Therapeutic Advances in Gastroenterology

Background: Clostridium difficile infection (CDI) is a recent epidemic in the United States, particularly in the hospital setting. Oral metronidazole is standard therapy for C. difficile infection, but resistance to metronidazole is becoming a clinical challenge.

Methods: We evaluated the efficacy of the nonsystemic oral antibiotic rifaximin for the treatment of metronidazole-resistant C. difficile infection. Twenty-five patients with C. difficile infection were enrolled in the study. All had mild-to-moderate C. difficile infection (5—10 bowel movements a day without sepsis) unresponsive to metronidazole (i.e. stools positive for toxins A and B after oral metronidazole 500 mg three times daily [t.i.d.] for 5 days). After discontinuation of metronidazole, rifaximin 400 mg t.i.d. for 14 days was prescribed. Patients were followed for 56 days and stool was tested for C. difficile using polymerase chain reaction (PCR) to assess the effect of treatment. A negative PCR test result was interpreted as a favorable response to rifaximin.

Results: Sixteen of 22 patients (73%) were eligible for study inclusion and completed rifaximin therapy experienced eradication of infection (stool negative for C. difficile) immediately after rifaximin therapy and 56 days post-treatment. Three patients (12%) discontinued therapy because of abdominal distention. Rifaximin was generally well tolerated.

Conclusions: In conclusion, rifaximin may be considered for treatment of mild-to-moderate C. difficile infection that is resistant to metronidazole. Larger randomized trials are needed to confirm these positive findings.

In Barrett’s esophagus, the stratified squamous epithelium lining the esophagus is replaced by specialized intestinal-type columnar epithelium. The prevalence of Barrett’s esophagus has ranged from 0.9% to 4.5%. The rate of progression from Barrett’s esophagus to esophageal adenocarcinoma is 0.5% per patient-year. Proton-pump inhibitors are the mainstay of symptom control in Barrett’s patients. Nondysplastic Barrett’s and Barrett’s with low-grade dysplasia (LGD) are typically managed by periodic surveillance. Radiofrequency ablation is being evaluated as a modality for managing nondysplastic Barrett’s and Barrett’s with LGD. The options for the management of Barrett’s patients with high-grade dysplasia (HGD) include endoscopic therapy, surgery, and intensive surveillance until biopsy reveals adenocarcinoma. Endoscopic therapy involves endoscopic mucosal resection (EMR) and ablation. More aggressive techniques such as endoscopic submucosal dissection and larger segment endoscopic mucosal resection are under study. In this review, we discuss the diagnosis and management of Barrett’s esophagus. The recommendations from the major gastroenterologic societies and the current and investigational endoscopic modalities for the management of Barrett’s esophagus with and without dysplasia are reviewed.

Although biologic agents directed against tumor necrosis factor alpha (TNFα) continue to be an effective therapeutic strategy for patients with inflammatory bowel disease (IBD), approximately 30% of patients with Crohn’s disease (CD) who are refractory to standard treatment do not respond to induction therapy with TNFα inhibitors and, of those who initially respond, 50% or more cease to respond within a year. Moreover, their use can be associated with significant safety issues. Clearly, there is a need to target alternative pathways involved in the inflammatory process. IBD is driven by the trafficking of lymphocytes from the circulation into the gut tissue that is mediated by adhesive interactions between the lymphocytes and endothelial cells. The adhesion molecules involved represent attractive targets for the development of new therapeutics which should aid in the resolution of existing inflammation, prevent recurrence of inflammation, and may potentially lead to long-term control of disease. In this article we review current opportunities and challenges facing anti-adhesion therapy in IBD, and discusses recent clinical development efforts that have focused on having an impact on two particular adhesive interactions: α₄-integrin/MAdCAM-1 and β₂-integrin/ICAM-1. Of particular interest is natalizumab, a humanized monoclonal antibody against human α₄ integrin that is approved for the treatment of patients with moderately-to-severely active CD and evidence of active inflammation. This agent represents an efficacious therapeutic option for patients who do not respond to, or have failed, a TNF-α inhibitor.

Medical therapies have entered center stage in the treatment of hepatocellular carcinoma (HCC) little more than a year after the positive results of a large phase III trial of sorafenib showed a clear survival benefit with sorafenib, a targeted agent, in this setting. Even though this marks a breakthrough in the treatment of HCC, the narrow patient profile necessary for the study to be successful has generated a number of questions regarding the efficacy of this approach in other clinical settings. New studies aiming to define the role of sorafenib from in the adjuvant setting, through patients with more advanced liver disease, all the way to combination treatments of HCC have been initiated. The success of one targeted drug has stimulated enormously the efforts of competitors to develop additional and better drugs, either in a first-line or a second-line setting. These are exciting times for the treatment of HCC, both for physicians and patients. In the years to come we will see an extension of treatment options in different clinical situations in patients with HCC, and survival will be improved in many stages of the disease, except for the most advanced. The rapid increase in knowledge about the molecular mechanisms underlying the development and progression of HCC will lead to a more tailored approach to treatment depending on the molecular characteristics of the tumor and the disease stage.