Management of Clostridium difficile Infection: Thinking Inside and Outside the Box

H E A LT H C A R E E P I D E M I O L O G Y INVITED ARTICLE Robert A. Weinstein, Section Editor Management of Clostridium difficile Infection: Thinking Inside and Outside the Box Dale N. Gerding1 and Stuart Johnson2 1 Edward Hines Jr. Veterans Affairs Hospital, Hines, and 2Loyola University Chicago Stritch School of Medicine, Maywood, Illinois Treatment of Clostridium difficile infection (CDI) has relied on 2 antimicrobial agents, metronidazole and vancomycin, since the recognition of this disease entity. While effective, these “inside the box” approaches to CDI management have the disadvantage of further microbial disruption of the host indigenous microflora. “Outside the box” therapies use nonantimicrobial approaches to management and are theoretically less prone to causing recurrent CDI episodes. Recent advances in understanding of “inside the box” approaches include appreciation of the decreased efficacy of metronidazole overall and the superior efficacy of vancomycin for treatment of severe CDI, as well as a new agent under development, fidaxomicin, which appears to be equal in efficacy to vancomycin but with less risk of subsequent CDI recurrences. Several “outside the box” approaches have also entered clinical development, including use of monoclonal antibodies, active vaccination, luminal toxin binders, and nontoxigenic C. difficile. These reports provide optimism that more-effective management of CDI is forthcoming. Antimicrobials have been the agents of choice for treatment of Clostridium difficile infection (CDI) for 130 years, primarily metronidazole and vancomycin. Antimicrobials have been highly successful and are likely to continue to play a major role in the treatment of patients who already have CDI. However, there remain several areas of CDI treatment that are suboptimal—namely, the management of fulminant or complicated severe CDI and management of recurrent CDI. Patients with fulminant disease frequently experience failure to respond to medical management with antimicrobials and either die or require subtotal colectomy as a life-saving measure. Antimicrobial treatment is thought to be, at least in part, responsible for frequent CDI recurrences, presumably as a result of the unintended effects on the normal gastrointestinal microbiota that leave patients vulnerable to relapse or reinfection. As a result, a number of non-antimicrobial management approaches have been proposed and under development, some of which have entered clinical trials. In addition, new antimicrobial treatments designed to improve response and to Received 16 April 2010; accepted 23 August 2010; electronically published 27 October 2010. Reprints or correspondence: Dr Dale N. Gerding, Hines Veterans Affairs Hospital, 5000 S 5th Ave, PO Box 5000, Hines, IL 60141 (). Clinical Infectious Diseases 2010; 51(11):1306–1313  2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5111-0013$15.00 DOI: 10.1086/657116 1306 • CID 2010:51 (1 December) • HEALTHCARE EPIDEMIOLOGY avoid damage to the microbiota are also under clinical development. The prevention and treatment of CDI may include infection control measures, antimicrobial stewardship, restoration of the protective microbiota, and increased immunity to C. difficile toxins, in addition to antimicrobial treatment agents (Figure 1). It is our purpose to review the progress in antimicrobial treatment, the “inside the box” approach to CDI management, as well as to review non-antimicrobial “outside the box” strategies for CDI management that are in trials involving humans or that are currently available for treatment. ANTIMICROBIAL “INSIDE THE BOX” CDI MANAGEMENT Shortly after the infectious cause of pseudomembranous colitis was recognized, oral vancomycin and metronidazole were demonstrated as effective treatments, although vancomycin is the only agent that has received US Food and Drug Administration (FDA) approval for this indication (Table 1). Early prospective, randomized trials concluded that metronidazole was not inferior to vancomycin, with initial cure rates 190% [1, 2]. Recurrent infections, however, occurred at substantial rates for both agents, and avoiding this complication remains a major unmet need in CDI management. Decreased response rates and slower responses for metronidazole have been noted since 2004 [3–7]. A microbiological and clinical observational study Figure 1. Schematic of current hospital epidemiology and management strategies to prevent and treat Clostridium difficile infection (CDI). Current methods being employed are designated by white arrows (items 1–3). Future prevention and treatment strategies are designated by gray arrows (items 4–6). showed that patients treated with metronidazole were less likely to have resolution of diarrhea and were more likely to have C. difficile detected in feces at day 5, compared with those treated with vancomycin [8]. In 2007, Zar et al [9], in a randomized, prospective clinical study, showed that vancomycin was superior to metronidazole for treatment of severe CDI. Other, older agents that have been evaluated as treatment for CDI include bacitracin, teicoplanin, and fusidic acid [10–12]. These drugs, however, either offer no advantage over metronidazole and vancomycin or have been unavailable to clinicians in the United States. Rifaximin has FDA approval for indications other than CDI but has also been used to treat CDI. Rifaximin was compared with vancomycin in a small study (20 patients) that showed comparable cure rates [13]. Recently, rifaximin has been used as an adjunct agent to treat patients with multiple CDI recurrences. We used a 2-week course of rifaximin (usually at 400 mg twice a day) immediately following the last course of vancomycin treatment (the “rifaximin chaser”) for a group of patients who had a mean of 6 recurrences within 1–2 weeks after stopping treatment for the previous episode [14]. With this approach, there were no additional recurrences in 11 (79%) of 14 patients who had recurrent CDI [15]. Garey et al [16] took a different approach and used rifaximin to treat the symptomatic CDI episode and continued rifaximin for a total of 4 weeks (at 400 mg 3 times a day for 2 weeks, followed by 200 mg 3 times a day for 2 weeks). Five of the 6 rifaximin-treated patients had no additional episodes. One caution in using rifaximin is the increasing recognition of clinical C. difficile isolates with high-level resistance (minimum inhibitory concentration [MIC] values, 1256 mg/mL), including isolates from 2 of the 3 patients whose “rifaximin chaser” protocol failed [14, 15]. Widespread dissemination of these strains or prior CDI treat- ment with rifaximin may limit its efficacy. Another rifamycin, rifampin, has been used successfully when coadministered with vancomycin in a small group of patients with recurrent CDI [17]. A more recent randomized study of rifampin coadministered with metronidazole for treatment of a prim (...truncated)