A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. A double-blind randomized controlled trial of fusidic acid and metronidazole for treatment of an initial episode of Clostridium difficile-associated diarrhoea. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Nitazoxanide for the treatment of Clostridium difficile colitis. Treatment of Clostridium difficile associated diarrhea and colitis with an oral preparation of teicoplanin; a dose finding study. The Swedish CDAD Study Group. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin. Comparison of four nitroimidazole compounds for treatment of symptomatic amoebiasis in Kenya.
The incidence and severity of Clostridium difficile-associated diarrhea (CDAD) has been increasing, and there have been recent reports of metronidazole treatment failure. Metronidazole is still commonly used as first-line treatment for CDAD but has never been compared with vancomycin in a prospective, randomized, double-blind, placebo-controlled trial. We conducted such a trial, stratifying patients according to disease severity, to investigate whether one agent was superior for treating either mild or severe disease.
                From October 1994 through June 2002, patients with CDAD were stratified according to whether they had mild or severe disease based on clinical criteria and were randomly assigned to receive oral metronidazole (250 mg 4 times per day) or oral vancomycin (125 mg 4 times per day) for 10 days. Both groups received an oral placebo in addition to the study drug. Patients were followed up for 21 days to assess cure, treatment failure, relapse, or intolerance.
                One hundred seventy-two patients were enrolled, and 150 of these patients successfully completed the trial. Among the patients with mild CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 90% and 98% of the patients, respectively (P=.36). Among the patients with severe CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 76% and 97% of the patients, respectively (P=.02). Clinical symptoms recurred in 15% of the patients treated with metronidazole and 14% of those treated with vancomycin.
                Our findings suggest that metronidazole and vancomycin are equally effective for the treatment of mild CDAD, but vancomycin is superior for treating patients with severe CDAD. We conducted a prospective, randomized study to compare the efficacy of oral fusidic acid, oral metronidazole, oral vancomycin, and oral teicoplanin for the treatment of Clostridium difficile-associated diarrhea. Treatment resulted in clinical cure for 94% of the patients who were treated with vancomycin, 96% of those treated with teicoplanin, 93% of those treated with fusidic acid, and 94% of those treated with metronidazole. Clinical symptoms recurred in 16% of patients treated with vancomycin, 7% of those treated with teicoplanin, 28% of those treated with fusidic acid, and 16% of those treated with metronidazole. There was asymptomatic carriage of C. difficile toxin in 13% of patients treated with vancomycin, 4% of those treated with teicoplanin, 24% of those treated with fusidic acid, and 16% of those treated with metronidazole. No adverse effects related to therapy with vancomycin or teicoplanin were observed. Considering the costs of treatment, our findings suggest that metronidazole is the drug of choice for C. difficile-associated diarrhea and that glycopeptides should be reserved for patients who cannot tolerate metronidazole or who do not respond to treatment with this drug. A prospective, randomized study comparing oral teicoplanin with oral vancomycin in the treatment of pseudomembranous colitis (PMC) and Clostridium difficile-associated diarrhea (CDAD) was performed. Teicoplanin was administered at a dosage of 100 mg twice a day for 10 days, and vancomycin was administered at a dosage of 500 mg four times a day for 10 days. CDAD was diagnosed by demonstrating both C. difficile and cytotoxin in the feces of symptomatic patients (more than three loose stools per day). The diagnosis of PMC was also based on colonoscopy. Cytotoxin assay and cultures were checked in all patients 7 to 10 days after discontinuation of therapy and 25 to 30 days thereafter. Of the 51 patients enrolled, 46 were judged to be assessable. Among these, 26 received teicoplanin and 20 received vancomycin. At enrollment, both groups were comparable in terms of age, sex, occurrence of PMC or CDAD, and previous antibiotic treatment. Eighteen of the 20 patients in the vancomycin group and 10 of the 26 patients in the teicoplanin group had previously undergone surgery (P = 0.0004). Treatment resulted in the clinical cure of 20 (100%) vancomycin and 25 (96.2%) teicoplanin patients (P = 0.56). After discontinuation of therapy, clinical symptoms recurred in four (20%) vancomycin patients and two (7.7%) teicoplanin patients (P = 0.21). Posttherapy asymptomatic C. difficile carriage (positive follow-up cultures without any clinical symptoms) occurred in five (25%) vancomycin patients and two (7.7%) teicoplanin patients (P = 0.11).Overall, 9 of 20 (45%) vancomycin patients and 5 of 26 (19.2%) teicoplanin patients (P=0.059) appeared not to be cleared of C. difficile after treatment. No adverse effects related to vancomycin or teicoplanin therapy were observed. Few treatment options are currently available to treat patients suffering from an initial episode of Clostridium difficile-associated diarrhoea (CDAD).
                A prospective, randomized controlled, double-blind trial was conducted to compare the efficacy of fusidic acid and metronidazole for treatment of patients experiencing a first episode of CDAD. The primary outcomes were clinical cure and clearance of C. difficile toxin determined on days 8-13, and secondary outcomes were clinical recurrence and reappearance of C. difficile toxin evaluated on days 35-40.
                Of the patients in the fusidic acid group, 83% were clinically cured in comparison to 93% in the metronidazole group (P=0.116) at the first follow-up visit. Clearance of C. difficile toxin did not differ between the two groups at that time. Clinical recurrence and reappearance of C. difficile toxin were noted in 27% and in 13% of the patients receiving fusidic acid, respectively and in 29% and 10% of those given metronidazole at the second follow-up on days 35-40.
                Since three of the four primary and secondary outcomes were almost identical for the two groups, the results indicate that fusidic acid is as effective as metronidazole in curing an initial episode of CDAD and can therefore be considered as an adequate alternative for treatment of this disease. Vancomycin is the only US Food and Drug Administration-approved drug for treatment of Clostridium difficile infection (CDI). Metronidazole has been widely used for this purpose but may be inferior to vancomycin, especially for hospitalized patients with severe disease. We report a prospective, double-blind, randomized controlled trial comparing nitazoxanide with vancomycin for treatment of CDI.
                Fifty patients with CDI were randomized to receive vancomycin or nitazoxanide for 10 days. An initial response was considered to be the absence of all CDI symptoms between days 11 and 13, and a final response was considered to be lack of symptom recurrence by day 31.
                One patient fulfilled an exclusion criterion and was removed from the study. Twenty-seven patients received vancomycin, and 23 received nitazoxanide; 23 and 18 patients, respectively, completed the full course of treatment. Initial responses occurred in 20 (74%) of 27 patients treated with vancomycin and in 17 (77%) of 22 patients treated with nitazoxanide (95% confidence interval, -24% to +28%). In those who completed therapy, response rates were 87% (20 of 23 patients) in the vancomycin group and 94% (17 of 18 patients) in the nitazoxanide group (95% confidence interval, -18% to +30%). Times to complete resolution of symptoms were similar in the 2 groups (P = .55). Two patients in the vancomycin group and 1 patient in the nitazoxanide group experienced relapse within 31 days after beginning treatment. Sustained response rates were 78% (18 of 23 patients) for the vancomycin group, and 89% (16 of 18 patients) for the nitazoxanide group (95% confidence interval, -18% to +35%).
                The small sample precludes conclusions about noninferiority of nitazoxanide to vancomycin. Nevertheless, this is the first recent randomized controlled trial to compare any antimicrobial agent other than metronidazole with vancomycin. Results suggest that nitazoxanide may be as effective as vancomycin in treating CDI.
                ClinicalTrials.gov identifier: NCT00384527. 101 patients with Clostridium-difficile-associated diarrhoea or colitis were prospectively randomised to 10-day oral courses of metronidazole, 250 mg four times a day, or vancomycin, 500 mg four times a day. 7 did not complete the protocol and were dropped from analysis. Pseudomembranous colitis (PMC) was diagnosed after endoscopy in 33 patients. Of the remaining patients without PMC, 38 had both C difficile culture and cytotoxin and 23 had only culture evidence of C difficile. 52 evaluable patients received vancomycin and 42 received metronidazole. There were two treatment failures with metronidazole and none with vancomycin (p = 0.20); and two relapses with metronidazole versus six with vancomycin (p = 0.17). Treatment in 1 patient in each group was discontinued because of drug intolerance. Response and relapse rates of the 33 patients with PMC were no different from those of the remaining patients. Pharmacy cost for the dosage used was $387.48 to $520.00 for vancomycin and $11.84 for metronidazole. Metronidazole and vancomycin have equivalent efficacy and relapse rates and are tolerated to a similar extent by patients with C-difficile-related diarrhoea and colitis, but metronidazole is considerably more economical. Clostridium difficile colitis has increased in incidence and severity, and treatment failure with metronidazole therapy has increasingly been documented. It is uncertain whether treatment with vancomycin is more effective than treatment with metronidazole, but concern over the emergence of vancomycin resistance has motivated the search for alternative therapy. Nitazoxanide, a nitrothiazolide, blocks anaerobic metabolism of eukaryocyes and effectively treats intestinal infestation due to Cryptosporidium or Giardia species. At low concentrations, this compound inhibits C. difficile in vitro.
                We designed a prospective, randomized, double-blind study to compare nitazoxanide to metronidazole in treating hospitalized patients with C. difficile colitis.
                Thirty-four patients received metronidazole at a dosage of 250 mg 4 times per day for 10 days, 40 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 7 days, and 36 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 10 days. After 7 days of treatment, 28 (82.4%) of 34 patients had responded to metronidazole therapy, compared with 68 (89.5%) of 76 who had received nitazoxanide therapy (difference, 7.1%; 95% confidence interval, -7.1% to 25.5%). Thirty-one days after beginning treatment, sustained responses were observed in 19 (57.6%) of 33 patients who had received metronidazole therapy for 10 days, compared with 25 (65.8%) of 38 who had received nitazoxanide for 7 days and 26 (74.3%) of 35 who had received nitazoxanide for 10 days (P = .34).
                Nitazoxanide is at least as effective as metronidazole in treating C. difficile colitis. 92 patients with antibiotic-associated diarrhea were randomized to receive oral teicoplanin 100 mg twice daily for 7 days (BID group); or 50 mg 4 times daily for 3 days, followed by 100 mg twice daily for 4 days (QID group) in a randomized, double-blind, multicentre study. Clostridium difficile was demonstrated by culture and/or cytotoxin test in 49 (53%) patients, of whom 47 (23 male, 24 females, mean age 65 years; 23 in the BID group, 24 in the QID group) were evaluable for clinical efficacy. Prior treatment with cephalosporins was registered in 49%, isoxazolyl-penicillins in 33% and clindamycin in 20% of the C. difficile positive patients. On the last day of treatment, 96% (23 of 24 patients) in the QID group were found cured, compared with 70% (16 of 23 patients) in the BID group (p = 0.02). On days 2 and 3 of treatment, QID group patients had significantly fewer loose stools per day (p < 0.05) than those of the BID group. Clinical recurrence, within 4 weeks post-treatment, occurred in 35% and 33% of the patients in the BID and QID groups, respectively. The bacteriological elimination rate 4 weeks post-treatment was 55% in the BID group and 59% in the QID group. The study was terminated prematurely due to the unexpectedly high clinical failure and recurrence rate in C. difficile positive patients treated with the BID dosage regimen. OBJECTIVE--To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). DESIGN--A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. SETTING--National referral study of ambulatory or hospitalized patients from three main study coordinating centers. PATIENTS--A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. INTERVENTION--Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. MAIN OUTCOME MEASURE--Recurrence of active CDD. RESULTS--A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P = .04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P = .86). There were no serious adverse reactions associated with S boulardii. CONCLUSIONS--The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD. Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 10 days and then added either S. boulardii (1 g/day for 28 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (2 g/day) and S. boulardii (16.7%), compared with those who received high-dose vancomycin and placebo (50%; P=.05). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii. To date, no randomized trial to address the use of adjunctive rifampin in addition to metronidazole for the treatment of Clostridium difficile-associated diarrhea has been reported. Rifampin has excellent in vitro activity against C. difficile and penetrates into cellular materials where the organisms may persist.
                This was a prospective, randomized, single-blinded study of 39 patients that compared therapy with metronidazole alone versus therapy with metronidazole and rifampin for 10 days to treat laboratory-confirmed primary episode C. difficile-associated diarrhea. Twenty patients were randomly assigned to the metronidazole group, and 19 were randomly assigned to the metronidazole and rifampin group. Data were analyzed by intention-to-treat analysis using the 2-tailed Kaplan-Meier method and the log-rank test.
                Adjunctive rifampin treatment for 10 days, compared with treatment with metronidazole alone for 10 days, was associated with a similar median time to symptom improvement (9.0 days vs. 6.5 days; P=.74), a similar median time to first relapse (26 days vs. 16 days; P=.23), a similar proportion of patients with relapse by study day 40 (42% vs. 38%; P=1.0), and a similar proportion of patients experiencing nonfatal adverse events (37% vs. 40%; P=.55). There were a significantly higher number of deaths in the metronidazole and rifampin group, compared with the metronidazole group (6 of 19 patients vs. 1 of 20 patients; P=.04), but there were fewer laboratory-confirmed relapses by study day 40 (2 vs. 4; P=.66).
                We conclude that there is no role for routine rifampin as an adjunct to treatment with metronidazole for hospitalized patients with C. difficile-associated diarrhea. The cure rates for both treatment groups remain unacceptably low, and better treatments are urgently needed. OPT-80, a novel, minimally absorbed macrocycle, is a candidate treatment option for Clostridium difficile infection (CDI) based on cure without recurrence of CDI in the hamster challenge model, good in vitro activity against C. difficile, and relative sparing of commensal gram-negative anaerobes. In this open-label, dose-ranging clinical trial, 48 evaluable subjects were randomized to receive either 50, 100, or 200 mg of OPT-80 orally every 12 h for 10 days as treatment for mild to moderately severe CDI. OPT-80 was well tolerated by all subjects. Plasma concentrations were below the lower limit of quantitation in almost one-half of patients and typically <or=20 ng/ml across the dose range; the mean fecal concentrations exceeded the MIC at which 90% of the isolates tested are inhibited by 2,000- to 10,000-fold with increasing dosages. Resolution of diarrhea within 10 days was achieved in 10/14 patients (71%), 12/15 patients (80%), and 15/16 patients (94%), and the median time to resolution of diarrhea was reduced from 5.5 to 3.0 days with increasing dosages. Across all groups, the clinical cure rate, which was defined as resolution of diarrheal disease without the need for further treatment, was 41/45 patients (91%). Recurrence of CDI at approximately 1 month after treatment was observed in two (5%) patients, one each in the 100-mg and 400-mg groups. The apparent high clinical response, good tolerance, low recurrence rate, and more-complete and rapid symptom control with the highest dosage support the selection of the 200-mg twice-daily dose for further clinical development of OPT-80 for treatment of CDI. A randomized double-blind study was carried out in patients with unresolving antibiotic-associated colitis due to Clostridium difficile, to compare the effect of bacitracin (80,000 U/day) with vancomycin (500 mg/day) on the resolution of symptoms, clearance of organism, and prevention of relapse. Forty-two patients with colitis, 9 of whom had a pseudomembrane, were randomized, 21 patients to each treatment group. The two groups were comparable in age, disease severity, and antibiotic exposure. For a 50% reduction in stool frequency the mean times (+/- SE) were 4.1 +/- 0.4 days for bacitracin and 4.2 +/- 0.4 days for vancomycin. Sixteen patients (76%) had symptom resolution after 7 days of treatment with bacitracin, compared with 18 patients (86%) given vancomycin. Patients who failed to respond were crossed over (blind) to the alternative antibiotic, but tended to be refractory to the alternative medication as well. Vancomycin-treated patients had negative toxin (83% vs. 53%, p = 0.04) and negative stool cultures (81% vs. 52%, p = 0.02) more frequently than did those patients given bacitracin. Similar numbers of patients in each group had symptomatic relapse during 1 mo of follow-up, but most of them relapsed yet again after blinded crossover therapy. Although bacitracin was significantly less effective than vancomycin in clearing C. difficile from the stools, both were of similar value in the control of symptoms in a group of patients with predominantly nonpseudomembranous colitis. In view of its low cost, bacitracin is a reasonable first-line alternative to vancomycin in the treatment of antibiotic-associated colitis. Four antiamoebic drugs currently used in many Kenyan hospitals and health centres were compared for their efficacy on symptomatic luminal amoebiasis in Kiambu, Kilifi, and Machakos hospitals during this study. The drugs were; the brand metronidazole (Flagyl, May & Baker, Kenya Ltd.), the generic metronidazole (Metrozol, Cosmos Ltd., Nairobi, Kenya), the brand tinidazole (Fasigyn, Pfizer Laboratories Ltd.) and the generic tinidazole (Tynazole Laboratory and Allied Equipments, Kenya Ltd). Clinical cure was achieved in all individuals receiving any of the four drugs. Parasitological cure was better for those receiving either Flagyl or Fasigyn, than those receiving the generic counterparts. Both parasitological and clinical cures were achieved in about 50% of all those who received either Flagyl or Fasigyn. It appears that Flagyl and Fasigyn are not as efficacious as previously reported but are still much better than their generic counterparts for the treatment of symptomatic Entamoeba histolytica infections.
Current evidence leads to uncertainty whether mild CDAD needs to be treated. The studies provide little evidence for antibiotic treatment of severe CDAD as many studies excluded these patients. Considering the two goals of therapy: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. A recommendation to achieve these goals cannot be made because of the small numbers of patients in the included studies and the high risk of bias in these studies, especially related to dropouts. Most of the active comparator studies found no statistically significant difference in efficacy between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide or rifaximin. Teicoplanin may be an attractive choice but for its limited availability (Teicoplanin is not available in the USA) and great cost relative to the other options. More research of antibiotic treatment and other treatment modalities of CDAD is required.