Metronidazole for Clostridium difficile-Associated Disease: Is It Okay for Mom?

Received 18 February 2005; accepted 18 February 2005; electronically published 25 April 2005. The views expressed are solely those of the author and not the US government. Reprints or correspondence: Dr. Dale N. Gerding, ACOS Research and Development, Hines VA Hospital, 5th Ave. and Roosevelt Rd., Bldg. 1, Rm. C344, Hines, IL 60141 (dale .gerding2@med.va.gov). Clinical Infectious Diseases 2005; 40:1598–1600 This article is in the public domain, and no copyright is claimed. 1058-4838/2005/4011-0004 The best treatment practices for Clostridium difficile–associated disease (CDAD) have advanced little from what was known 20 years ago, when John Bartlett [1] wrote an excellent editorial about the subject, which addressed virtually all of the issues of current interest. In 1992, Sherwood Gorbach [2], in a tongue-in-cheek editorial about drugs for your mother-in-law but not your mother, included metronidazole among the treatments for CDAD. In 1997, Dr. Gorbach’s then coeditor, Michael Barza [3], recommended the use of metronidazole for most patients with CDAD, because it was inexpensive and was shown to be comparable in efficacy to vancomycin in a randomized, prospective trial by Wenisch et al. [4]. I surmise (but have no data) that the era of widespread use of metronidazole in US hospitals for the treatment of CDAD began in the late 1990s, after publication of the recommendations by the Centers for Disease Control and Prevention’s Healthcare Infection Control Practices Advisory Committee for preventing the spread of vancomycin resistance [5]. Oral vancomycin use was discouraged as treatment for primary antibiotic-associated colitis (AAC) and was recommended only for persons who had severe and potentially life-threatening AAC or did not respond to metronidazole therapy [5]. This was followed by a position statement by the American Society for Health-System Pharmacists on the preferential use of metronidazole for treatment of CDAD, reserving vancomycin therapy for “severe, potentially life-threatening cases or when oral metronidazole cannot be used” [6, p. 1410]. A recent Cochrane Database Review about CDAD treatment concluded that metronidazole (and bacitracin, fusidic acid, teicoplanin, and rifaximin) were as effective as vancomycin for initial symptomatic resolution [7]. The only US Food and Drug Administration (FDA)–approved treatment for CDAD is oral vancomycin. Metronidazole (and bacitracin, fusidic acid, teicoplanin, and rifaximin) have never been subjected to the rigors of an FDA approval process for a CDAD indication. In this issue of Clinical Infectious Diseases, 2 articles [8, 9], both of which are observational in methodology, suggest that metronidazole may not be as effective for treating CDAD as has been demonstrated in previous prospective, randomized trials [4, 10]. If the allegations of poor clinical response are supportable and generalizable, they have important implications for the treatment of CDAD with metronidazole, especially in view of recent reports of increasing CDAD frequency, mortality rates, and morbidity rates, and they will surely result in increased treatment with oral vancomycin in hospitals on the basis of the assumption that vancomycin, the only alternative to metronidazole, will be more effective. To try to dissect the observations of the 2 new studies, I have compared them to the only 2 previously published prospective, randomized, controlled studies of metronidazole for CDAD [4, 10]. It is important to note that these prospective clinical trials had specific entry and exclusion criteria, fixed dosing regimens, predefined criteria for success or failure, and the need for informed patient consent, requirements that are not present in the observational trials. In addition, the randomized trials were performed at an earlier time and contained fewer patients. Two clinical outcome end points are critical for comparison: the initial end-of-treatment clinical response of CDAD and the subsequent rate of recurrence of CDAD after successful treatment, which is a long-recognized deficiency for all treatment agents. In an attempt to make the data more comparable, I took the liberty of recalculating the recurrence rates in the current articles as percentages of initial responders