- Email: [email protected]
Corticosteroid-sparing effect of rifaximin, a nonabsorbable oral antibiotic, in active ulcerative colitis: Preliminary clinical experience
VOLUME 65, NO. 3, MAY/JUNE 2004
Brief Report Corticosteroid-Sparing Effect of Rifaximin, a Nonabsorbable Oral Antibiotic, in Active Ulcerative Colitis: Preliminary Clinical Experience Mario Guslandi, MD, Patrizia Giollo, MD, and Pier Alberto Testoni, M D
Gastroenterology Unit, S. Raffaele University Hospital, Milan, Italy
ABSTRACT
Background: The role of enteric flora in the pathogenesis of inflammatory bowel disease constitutes the rationale for the use of antibiotics as adjuvant agents in the treatment of ulcerative colitis (UC) and Crohn's disease. Objective: The aim of this study was to assess, in a preliminary fashion, the efficacy of the nonabsorbable antibiotic rifaximin in the treatment of exacerbation of UC in patients with a history of p o o r corticosteroid tolerance. Methods: This open-label pilot study was c o n d u c t e d in the Gastroenterology Unit, S. Raffaele University Hospital (Milan, Italy). Male and female patients aged 18 to 65 years with an established diagnosis of left-sided UC who were experiencing a clinical relapse during maintenance treatment with mesalamine and with a history of poor tolerance to corticosteroid t herapy were included in the study. They received rifaximin 400 mg BID for 4 weeks while continuing to receive mesalamine 2.4 g/d. Disease activity before and after treatment was assessed using Rachmilewitz's Activity Index (PAl). A final RAI score <6 was considered clinical remission. Results: Ten patients (9 men, 1 woman; mean [SD] age, 48.1 [12.3] years [range, 23-64 years]) participated in the study. The RAI decreased in all patients. Rifaximin treatment induced clinical remission in 7 patients (70%). No adverse effects were reported. Conclusions: Due to our study design, no definitive conclusions can be drawn. However, our preliminary data suggest that rifaximin may be beneficial in the treatment of active UC, obviating corticosteroid t herapy in most cases. (Curr Ther Res Clin Exp. 2004;65:292-296) Copyright @ 2004 Excerpta Medica, Inc. Key words: ulcerative colitis, mesalamine, rifaximin, corticosteroids. Accepted for publication May 12, 2004. Reproduction in whole or part is not permitted.
292
0011-393X/04/$19.00
Copyright © 2004 Excerpta Medica, Inc.
M. Guslandi et aL
INTRODUCTION It is now well recognized that enteric flora play a pathogenetic role in inflammatory bowel disease 0BD). 1-3 It has been found that in genetically predisposed patients with immunologic dysregulation, bacteria trigger and maintain intestinal inflammation, and that the concentration of intestinal bacteria in IBD is higher than normal in these patients and increases progressively with the severity of the disease. 2 Other investigators 3 have p r o p o s e d a breakdown in the qualitative balance between protective and harmful bacteria (dysbiosis) as one of the potential mechanisms involved in ulcerative colitis (UC) and Crohn's disease. Clinical studies 4 using antibiotics as adjuvant therapy in the medical treatment of IBD have yielded promising results, but long-term administration of drugs such as metronidazole and ciprofloxacin hydrochloride is accompanied by systemic adverse effects (AEs). Rifaximin (a derivative of rifampicin), a locally acting antibiotic that is virtually u n abs or bed after oral administration, 5 has been shown to be effective in the treatment of intestinal disorders (eg, diverticulitis, traveler's diarrhea). An open-label pilot study 6 has suggested that rifaximin 200 mg TID prom ot es clinical improvement in patients with Crohn's disease. The aim of the present preliminary study was to assess the efficacy of rifaximin as an alternative therapeutic approach in patients undergoing an exacerbation of UC who should avoid corticosteroid therapy.
PATIENTS AND METHODS Study Design This open-label pilot s t udy was c o n d u c t e d in t he G a s t r o e n t e r o l o g y Unit, S. Raffaele University Hospital (Milan, Italy). Approval for the study protocol was obtained from the hospital institutional review board.
Patients Male and female patients aged 18 to 65 years who experienced a clinical exacerbation of UC (based on Truelove & Witts criteria) while receiving maintenance treatment with oral mesalamine 2.4 g/d during the 3 months before the study were enrolled. Patients were required to have an endoscopically and histologically confirmed diagnosis of left-sided UC ->6 months earlier. Endoscopy was not repeated at the time of inclusion because relapse was clinically evident. For ethical reasons, only patients with a history of poor tolerance to corticosteroid t her a py were enrolled. In their medical history, due to steroid treatment, 4 patients (40%) had sodium retention, 3 (30%) had d e c o m p e n s a t e d diabetes, 2 (20%) had severe rash, and 1 (10%) had severe dyspepsia unresponsive to p r o t on pump inhibitors. In all cases, the patient and/or physician was reluctant to restart a course of corticosteroids, and thus provided verbal informed consent to first try a course of t herapy with rifaximin while continuing
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CURRENT THERAPEUTIC RESEARCH®
mesalamine treatment. Also, only patients with an initial score of -~9 on the Rachmilewitz's Activity Index (RAI) 7 (calculated on the basis of stool frequency, blood in the stool, general conditions, fever, abdominal pain, e r y t h r o c y t e sedimentation rate, and hemoglobin concentration) were included.
Treatment Rifaximin 400 mg BID PO was self-administered for 4 weeks while patients continued to receive mesalamine 2.4 g/d. No other oral or rectal medications were permitted during the study.
Efficacy Assessment Clinical assessment before and after treatment was performed using the RAT. 7 A final score of <6 on the RAT 7 w a s considered a therapeutic success (ie, clinical remission). In the event of worsening of symptoms, patients were instructed to return to the clinic to be switched to corticosteroid therapy.
Tolerability Analysis AEs were r e c o r d e d and assessed using patient interview and spontaneous reporting.
RESULTS Ten patients (9 men, 1 woman; mean [SD] age, 48.1 [12.3] years [range, 23-64 years]) participated in the study.
Efficacy Seven patients (70%) achieved clinical remission (score <6 on RAI7); corticosteroid treatment was avoided in these patients. A reduction in the RAI,7 indicating partial clinical improvement, was observed in 3 patients (30%) (Figure).
Tolerability All patients completed the prescribed treatment with rifaximin without reporting any AEs.
DISCUSSION Typically, patients with an exacerbation of UC while receiving maintenance treatment with mesalamine receive a course of corticosteroids to suppress the acute inflammatory process. However, corticosteroid t herapy is poorly tolerated in some patients; thus, alternative therapeutic approaches must be considered. In view of the pathogenetic role of intestinal bacteria in IBD,1-3 the use of antibiotics is an option. A nonabsorbable antibiotic, such as rifaximin, which has not been associated with the systemic AEs of antibiotics such as metroni-
294
M. Guslandi et al.
14 12 c
10
>
~
8
~
6
E e-
4 2 0
I
I
Baseline
Month 1
Figure. Individual patient values on Rachmilewitz's Activity Index 7 before (baseline) and after 1 month of treatment with rifaximin plus mesalamine.
dazole and ciprofloxacin, is particularly attractive in this respect. Preliminary u n c o n t r o l l e d data on the use of rifaximin 600 mg/d in active C r o h n ' s disease for -<16 weeks was p r o v i d e d by Shafran et al. 6 That s t u d y s h o w e d promising resuits in t e r m s of clinical r e s p o n s e . However, o u r pilot s t u d y was different from the s t u d y by Shafran et al 6 in that we a d m i n i s t e r e d c o m b i n a t i o n t h e r a p y with m e s a l a m i n e plus rifaximin during active UC to try to avoid c o r t i c o s t e r o i d therapy. Despite the differences in d o s e and duration of rifaximin t r e a t m e n t and in the t y p e of IBD studied, b o t h pilot studies s u g g e s t that the antibiotic might be clinically useful in m o s t patients with active intestinal inflammation. In particular, o u r s t u d y indicated that by adding rifaximin to the m e s a l a m i n e regimen, it is possible to achieve clinical remission, as e v i d e n c e d by the fact that c o r t i c o s t e r o i d t r e a t m e n t was avoided in 70% of patients. W e a k n e s s e s of our s t u d y included its open-label, pilot characteristics; the lack of a c o n t r o l group; and the small s a m p l e size used. However, our data and t h o s e of o t h e r investigators are e n c o u r a g i n g and w a r r a n t further c o n t r o l l e d studies with rifaximin in the t r e a t m e n t of IBD.
CONCLUSIONS Due to our s t u d y design, no definitive c o n c l u s i o n s can be drawn. However, o u r preliminary data s u g g e s t that rifaximin m a y be beneficial in the t r e a t m e n t of active UC, obviating c o r t i c o s t e r o i d t h e r a p y in m o s t cases.
295
CURRENT THERAPEUTIC RESEARCH@
REFERENCES 1. Balfour Sartor R. The role of luminal bacteria in colitis: More t h a n an antigenic drive. Eur J Clin Invest. 1998;28:1027-1029. 2. Swidsinski A, Ladhoff A, Pernthaler A, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002; 122:44-54. 3. Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut. 2004;53:1--4. 4. Marteau P, Seksik P, Shanahan F. Manipulation of the bacterial flora in inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2003;17:47-61. 5. Gillis JC, Brogden RN. Rifaximin. A review of its antibacterial activity, pharmacokinetic p r o p e r t i e s and t h e r a p e u t i c potential in conditions m e d i a t e d by gastrointestinal bacteria. Drugs. 1995;49:467--484. 6. Shafran I, Johnson K, Hamm L, Murdock RH Jr. Efficacy and tolerability of rifaximin, a n o n a b s o r b e d oral antibiotic, in the t r e a t m e n t of active Crohn's disease: Results of an open-label study. A m J Gastroenterol. 2003;98(Suppl):S250. Abstract. 7. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the t r e a t m e n t of active ulcerative colitis: A r a n d o m i s e d trial. BMJ. 1989;298:82-86.
Address correspondence to: M a r i o G u s l a n d i , MD, FACG, G a s t r o e n t e r o l o g y Unit, S. R a f f a e l e U n i v e r s i t y H o s p i t a l , Via O l g e t t i n a 60, 20132 Milan, Italy. E-mail: [email protected]
296
Brief Report Corticosteroid-Sparing Effect of Rifaximin, a Nonabsorbable Oral Antibiotic, in Active Ulcerative Colitis: Preliminary Clinical Experience Mario Guslandi, MD, Patrizia Giollo, MD, and Pier Alberto Testoni, M D
Gastroenterology Unit, S. Raffaele University Hospital, Milan, Italy
ABSTRACT
Background: The role of enteric flora in the pathogenesis of inflammatory bowel disease constitutes the rationale for the use of antibiotics as adjuvant agents in the treatment of ulcerative colitis (UC) and Crohn's disease. Objective: The aim of this study was to assess, in a preliminary fashion, the efficacy of the nonabsorbable antibiotic rifaximin in the treatment of exacerbation of UC in patients with a history of p o o r corticosteroid tolerance. Methods: This open-label pilot study was c o n d u c t e d in the Gastroenterology Unit, S. Raffaele University Hospital (Milan, Italy). Male and female patients aged 18 to 65 years with an established diagnosis of left-sided UC who were experiencing a clinical relapse during maintenance treatment with mesalamine and with a history of poor tolerance to corticosteroid t herapy were included in the study. They received rifaximin 400 mg BID for 4 weeks while continuing to receive mesalamine 2.4 g/d. Disease activity before and after treatment was assessed using Rachmilewitz's Activity Index (PAl). A final RAI score <6 was considered clinical remission. Results: Ten patients (9 men, 1 woman; mean [SD] age, 48.1 [12.3] years [range, 23-64 years]) participated in the study. The RAI decreased in all patients. Rifaximin treatment induced clinical remission in 7 patients (70%). No adverse effects were reported. Conclusions: Due to our study design, no definitive conclusions can be drawn. However, our preliminary data suggest that rifaximin may be beneficial in the treatment of active UC, obviating corticosteroid t herapy in most cases. (Curr Ther Res Clin Exp. 2004;65:292-296) Copyright @ 2004 Excerpta Medica, Inc. Key words: ulcerative colitis, mesalamine, rifaximin, corticosteroids. Accepted for publication May 12, 2004. Reproduction in whole or part is not permitted.
292
0011-393X/04/$19.00
Copyright © 2004 Excerpta Medica, Inc.
M. Guslandi et aL
INTRODUCTION It is now well recognized that enteric flora play a pathogenetic role in inflammatory bowel disease 0BD). 1-3 It has been found that in genetically predisposed patients with immunologic dysregulation, bacteria trigger and maintain intestinal inflammation, and that the concentration of intestinal bacteria in IBD is higher than normal in these patients and increases progressively with the severity of the disease. 2 Other investigators 3 have p r o p o s e d a breakdown in the qualitative balance between protective and harmful bacteria (dysbiosis) as one of the potential mechanisms involved in ulcerative colitis (UC) and Crohn's disease. Clinical studies 4 using antibiotics as adjuvant therapy in the medical treatment of IBD have yielded promising results, but long-term administration of drugs such as metronidazole and ciprofloxacin hydrochloride is accompanied by systemic adverse effects (AEs). Rifaximin (a derivative of rifampicin), a locally acting antibiotic that is virtually u n abs or bed after oral administration, 5 has been shown to be effective in the treatment of intestinal disorders (eg, diverticulitis, traveler's diarrhea). An open-label pilot study 6 has suggested that rifaximin 200 mg TID prom ot es clinical improvement in patients with Crohn's disease. The aim of the present preliminary study was to assess the efficacy of rifaximin as an alternative therapeutic approach in patients undergoing an exacerbation of UC who should avoid corticosteroid therapy.
PATIENTS AND METHODS Study Design This open-label pilot s t udy was c o n d u c t e d in t he G a s t r o e n t e r o l o g y Unit, S. Raffaele University Hospital (Milan, Italy). Approval for the study protocol was obtained from the hospital institutional review board.
Patients Male and female patients aged 18 to 65 years who experienced a clinical exacerbation of UC (based on Truelove & Witts criteria) while receiving maintenance treatment with oral mesalamine 2.4 g/d during the 3 months before the study were enrolled. Patients were required to have an endoscopically and histologically confirmed diagnosis of left-sided UC ->6 months earlier. Endoscopy was not repeated at the time of inclusion because relapse was clinically evident. For ethical reasons, only patients with a history of poor tolerance to corticosteroid t her a py were enrolled. In their medical history, due to steroid treatment, 4 patients (40%) had sodium retention, 3 (30%) had d e c o m p e n s a t e d diabetes, 2 (20%) had severe rash, and 1 (10%) had severe dyspepsia unresponsive to p r o t on pump inhibitors. In all cases, the patient and/or physician was reluctant to restart a course of corticosteroids, and thus provided verbal informed consent to first try a course of t herapy with rifaximin while continuing
293
CURRENT THERAPEUTIC RESEARCH®
mesalamine treatment. Also, only patients with an initial score of -~9 on the Rachmilewitz's Activity Index (RAI) 7 (calculated on the basis of stool frequency, blood in the stool, general conditions, fever, abdominal pain, e r y t h r o c y t e sedimentation rate, and hemoglobin concentration) were included.
Treatment Rifaximin 400 mg BID PO was self-administered for 4 weeks while patients continued to receive mesalamine 2.4 g/d. No other oral or rectal medications were permitted during the study.
Efficacy Assessment Clinical assessment before and after treatment was performed using the RAT. 7 A final score of <6 on the RAT 7 w a s considered a therapeutic success (ie, clinical remission). In the event of worsening of symptoms, patients were instructed to return to the clinic to be switched to corticosteroid therapy.
Tolerability Analysis AEs were r e c o r d e d and assessed using patient interview and spontaneous reporting.
RESULTS Ten patients (9 men, 1 woman; mean [SD] age, 48.1 [12.3] years [range, 23-64 years]) participated in the study.
Efficacy Seven patients (70%) achieved clinical remission (score <6 on RAI7); corticosteroid treatment was avoided in these patients. A reduction in the RAI,7 indicating partial clinical improvement, was observed in 3 patients (30%) (Figure).
Tolerability All patients completed the prescribed treatment with rifaximin without reporting any AEs.
DISCUSSION Typically, patients with an exacerbation of UC while receiving maintenance treatment with mesalamine receive a course of corticosteroids to suppress the acute inflammatory process. However, corticosteroid t herapy is poorly tolerated in some patients; thus, alternative therapeutic approaches must be considered. In view of the pathogenetic role of intestinal bacteria in IBD,1-3 the use of antibiotics is an option. A nonabsorbable antibiotic, such as rifaximin, which has not been associated with the systemic AEs of antibiotics such as metroni-
294
M. Guslandi et al.
14 12 c
10
>
~
8
~
6
E e-
4 2 0
I
I
Baseline
Month 1
Figure. Individual patient values on Rachmilewitz's Activity Index 7 before (baseline) and after 1 month of treatment with rifaximin plus mesalamine.
dazole and ciprofloxacin, is particularly attractive in this respect. Preliminary u n c o n t r o l l e d data on the use of rifaximin 600 mg/d in active C r o h n ' s disease for -<16 weeks was p r o v i d e d by Shafran et al. 6 That s t u d y s h o w e d promising resuits in t e r m s of clinical r e s p o n s e . However, o u r pilot s t u d y was different from the s t u d y by Shafran et al 6 in that we a d m i n i s t e r e d c o m b i n a t i o n t h e r a p y with m e s a l a m i n e plus rifaximin during active UC to try to avoid c o r t i c o s t e r o i d therapy. Despite the differences in d o s e and duration of rifaximin t r e a t m e n t and in the t y p e of IBD studied, b o t h pilot studies s u g g e s t that the antibiotic might be clinically useful in m o s t patients with active intestinal inflammation. In particular, o u r s t u d y indicated that by adding rifaximin to the m e s a l a m i n e regimen, it is possible to achieve clinical remission, as e v i d e n c e d by the fact that c o r t i c o s t e r o i d t r e a t m e n t was avoided in 70% of patients. W e a k n e s s e s of our s t u d y included its open-label, pilot characteristics; the lack of a c o n t r o l group; and the small s a m p l e size used. However, our data and t h o s e of o t h e r investigators are e n c o u r a g i n g and w a r r a n t further c o n t r o l l e d studies with rifaximin in the t r e a t m e n t of IBD.
CONCLUSIONS Due to our s t u d y design, no definitive c o n c l u s i o n s can be drawn. However, o u r preliminary data s u g g e s t that rifaximin m a y be beneficial in the t r e a t m e n t of active UC, obviating c o r t i c o s t e r o i d t h e r a p y in m o s t cases.
295
CURRENT THERAPEUTIC RESEARCH@
REFERENCES 1. Balfour Sartor R. The role of luminal bacteria in colitis: More t h a n an antigenic drive. Eur J Clin Invest. 1998;28:1027-1029. 2. Swidsinski A, Ladhoff A, Pernthaler A, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002; 122:44-54. 3. Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut. 2004;53:1--4. 4. Marteau P, Seksik P, Shanahan F. Manipulation of the bacterial flora in inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2003;17:47-61. 5. Gillis JC, Brogden RN. Rifaximin. A review of its antibacterial activity, pharmacokinetic p r o p e r t i e s and t h e r a p e u t i c potential in conditions m e d i a t e d by gastrointestinal bacteria. Drugs. 1995;49:467--484. 6. Shafran I, Johnson K, Hamm L, Murdock RH Jr. Efficacy and tolerability of rifaximin, a n o n a b s o r b e d oral antibiotic, in the t r e a t m e n t of active Crohn's disease: Results of an open-label study. A m J Gastroenterol. 2003;98(Suppl):S250. Abstract. 7. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the t r e a t m e n t of active ulcerative colitis: A r a n d o m i s e d trial. BMJ. 1989;298:82-86.
Address correspondence to: M a r i o G u s l a n d i , MD, FACG, G a s t r o e n t e r o l o g y Unit, S. R a f f a e l e U n i v e r s i t y H o s p i t a l , Via O l g e t t i n a 60, 20132 Milan, Italy. E-mail: [email protected]
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