fever, TM, colonic perforation, multiple organ failure Fever, TM, multiple organ failure Colectomy and sigmoidostomy Colectomy and sigmoidostomy Death Death TM None Clinical resolution Coadministered None None Unknown Fever, vomiting, sepsis None Death Ascites, TM None Clinical resolution 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. a Unpublished data. 601

5 Table 2. Characteristics of and outcomes in 17 patients with Clostridium difficile infection and toxic megacolon or colonic dilation. Variable No. of patients, by outcome Clinical resolution Death Unknown Total Surgical intervention Medical treatment 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 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 602 CID 2009:48 (1 March) Koo et al.

6 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. 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