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| |  Metronidazole as Effective as Vancomycin for []Clostridium Difficile[] Diarrhoea, and Tolevamer Reduces Recurrence: Presented at ECCMID By Chris Berrie BARCELONA, Spain -- April 24, 2008 -- Metronidazole is noninferior to vancomycin for patients with Clostridium difficile-associated diarrhoea (CDAD), according to a multicentre, randomised, noninferiority, phase 3 trial. In addition, the study showed that while the novel nonantibiotic toxin binder tolevamer is inferior to vancomycin for CDAD, its use appears to reduce the rates of CDAD recurrence, indicating a potential area of benefit from this new flora-sparing approach, researchers reported here at the 18th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Results from this study were presented on behalf of the Polymer Alternative for CDAD Treatment group by coinvestigator Joanne Donovan, MD, PhD, Vice President, Clinical Research, Genzyme Corporation, Cambridge, Massachusetts. C difficile is the major cause of hospital-acquired infectious diarrhoea and colitis, and this spore-forming Gram-positive anaerobic bacillus typically proliferates following antibiotic disruption of the normal enteric bacteria. "The standard therapy consisting of metronidazole and vancomycin is associated with a substantial recurrence rate," Dr. Donovan noted in her presentation on April 22. As CDAD is a toxin-mediated disease restricted to the intestinal lumen, tolevamer could provide major advantages: in theory, it should preserve the normal protective gut flora, reduce the CDAD recurrence rate, avoid systemic antibiotic adverse events, and reduce colonisation by antibiotic-resistant bacteria This noninferiority study was designed as a direct head-to-head comparison of the standard treatments -- vancomycin and metronidazole. The primary endpoint was clinical success, as resolution and absence of severe abdominal discomfort due to CDAD for 2 contiguous days, including day 10. Secondary endpoints were time to resolution of diarrhoea and recurrence, as assessed in the patients with diarrhoea resolution through active treatment. A total of 544 patients with CDAD were randomised to receive 1 of 3 treatments: 278 received tolevamer 3 g TID; 126 received vancomycin 125 mg QID; and 140 received metronidazole 375 mg QID. Patient characteristics in the 2 treatment arms were similar in terms of age, sex, CDAD severity, and CDAD history, where the vast majority of patients had no prior episodes. Discontinuation rates were 51.5% with tolevamer, 24.8% with vancomycin, and 28.8% with metronidazole. The rate of nonresponse to treatment was 26.6% with tolevamer, 4.0% with vancomycin, and 5.0% with metronidazole. For the primary endpoint of clinical success in the intent-to-treat populations, noninferiority for metronidazole versus vancomycin was satisfied (81% vs. 73%; 95% confidence interval [CI] for difference, -18%, 3%). However, with a 42% success rate, tolevamer failed to reach noninferiority. When clinical success was evaluated according to CDAD severity, all treatment groups showed decreases as disease severity progressed; similarly, patients with any history of recurrent disease had lower clinical success rates. A significantly lower rate of CDAD recurrence was seen with tolevamer (6%), compared with vancomycin (18%; P = .009) and metronidazole (19%; P = .006). However, Dr. Donovan said, "We need to view this result with caution because only a minority of tolevamer patients reached clinical success, so this is a select population." In the safety analysis, rates of serious adverse events (SAEs) and deaths were evenly distributed among the tolevamer, vancomycin, and metronidazole arms: deaths (12.0%, 12.0%, 7.2%, respectively); patients with SAEs (27.0%, 32.0%, 24.5%, respectively); C difficile colitis (7.7%, 7.2%, 6.5%, respectively); sepsis (1.1%, 2.4%, 0.0%, respectively). Dr. Donovan concluded that tolevamer is less effective than standard therapies for CDAD. And although the noninferiority of metronidazole with vancomycin showed differences that were not significant, she did note that the clinical success rate in patients treated with vancomycin was numerically higher.
[Presentation title: Results of a Phase 3 Trial Comparing Tolevamer, Vancomycin and Metronidazole in Patients With Clostridium Difficile-Associated Diarrhoea (CDAD). Abstract O464]
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