Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis

Authors


Dr P. Gionchetti, Dipartimento di Medicina Interna e Gastroenterologia, Policlinico S.Orsola-Malpighi, Via Massarenti, 9-40138 Bologna, Italy. E-mail: paolo@med.unibo.it

Abstract

Background

: Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. About 15% of patients have a chronic, treatment-resistant disease.

Aims

: To evaluate the efficacy of an antibiotic combination for chronic active, treatment-resistant pouchitis.

Patients and Methods

: Eighteen patients were treated orally with rifaximin 1 g b.d. + ciprofloxacin 500 mg b.d. for 15 days. Symptoms assessment, endoscopic and histological evaluations were performed at screening and after 15 days using the Pouchitis Disease Activity Index (PDAI). Improvement was defined as a decrease of at least 3 points in PDAI score, and remission as a PDAI score of 0. Systemic absorption of rifaximin was determined by high performance liquid chromatography. Faecal samples were collected before and after antibiotic treatment for stool culture.

Results

: Sixteen out of 18 patients (88.8%) either improved (n=10) or went into remission (n=6); the median PDAI scores before and after therapy were 11 (range 9–17) and 4 (range 0–16), respectively (< 0.002). No side-effects were reported. Rifaximin plasma levels and urinary excretion were negligible, confirming its mainly topical activity. A significant decrease in total anaerobes and aerobes, enterococci, lactobacilli, bifidobacteria and bacteroides in faecal samples was observed, while the reduction in number of coliforms and Clostridium perfringens did not reach a statistical significance.

Conclusions

: A combination of rifaximin and ciprofloxacin was effective in patients with active chronic, treatment-resistant pouchitis, suggesting the need, in these patients, for treatment using antibiotic agents with wide antibacterial spectrum of activity.

INTRODUCTION

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is a well-established surgical procedure for the management of ulcerative colitis and familial adenomatous polyposis.1, 2

Pouchitis, a non specific inflammation of the ileal reservoir, is the most frequent long-term complication following pouch surgery for ulcerative colitis.3 Its cumulative frequency varies between 7 and 50% depending on the duration of follow-up and definition of pouchitis used.4[5]–6

This syndrome is characterized clinically by the presence of diarrhoea, rectal bleeding, faecal urgency, abdominal cramping, malaise and fever, endoscopically by oedema, granularity, mucus exudate and ulcerations, and histologically by neutrophil infiltration, crypt abscesses and ulcerations in addition to chronic inflammatory infiltrate.7, 8

Its exact cause(s) are poorly understood and pathogenetic theories abound, including faecal stasis with bacterial overgrowth, mucosal ischaemia, Crohn's disease and recurrent ulcerative colitis.9

Treatment of pouchitis is empirical and broad-spectrum antibiotics are the mainstay of treatment. Most patients have a good response to metronidazole, which is the only drug with efficacy shown in a controlled study.10 About 15% of patients with pouchitis have a chronic disease, either a treatment responsive form, which requires maintenance metronidazole therapy, with a high incidence of side-effects, or a treatment-resistant form that does not respond to the antibiotic treatment.

The aim of our study was to evaluate the efficacy of the association of two antibiotics, ciprofloxacin + rifaximin, with a wide antibacterial spectrum and high level of faecal excretion, in achieving remission in a group of patients with chronic, treatment-resistant pouchitis. The influence of this treatment on intestinal flora composition, and the systemic absorption of rifaximin were also determined.

MATERIALS AND METHODS

Selection of patients

Eligible patients were older than 18 years of age, with a confirmed diagnosis of chronic treatment-resistant pouchitis.

Pouchitis was defined as a score of ≥ 7 using an 18 points Pouchitis Disease Activity Index (PDAI), which includes clinical, endoscopic and acute histological criteria (Table 1).11

Table 1.  . Pouchitis disease activity index (PDAI) Thumbnail image of

Chronic pouchitis was defined as continuous symptoms for more than 4 weeks and the need for drugs (antibacterial/anti-inflammatory drugs) for more than 15 days per month in order to control symptoms.

Treatment-resistance was defined as no response after treatment with antibiotics (such as metronidazole, or ciprofloxacin or amoxycillin/clavulanic acid) for at least 4 weeks.

Failed therapy during the current pouchitis flare, included metronidazole 1.2 g o.d. (12 patients); amoxycillin/clavulanic acid 1 g b.d. (four patients) and ciprofloxacin 500 mg b.d. (two patients).

Eighteen patients (eight females, 10 males; median age 33 years, range 20–44) with chronic treatment-resistant pouchitis, and chronic ongoing symptoms, were studied. Mucosal inflammation, determined by endoscopic examination, was limited to the pouch and did not extend into the ileum proximal to the pouch.

The median follow-up time after pouch surgery was 54 months (range 9–123) and the median follow-up from onset of pouch function was 37 months (range 9–86).

Patients with clinically important hepatic, renal, cardiovascular or psychiatric conditions, patients with perianal disease (abscess, fistula, fissure and anal weakness) or stricture were excluded.

This study was approved by the Local Ethical Committee and all patients gave their consent.

Study drugs

Rifaximin (Alfa-Wassermann, Bologna-Italy) was administered as five tablets of 200 mg b.d. for 15 days.

Ciprofloxacin was administered as 1 tablet of 500 mg b.d. for 15 days.

All patients discontinued antibacterial treatment therapy on entry to the study.

Compliance was checked by the study personnel; patients were considered non-compliant if they consumed less than 75% of the study drug during their actual treatment period.

Evaluation and scheduling

Symptoms assessment, endoscopic and histological evaluations were performed at screening and after 15 days using the PDAI score. Patients demography, medical history and physical examination were recorded.

Endoscopic mucosal biopsies were taken in the pouch from areas that appeared to have the most active inflammation.

During the treatment period, patients recorded the following each day: number of stools, rectal bleeding, faecal urgency or abdominal cramps, fever and any new symptoms.

Safety assessment

Laboratory screening, including a complete blood count and blood chemistries, was performed at baseline and at the end of treatment.

All unfavourable, unexpected symptoms or signs reported by the patients were recorded in the patient's diary.

Microbiological determination

Faeces were collected from each subject before taking the antibiotics and immediately after stopping treatment. The specimens were collected into sterile plastic containers and stored at –20 °C until assayed. Faecal samples were homogenized and serially diluted in an anaerobic cabinet (Anaerobic System, Mod.2028, Forma Scientific Co, Marietta, OH) with half strength Wilkins Chalgreen anaerobic broth (Oxoid, Basingstoke, UK). Plates were incubated in triplicate using selective media for enumeration of total aerobes (Nutrient agar, Oxoid, Basingstoke, UK), total anaerobes (Schaedler agar, Oxoid, Basingstoke, UK), enterococci (Azide maltose agar, Biolife, Milano, Italy), coliforms (MacKonkey agar, Merck, Darmstadt, Germany), Bacteroides (Schaedler agar plus vancomycin and gentamycin, Oxoid, Basingstoke, UK), bifidobacteria (PYG, plus polymyxin [50 μg/mL] and kanamycin [50 μg/mL]), Clostridium perfringens (O.P.S.P., Oxoid, Basingstoke, UK). Plates were incubated aerobically or anaerobically as appropriate. The lower limit of detection was 10 microorganisms/g faeces.

Pharmacokinetic study

Before the trial was initiated (time 0) a reference sample of plasma and urine was collected. Final plasma samples were obtained at 08.00 hours on the 16th day, 12 h after the last drug administration, and stored in two aliquots at –20 °C until determination. A 24-h urine collection was performed from 08.00 hours on the 15th day (last administration day) to 08.00 hours on the 16th day. Determination of rifaximin in plasma and urine was performed by reversed-phase high performance liquid chromatograph (HPLC) with electrochemical detection after extraction of rifaximin from plasma and urine as described previously.12

The method's limit of rifaximin quantification had been calculated at 2 ng/mL.

Statistical analysis

The primary measure of efficacy was the comparison of the pre-treatment PDAI and post-treatment PDAI, with remission defined as a reduction in the PDAI to 0 and improvement defined as a reduction in the PDAI by at least three points.

Pre-treatment and post-treatment histology scores and laboratory parameters were also compared.

The Wilcoxon signed rank test was used to compare pre-treatment and post-treatment PDAI scores.

The Mann–Whitney U-test was used to compare pre-treatment and post-treatment faecal concentration of different bacterial groups.

RESULTS

Baseline characteristics of patients are shown in Table 2.

Table 2.  . Baseline characteristics of patients Thumbnail image of

No patients withdrew from the study and all patients were compliant. Sixteen out of 18 treated patients (88.8%) either improved (n=10) or went into remission (n=6) after 15 days. The median PDAI scores before and after therapy were 11 (range 9–17) and 4 (range 0–16), respectively (< 0.002). Figure 1 shows the changes in total PDAI score for all treated patients; as it can be seen there was a significant decrease in the overall PDAI score in 16 out of 18 patients which was the result of a significant decrease in the score of either the clinical symptoms (median [range]; before therapy: 4 [3–6]; after therapy: 0 [0–6] [< 0.02]) or the sigmoidoscopic (4 [3–6] vs. 1.5 [0–6] [< 0.02]) or histologic (4 [3–5] vs. 2 [0–5] [< 0.02]) portion of PDAI. The two non-responding patients were not the two patients previously resistant to ciprofloxacin.

Figure 1.

. PDAI scores modification before and after antibiotic therapy.

Microbiological results

Table 3 shows the bacterial counts in faecal samples obtained before and after treatment; it can be observed that treatment with ciprofloxacin and rifaximin determined a significant decrease in total anaerobes and aerobes, of enterococci and lactobacilli (< 0.01) and, to a minor extent, in bifidobacteria and bacteroides (< 0.05), while the reduction in number of coliforms and Clostridium perfringens did not reach a statistical significance.

Table 3.  . Bacterial counts in faecal samples in patients with active chronic pouchitis before and after combined antibiotic treatment Thumbnail image of

Pharmacokinetic results

Twelve hours after the last dosing of rifaximin, the drug was not detectable in any of the plasma samples.

In 24 h urine samples after 15 days of treatment, a very limited amount of the unchanged active principle was found (median [range]: 24.563 ng/mL [0–134.181]).

Safety

Administration of the antibiotics was well tolerated.

No side-effects and no significant changes from baseline values in any of the laboratory parameters examined were registered.

DISCUSSION

The results of this open study suggest that the asso- ciation of ciprofloxacin (500 mg b.d.) and rifaximin (1 g b.d.) is safe and effective in patients with chronic pouchitis. These results are particularly striking when considering that the studied patients had chronically active pouchitis resistant to therapy.

Treatment of pouchitis is empirical and broad-spectrum antibiotics are the mainstay of treatment. Most patients have a good response to metronidazole, which reduces the bacterial counts of bacteroides13 and the leucocyte infiltration in the pouch.14 One double-blind placebo-controlled trial showed a significant reduction in bowel movements, without improvement of endoscopic appearance or histological grade of activity.10 No attempt has been made to compare metronidazole with other modes of therapy. About 15% of patients with pouchitis have a chronic disease, either a treatment responsive form, which requires maintenance metronidazole therapy, with a high incidence of side-effects, such as disgeusia, nausea and peripheral neuropathy (occurring in up to 80% of patients over 6–12 months), or a treatment-resistant form that does not respond to the antibiotic treatment.9 Alternative approaches have been tried in patients resistant to antibiotic treatment such as corticosteroid3 or 5-aminosalicylic enemas15 and short chain fatty acid enemas,16 with only some clinical benefit. More recently an open study suggested the efficacy of long-term treatment with bismuth–carbomer enemas,17 while in a 3-week controlled trial, bismuth–carbomer foam enemas were not more effective than placebo.18

Treatment with ciprofloxacin + rifaximin in this study, in contrast, resulted in a significant improvement in clinical symptoms, endoscopic and histological activity, together with a significant decrease in bacterial counts in faecal samples of total anaerobes and aerobes and of some important Gram-positive and Gram-negative bacterial groups.

Rifaximin is a rifamicyn derivative with a wide antibacterial spectrum against Gram-positive and Gram-negative, both aerobic and anaerobic.19, 20 After oral administration it undergoes virtually no systemic absorption and is almost totally excreted in faeces,12, 21, 22 and pharmacokinetic results of this study confirms its mainly topical antibacterial activity, even when administered at very high dosage. Recently rifaximin was shown to be useful in patients with steroid-refractory severe ulcerative colitis.23 Ciprofloxacin is active against a broad spectrum of Gram-positive and Gram-negative microbes, and is found in considerable amounts in the stool.24, 25 Recently ciprofloxacin has shown promising results in treatment of active Crohn's disease, either alone26 or in combination with metronidazole.27

In conclusion, the combination of rifaximin and ciprofloxacin is effective in patients with chronic pouchitis resistant to treatment, suggesting the need, for these patients, of treatment with antibiotic agents with a wide antibacterial activity against either Gram-positive and Gram-negative or anaerobes and aerobes.

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