Case Studies of Antibiotic Therapy in the Management of Functional Gastrointestinal Disorders

Introduction: Antibiotics for Functional Gastrointestinal Symptoms

Irritable bowel syndrome (IBS) is a substantial health problem, affecting an estimated 10–20% of individuals in the United States.¹ Symptoms commonly associated with IBS include bloating, abdominal pain, constipation, diarrhea, and flatulence.² The causes of IBS are not well defined but appear to be multifaceted. Underlying factors contributing to IBS pathogenesis include visceral hypersensitivity, altered gastrointestinal motility, chronic inflammation, and small intestinal bacterial overgrowth (SIBO).^3,4 These factors are not mutually exclusive, and specific gastrointestinal symptoms may vary among patients. For instance, SIBO may account for the increased gas production that occurs in many patients with IBS, and methane production is strongly associated with constipation-predominant IBS.⁴

Many potential mechanisms have been proposed to explain the pathophysiologic symptoms of IBS, including genetic predisposition; food intolerance; social, environmental, or behavioral factors; and previous enteric infection.³ The complex nature of IBS pathology makes optimal treatment challenging. Treatment options for IBS include bulking agents, 5-hydroxytryptamine-modifying agents, antidepressants, antispasmodics, antiinflammatory agents, laxatives, antidiarrheals, antibiotics, and probiotics. Notably, antibiotics have a favorable efficacy profile in the treatment of individuals with SIBO.^5–9,11

The cases included in this supplement provide examples of the pathogenic role of bacteria in IBS and suggest that therapeutic approaches that affect gut bacteria and the respective host responses to these pathogens might alleviate symptoms in patients with functional gastrointestinal symptoms. This notion is supported by observations from several open-label investigations as well as randomized, double-blind, controlled studies that have characterized the therapeutic benefit of antibiotics in the treatment of functional gastrointestinal symptoms in patients with or without a diagnosis of IBS.^5–12

The cases described in this supplement also provide real-world examples of antibiotic treatment of functional gastrointestinal symptoms in clinical practice. Although no conclusions about the efficacy of antibiotics for functional gastrointestinal symptoms can be drawn on the basis of these cases alone, the present observations illustrate the potential applications of antibiotics for the treatment of functional gastrointestinal disorders and suggest areas for further investigation.

Ciprofloxacin in a Patient With Exacerbation of Functional Gastrointestinal Symptoms After an Episode of Gastroenteritis

Charles Cattano

A 50-year-old white woman presented with a 20-year history of functional gastrointestinal symptoms, manifesting as recurrent abdominal cramps, excessive gas, and stool urgency without hematochezia or nocturnal stooling. The patient complained of severe diarrhea and moderate bloating, gas, and abdominal pain. Fatty meals exacerbated symptoms, and abdominal pain and bloating improved following bowel movements. A previous evaluation in 2004 resulted in a diagnosis of Rome II-positive, diarrhea-predominant IBS. Additionally, in August 2005, the patient's symptoms flared after an 8-day episode of acute viral gastroenteritis. Her medical history included a longstanding history of anxiety, but no history of diabetes, thyroid disease, or neurologic issues. Her only surgery was hysterectomy for fibroids, preceded by two uncomplicated childbirths. She denied tobacco use but admitted prior marijuana smoking. She has consumed alcohol socially. Her family history was notable for the presence of “colitis” in her mother and sister, who had similar gastrointestinal symptoms.

Current medications included dicyclomine 10 mg daily, which was initiated in June 2004. Previously the patient had been taking alprazolam as needed for restlessness but elected to discontinue use in order to “avoid addiction.” Her response to dicyclomine was rated as “50% better.” The patient also received a trial regimen of chlordiazepoxide 5 mg plus clidinium 2.5 mg twice daily (bid) with a reported 60% response, but discontinued the medication after 2 weeks due to oversedation. Thus, the patient was referred for gastroenterology consultation for further evaluation and treatment.

On physical examination, the patient weighed 142 lbs at a height of 5 ′ 4″. Her skin was nonicteric and lungs clear to posterior and anterior auscultation bilaterally. Heart sounds revealed S1S2 with a mitral click but no murmur. Her abdomen was scaphoid with mild tenderness in the right and left lower quadrants, without rebound. Bowel sounds were active in all four quadrants. Rectal examination revealed guaiac-negative brown stool and no digital tenderness. Review of colonoscopic findings from August 2004 indicated diffuse spasm, but random biopsy was negative for inflammation. Results of complete blood count and blood chemistry tests provided by her referring primary care physician were normal, as was the baseline level of serum thyreotropic hormone. Stool analysis proved negative for Giardia, enteric pathogens, and leukocytes. No breath test for bacterial overgrowth was available within our community.

On the basis of her post-infectious symptoms, a diagnosis of SIBO was suspected. She received ciprofloxacin 500 mg bid for 10 days. At a follow-up visit in August 2005, 3 weeks after discontinuing ciprofloxacin treatment, her gastrointestinal symptoms were moderately improved and she reported no adverse effects related to ciprofloxacin treatment.

The patient was lost to follow-up thereafter, due to a lack of interest in maintenance therapy. She telephoned again |6 months later to report recurrence of diarrhea without bleeding and requested a refill of her ciprofloxacin prescription. Based on available data, the patient was offered a 14-day trial regimen of rifaximin 400 mg three times daily, with the expectation of consolidating symptom improvement. Her prior history of improvement with ciprofloxacin provided support for a presumption of SIBO; however, formal breath testing was deferred. Tegaserod was initiated concomitantly with low-dose rifaximin 200 mg bid. Within 7 days on the combined regimen of tegaserod and rifaximin, the patient reported significant reduction in diarrhea (from 7 to 2 stools daily), as well as reductions in fecal urgency and abdominal cramping.

Discussion

The merits of rifaximin treatment in IBS patients are under investigation, and preliminary data discussed elsewhere herein suggest benefit. The empiric use rifaximin in patients with SIBO symptoms, however, bears consideration, even without formal SIBO documentation. As noted in the case above, breath testing is not always readily ordered, and where available the cost of analysis is often substantial. Therefore, empiric rifaximin treatment in IBS patients may be justified, particularly because, unlike with systemic antibiotics, the GI selectivity of rifaximin permits few side effects and little expectation of significant bacterial resistance.¹

Rifaximin Therapy in a Patient With Constipation-predominant IBS

Jennifer Christie

A 38-year-old Hispanic woman presented on August 10, 2005, with a 2-year history of postprandial bloating, gas, abdominal pain, and constipation, which was spontaneous, intermittent, and self-limiting. Her medical history included migraine headaches and cholecystectomy. Medications included sumatriptan as needed. The patient denied smoking, drinks alcohol socially, denied extraordinary stress, and had no known history of gastroenteritis and no known drug allergies.

Functional gastrointestinal symptoms were refractory to treatment with simethicone (2-month course), alphagalactosidase (Beano), and dietary modifications, which included high-fiber foods and avoidance of lactose-containing products, raw vegetables, and beans. The patient reported worsening of gas and bloating. Another IBS drug was prescribed, which resulted in severe diarrhea. Upon presentation to the gastroenterologist, the patient was taking no prescription medications.

Upon physical examination, the patient appeared in no acute distress. Abdominal examination revealed mild distention, a right upper quadrant surgical scar, positive bowel signs, mild diffuse tenderness, no rebound, and no guarding. Based on her symptoms of very severe bloating and gas, abdominal pain, and constipation, she was diagnosed with constipation-predominant IBS. Basic blood work consisting of metabolic panel and thyroid-stimulating hormone (TSH) was negative. A glucose breath test was negative for SIBO, based on hydrogen measures only. Despite her negative breath test but because of her symptom profile, the patient was administered rifaximin 400 mg three times daily for 10 days.

Two weeks later, the patient reported improvement in bloating and gas. However, she still complained of slight constipation. Tegaserod 2 mg twice daily was prescribed with resolution of constipation.

Discussion

Irritable bowel syndrome is commonly associated with symptoms of gas and bloating. Investigators have found that small bowel gas is found in excess in patients with IBS compared to controls.¹ Additionally, Pimentel and colleagues² found that treatment with oral antibiotics after a positive lactulose breath test was associated with improvement in IBS symptoms as well as normalization of breath test results. Interestingly, the hydrogen breath test using glucose in this patient was negative, yet the patient's symptoms improved with empiric rifaximin treatment. This may have been due to the elimination of methaneproducing intestinal bacteria that were not detected during the hydrogen breath test. In a study measuring methane production during lactulose breath testing, a 100% association was found between constipation-predominant IBS and a methane-positive breath test.³ Breath testing may be falsely negative in patients with primarily methanogenic bacteria causing symptoms of IBS. Therefore, we must consider methane to be an important intestinal gas in the production of gastrointestinal symptoms.

Rifaximin in a Patient With Relapsing Functional Gastrointestinal Symptoms

Venkat Mohan

A 47-year-old white woman presented in December 2004 with a 10-year history of functional gastrointestinal symptoms, including abdominal discomfort, loose stools, and a 2-year worsening of symptoms manifesting as excessive flatulence, bloating, and gas, without constipation or diarrhea. Milk, cheese, and stress exacerbated her symptoms. The patient's medical history indicated abdominal cramps and acid reflux, with no known history of gastroenteritis, neurologic disease, diabetes, or thyroid disease. Review of symptoms was unremarkable, with no weight loss, blood in the stool, or nausea. Her surgical history included appendectomy and hysterectomy. Her psychiatric history was noted for complaints of anxiety. In regard to related familial history, her father had colon cancer and her mother had diverticulosis. Her alcohol intake was reported as a once-weekly glass of wine. She was a nonsmoker.

Gastrointestinal symptoms were refractory to dietary changes, which included replacement of dairy intake with soy products; consumption of small, low-fat meals; and avoidance of carbonated beverages, coffee, and artificial sweeteners. Over-the-counter treatment with simethicone or alpha-galactosidase supplements provided only a minimal response. No specific medications had been prescribed for treatment of her functional gastrointestinal symptoms, and the patient was not receiving medications for other disorders. Because of persistent symptoms, the patient was referred for gastroenterology consultation.

On physical examination, the patient could be characterized as a pleasant, well-nourished female weighing 157 lbs at 5′ 6″. Cardiovascular, lung, and abdominal examinations were unremarkable. Results of routine screening laboratory tests for complete blood count, chemistry profile, TSH, erythrocyte sedimentation rate, and anti-endomysial antibody were normal. Stool test for fecal fat was normal. Breath tests were not performed. Results of a colonoscopy performed in November 2004 were negative. Based on symptom-based clinical data, the patient was diagnosed with functional bowel disorder and SIBO.

The patient received rifaximin 400 mg twice daily (bid) for 10 days in combination with the probiotic Flora-Q once daily for 2 weeks and tegaserod 6 mg nightly for 2 months. She had a mild increase in loose bowel movements in the initial days of therapy due to the effect of tegaserod, which ultimately normalized. At a follow-up visit 4 weeks after initiation of rifaximin adjunct therapy, the patient reported improved symptoms of bloating, gas, and abdominal discomfort, as well as normal stool consistency. At a routine follow-up office visit in May 2005, the patient reported that symptoms were greatly improved. No side effects attributed to the treatment regimen were reported.

No maintenance treatment was prescribed. The patient experienced a relapse in August 2005 and received rifaximin 400 mg bid for 2 weeks. Her symptoms of bloating, gas, and abdominal pain markedly improved. She was placed on a course of tegaserod 6 mg nightly for 2 months and currently remains symptom-free.

Discussion

Emerging evidence supports the hypothesis that SIBO contributes to the pathogenesis of IBS.¹ Many individuals with IBS also have SIBO, as indicated by reports of abnormal breath test results in up to 84% of individuals with IBS.^2,3 Furthermore, multiple randomized, double-blind, placebocontrolled studies have demonstrated that patients who experienced normalization of breath test results following antibiotic treatment experience greater improvement of functional bowel symptoms.^2–5 Specifically, the nonsystemic antibiotic rifaximin has been shown to safely and effectively eliminate bacterial overgrowth and improve global symptoms of IBS.^5,6

Abnormal motility of the phase III “housekeeper” waves of the migrating motor complex in the small intestine may contribute to the development of SIBO in individuals with IBS.⁷ The recurrence of symptoms in this patient may be related to a lack of stimulation of this housekeeper wave. The administration of promotility agents such as tegaserod may help stimulate the phase III complex and prevent recurrence of SIBO. An additional agent administered to promote normal intestinal motility is oral erythromycin 50 mg daily.

Rifaximin as Acute Therapy and Maintenance Treatment for Functional Gastrointestinal Symptoms

Charles Loewe

A 55-year-old white woman presented with a 10-year history of functional gastrointestinal symptoms, including mild diarrhea, severe constipation, abdominal pain, bloating, and gas. Symptoms were exacerbated by certain carbohydrates and alleviated only by not eating. A medical consultation in 1998 resulted in a diagnosis of Rome II-positive, alternating-form IBS. The patient's medical history was notable for recurrent episodes of diverticulitis, appendectomy, cholecystectomy, total abdominal hysterectomy, and a family history of colorectal cancer. The patient had no known history of gastroenteritis, diabetes, thyroid disease, neurologic disorder, or psychiatric problems, and reported no significant weight loss, no tobacco use, and only occasional consumption of alcohol. Symptoms were refractory to previous interventions, including oral dicyclomine 20 mg before meals, over-the-counter laxatives, and a high-fiber diet. The patient was referred to a gastroenterologist for recurrent diverticulitis and alternating symptoms of constipation and diarrhea.

On physical examination, the patient's temperature was normal and her pulse rate was 75 bpm with a blood pressure of 120/75 mm Hg. Her height measured 5′ 3″ and weight 125 lbs. Abdominal examination revealed no hepatosplenomegaly, no abnormal mass, and slight tenderness in the lower quadrants. Results of all stool studies were negative, with no detection of blood. Results of thyroid studies, complete blood count and C-reactive protein levels, and liver profile studies were normal. A 3-hour lactulose breath test revealed an abnormal hydrogen peak. Results of a colonoscopy performed in August 2004 revealed diverticulosis. A CT scan also showed evidence of diverticulosis with muscular hypertrophy.

Based on clinical symptoms, the patient was administered oral rifaximin 400 mg twice daily for 10 days. A lactulose breath test administered after initiation of rifaximin treatment was normal. Following completion of rifaximin treatment, probiotic therapy and tegaserod 2 mg daily were administered as maintenance therapy. At her 3-month follow-up evaluation, the patient had not experienced symptom recurrence.

Discussion

Irritable bowel syndrome is a very common chronic medical condition with no known cause. Dr. Douglas Drossman first presented the biopsychosocial model of IBS,¹ which has gained much acceptance as a pathophysiologic cause, as have the application of symptom-based diagnostic criteria originally put forth by Manning and colleagues² and further applied in the Rome diagnostic criteria. Research currently focuses on altered motility, neuroenteric signaling, visceral hypersensitivity, and brain-gut dysfunction.

Irritable bowel syndrome is a complex gastrointestinal disorder characterized by a heterogeneous pathophysiology. A primary focus of recent research is the role of enteric bacteria in IBS pathogenesis, as demonstrated by the correlation between postinfectious IBS and a previous episode of bacterial gastroenteritis (eg, travelers' diarrhea). Pimentel and colleagues have utilized the lactulose breath test to identify a subset of IBS patients with SIBO.³ Their therapeutic method began with neomycin and has evolved into a rifaximin-based primary treatment to normalize the abnormal breath test and to achieve global improvement of IBS symptoms, including bloating, abdominal discomfort, diarrhea, and constipation.⁴

Commentary

Mark Pimentel

Among patients with any form of Rome criteria-defined IBS, approximately 80–90% experience distension and bloating, which are the hallmark symptoms of SIBO. These patients are candidates for treatment with antibiotic therapies to reverse the bacterial overgrowth and provide long-term relief of symptoms.

As illustrated in some of the aforementioned cases, lactulose breath testing has a role in both the diagnosis and monitoring of antibiotic efficacy in patients with SIBO. Administration of a breath test following therapy has shown a correlation between normalized post-therapy tests and higher levels of overall IBS-patient benefit. Breath tests can also provide diagnostic information for other disease states. In cases of classic IBS symptoms, general screening procedures require blood work and perhaps examination via flexible sigmoidoscopy to rule out other causes of disease. The addition of a negative breath test result provides a signal to screen more aggressively for celiac disease or to perform colonoscopy, depending on patient symptoms. Further, if overgrowth eradication can be demonstrated through post-therapy breath test result but symptoms persist, investigation of other causes (eg, inflammatory bowel disease) is warranted.

In 2003, our group at Cedars-Sinai published a study examining the use of neomycin as antibiotic therapy for SIBO and found that it improved symptoms and normalized breath tests in approximately 20-25% more patients than did placebo. Our more recently published study of rifaximin in a similar patient population was designed as a follow-up utilizing a more effective antibiotic, as demonstrated in the 2000 trial by Di Stefano and associates, which showed that rifaximin could eradicate overgrowth in 70% of patients.

Our rifaximin study included a longer follow-up period than the initial work with neomycin, in order to test both the efficacy and the durability of overgrowth eradication and symptom relief in IBS patients treated with this agent. Most previous IBS studies, including those of tegaserod and alosetron, have required the use of active therapy in order to achieve benefit. Patients needed to be on the drug in order for the drug to work because these drugs compensate for a motility problem. We reasoned that if bacterial overgrowth is causing IBS, then 10 days of therapy to eradicate it should provide lasting benefit. This was borne out in the study, as patients who took rifaximin maintained an average symptom improvement of 36.4% over the course of 10 weeks of follow-up and consistently scored better than patients given placebo, despite a lack of active therapy after the first 10 days.

In addition, at the 2006 meeting of the American College of Gastroenterology, we presented retrospective data on the use in our clinic of rifaximin for the treatment of IBS-associated SIBO. Among patients with SIBO confirmed by breath test, 69% showed clinical improvement in their IBS symptoms. Further, subsequent re-treatment with rifaximin in the patients showing initial response proved equally effective. This data indicates that patients taking repeated courses of rifaximin do not develop resistance.

Our current practice of antibiotic therapy calls for the administration of an additional agent to improve small bowel function and cleaning waves, which extends the durability of overgrowth eradication. We have found that nighttime dosing of tegaserod can significantly widen the interval between courses of rifaximin in those patients who may need repeat therapy, providing even longer-lasting benefit.

Among community physicians, there is a valid concern regarding the use of antibiotic therapy in any large population, such as that constituted by IBS patients. It should be stressed that rifaximin is a nonabsorbed antibiotic that works differently from traditional systemic agents. The biologic effect of rifaximin manifests almost entirely in the small bowel. There is very little activity in the colon, as has been shown by stool cultures taken before and after rifaximin treatment.

One potential problem in the use of rifaximin is that of effective dosing. The US Food and Drug Administration has approved rifaximin at 200 mg three times daily (tid) for the treatment of travellers' diarrhea. Unfortunately, this dose is not effective in the treatment of SIBO and will not impart the benefit seen with the widely studied dose of 400 mg tid. Currently, registration studies are examining multiple doses of rifaximin to determine the most effective regimen. Until these results are available, it is important to administer the drug at the higher, studied dose in order for it to work in IBS patients.