Antibiotics

After an initial report that metronidazole "closed" perianal fistulae in three patients [16], the drug was frequently used in the management of fistulizing CD. However, most studies on its efficacy were on small numbers of patients and were uncontrolled (Fig. 3).

Bernstein et al. [17], in an open study with metronidazole 20 mg/kg/day on patients with longstanding perianal fistulae, observed an initial clinical response in 20/21, with complete healing at 8 weeks in 56% of cases. However, at follow-up, 78% of these patients recurred 4 months after discontinuation and only 5 of 18 patients could discontinue the metronidazole [18]. Other open studies with metronidazole confirmed closure rates of perianal Crohn's fistula of 35-50% [19-21]. Clinical improvement is usually seen within the first 6-8 weeks. So far, no controlled trials have been performed on the short and long-term efficacy of metronidazole on fistulae healing. Based on a cost-utility analysis [21], metronidazole in combination with an immunomodulatory medication, such as azathioprine (AZA), may be the most cost-effective initial therapy for fistulizing CD. Metronidazole is often poorly tolerated because of adverse effects including paresthesias, dyspepsia, a metallic-taste and a disulfiram-like response to alcohol. Peripheral neurological dysfunction has been demonstrated by physical examination and nerve conduction studies in 85% of patients, although almost 55% were asymptomatic. Peripheral neuropathy improved or resolved in 90% after antibiotic discontinuation [22].

Because of the toxicity of metronidazole, ciprofloxacin is often used, even though no controlled trial of this drug for fistulizing CD has been reported. Turunen et al. [23] first reported the use of ciprofloxacin in eight patients with perineal CD refractory to metronidazole. All patients improved with 1-1.5 g/day of ciprofloxacin for 3-12 months; however, four of eight had persistent perianal drainage and several required surgery. Recurrences of fistulae were frequent but usually responded to the restarting of ciprofloxacin.

A retrospective analysis of combination of ciprofloxacin (1 000-1 500 mg/day) and metronida-zole (500-1 500 mg/day) on 14 patients, produced a clinical improvement in nine and fistula closure in three. Again, prompt recurrence of the disease was seen after cessation of therapy [24].

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