US Pharm. 2011;36(12):HS4-HS14.
Clostridium difficile is one of the most common pathogens that cause pseudomembranous colitis in hospitalized patients, and C difficile–associated disease (CDAD) is one of the most common nosocomial infections. The bacterium secretes a large amount of toxins A and B, which cause inflammation of the colonic mucosa. The inflammation results in severe watery diarrhea, fever, abdominal pain, and leukocytosis. Vancomycin was the first drug FDA approved for CDAD, but its cost and the threat of selective bacterial resistance limit its use.1-5 In May 2011, Fidaxomicin was approved for the treatment of C difficile in adults.6 Since there is limited experience with its use, the drug will not be discussed in this article. Metronidazole has been a first-line treatment following the early studies showing a result comparable to that of vancomycin7,8; however, recent studies have shown an increased relapse in patients treated with metronidazole and vancomycin.1,9
The purpose of this article is to review the literature for approaches to manage recurrent CDAD (RCDAD) and to examine the management efforts of this infection at UT Southwestern Medical Center, Dallas, Texas. A new strategy will be implemented based on this evaluation to improve the current treatment methods at this institution.
Evaluation of Practice Guidelines
Treatment guidelines from the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the CDC, and the American Gastroenterology Association have suggested metronidazole as the first-line agent, followed by oral vancomycin.4,10,11 Reports from Pepin et al (2005), Aslam et al (2005), McMaster-Baxter et al (2007), and Kuijper et al (2008) suggested that the recurrent rates of CDAD treated with metronidazole and vancomycin were 29% and 28%, respectively.2,9,12,13
Signs, symptoms, and diagnostic methods for RCDAD are shown in FIGURE 1,14-16 with its complications reviewed in FIGURE 2.17-19
Evaluation of Strategies to Improve the Treatment of RCDAD
Many studies have been conducted regarding the treatment of RCDAD. Although there have been no controlled studies using probiotics for the primary prevention of CDAD, there have been trials that have used Saccharomyces boulardii in patients with RCDAD.20,21 The hypothesis was that the residual C difficile spores grew after the antibiotic treatment was completed, causing RCDAD. S boulardii produced protease that inactivated C difficile toxin receptors in the lumen cells so that the newly grown C difficile toxin could not bind to these receptors to cause pseudomembranous colitis. The following section and TABLE 1 review this research in detail.3,20-26
McFarland et al (1994) conducted a randomized, double-blind, placebo-controlled, parallel trial in a group of 124 patients with CDAD.20 About half of the subjects (n = 60) had experienced at least one recurrent C difficile infection prior to the study. Patients were treated with standard doses of metronidazole or vancomycin. After 4 days of continuous antibiotic treatment, patients were randomized to the probiotic S boulardii 500 mg twice daily or to placebo, then followed for 4 weeks. The study suggested that S boulardii might benefit patients with RCDAD.20
Surawicz et al (2000) conducted a double-blind, placebo-controlled trial for the treatment of RCDAD by using high-dose vancomycin combined with S boulardii.21 The inclusion criteria consisted of patients aged 18 to 100 years with diarrhea who tested positive for C difficile by either positivity for toxin A/B or positive culture. In addition, patients must have had at least one RCDAD within 1 year. All patients were stratified by their history of exposure, tolerance, and severity of RCDAD to receive oral vancomycin either 2 g/day or 500 mg/day, or metronidazole 1 g/day for 10 days. All patients were randomized to S boulardii 1 g/day or placebo on day 7 of the 10-day course of antibiotic, and continued on it until day 28. Patients were required to keep a standardized daily diary to record bowel characteristics. This study suggested that short-course, high-dose vancomycin combined with S boulardii reduced the recurrence of RCDAD.21
McFarland et al (2002) investigated vancomycin taper and vancomycin pulsing methods to manage RCDAD.22 The inclusion criteria consisted of patients who had been treated for C difficile with standard antibiotic vancomycin or metronidazole. Patients ranged from 18 to 100 years, with positive C difficile assay by the presence of A/B toxins or positive culture. Additionally, they also had one or more episodes of RCDAD within 1 year. Patients were excluded if they were immunosuppressed, had negative C difficile assays, were on antifungal drugs, or were pregnant. Patients were observed for 2 months after they finished the standard treatments with metronidazole or vancomycin. If infection recurred, they were retreated with the same regimen for 10 to 16 days or with a tapered regimen to doses of 125 to 750 mg/day for 10 to 14 days, or were pulsed with vancomycin 125 to 500 mg every 2 to 3 days for 3 weeks. The vancomycin pulsed regimen resulted in 14.3% recurrence (P = .02). With tapering, the best response was seen with tapering doses from 500 mg to 1 g/day down to 125 mg/day over 19 to 25 days (P = .01). In the metronidazole group, there was no significant difference in the rate of recurrence in any regimen given. The authors suggested that pulsing and/or tapering vancomycin provided an effective strategy.22
Besides metronidazole and vancomycin, rifaximin and nitazoxanide have been studied in patients who developed RCDAD. In an observational study, Johnson et al (2007) used sequential therapy with vancomycin and rifaximin to treat RCDAD.23 Rifaximin treatment was initiated when patients had completed the standard drug treatments, but before they had any recurrence symptoms. The treatment population included a total of 8 women, age ranging from 43 to 88 years. All patients had experienced at least four RCDAD episodes and had been treated with multiple approaches. Patients were administered rifaximin 400 to 800 mg per day in 2 to 3 divided doses for 2 weeks. Patients responded to the treatment, although resistance emerged.23
Musher et al (2007) conducted an open-label study of nitazoxanide in patients who developed RCDAD after treatment with metronidazole.3 This trial was based on a hypothesis that nitazoxanide was at least as effective as metronidazole and might be used as an alternate treatment when metronidazole failed.24 A total of 35 patients with average an age of 67.5 years who had failed conventional treatment with metronidazole were enrolled in this study. The dosage was 500 mg oral twice daily for 10 days. The study concluded that nitazoxanide seemed to be effective in patients who failed metronidazole.3
A head-to-head study by Musher et al (2009) compared the efficacy of nitazoxanide to vancomycin in the primary treatment of CDAD.25 In this randomized, double-blind, controlled trial, 50 patients were randomized to the nitazoxanide or the vancomycin group. Patients received either oral nitazoxanide 500 mg q12h or vancomycin 125 mg q6h for 10 days. The authors suggested the noninferiority of nitazoxanide to vancomycin, which requires further investigation.25
There are a limited number of studies examining the role of IV immune globulin (IVIG) in RCDAD. Wilcox (2004) reported 5 patients, aged 66 to 97 years, with protracted and/or RCDAD and significant morbidity.26 IVIG was administered at 300 to 500 mg/kg. The case report suggested that an immediate response to IVIG should not be expected. Further study is needed to assess the benefit of IVIG in the elderly population, whose response to RCDAD is partly attributable to their immune status.
Practice Experience
The American Gastroenterology Association recommends discontinuance of the offending antibiotic and administration of supportive treatment for 2 to 3 days.2,4,12 In practice, the patient may be unpredictably clear of C difficile spontaneously, and sometimes it is impossible to discontinue the drug. More important, discontinuation of the antibiotic does not improve the symptoms.
As a standard of care at UT Southwestern Medical Center, a patient with mild-to-moderate symptoms is tested for C difficile toxins with immunoassay (TABLE 2).27-30 A thorough medical history and physical examination, including stool quality and frequency, abdominal tenderness, rigidity, bowel sounds, location of pain, fever, unexplained leukocytosis, and elevated serum creatinine (CrSr), are necessary to make a diagnosis. Other manifestations include protein-losing syndromes, such as ascites, peripheral edema, and low albumin. First-line treatment usually starts with oral metronidazole 500 mg 3 times a day for 10 days for mild-to-moderate cases. In patients with more severe symptoms, oral vancomycin 125 mg 4 times a day for 10 to 14 days is indicated. For severe, complicated C difficile infection, the therapeutic options are vancomycin 500 mg via oral, nasogastric tube, or rectal enema administration 4 times a day and/or metronidazole 500 mg to 750 mg every 8 hours.31 Fluid and electrolytes are assessed and corrected, if necessary.
Many times issues arise regarding the assessment of severity of C difficile infection. The diagnosis of “mild, moderate, or severe” is varied among the treating physicians. Since the treatment is different based on the severity, a definition of severity must be established. A mild-to-moderate case is characterized by symptoms of 2 to 3 loose or watery stools per day, abdominal pain, nausea, and vomiting. A severe case includes diarrhea up to 10 to 15 times a day accompanied by fever with temperature ³37.6°C, leukocytosis ³15,000, and CrSr ³1.5 times baseline. A severe, complicated case presents with a need for intensive care unit (ICU), colectomy, toxic megacolon, ileus, hypotension, or colonic perforation.
The decision to discontinue C difficile treatment is also varied among physicians. The rationale differs in terms of improvement of symptoms, stool assay result, and length of treatment. Treatment is stopped if the patient responds with resolution of diarrhea to £2 watery or loose stools a day or hard or formed stools for 2 consecutive days, no abdominal pain and tenderness, and fever and leukocytosis resolved.
Treatment failure is suspected if patients have persistent fevers, diarrhea ³3 episodes of loose to watery stools per day, abdominal pain, unresolved leukocytosis, and positive enzyme immunoassay (EIA) for C difficile toxins after ³14 days of treatment. Failure may also include an initial response to metronidazole ³1.5 g/day and/or vancomycin oral 500 mg/day, but relapse on at least two occasions after initial response to such treatment within 2 months. A repeat course of the previous antibiotic and dosage for C difficile is often given. The antibiotic is tapered over 2 to 3 days, then pulsed at the same dosage for 2 to 3 weeks. Treatment strategies with pulse vancomycin and S boulardii have shown benefit in patients with RCDAD and may be considered. Sequential treatment with vancomycin and rifaximin can be considered as an alternate therapy for recurrent cases.23 Nitazoxanide can be used as an alternate to metronidazole.3,24,25 Even with some success, IVIG therapy is still largely investigational. Further studies are needed to assess its role in treating RCDAD.28,32,33
The option to give probiotics to an immunocompromised patient is often overlooked. Bacteremia has occurred in this patient population when probiotics were given.34-37 A low request for gastroenterology consultation indicates the emphasis on clinical diagnosis. Endoscopy provides a definitive diagnosis of CDAD and should be encouraged.15,16 Diagnosis of CDAD in patients with inflammatory bowel disease (IBD) can be difficult because of the similarity of presenting symptoms such as diarrhea, abdominal pain, and low-grade fever. A misdiagnosis in the patient with IBD can lead to inappropriate use of glucocorticoids or immunosuppressants. Endoscopy does not provide useful evidence because patients with IBD do not develop pseudomembrane formation. The diagnosis of CDAD in this patient population should be based on the laboratory results (TABLE 2).27-30 Repeating stool toxin assays should be discouraged. Up to 50% of patients continue to have positive stool assays for as long as 6 weeks after treatment.38
Summary
A better understanding of C difficile’s mode of transmission helps the development of new treatment strategies for RCDAD. Literature reviews have shown promising results with vancomycin and S boulardii, vancomycin and rifaximin, and tapered and pulsed vancomycin. Alternative therapy with nitazoxanide has also achieved some initial success. The current practice of treating C difficile infection at UT Southwestern Medical Center was reviewed, and practice implementations were made to improve patient outcomes.
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