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Metronidazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Further evidence for the increased efficacy of vancomycin versus metronidazole in relation to C. difficle–related diarrhea comes from two other studies. An observational study found that although there was no difference in the resolution of diarrhea after 10 days of treatment between the two antibiotics, vancomycin-treated patients had a more rapid response and were more likely to have undetectable levels of C. difficile and resolution of diarrhea during the first 5 days of treatment (Al-Nassir et al., 2008b). The findings of two identical phase 3, randomized, double-blind, active-controlled, parallel-design studies of the efficacy of tolevamer, a toxin-binding polymer, were reported by Johnson et al. (2014). Patients in the three treatment arms received tolevamer, vancomycin, and metronidazole. Tolevamer was found to be inferior to both metronidazole and vancomycin. When metronidazole was compared to vancomycin, the clinical success rate in patients in the metronidazole arm was 202/278 [72.7%], versus 210/259 [81.1%] in the vancomycin arm (p = 0.02). In patients with severe C. difficile infection, the clinical success rate in those who received metronidazole was 66.3%, compared with the rate in patients who received vancomycin, which was 78.5%. (p = 0.059). A summary of the studies comparing metronidazole with vancomycin is shown in Table 99.3.
Clostridium difficile Infection: Overview and Update with a Focus on Antimicrobial Resistance as a Risk Factor
Published in Robert C. Owens, Lautenbach Ebbing, Antimicrobial Resistance, 2007
Robert C. Owens, August J. Valenti, Mark H. Wilcox
Tolevamer (Genzyme Corp., Cambridge, Massachusetts, U.S.A.) is a liquid polystyrene preparation that binds to C. difficile toxins A and B. The results of a randomized, double-blind, active-controlled phase II study in patients with mild to moderate CDI were recently reported (143). Two doses of tolevamer (3 g/day, 6 g/day) were evaluated against vancomycin (125 mg q 6 hr). Tolevamer 6 g/day, but not 3 g/day, demonstrated noninferiority to vancomycin, with a trend toward reduced recurrence in the high-dose tolevamer arm (p = 0.05) (143). Because tolevamer is not an antibiotic per se, commensal microbiota are not impacted and its therapeutic effect is purely due to toxin neutralization. Overall, tolevamer was well tolerated except for hypokalemia, which occurred in 23% of the tolevamer treated patients versus 7% of vancomycin recipients, (p < 0.05) (143). As a result of this study, a new liquid formulation of tolevamer that allows for higher doses to be administered and that contains potassium as a counter ion to minimize hypokalemia has been studied in a phase I trial (143). The most recent three-armed study involves tolevamer at a daily dose of 9 g/day, and is compared with oral vancomycin and oral metronidazole for the treatment of CDI (138). Data from one of two phase II studies demonstrated that tolevamer did not meet its endpoint of noninferiority against comparators (i.e., metronidazole and vancomycin), and therefore is not likely to be pursued (at least for monotherapy) (144,163).
Clostridium difficile
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
For patients who are on antibiotics and who develop diarrhea, one should stop the antibiotics if at all possible. Such a decision is on a case by case basis. The first-line treatment of CDAD is either metronidazole or vancomycin for 14 days (Table 1). Vancomycin and metronidazole must be given orally, although metronidazole may also be given parenterally. Pulsed or tapering doses of both antibiotics have been given at the end of the course of treatment and vancomycin has also been given by enema. In mild to moderate disease both are equally effective but in severe disease vancomycin was more effective in a controlled trial. In vitro studies, on the other hand, indicate that metronidazole has a more rapid bactericidal effect compared with vancomycin. Other antibiotics that have been used are bacitracin, fusidic acid, nitazoxanide, and rifaximin. Tolevamer and difimicin also show some promise in the treatment. Rifampin, which had been recommended, has not been effective in a controlled trial. Alternative treatments are also available including cholestyramine (which binds the toxin but also binds vancomycin, so the two should not be given simultaneously); monoclonal anti-toxin antibodies; intravenous immune globulin (although there are no controlled trials and reported results are contradictory); probiotics such as Saccharomyces boulardiae (which is really a strain of S. cerevesiae) have been used in conjunction with antibiotics; and fecal enema (or fecal administration by oral–duodenal tube) from a close relative, to re-establish a ‘normal’ flora.
Clinical management of severe, fulminant, and refractory Clostridioides difficile infection
Published in Expert Review of Anti-infective Therapy, 2020
A number of alternative treatments were studied extensively. Tolevamer is a soluble linear polymer of styrenesulfonate that binds and neutralizes C. difficile toxin in vitro that was directly compared to metronidazole and vancomycin in two phase III multicenter, randomized, double-blinded trials [36]. Unfortunately, CDI cure rate was markedly inferior by tolevamer compared to both metronidazole and vancomycin. Interestingly, the rate of recurrence was significantly lower with tolevamer (4.5%) compared to metronidazole (23%) and vancomycin (20.6%) (p < 0.001), though subgroup analysis for SCDI cases was not published. The results suggest that tolevamer could possibly be an adjunctive agent to decrease rates of CDI recurrence, but should not be used as monotherapy for the treatment of CDI. Due to the disappointing results for CDI cure, it appears that further research and development of tolevamer has stalled.
Strategies to prevent adverse outcomes following Clostridioides difficile infection in the elderly
Published in Expert Review of Anti-infective Therapy, 2020
Adriana M Rauseo, Margaret A Olsen, Kimberly A Reske, Erik R Dubberke
In 2014, the results of two multinational trials to compare the efficacy of tolevamer, a nonantibiotic, toxin-binding polymer, with vancomycin and metronidazole were published [108]. While tolevamer failed as a treatment for CDI, these were seminal studies on the treatment for CDI. These studies are the only adequately powered double blinded randomized controlled trials that compared metronidazole to vancomycin. Metronidazole was found inferior to vancomycin for clinical cure of CDI (72.7 vs 81.1%). This held true in multivariable analyses when controlling for CDI severity [108]. There is also a mortality benefit when using vancomycin over metronidazole in severe CDI with an approximately 20% reduced risk of all-cause 30-day mortality [109]. As a result, the 2017 SHEA/IDSA guidelines no longer recommend metronidazole as a first-line treatment for CDI, regardless of CDI severity [24] (Table 3).
Non-antibiotic therapy for Clostridioides difficile infection: a review
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
In terms of their cure rate and range of application, antibiotics are the first choice in the treatment of almost all bacterial diseases. Compared with the therapeutic effect of other drugs in bacterial- or fungal-induced gastrointestinal infections, antibiotics possess high-quality efficacy and a short treatment period. First-line antibiotics such as metronidazole, vancomycin and fidaxomicin are widely used in the clinical treatment of CDI [28]; these antibiotics have benefited hundreds of millions of people and promise to benefit many times more. Beinortas et al. [46] performed a systematic review and network meta-analysis to compare and rank the efficacy of different treatments for nonmultiple recurrent infections with C. difficile in adults (Figure 2), finding that fidaxomicin and teicoplanin were significantly better than vancomycin in their cure rate of sustained CDI; teicoplanin, ridinilazole, fidaxomicin, surotomycin, and vancomycin were better than metronidazole. Bacitracin was weaker than teicoplanin and fidaxomicin, and tolevamer was weaker than all drugs except for LFF571 and bacitracin. Overall, the frequency of fidaxomicin used in sustained CDI was the highest, followed by vancomycin and metronidazole. Fidaxomicin is an emerging antibiotic that exhibits effective and well-tolerated treatment for severe CDI and for patients with a high recurrence risk [47,48]. These data indicated that the status of metronidazole, vancomycin and fidaxomicin is still entrenched in CDI treatment over a short time.