Oral bacitracin vs vancomycin therapy for Clostridium difficile-induced diarrhea. A randomized double-blind trial

The effectiveness of a ten-day course of either oral bacitracin or oral vancomycin hydrochloride for treatment of Clostridium difficile-induced antibiotic-associated diarrhea was compared in a randomized double-blind study. Bacitracin was as effective as vancomycin in resolving diarrhea; most patients responded within five days of therapy with either drug. Three patients receiving bacitracin worsened during therapy; two of these were considered treatment failures. Neither C difficile nor its toxin was detected in stool samples collected on the final day of therapy in 71% of patients (10/14) receiving vancomycin and in 30% (3/10) receiving bacitracin. Five patients receiving bacitracin and three receiving vancomycin had at least one recurrence. Low but nontoxic concentrations of bacitracin were detected in serum samples collected from 11 patients. Oral bacitracin at this dosage level was as effective as vancomycin in resolving the symptoms of C difficile-induced antibiotic-associated diarrhea in most patients but was less effective in eradicating C difficile and its toxin from patients' stools.     

Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin

Seven patients with multiple bacteriologic and symptomatic relapses of Clostridium difficile-associated diarrhea and/or colitis were treated with vancomycin and rifampin in combination. Diarrhea and abdominal pain promptly resolved in all, and neither C. difficile nor its toxin could be recovered from their stools shortly after therapy. However, stools of all patients subsequently became culture-positive for C. difficile and occasionally had demonstrable cytotoxin. Except in one instance following oral antibiotic use, all patients remained free of symptoms. Resistance to either vancomycin or rifampin was not encountered. Biotyping of isolates with clostridial bacteriophages and bacteriocins suggested true relapse with the same organism in all patients studied, rather than reinfection with another strain. Vancomycin and rifampin in combination appear to be useful in the therapy of relapsing antibiotic-associated diarrhea due to C. difficile.     

Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens

PURPOSE: High-dose (500 mg orally four times daily) vancomycin is considered by many investigators to be the most effective treatment for antibiotic-associated Clostridium difficile colitis. However, a lower dosage of 125 or 150 mg given three or four times a day has become popular, has been shown to be effective, and is less expensive than the high-dose regimen. We therefore decided to compare two vancomycin dosage regimens in a randomized trial. PATIENTS AND METHODS: The study involved 46 hospitalized patients with serious underlying diseases complicated by C. difficile diarrhea or colitis. Patients were assigned (according to a table of random numbers) to treatment with either 125 or 500 mg of vancomycin orally four times daily for an average of 10 days. RESULTS: No significant differences in measurable responses to the two regimens were noted. There were no treatment failures. The mean duration of diarrhea after initiation of therapy was about four days, and almost all patients had no diarrhea after one week. The organism continued to be demonstrated in the stools of about 50 percent of patients for the first few weeks after completion of therapy, and nine (20 percent) patients developed a recurrence of their diarrheal illness. Vancomycin was well tolerated by all patients. CONCLUSION: Since the dose of 125 mg appeared to be as effective as the 500-mg dose, which is more expensive, the 125-mg dose is preferred when vancomycin is used in treatment of this disease, unless the patient is critically ill.     

Who are Susceptible to Pseudomembranous Colitis Among Patients with Presumed Antibiotic-Associated Diarrhea?

Purpose Pseudomembranous colitis is a severe form of antibiotic-associated diarrhea. However, there have been no reports about the factors that make patients with presumed antibiotic-associated diarrhea susceptible to pseudomembranous colitis. This study was designed to determine the clinical risk factors for pseudomembranous colitis among the patients with presumed antibiotic-associated diarrhea. Methods This was a retrospective study of 150 consecutive patients admitted to our institution between January 2000 and December 2004 with a diagnosis of presumed antibiotic-associated diarrhea. All patients underwent sigmoidoscopy or colonoscopy because of diarrhea after administration of antibiotics. Pseudomembranous colitis was confirmed both endoscopically and histologically. Various clinical parameters were compared between the pseudomembranous colitis group and non-pseudomembranous colitis group. Results The mean age of patients was 61 years, and 60 percent (90/150) was female. Pseudomembranous colitis was diagnosed in 53 percent (80/150). On univariate analysis, older than aged 70 years (P = 0.014), antibiotic therapy for more than 15 days (P < 0.0001), hospital stay for more than 20 days (P < 0.0001), number of antibiotics used more than one (P = 0.01), and surgical procedures (P = 0.029) were significant parameters for pseudomembranous colitis. On multivariate analysis, the important clinical risk factors were advanced age (older than aged 70 years; adjusted odds ratio, 2.7; 95 percent confidence interval, 1.208–6.131; P < 0.016) and long hospital stay (more than 20 days; adjusted odds ratio, 5.1; 95 percent confidence interval, 2.1–12.259; P < 0.0001). When both risk factors were present, the positive predictive value of pseudomembranous colitis was 0.86. Conclusions Advanced age and long hospital stay may make patients with presumed antibiotic-associated diarrhea susceptible to pseudomembranous colitis. Therefore, pseudomembranous colitis should be first suspected in cases with presumed antibiotic-associated diarrhea having such risk factors. Poster presentation at the meeting of the Asian-Pacific Digestive Week 2005, Seoul, Republic of Korea, September 25 to 28, 2005.     

Approach to Patients with Multiple Relapses of Antihiotic-Associated Pseudomembranous Colitis

Twenty-two patients with multiple relapses of antibiotic-associated pseudomembranous colitis underwent a tapering dose of oral vancomycin for 21 days and a pulse dose of vancomycin for 21 days. In follow-up ranging from 2-12 months with a mean of 6 months, all patients have been without recurrence of the antibiotic-associated pseudomembranous colitis.     

Bacitracin therapy in antibiotic-associated pseudomembranous colitis

Two patients with antibiotic-associated pseudomembranous colitis and stool positive forClostridium difficile cytotoxin were successfully treated with oral bacitracin. One patient had previously suffered two relapses of pseudomembranous colitis following successful treatment with vancomycin and one patient was allergic to vancomycin. Bacitracin appears to be a reasonable choice to treat patients with antibiotic-associated colitis who are allergic to vancomycin. Further studies comparing vancomycin and bacitracin are needed.     

Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin

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.     

Yersinia colitis masquerading as pseudomembranous colitis

Summary We describe a 15-month-old male who presented with fever and diarrhea 24 hr after receiving antibiotics for otitis media. A flexible sigmoidoscopy was initially interpreted endoscopically as antibiotic-associated pseudomembranous colitis, and the patient was treated with vancomycin. The diagnosis of antibiotic-associated colitis was excluded in our patient by the negative stool examination forClostridium difficile toxin, the failure to obtain supportive features on rectal biopsy, and the failure to demonstrate sigmoidoscopic improvement with vancomycin therapy. Thirteen days later,Y. enterocolitica was cultured from the initial stool specimens. In this case, the raised central whitish area on an erythematous base was misinterpreted as pseudomembranous colitis.     

Antibiotic-associated diarrhea

The incidence of antibiotic-associated diarrhea (AAD) differs with the antibiotic and varies from 15 - 25 %. Most cases of AAD are directly or indirectly caused by alterations of gut microflora by the antibiotics resulting in clinically mild AAD cases due to functional disturbances of intestinal carbohydrate or bile acid metabolism. Alternatively, changes in the gut flora allow pathogens to proliferate. Clostridium difficile is responsible for 10 - 15 % of all cases of AAD and almost of all cases of antibiotic-associated pseudomembraneous colitis. There is also a growing body of evidence which supports the responsibility of Klebsiella oxytoca for the development of antibiotic-associated hemorrhagic colitis. Diagnosing Clostridium difficile-associated diarrhea should be based both on fecal-cytotoxin detection and culture. With respect to specific therapy, metronidazol has become the first choice whereas treatment with oral vancomycin should be reserved for patients who have contraindications or intolerance to or who have failed to respond to metronidazole. Probiotics such as Sacharomyces boulardii can reduce the risk of development. Restrictive antibiotic policies (e. g. restricting clindamycin and cephalosporins) and the implementation of a comprehensive hospital infection control have also been shown to be effective in reducing the incidence of AAD.     

Clostridium difficile infection: risk factors, medical and surgical management

BACKGROUND: Clostridium difficile has become recognized as a cause of nosocomial infection which may progress to a fulminant disease. METHODS: Literature review using electronic literature research back to 1966 utilizing Medline and Current Contents. All publications on antibiotic-associated diarrhea, antibiotic-associated colitis, and pseudomembranous colitis as well as C. difficile infection were included. We addressed established and potential risk factors for C. difficile disease such as an impaired immune system and cost benefits of different diagnostic tests. An algorithm is outlined for diagnosis and both medical and surgical management of mild, moderate and severe C. difficile disease. RESULTS: Diagnosis of C. difficile infection should be suspected in patients with diarrhea, who have received antibiotics within 2 months or whose symptoms started after hospitalization. A stool specimen should be tested for the presence of leukocytes and C. difficile toxins. If this is negative and symptoms persist, stool should be tested with 'rapid' enzyme immunoabsorbent and stool cytotoxin assays, which are the most cost-effective tests. Endoscopy and other imaging studies are reserved for severe and rapidly progressive courses. Oral metronidazole or vancomycin are the antibiotics of choice. Surgery is rarely required for selected patients refractory to medical treatment. The threshold for surgery in severe cases with risk factors including an impaired immune system should be low. CONCLUSION: C. difficile infection has been recognized with increased frequency as a nosocomial infection. Early diagnosis with immunoassays of the stool and prompt medical therapy have a high cure rate. Metronidazole has supplanted oral vancomycin as the drug of first choice for treating C. difficile infections.     

Colitis induced by Clostridium difficile

Clostridium difficile has been implicated as the major cause of antibiotic-associated pseudomembranous colitis. The current laboratory diagnostic test of choice is a tissue culture assay that demonstrates the presence of a cytopathic toxin neutralized by antitoxin to Clostridium sordellii. This toxin was found in stools from 42 of 43 patients with antibiotic-associated pseudomembranous colitis and in stools from 12 of 78 patients with antibiotic-associated diarrhea. Specimens from patients with gastrointestinal conditions unrelated to administration of antibiotics and those from healthy controls were uniformly negative. Neutralization of toxin by antitoxin to C. sordellii appears to represent antigenic cross-reactivity, since broth cultures of C. difficile also contain a cytopathic toxin neutralized by this antitoxin. Strains of C. difficile are susceptible to vancomycin, and the initial clinical experience with oral administration of this agent shows promising results.     

Therapy of antibiotic-associated pseudomembranous colitis.

Seven patients treated with oral cholestyramine for antibiotic-associated pseudomembranous colitis are reported. Response was variable with only one patient having a totally satisfactory clinical outcome. Five of seven patients had continued systemic signs with fever and leukocytosis throughout the course of cholestyramine. Two observations were relatively consistent. First, six of the seven patient had a decrease in the number of daily stools during therapy. Second, all patients showed persistence of the cytopathic toxin in stools obtained after three to seven days of cholestyramine therapy. Six patients who were subsequently treated with oral vancomycin had a prompt clinical improvement and clearance of the cytopathic toxin in the stool.     

Incidence and outcome of Clostridium difficile infection following autologous peripheral blood stem cell transplantation.

A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence and outcome of infection with Clostridium difficile. The diagnosis was confirmed in 14 patients with diarrhea (15 episodes) at a median of 33 days after stem cell infusion. Five patients were neutropenic at the time of diagnosis. Every individual had adverse known risk factors such as recent or current use of antibiotic, corticosteroid and antiviral therapy, recent administration of myeloablative chemotherapy and numerous, prolonged periods of hospitalization. Diarrhea, frequently hemorrhagic, was the most common presenting feature along with fever, abdominal cramps and abdominal distention. Diagnosis was established by the stool-cytotoxin test. Response to standard treatment with oral vancomycin or metronidazole was prompt despite the presence of several adverse prognostic features in these patients. There was only one instance of relapse which was also treated successfully. Several transplant-related variables such as age, sex, underlying malignancy, myelo-ablative regimen, duration of neutropenia, and prophylactic use of oral ampicillin underwent statistical analysis but failed to be predictive of C. difficile infection in such a setting. Finally, C. difficile is not uncommon after autologous PBSCT and must be included in the differential diagnosis in any such patient with diarrhea.     

Post-antibiotic diarrheas: role of Klebsiella oxytoca]

From May 1989 to January 1991, 20 patients were investigated for antibiotic-associated acute diarrhea. Colonoscopy or rectosigmoidoscopy was performed in each patient. Cultures of colonic mucosal biopsies were carried out using conventional culture grounds (cystine-lactose-electrolyte-deficient). The aim of this study was to investigate the role of a gram negative bacillus: Klebsiella oxytoca. Among the 20 patients with antibiotic-associated acute diarrhea, 11 had bloody and mucus diarrhea and colitis ranging from a right-sided hemorrhagic to diffuse acute ulcerative or erosive colitis, 7 had a grossly normal colonic appearance, while 2 had mucus diarrhea and pseudomembranous colitis. Of colonic biopsies cultures obtained from 36 control patients, 15 had a normal colonic appearance, 15 had ulcerative or crohn's colitis, 6 had well-tolerated amoxicillin therapy. Klebsiella oxytoca was never found in the 36 control patients; Klebsiella oxytoca was noted among 8/11 patients with mucus-discharging and bloody diarrhea. These results suggest that antibiotic-associated, non pseudomembranous colitis is frequently associated with Klebsiella oxytoca infection, which may be the cause of this type of colitis.     

Bacteremia due to Clostridium difficile

We describe a case of bacteremia due to Clostridium difficile, which was successfully treated by intravenous vancomycin. A 69-year-old woman was admitted to our hospital because of third degree burn injuries. She was treated with cefazolin for two weeks followed with flomoxef for one week before the operation (debridement and grafting of skin). On the third postoperative day high fever (temperature 40 degrees C), abdominal pain and severe watery diarrhea developed. Antibiotic-associated colitis with bacteremia was diagnosed presumptively, flomoxef was stopped, and oral and intravenous therapy with vancomycin was started. A blood culture taken before the administration of vancomycin yielded C. difficile accompanied with Enterococcus faecalis and Enetrococcus casseliflavus. A stool culture taken on the next day yielded C. difficile, and a stool latex agglutination test was also positive. The patient improved slowly. Parenteral vancomycin was discontinued after two weeks. One week later, the patient developed pneumonia, and imipenem/cilastatin was added. Soon after addition of the agent, she developed recurrent diarrhea despite continual oral vancomycin therapy. The fecal samples obtained at this time were positive for C. difficile by culture and positive for toxins A & B. She was satisfactorily treated with oral vancomycin for a total of four weeks. After the following two weeks, however, recurrence of diarrhea developed again, which rapidly decreased with oral vancomycin for seven days. The patient did well thereafter and was discharged. All three C. difficile isolates from blood and fecal specimens were positive for toxins A & B, and identified the same PCR ribotyping pattern.     

Convulsions induced by metronidazole treatment for Clostridium difficile-associated disease in chronic renal failure

Clostridium difficile-related diarrhea and colitis are common health problems, especially in elderly, frail hospitalized patients. The drug of choice is metronidazole, which can be associated, in long or high doses, with neurotoxic side effects. We report convulsions induced by short-term metronidazole therapy used in conventional doses for Clostridium difficile colitis in an elderly patient with chronic renal failure.     

High prevalence of diarrhea but infrequency of documented Clostridium difficile in autologous peripheral blood progenitor cell transplant recipients

Autologous peripheral blood progenitor cell (PBPC) transplant recipients frequently receive multiple antibiotics for neutropenic fever in addition to high-dose chemotherapy. Although there are many possible causes for diarrhea in this population, empiric therapy for possible C. difficile colitis is common in some centers. This study sought to define the frequency of diarrhea and of a positive C. difficile toxin assay in PBPC transplant recipients. Data were collected on 80 patients enrolled in a randomized trial of two different antibiotic regimens during PBPC transplant. Data included the presence or absence of diarrhea, all microbiologic studies performed during the transplant admission, and all antimicrobials administered during the transplant admission. Of 80 patients enrolled, 61 (76.3%) developed diarrhea. Only 3/61 (4.9%) had a positive C. difficile toxin assay. A total of 122 C. difficile toxin assays were performed; for each positive C. difficile assay, 41 stool samples were analyzed. Twenty courses of oral metronidazole (18/20 empiric) and 10 courses of oral vancomycin (8/10 empiric) were given. A total of 25 of 61 patients with diarrhea (41%) received therapy for possible C. difficile. Diarrhea is common during autologous PBPC transplant but a positive C. difficile assay is uncommon. The practice of empiric therapy for C. difficile in this population in a non-outbreak setting should be re-evaluated. Bone Marrow Transplantation (2000) 25, 67-69.     

Treatment of <Emphasis Type="Italic">clostridium difficile</Emphasis> infection

Opinion statement With the introduction of broad-spectrum antibiotics into clinical practice, Clostridium difficile infection has become the most common cause of infectious diarrhea in hospitalized patients. Although mild cases may resolve by discontinuing antibiotics, thus allowing re-establishment of colonic microflora, oral metronidazole or vancomycin is indicated if the process is more severe. Metronidazole may be given intravenously, with intracolonic therapeutic levels achieved by excretion of drug into bile and exudation across inflamed tissue. Vancomycin is preferred treatment of severe cases. Bacitracin given orally is a therapeutic alternative and cholestyramine is a useful adjunct. Most patients with diarrhea or colitis caused by C. difficile respond to initial therapy; however, up to 20% experience relapse when treatment is discontinued. Repeating initial therapy for 10 to 14 days is indicated for first relapse. Multiple relapses require prolonged treatment with vancomycin, which may be supplemented with cholestyramine. Saccharomyces boulardii alone or in combination with vancomycin has been reported to be an effective therapeutic alternative for recurrent infection. Intravenous immunoglobulin can be effective in patients with severe recurrent Clostridium difficile colitis and immune deficiency or low pretreatment levels of serum antitoxin. Surgery is indicated only if recurrent infections are severe and associated with serious complications.     

Clindamycin-associated colitis

Four cases of clindamycin-associated colitis have recently been observed at Kansas University Medical Center. There have been a few reports in the literature of colitis associated with this antibiotic, and our 4 cases are similar to those noted previously. All had the onset of diarrhea 7–14 days following the initiation of clindamycin therapy; the diarrhea persisted for weeks after the drug was discontinued. Mucosal changes ranged from focal ulceration to pseudomembrane formation. Diarrhea in a patient on clindamycin should alert the physician to the possibility of antibiotic induced colitis, a condition with significant morbidity and occasional mortality.     

Antibiotic-associated fulminant pseudomembranous colitis without toxic megacolon.

Presented is a middle-aged male who developed a fulminant case of antibiotic-associated pseudomembranous colitis characterized by leukocytosis, hypoalbuminemia, ascites, and anasarca without toxic megacolon. The patient responded slowly to medical therapy consisting of intravenous metronidazole, oral vancomycin, and parenteral nutrition. Subsequently, cholestyramine was administered. A review of the literature concerning similar cases of fulminant pseudomembranous colitis is presented.