Medical Interventional Treatment of Adult Fistula-in-ano. a Pilot Study for Curative Response of Intra-tract Injections of Ceftazidine and Metronidazol

The treatment of fistula in-ano is surgical but not always. Considering the recurrence and incontinence, alternative medical interventions may berequired. 25 (18 males, 7 females) cases of referral perianal fistulas recruited in a randomized interventional clinical trial in hospitals affiliated to Jundishapour University, Ahwaz-Iran. The participantshave been managed in three groups regardless of the type, age and gender by intermittent multiple intra-tract injections of selective drugs: Sodium Tetra Decyle Sulphate (STDS,1%), Metronidazol and Ceftazidine during 15 months and were followed by ten months of treatment. 16 cases (64%) were completely cured for 10 months of fallow up. 9 cases (36%) were recurred and referred for surgery. Metronidazol + Ceftazidim (5 cures versus 2 recurrences and 71.42% success) with STDS + Metronidazol (7 cures versus 3 relapses with 70% success) were more effective respectively. STDS + Ceftazidim group resulted in 4 cures versus 4 recurrences with 50% success. There were no significant differences between cured and recurrent fistulas considering gender, age, duration of involvement, number of injections, length of fistula and distance from anal verge. There was a significant relation between recurrence and anterior type of fistulas in the study (P = 0.023). Direct injection of selective drugs and antibiotics iscurative and effective in treatment of perianal fistulas as the first step. Anterior fistulas, cavitated active fistulas and lack of patient's consent should not be considered.


INTRODUCTION
Perianal fistulas are mostly easy but difficult to imitate as a surgical treatable entity.Determination of the type and the pathway of this prevalent complication of cryptogenic perianal abscess for selecting the wide range of treatment from simple fistulotomy toward mucosal flap advancement or even diversion of rectum, is necessary.As surgery is the best treatment, both fistulotomy and fistulectomy are now commonly performed surgical procedures, however, in such procedures anal continence as the goal treatment and a full healing response may not be achieved [1][2][3][4] .On the other hand, high, posterior curved, unilateral multi-orifice, bilateral multi-orifice (horseshoe) and recurrent fistulas are typically problematic and the sphincteric continence would be endangered by repeated surgeries.Complicated fistulas are currently best treated by different invasive and noninvasive combined medical-surgical procedures.Yet, as a general concept, all these procedures besides other new techniques may notprovide the ultimate for cure in all 3 ; nevertheless, they have to be accomplished though as a rule, whenever the continence is being endangered, should regress and choose an alternative treatment strategy.Currently, there is no convincing accepted medical procedure alone as an alternative.Application of local antibiotics, chemotherapeutic drugs into the fistulas with inflammatory bowel disease (IBD), Fibrin glue injection and mixed seton or threads placement are examples of current treatment options.The main advocated advantages of individualized non-surgical minor invasive medical treatments are preserving anal continence in spite of long-lasting healing processas compared to surgery.Their effectiveness varies, howeverthey are nowbeing considered particularly in treatment of IBD.The aimof this study was to establish the efficiency and of direct local intra-tract injection of selective antiseptics as an independent treatment for fistula in-ano.

METHODS
This is a case series, interventional clinical study of selected cases for the study of referrals in our surgical clinics affiliated to Jundishapour University of Medical Science, Ahwaz-Iran.During 15 months from August 2011 to November2012, patients referred for treatment of perianal discharges diagnosed as perianal fistulas by physical examination with their agreement and consent for this type of treatment were selected.Thirty patients were randomized in three groupsregardless of age, gender and type of the fistula and were followed 10 months for complete cure.5 cases were excluded due to g late abruption to continue and poor compliance to the study protocol.Short anterior epithelialized superficial fistulas (up to 20 mm length) and active cavitated post abscess types and others with underline disease (IBD) were also in the study exclusion criteria.Firstly, fistulas were probed by a fine blunt head semi-flexible plastic probe to find the direction, height and the length accompanied with injection of Povidin Iodine for determining the level of internal orifice during proctoscopy in outpatient.Three groups of drugs were selected on the bacterial basis of colorectal region for intra-tract direct injections at random; first, Sodium Tetra Decyl Sulphate (STDS) and Ceftazidim; second, STDS and Metronidazol; third, Ceftazidim and Metronidazol.We speculated thatSTDS has the ability to abrade internal tract epithelialization as a resistant ground and also a sclerosing detergent which could reinforce antibiotics to accelerate granulation and healing.Injections were performed very slowly about minutes through a fine blunt head injector needle to lodge the drug copiously into the tract, in amanner of "every other day injection" intermittently, which were followed twice weekly on the basis of discharges.For Metronidazol drip injection by the set from the external orifice was used.Following weeks, injections were continued until external orifice was being closed and its over skin was completely healed.Patients were followed up for early and late recurrence during the first and second week followed by monthly follow up until 3 and every two months for 6 months respectively; unless any discharges were reported.For recurrence, if the external orifice was active after injections,the second cycle was repeated until closure.In instances where recovery was not achieved or the patient did not accept the second session, patient was accounted as un-responsive and was referred for surgery.Cure was accepted as complete asymptomatic patient for at least over 10 months.The data were calculated and analyzed by independent sample test, T test, Spearman'scorrelation, Chi-square test where p<0.05 was considered statistically significant (Pearson, Fisher) through the SPSS software.

RESULTS
There were 18 (72%) Male and 7 (28%) female, 28 -63 (mean: 40.96) years old with 6 anterior and 19 posterior fistulas in which 15 were trans sphincteric and 10 Inter-sphincteric with short distance from anal verge (about:1.3-3.6 Cm, mean: 2.428) without supra or extra-spincteric or high type fistula .All were uni-tract with single orifice.Their internal orifices were juxta-dentate or below the dentate line mostly lateral and postero-lateral.The length of tract was between 28 -57 mm (mean: 42.04).Duration of involvement until referral was 2 -27 (mean: 5.76) months.The numbers of injections were between 6 -14 (Mean: 8.92).There wereno complication and all of the symptoms of pain, inflammation, and discharges were dramatically subsided until the termination ofinjections and days before recurrence and patients were satisfied., 8 patients had intra tract injections of STDS + Ceftazidine in whom 4 were completely cured and 4 had recurrence after between1-3 months (50% success) and 2 missed follow up.In second group, 10 patients were injected with STDS + Metronidazol that 6 of them had cure by first session of injections in follow up, however, 4 patients recurred after approximately 1-4 months.Two of recurrent fistulas received 5 and 8 times second session re-injections due to very low discharges and one cured untilfollowed up (70% success).Other 3, referred to surgery after 3 months for bulging and new Recurrence× type of fistula (Pearson chi -square P = 0.013 ) P = 0.023 Gender × type of fistula P = 0.298 Gender × Recurrence P = 0.378 symptoms.In the third group, 7 patients received Ceftazidine + Metronidazol injections.Five patients were cured and 2 had relapses (71.42% success)(Table1).One patient was a case of previous fistulectomy with two recurrences and re operation by seton placement during 20 months wherethe main tract was cured but has been referred again with an accessory tract in posterior side near the border of coccyx after 7 months.Overall, 16 (64%) patients were cured and had no symptom during 10 months of follow up and 9 (36%) relapsed.Of patients who had recurrence, relapse intervals were in between 3 to16 weeks from recovery.From those were relapsed 5 fistulas (55.5%) with the length of 29-40 mm were anterior type and 4 (44.4%) were posterior with the length of 37-50 mm.There were no complications or incontinence.Comparing the results, there were no significant differences between cured and recurrent fistulas considering gender, age, duration of involvement, number of injections, length of fistula and distance from anal verge (Table2).However, there was a significant relation between recurrence and anterior type of fistulas in the study (P = 0.023) and gender had no meaningful difference compared to recurrence and the type (Table3).

DISCUSSION
Treatment of fistula-in-ano has a fluctuated remedy, originated from multi factorial causes that directly affect the therapeutic outcome.Selective therapeutic protocols depend on fistula's anatomy and patient's habitual conditions .Long lasting constipation, high protein-fat diets and crypt bacterial reservoir are existing factors that facilitate resistance against healing.Having their considered, insight necessitates changing the glance more towards medical interventional remedy for most fistulas.Since, ancient medicine had experienced the thought of using thread or seton weltering to materials working as antiseptics for managing the fistula in ano, medical interventions had been propounded (Ksharsootra by Indian physician Sushruta in the 600 BC) 1,5 .Although, nowadays, surgery alone is the promising ultimate cure in simple fistulas however, saving the continence as a rule, has withdrawn it in the complex types.For instance, advancement flap is considered the gold standard for complex fistula; however it is associated with up to 31% post operative minor incontinence and also more than 12% major incontinence 3 .The procedure fails in one inthree patients 6 , which are about 2-5 times more than fistulotomy -fistulectomy with or without seton 7 .Seton placement alone has been substantially more effective in complex type with least incontinence 8 .Furthermore, sphincter saving procedures like plug placement, ligation of intersphincteric fistula tract (LIFT), Bio LIFT and stem cell injections are associated with technical disadvantages and were not trialed in details to be used with confidence as the standard methods 3,9,10 ; although, advocated reports are available [11][12][13] .Application ofalternative medical interventional treatments has been also well introduced.Fibrin Glue injection postulated that it possess safe and feasible usage in infants and children 14 ;However, in adults have been shown to have led to unsatisfactory outcomes compared to staged mucosal flap surgery in complex and IBD base fistulas 15,16 .Furthermore, the glue is accepted to be mostly promising in comparison to conventional surgery especially in simple fistulas 16,17 and even alone without accompanied procedures 18 .Its presented overall success was 83.3% 19 and 67.6% in high fistulas 20 .Yet, antibiotics are not clinically postulated to be directly curative alone in fistula but their effects were advocated for use, especially about Metronidazol and Silver phosphate 6,21 .As etiology, bacterial colonization and active internal recto-fistula communication besides following tract epithelialization are three well known important causes for corrupting the healing and closure of the fistula.In general, destruction of any two, leads to repair and omission of fistula in a controlled ground.Antibiotics in such circumstances are supplementary alternatives.We believe that if bacterial colonization and tract epithelialization is eliminated successively, internal mucosal orifice would rapidly repair and internal communication will cut.Since, STDS is a sclerosing drug, it has been used to destroy the tract epithelial cobblestone and also support antibiotics to suppress the bacterial overgrowth.Therefore, the ground for granulation formation will be facilitated to progress and thus, the tract will be obliterated and fibrosed.Based on our results, similarly, both STDS + Metronidazol group and Ceftazidine + Metronidazol were shown to be more effective in fistulas medical treatment (70 & 71.4% success rate respectively) with less recurrence compared to group.This may insist on the substantial role and direct effect of Metronidazol compared to ceftazidine.On the other hand, from the point of recurrence, the sum of relapses (5 recurrences of 6 anterior types) was strongly correlatedto anterior type fistulas according to Goodsal law (P = 0.023)( table3).Presumably, straight and shorter pathway of anterior types as they were in the lower range of tract length (29-40 mm), with more fecal or infected drainages due to fast epithelialization, play a role in tract resistance.Overall, in the study, lackof incontinence and independent treatment success rate of 64% are acceptable.Consequently, it can be suggested that mixed selected antibiotics will be optimistically effective in the first step of treating fistula-in-ano among selective situations.However, since the patients requested to be free of symptoms and persuading into full recovery immediately, they have to be explained for long lasting.To avoid leastcomplications, safe suggestion would be: patient selection, step treatment and close follow up.
Step treatment can be medical material injections (selective antibiotics as was shown in the study or alternatively fibrin glue), seton placement (cutting 22 or simple), fistulotomy or fistulectomy "using manometry" respectively.For recurrence or incontinence as complex fistulas: fistulotomy and simultaneously sphincter repair 23,24 , LIFT, advancement flaps and plugs, based on surgeon's experiences is suggested.In addition, we believe However this would require further studies to investigate in more population.