Antibiotic Treatment in Inflammatory Bowel Disease: Rifaximin, a New Possible Approach

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European Review for Medical and Pharmacological Sciences 1999; 3: 27-30 Review – Antibiotic treatment in inflammatory bowel disease: rifaximin, a new possible approach

P. GIONCHETTI, F. RIZZELLO, A. VENTURI, F. UGOLINI*, M. ROSSI**, P. BRIGIDI**, R. JOHANSSON, A. FERRIERI***, G. POGGIOLI*, M. CAMPIERI

Clinica Medica I, Nuove Patologie, Bologna University (Italy) *Istituto di Clinica Chirurgica II, Bologna University (Italy) **Dipartimento di Scienze Farmaceutiche, Bologna University (Italy) ***Direzione Medica Alfa Wassermann, Bologna (Italy)

Abstract. – The etiology of inflammatory ported the presence of a breakdown of toler- disease is still unknown, but a body of evidence ance to the normal commensal intestinal flora from clinical and experimental observation indi- in active IBD2-3. Reduction of microflora by cates a role for intestinal microflora in the pathogenesis of this disease. Reduction of mi- antibiotics, bowel rest and fecal diversion de- croflora using antibiotics, bowel rest and fecal creases inflammatory activity in Crohn’s dis- diversion decreases activity in Crohn’s disease ease and to a lesser extent in ulcerative colitis and in ulcerative colitis. Several trials have been (UC). The pathogenetic role of intestinal mi- carried out on the use of antibiotic treatment in croflora is further suggested by the observa- patients with active ulcerative colitis with con- tion that experimental colitis, in germ-free or trasting results. A number of trials have been antibiotic treated animals, is less severe com- carried out using Rifaximin, a non-absorbable broad-spectrum antibiotic, confirming the ab- pared to that inducible in normal animals or sence of systemic bioavalaibility of the drug at times is not inducible at all. Moreover, bac- even when administered at very high doses and terial products, such as N-formil-methionyl- for prolonged periods. It may therefore be useful leucyil-phenylalanine (FMLP), lipopolysac- in treatment of ulcerative colitis and pouchitis, charidase (LPS) and peptidoglycan-polysac- since its absorption through inflamed mucosa is charidase (LPS), can induce and perpetuate negligible, it maintains a topical action without 4-8 systemic effects and the lack of resistant bacte- experimental colitis . rial strains may allow prolonged and repeated Pouchitis, a non-specific inflammation of treatments. the ileal reservoir (pouch) mucosa, is the ma- Key Words: jor long-term complication encountered after proctocolectomy and ileo-anal anastomosis Rifaximin, Antibiotic, IBD, Ulcerative colitis. for UC. The etiology and pathophysiology of pouchitis are not well understood, and a vari- ety of hypotheses have been proposed to ex- plain this inflammatory condition. Among this, a major role has been attributed to fecal Introduction stasis and bacterial overgrowth, recurrent UC, misdiagnosed Crohn’s disease and mucosal is- The ethiology of inflammatory bowel dis- chemia of the pouch9. However, pouchitis ease (IBD) remains unknown, but a body of most likely seems to be the result of a com- evidence from clinical and experimental ob- plex interaction between a genetical or im- servations indicates a pathogenetic role munological susceptibility of the patient and among others for intestinal microflora1. The the morphological and functional modifica- distal ileum and the colon are the areas with tions of the ileal-pouch, due to the fecal stasis the highest intraluminal bacterial concentra- and consequent bacterial overgrowth10-11. tion, and represent the sites of primary in- Several trials have been carried-out on the flammation in IBD. Recent studies have re- use of antibiotic treatment in patients with ac-

27 P. Gionchetti, F. Rizzello, A. Venturi, F. Ugolini, M. Rossi, P. Brigidi, R. Johansson et al tive UC, with contrasting results. Intravenous ative, aerobic and anaerobic species associat- metronidazole was not found to be superior ed with gastro-intestinal infection17-18. to placebo when used in association with cor- Resistance to rifaximin has been demon- ticosteroids in severe UC12, while oral van- strated to occur either in vitro and in vivo in comicyn showed a certain efficacy, that how- residual intestinal flora; drug resistance however did not reach statistical significance13. ever decreases rapidly after the end of the Favorable results have been obtained with treatment, and disappeares completely after 1 tobramicyn, an aminoglycoside active against to 2 weeks for anaerobic cocci, enterococci Gram negative bacteria, administered togeth- and Enterobacteriacee, and after 8 to 16 er with standard steroid treatment; 74% of weeks for Clostridium and Bacteroides patients achieved a complete symptomatic re- species. Therefore it appears that rifaximin mission compared with only 43% in the place- resistant strains are unable to permanently bo treated group14. However, a more recent colonize the gastro-intestinal tract19. trial with cyprofloxacin has not been able to Several experimental and clinical observa- demonstrate a favourable effect of antibiotic tions have shown that rifaximin is virtually treatment when compared to placebo15. not absorbed. Recent experiments with Treatment of pouchitis remains empirical, 14C-rifaximin performed in rat and dog mod- and antibiotics are the mainstay of therapeu- els showed that, after intravenous administra- tic regimens; metronidazole is the most com- tion, plasma levels were detectable for 4 and mon administered first-line antibiotic, and 12 hours respectively, whereas after oral ad- most patients show remission of clinical ministration, serum radiolabelled product symptons within a few days. One double- levels were very low and detectable only for 1 blind, placebo-controlled study utilizing and 6 hours, respectively. Following oral ad- metronidazole showed a significant reduction ministration in rats, after 48 hours the excre- of bowel motions however without improve- tion of radioactivity in urine was about 0.7% ment of endoscopic appearance of the in- of the dose, whereas in faeces the radiola- flammed intestinal tract or of the histological belled product was found in quantities that inflammatory activity16. Other antibacterial reached 90% or more of the oral dose; simi- agents that have shown some positive results lar results were observed in dogs. Following are ciprofloxacin, the association of amoxi- intravenous administration in dogs, within cyllin+clavulanic acid, tetracycline and ery- 24/48 hours most of the radioactivity was ex- thromycin. creted in faeces (83% dose), whereas urinary No attempt has been made to compare excretion was about 6% of the administered metronidazole with other therapeutic regi- dose; 168 hours after administration, radioac- mens. About 15% of patients with pouchitis tivity was totally excreted in faeces, possibly present a chronic inflammatory condition. In as a consequence of enterohepatic circulation same cases, this inflammation is treatment-re- of 14C-rifaximin or its metabolites20. sponsive and requires maintainance metron- Blood levels in healthy volunteers, after idazole therapy with a high incidence of side single oral administration of a dose of 400 effects (dysgeusic nausea and peripheral neu- mL, were undetectable in 50% of volunteers ropathy). In other cases pouchitis shows no and below 5 ng/mL in the other 50%, using response to antibiotic-treatment and is de- techniques with detection limit of 2 ng/mL. fined as treatment-resistant. After 48 hours, urinary recovery of the drug Rifaximin is a non-absorbable antibiotic. did not exceed 0.025% of the administered Its mechanism of action is based on the inhi- dose (unpublished observation). bition of prokaryotic RNA-polymerase. The More recently, in one study which investi- inhibition of this enzyme suppresses initiation gated the systemic absorption of rifaximin af- of chain formation during RNA synthesis. ter single oral administration of 400 mg, in The drug has bactericidal rather than bacte- patients with mild to moderate ulcerative col- riostatic property having a low ratio between itis, urinary excretion was found to be negligi- bactericidal and inhibitory activity (1:1 to 4:1 ble, and plasma concentration was unde- in susceptible strains)17. It shares the same tectable in almost all patients21. antibacterial spectrum with other rifamycins, Largely variable amounts of rifaximin have covering all the main Gram positive and neg- been recovered in faeces, depending on mass

28 Review – Antibiotic treatment in inflammatory bowel disease: rifaximin of the faeces and transit time. In some cases the absence of the drug in any at the plasma up to 76% of the administered dose could be samples 12 hrs after from the last dose, and recovered in faeces in 24 hours. Therefore, the presence of negligible levels of the un- independently from its poor absorption, ri- changed active principle in 24 hrs urine sam- faximin is not distributed at a systemic level ples. These data further confirm the absence but undergoes a first pass removal by the liv- of systemic bioavailability of the drug even er and its behaviour is like rifamycin SV, when administered at very high dosage (2 which does not show any systemic absorp- g/day) and for a prolonged period27. tion, remaining in the enterohepatic circula- It is possible to conclude that rifaximin tion, and being subsequently almost totally may be useful in treatment of ulcerative coli- excreted in faeces. tis and pouchitis; its absorption through in- Rifaximin has been used successfully in the flamed mucosa is negligible as in normal mu- treatment of hepatic encephalopathy, acute in- cosa. The drug maintains a topical action fectious diarrheal disease, preparation for without systemic effects. The absence of re- colonic and biliary surgery and diverticulitis22-25. sistant bacterial strains, able to permanently Because of its broad spectrum and its colonize the gastro-intestinal tract, may allow mainly topical activity, we recently conducted prolonged and repeated treatment cycles. a pilot placebo-controlled study in a group of patients with severe UC refractory to steroid treatment using rifaximin as an adjunct to standard steroid treatment. References Fourteen patients received rifaximin (800 mg/day) and 14 received an identical placebo. 1) SARTOR RB. Role of intestinal microflora in initiation Overall nine patients (64.3%) receiving rifax- and perpetuation of inflammatory bowel disease. Can J Gastroent 1990; 4: 271-277. imin and five (41.7%) (p NS) receiving placebo showed a positive response to the treat- 2) DUCHMANN R, KAISER I, HERMANN E et al. Tolerance exists towards resident intestinal flora but is bro- ment, as defined by an improvement of the ken in active inflammatory bowel disease. Clin disease’s clinical activity from baseline to the Exp Immunol 1995; 102: 448-455. th l0 day, and tapered steroids gradually. 3) MACPERSON A, KHOO UY, FORGACS I et al. Mucosal Moreover rifaximin determined a significant antibodies in inflammatory bowel disease are di- reduction in stool frequency (p<0.02), rectal rected against intestinal bacteria. Gut 1996; 38: bleeding (p<0.05) and sigmoidoscopic score 365-375 (p<0.01) compared with placebo. Twelve 4) CHADWICK VS, ANDERSON RP. Microorganism and hours after the last dose of rifaximin, it was their products in inflammatory bowel disease. In: not possible to identify the drug in any of the Mc Dermott RP, Stenson WF (eds.) Inflammatory bowel disease. Elsevier, New York 1992, pp plasma samples (2 ng/mL was the detection 241-258. limit of the analytical method). The total 5) SARTOR RB (1992). Animal models of intestinal in- amount of rifaximin excretion in 24-hrs urine flammation: Relevance in IBD. In: Mc Dermott after 10 days was 64,617.14 ± 20,976.57 ng/mL RP, Stenson WIF (eds.) Inflammatory bowel dis- (mean±SEM)26. These findings suggest that ease. Elsevier, New York 1992, pp 337-354 rifaximin may be useful in patients with 6) DAVIS SW, HOLT LC, SARTOR RB. Luminal bacteria and steroid refractory UC. More recently we uti- bacterial polymers potentiate indomethacin- in- lized rifaximin (1 g b.d.) in association with duced intestinal injury in the rat. Gastroenterology ciprofloxacin (500 mg b.d.), given for 15 days, 1990; 98; 444A. in patients with chronic, antibiotic-resistant 7) CHESTER JF, ROSS JS, MALT RA et al. Acute colitis pouchitis. Eighteen patients, who failed to re- produced by chemotactic peptides in rats and mices. Am J Pathol 1985; 121: 284-290. spond to metronidazole as well as to other commonly used treatments for pouchitis, en- 8) VON RITTER C, SEKIZUKA E, GRISHAM MB et al. The chemotactic peptide N-formylmethionyl-leucyl- tered the study. Sixteen of 18 treated patients phenylalanine increases mucosal permeability in (88.8%) either improved (n=10) or went into the distal ileum of the rat. Gastroenterology 1988; remission (n=6), with a decrease of the medi- 95: 651-656. an Pouchitis Disease Activity Index (PDAI) 9) SANDBOM WJ. Pouchitis following ileal pouch-anal score from 12 (range 8-17) to 4 (range 0-16). anastomosis: Definition, pathogenesis, and treat- Pharmacokinetic study of rifaximin showed ment. Gastroenterology 1994; 107: 1856-60.

29 P. Gionchetti, F. Rizzello, A. Venturi, F. Ugolini, M. Rossi, P. Brigidi, R. Johansson et al

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