Antibiotics such as ciprofloxacin and metronidazole are the most commonly prescribed treatment for pFCD in spite of the lack of evidence from placebo-controlled trials . They are prescribed as both a primary treatment and as a secondary treatment for complications such as abscesses that arise from fistulas. In one of the earliest published case series by Bernstein et al., 10 of 18 Crohn’s patients (56 %) with perineal disease demonstrated complete healing with a 10-week course of metronidazole [10]. Topical 10 % metronidazole ointment has also been studied in 74 patients in a randomized placebo-controlled study, suggesting a beneficial effect on perianal discharge and pain [11]. Nevertheless, the majority of patients experience a recurrence of perineal disease months after metronidazole cessation. In the only randomized, double-blind, placebo-controlled trial involving antibiotics, there was a trend towards clinical remission and response occurring more frequently in the group treated with ciprofloxacin compared to patients treated with either metronidazole or placebo [12]. However, this trial was underpowered (n = 25) and the majority of patients assigned to the metronidazole arm did not complete the prescribed 10-week course.

Evidence suggests that combination antibiotic therapy with anti-tumor necrosis factor α (anti-TNF α) therapy provides additional symptomatic benefit. In a double-blind, placebo-controlled trial, 76 CD patients with active perianal fistulizing disease were randomized to either adalimumab (ADA) monotherapy or ADA and ciprofloxacin for 12 weeks after ADA induction [13]. A significantly higher number of patients demonstrated both a partial (71 % vs. 47 %, p = 0.047) and complete (65 % vs. 33 %, p = 0.009) clinical response of fistula closure at 12 weeks in the combination therapy group. While the difference in fistula closure rates was not maintained at 24 weeks, the trend in favor of combination therapy remained. In a similarly designed study with IFX and ciprofloxacin , patients treated with combination therapy tended to have a better clinical response at week 18 (OR = 2.37 [0.94–5.98], p = 0.07) [14]. Accordingly, antibiotics should be used as a co-induction agent in pFCD with ciprofloxacin being better-tolerated than metronidazole .

Although historically the daily recommended doses for 6-mercaptopurine (6-MP) and azathioprine (AZA) have been 1.5 and 2.5 mg/kg respectively, the ideal dosing regimen or optimal thiopurine metabolite levels are unknown in the setting of pFCD. In one of the first randomized, double-blinded studies of thiopurines, there was a trend towards fistula closure in the 6-MP group (31 % vs. 6 %) [15]. Subsequently, a meta-analysis of 6-MP and AZA use in CD demonstrated that fistulae improved with therapy (OR 4.44 [1.50–13.20]) [16]. While data exists for the use of thiopurines as maintenance treatment for pFCD, they are second-line therapies when compared to anti-TNF α drugs and are best used as concomitant therapy.

Calcineurin inhibitors have been used with modest benefit in cases of medically refractory pFCD. In both a randomized placebo-controlled trial and small pilot study of oral tacrolimus, tacrolimus-treated patients were significantly more likely to experience fistula closure that was documented clinically in the former study and radiologically by MRI in the latter [17, 18]. Topical tacrolimus was also explored in a small randomized, placebo-controlled study of 12 patients with pFCD [19]. Only one of six patients in the active treatment group had a complete response defined as cessation of drainage of all fistulas after 12 weeks. Evidence for the use of cyclosporine is equally sparse. In a case series of nine patients with fistulizing CD, the majority initially responded to IV cyclosporine, but after transitioning to oral cyclosporine and subsequent discontinuation, only two patients remained in prolonged remission [20]. The authors postulated that this outcome related to the inadequate overlap of concomitant therapy with either 6-MP or AZA prior to the withdrawal of cyclosporine.