Aliment. Pharmacol. Therap. (1990), 4, 123-129.
The eficacy of tobramycin in the treatment of ul cerafive co1itis
D. A. BURKE, A. T. R. AXON, S. A. CLAYDEN," M. F. D I X O N , t D. J O H N S T O N * & R. W. LACEY" Gasfroenferology Unit, and Universify Departrnenfs of Surgery, " Microbiology, and t Pathology, The General Infirmary, Leeds
*
Accepted for publication 6 October 1989
SUMMARY
This paper reports a double-blind placebo-controlled trial of oral tobramycin in acute ulcerative colitis. Eighty-four patients with an acute relapse of ulcerative colitis were randomized to receive oral tobramycin or placebo for 1week as an adjunct to steroid therapy. At endpoint, 31 of 42 (74%) in the tobramycin group achieved complete symptomatic remission compared with 18 of 42 (43%) in the placebo group (P = 0.008). The tobramycin group achieved better histological scores (P < 0.05) at endpoint. These findings show that treatment with oral tobramycin improves the short-term outcome of patients with ulcerative colitis in relapse. INTRODUCTION
The aetiology of ulcerative colitis is unknown, but some of the clinical and pathological features are similar to infectious colitis. Experimental colitis cannot be produced in germ-free animals, which suggests that a component of the faecal flora is necessary for its development.' Pre-treatment of animals with metronidazole has been shown to prevent the development of experimental colitis' and in other
Correspondence to : Dr A. T. R. Axon, Gastroenterology Unit, The General Infirmary, Leeds LSI 3EX, UK. Dr D. A. Burke is now Senior Registrar at the Royal Victoria Infirmary, Newcastle NEI 4LP, UK.
123
124
D. A. B U R K E et al.
studies the mortality rate and severity of the lesions was limited using antibiotics active against Gram-negative organisms.2’ In man, various antibiotics have been included in treatment regimens, but the choice of agent has usually been empirical. Metronidazole, an antibiotic active against anaerobes, and vancomycin, which is active against many Gram-positive organisms, are the only agents that have been subjected to a controlled trial.4” Neither agent was found to be of benefit. However, antibiotics active against Gramnegative organisms (other than sulphasalazine) have not been formally tested in ulcerative colitis. This study was performed to assess whether any benefit might accrue from antibiotic treatment directed at Gram-negative organisms in acute ulcerative colitis. The aminoglycoside, tobramycin, was chosen and used orally as an adjunct to steroid therapy in a double-blind placebo-controlled trial.
PATIENTS A N D METHODS Ethics Committee approval was given, and each patient‘s informed consent was obtained before entry to the study.
Confrolled trial Consecutive patients who presented to the inflammatory bowel disease clinic at Leeds General Infirmary, over a 2-year period with an acute attack of colitis, were considered for entry with the following exclusions : patients known to have Crohn’s disease, those who had received antibiotics within the preceding 2 months (other than sulphasalazine), patients with fulminant disease, pregnant or lactating females, patients with renal impairment and those with evidence of an infective diarrhoea. Patients were randomized to receive either 120 mg oral tobramycin t.d.s. or placebo for 7 days as an adjunct to steroid therapy. Patients who were already receiving sulphasalazine were allowed to continue on this drug. The dose and mode of delivery of the steroid was decided by the supervising clinician who allocated them to receive either hydrocortisone enemas (Colifoam, Staff ord-Miller Ltd) or 30 mg prednisolone daily for 1 month as an out-patient, or 60 mg prednisolone (or intravenous equivalent of hydrocortisone) daily as an in-patient depending on the severity and extent of their disease. The in-patient steroid dosage was reduced according to a predetermined protocol in keeping with our current practice. The initial dose of prednisolone for in-patients was reduced at 72-h intervals by 10 mg until a dose of 30 mg was reached and then by 5-mg decrements to 15 mg, provided that bowel frequency was less than or equal to 3 per 24 h, there was absent to mild pain and malaise, no weight loss of greater than 1 kg, a temperature of less than 37.5OC, and the pulse rate remained less than 90 per minute. Randomization was stratified in blocks for each of the three treatment groups,
TOBRAMYCIN I N ULCERATIVE COLITIS
125
that is in-patient, out-patient with systemic steroid, or out-patient with steroid enema. They were further stratified for first attack or relapse. Patients were assessed clinically and sigmoidoscopically with rectal biopsy at entry, 7 days, and at an end-point of 21 days for in-patients and 28 days for outpatients. A clinical assessment of severity based on the Truelove and Witts criteria7was made on entry to the study. At endpoint patients were considered to be in symptomatic remission if their bowel actions were less than 3/day without blood, there was no malaise, abdominal pain, anorexia, vomiting, abdominal tenderness, fever, or any complication or active extraintestinal manifestation of ulcerative colitis. Sigmoidoscopic appearances were scored: 0 = normal; 1 = loss of vascular pattern but no granularity; 2 = granularity; 3 = granularity plus contact bleeding; 4 = spontaneous bleeding, friability and frank ulceration. Rectal biopsies were taken to obtain an independent histological activity score at each assessment point. Histological scoring was as described previously’ using a scale of 0-3 for mucus depletion, surface degeneration, and polymorph infiltration. Thus the total active inflammatory score ranged from 0-9, and was determined by MFD without knowledge of the clinical severity, treatment, or the source and timing of the biopsy. At entry and endpoint, stool and was also examined for the presence of recognized pathogens including Clostridium dificile and its toxin, Yersinia enterocolitica, Yersinia pseudotuberculosis, and Entamoeba hisfolyficainfection were excluded by serology.
Statistical mefhods Student’s t-test was used to assess differences between groups where data was measured on an interval scale and the Mann-Whitney U-test for data measured on an ordinal scale. For differences in frequency the Chi-square test was used and, when numbers were small, Fisher’s exact probability test. All P values are for twotailed tests. RESULTS Eighty-four patients (45 males, 39 females) with ulcerative colitis in relapse were recruited. Four patients, two with known ulcerative colitis but who had Campylobacfer enteritis, one patient who did not wish to enter, and one elderly patient with diabetes mellitus and renal impairment were excluded. The effect of randomization is shown in Table 1. At endpoint (21-28 days after the start of the study), one patient from each group had failed to attend for follow-up and one patient from each group had required surgery during the trial period. The two groups were well-matched. There was no significant difference between the clinical, histological or sigmoidoscopic scores at entry.
126
D. A. B U R K E et al.
Table 1. Details of patients in study. All differences are not significant
Males Females Age (years) Length of history of ulcerative colitis (years) Length of history of present relapse (weeks) Extent of ulcerative colitis Proctitis To splenic flexure Extensive First attack Relapse Severity" Mild Moderate Severe Treatment groups In-patients Prednisolone 60 mg Out-patients Prednisolone 30 mg Out-patients hydrocortisone
Tobramycin
Placebo
21 21 43.5 f15.8 5.6 5.8
24 18 43.3 7.5
11.2 f12.4
11.6 f13.4
I2 11 19 4 (IP) 6 (0) 13 (IP) 19 (OP)
10 16 16 6 (IP) 4 (OP) 10 (IP)
7 32 3
9 32 1
17 14 11
16 16 10
15.7 8.8
22 (OP)
IP = in-patient; OP = out-patient. * Criteria of Truelove & W i t t ~ . ~
Thirty-one patients in the tobramycin-treated group had achieved complete symptomatic remission compared with 18 in the placebo group ( P = 0.008), and seven had a histological score of 0 compared with none in the placebo group P = 0.025. The histological scores were significantly lower in the tobramycin group (Table 2) P < 0.05. The sigmoidoscopy scores in the tobramycin group, although lower than those in the placebo group, did not reach statistical significance. There was no significant difference in the amount of steroid received by the two in-patient groups or the number of patients continuing treatment with sulphasalazine. Three patients in each in-patient group were given 5-amino salicyclic acid enemas towards the end of the treatment period because of residual distal disease, and two patients in the tobramycin group and one patient in the placebo group received azathioprine to enable further reduction in steroid dosage towards the end of the trial period. The serum concentration of tobramycin at 7 days (mean 1.1If;:0.2 s.d. pglrnl) remained below the lower limit of the therapeutic range and well below potentially toxic levels.
TOBRAMYCIN IN ULCERATIVE COLITIS
127
Table 2. Results of scores for sigrnoidoscopy and histology (mean & s.d., median)
Sigmoidoscopy score Day 0 Day 7 Endpoint Histology score Day 0 Day 7 Endpoint
Tobrarnycin
Placebo
3.5 0.7 (4) 2.2 11.2 (2) 1.3 1.5 (0.5)
3.4k0.7 (4) N.S. 2 . 7 k 1.0 (3) N.S. 1 . 9 11.5 (2) N.S.
5.5 f2.7 (7) 4.4 & 2.7 (4) 2.8f2.5 (2)
6.412.1 (6) N.S. 5.5 2.7 (6) P = 0.06 4.0 f2.6 (3) P = 0.03
N.S. = Not significant.
Although the oral preparation of tobramycin has a slightly unpleasant taste, all patients completed their treatment. No side-effects were noticed and Clostriditrm dificile, or its toxin, was not detected in the endpoint sample. If we consider those patients who presented in their first attack, 10 of 10 patients in the tobramycin group compared with 6 of 10 patients in the placebo group achieved complete symptomatic remission by the endpoint ( P = 0.04).
DISCUSSION It is often difficult both clinically and histologically to distinguish ulcerative colitis from infective colitis9~''in the early stages of the disease. Inflammation is limited to the colon with its abundant microflora, and it is difficult to induce experimental colitis in germ-free animals.' A number of studies have shown that the condition may follow attacks of infective A recent report has shown that 25 % of individuals who return from the tropics with chronic diarrhoea have inflammatory bowel disease.14 These data suggest that an infective agent might be involved in the pathogenesis of ulcerative colitis, but no one pathogenic organism has been regularly identified in the majority of cases of ulcerative colitis. E. coli from patients with ulcerative colitis have been shown to differ qualitatively from those isolated from controls. Cooke demonstrated that E. coli from patients were more likely to produce haemolysin and necrotoxin, and more commonly possessed the ability to dilate rabbit ileal ~ O O P S . ' ~A significant proportion of E. coli from patients with ulcerative colitis has also been found to possess adhesive properties not found in those isolated from controls.'6~17 Higher titres of antibodies to E. coli" and E. coli antibodies that cross-react with the colonic epithelium" have been found in patients with ulcerative colitis. Cellular cytotoxicity to colonic epithelium can be induced in lymphocytes exposed to an E. coli lipopolysaccharide extract." This was one reason why the present study was undertaken using an antibiotic active against Gram-negative organisms and in particular E. coli.
128
D. A. B U R K E et a/.
The aminoglycoside tobramycin was chosen because it is known to be active against Gram-negative organisms that include E. coli, but leaves the majority of anaerobes that form the bulk of the faecal flora intact” and is known to be minimally absorbed from the colon. Furthermore, few coliforms are resistant to tobramycin, and the drug is not routinely used in the community or within our own hospital, thus we were unlikely to encounter bacterial resistance to this drug. The protocol used in the trial was designed to mirror our current practice in the management of ulcerative colitis both with regard to the mode of delivery and the dose of steroid. The endpoint assessment time for out-patients (28 days) was chosen to comply with our routine out-patient review period and the in-patient endpoint (21 days) was chosen to avoid unnecessary hospitalization if patients responded optimally. The results show that patients with ulcerative colitis in relapse, given a weeks oral tobramycin in addition to conventional steroid treatment, did better in the short-term than those given steroids alone. A substantially higher proportion of those who received tobramycin achieved complete symptomatic remission. This achievement was mirrored by that seen with independently assessed histological data. These differences are more relevant when viewed in the context that the improvement was over and above that obtained by conventional steroid therapy, which is itself an effective treatment for this condition. There have been few controlled trials of antibiotic therapy in ulcerative colitis, but antibiotics have often been included in treatment regimens. A similar study with oral vancomycin6did show a trend in favour of the antibiotic-treated group but did not reach statistical significance. The Oxford group5 initially included intravenous tetracycline in their treatment regimen and latterly intravenous metronidazole, until a controlled trial showed that this was of no benefit.4 It is tantalizing to speculate that the better results obtained in the test group are as a result of eliminating E. coli that might be either provoking or aggravating a relapse. More work is needed before this hypothesis can be advanced. It may be that the antibiotic conferred some benefit unrelated to any effect on E. coli. This study shows that the use of an aminoglycoside as an adjunct to conventional steroid therapy improves the clinical outcome in the short-term. Whatever its mechanism of action, the general use of aminoglycosides in ulcerative colitis may improve the short-term outlook of patients with ulcerative colitis. Further independent studies are needed to confirm these observations. ACKNOWLEDGEMENTS
We gratefully acknowledge a research grant from Eli Lilly & Company Limited. We would like to thank the Special Trustees of the General Infirmary, Leeds, for supporting Dr Burke under their Research Scheme, and Mrs Olive Bell for typing the manuscript.
TOBRAMYCIN I N ULCERATIVE COLITIS REFERENCES I Onderdonk A 8, Bartlett J G. Bacteriologi-
cal studies of experimental ulcerative colitis. Am J Clin Nutr 1979;32:258-265. 2 Onderdonk A 8, Hermos J A, Dzink J L, Bartlett J G. Protective effect of metronidazole in experimental ulcerative colitis. Gastroenterology 1978;74:521-6. 3 Van der Waaij D, Cohen B J, Anver M R. Mitigation of experimental inflammatory bowel disease in guinea pigs by selective elimination of aerobic Gram negative intestinal flora. Gastroenterology 1974; 67: 460-72. 4 Chapman
R W, Selby W S, Jewell D P.
Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986; 27: 1210-2.
5 Truelove S C, Jewell D P. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974;i: 1067-70. 6 Dickinson R J, O’Connor H J, Pinder I, Hamilton I, Johnston D, Axon A T R. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985 ; 26: 1380-4. 7 Truelove S C, Witts L J. Cortisone in ulcer-
ative colitis. Final report on a therapeutic trial. Br Med J I955 ; 2:1041-8. 8 Hamilton I, Pinder I F, Dickinson R J, Ruddell W S J, Dixon M F, Axon A T R. A comparison of prednisolone enemas with lowdose oral prednisolone in the treatment of acute distal ulcerative colitis. Dis Col Rect 1984;27:701-2. 9 Tedesco F J, Hardin R D, Harper R N,
Edwards B H. Infectious colitis endoscopically simulating inflammatory bowel disease; A prospective evaluation. Gastrointest Endosc 1983 ; 29:195-7. 10 Dickinson R J, Gilmour H M, McClelland D B L. Rectal biopsy in patients presenting
129
to an infectious disease unit with diarrhoea1 disease. Gut 1979;20:141-8. 11 Felsen J, Corenberg H. Chronic dysentery, distal ileitis and ulcerative colitis. A followup of the Jersey City epidemic of bacillary dysentery. Am J Med Sci 1936;192:553-6. 12 Banks B M,Korelitz Bi, Zetzel L. The course of non-specific ulcerative colitis: review of twenty years experience and late results. Gastroenterology 1957;32: 983-1012. 13 Stewart G T. Post-dysenteric colitis. Br Med
J 1950;I: 405-9. 14 Harries A D, Myers B, Cook G C. Inflammatory disease : a common cause of bloody diarrhoea in visitors to the tropics. Br Med J 1986;291:1686-7. 15 Cooke E M. Properties of strains of Escherichig cofi isolated from the faeces of patients
with ulcerative colitis, patients with acute diarrhoea, and normal persons. J Path Bact 1968;95 : 101-13. 16 Dickinson RJ, Varian S A , Axon A T R , Cooke EM. Increased incidence of faecal coliforms with in vitro adhesive and invasive properties in patients with ulcerative colitis. Gut 1980;21:787-92. 17 Burke D A, Axon A T R. Adhesive eschericia coli in inflammatory bowel disease and infective diarrhoea. Br Med J 1988; 297: 102-4. 18 Tabaqchali S, O’Donoghue D P and Bettelheim K A. Escherichia coli antibodies in
patients with inflammatory bowel disease. Gut 1978;19:108-13. 19 Lagercrantz R, Hammarstrom S, Perlrnann P, Gustafsson B E. Immunological studies in ulcerative colitis. IV Origin of autoantibodies. J Exp Med 1968;128:1139-52. 20 Kemler B J, Alpert E. Inflammatory bowel disease: study of cell mediated cytotoxicity for isolated human colonic epithelial cells. Gut 1980;21: 353-9. 21 Neu H C. Tobramycin: An overview. J Infec Dis 1976;134:(Suppl.)S3-sl9.
The eficacy of tobramycin in the treatment of ul cerafive co1itis
D. A. BURKE, A. T. R. AXON, S. A. CLAYDEN," M. F. D I X O N , t D. J O H N S T O N * & R. W. LACEY" Gasfroenferology Unit, and Universify Departrnenfs of Surgery, " Microbiology, and t Pathology, The General Infirmary, Leeds
*
Accepted for publication 6 October 1989
SUMMARY
This paper reports a double-blind placebo-controlled trial of oral tobramycin in acute ulcerative colitis. Eighty-four patients with an acute relapse of ulcerative colitis were randomized to receive oral tobramycin or placebo for 1week as an adjunct to steroid therapy. At endpoint, 31 of 42 (74%) in the tobramycin group achieved complete symptomatic remission compared with 18 of 42 (43%) in the placebo group (P = 0.008). The tobramycin group achieved better histological scores (P < 0.05) at endpoint. These findings show that treatment with oral tobramycin improves the short-term outcome of patients with ulcerative colitis in relapse. INTRODUCTION
The aetiology of ulcerative colitis is unknown, but some of the clinical and pathological features are similar to infectious colitis. Experimental colitis cannot be produced in germ-free animals, which suggests that a component of the faecal flora is necessary for its development.' Pre-treatment of animals with metronidazole has been shown to prevent the development of experimental colitis' and in other
Correspondence to : Dr A. T. R. Axon, Gastroenterology Unit, The General Infirmary, Leeds LSI 3EX, UK. Dr D. A. Burke is now Senior Registrar at the Royal Victoria Infirmary, Newcastle NEI 4LP, UK.
123
124
D. A. B U R K E et al.
studies the mortality rate and severity of the lesions was limited using antibiotics active against Gram-negative organisms.2’ In man, various antibiotics have been included in treatment regimens, but the choice of agent has usually been empirical. Metronidazole, an antibiotic active against anaerobes, and vancomycin, which is active against many Gram-positive organisms, are the only agents that have been subjected to a controlled trial.4” Neither agent was found to be of benefit. However, antibiotics active against Gramnegative organisms (other than sulphasalazine) have not been formally tested in ulcerative colitis. This study was performed to assess whether any benefit might accrue from antibiotic treatment directed at Gram-negative organisms in acute ulcerative colitis. The aminoglycoside, tobramycin, was chosen and used orally as an adjunct to steroid therapy in a double-blind placebo-controlled trial.
PATIENTS A N D METHODS Ethics Committee approval was given, and each patient‘s informed consent was obtained before entry to the study.
Confrolled trial Consecutive patients who presented to the inflammatory bowel disease clinic at Leeds General Infirmary, over a 2-year period with an acute attack of colitis, were considered for entry with the following exclusions : patients known to have Crohn’s disease, those who had received antibiotics within the preceding 2 months (other than sulphasalazine), patients with fulminant disease, pregnant or lactating females, patients with renal impairment and those with evidence of an infective diarrhoea. Patients were randomized to receive either 120 mg oral tobramycin t.d.s. or placebo for 7 days as an adjunct to steroid therapy. Patients who were already receiving sulphasalazine were allowed to continue on this drug. The dose and mode of delivery of the steroid was decided by the supervising clinician who allocated them to receive either hydrocortisone enemas (Colifoam, Staff ord-Miller Ltd) or 30 mg prednisolone daily for 1 month as an out-patient, or 60 mg prednisolone (or intravenous equivalent of hydrocortisone) daily as an in-patient depending on the severity and extent of their disease. The in-patient steroid dosage was reduced according to a predetermined protocol in keeping with our current practice. The initial dose of prednisolone for in-patients was reduced at 72-h intervals by 10 mg until a dose of 30 mg was reached and then by 5-mg decrements to 15 mg, provided that bowel frequency was less than or equal to 3 per 24 h, there was absent to mild pain and malaise, no weight loss of greater than 1 kg, a temperature of less than 37.5OC, and the pulse rate remained less than 90 per minute. Randomization was stratified in blocks for each of the three treatment groups,
TOBRAMYCIN I N ULCERATIVE COLITIS
125
that is in-patient, out-patient with systemic steroid, or out-patient with steroid enema. They were further stratified for first attack or relapse. Patients were assessed clinically and sigmoidoscopically with rectal biopsy at entry, 7 days, and at an end-point of 21 days for in-patients and 28 days for outpatients. A clinical assessment of severity based on the Truelove and Witts criteria7was made on entry to the study. At endpoint patients were considered to be in symptomatic remission if their bowel actions were less than 3/day without blood, there was no malaise, abdominal pain, anorexia, vomiting, abdominal tenderness, fever, or any complication or active extraintestinal manifestation of ulcerative colitis. Sigmoidoscopic appearances were scored: 0 = normal; 1 = loss of vascular pattern but no granularity; 2 = granularity; 3 = granularity plus contact bleeding; 4 = spontaneous bleeding, friability and frank ulceration. Rectal biopsies were taken to obtain an independent histological activity score at each assessment point. Histological scoring was as described previously’ using a scale of 0-3 for mucus depletion, surface degeneration, and polymorph infiltration. Thus the total active inflammatory score ranged from 0-9, and was determined by MFD without knowledge of the clinical severity, treatment, or the source and timing of the biopsy. At entry and endpoint, stool and was also examined for the presence of recognized pathogens including Clostridium dificile and its toxin, Yersinia enterocolitica, Yersinia pseudotuberculosis, and Entamoeba hisfolyficainfection were excluded by serology.
Statistical mefhods Student’s t-test was used to assess differences between groups where data was measured on an interval scale and the Mann-Whitney U-test for data measured on an ordinal scale. For differences in frequency the Chi-square test was used and, when numbers were small, Fisher’s exact probability test. All P values are for twotailed tests. RESULTS Eighty-four patients (45 males, 39 females) with ulcerative colitis in relapse were recruited. Four patients, two with known ulcerative colitis but who had Campylobacfer enteritis, one patient who did not wish to enter, and one elderly patient with diabetes mellitus and renal impairment were excluded. The effect of randomization is shown in Table 1. At endpoint (21-28 days after the start of the study), one patient from each group had failed to attend for follow-up and one patient from each group had required surgery during the trial period. The two groups were well-matched. There was no significant difference between the clinical, histological or sigmoidoscopic scores at entry.
126
D. A. B U R K E et al.
Table 1. Details of patients in study. All differences are not significant
Males Females Age (years) Length of history of ulcerative colitis (years) Length of history of present relapse (weeks) Extent of ulcerative colitis Proctitis To splenic flexure Extensive First attack Relapse Severity" Mild Moderate Severe Treatment groups In-patients Prednisolone 60 mg Out-patients Prednisolone 30 mg Out-patients hydrocortisone
Tobramycin
Placebo
21 21 43.5 f15.8 5.6 5.8
24 18 43.3 7.5
11.2 f12.4
11.6 f13.4
I2 11 19 4 (IP) 6 (0) 13 (IP) 19 (OP)
10 16 16 6 (IP) 4 (OP) 10 (IP)
7 32 3
9 32 1
17 14 11
16 16 10
15.7 8.8
22 (OP)
IP = in-patient; OP = out-patient. * Criteria of Truelove & W i t t ~ . ~
Thirty-one patients in the tobramycin-treated group had achieved complete symptomatic remission compared with 18 in the placebo group ( P = 0.008), and seven had a histological score of 0 compared with none in the placebo group P = 0.025. The histological scores were significantly lower in the tobramycin group (Table 2) P < 0.05. The sigmoidoscopy scores in the tobramycin group, although lower than those in the placebo group, did not reach statistical significance. There was no significant difference in the amount of steroid received by the two in-patient groups or the number of patients continuing treatment with sulphasalazine. Three patients in each in-patient group were given 5-amino salicyclic acid enemas towards the end of the treatment period because of residual distal disease, and two patients in the tobramycin group and one patient in the placebo group received azathioprine to enable further reduction in steroid dosage towards the end of the trial period. The serum concentration of tobramycin at 7 days (mean 1.1If;:0.2 s.d. pglrnl) remained below the lower limit of the therapeutic range and well below potentially toxic levels.
TOBRAMYCIN IN ULCERATIVE COLITIS
127
Table 2. Results of scores for sigrnoidoscopy and histology (mean & s.d., median)
Sigmoidoscopy score Day 0 Day 7 Endpoint Histology score Day 0 Day 7 Endpoint
Tobrarnycin
Placebo
3.5 0.7 (4) 2.2 11.2 (2) 1.3 1.5 (0.5)
3.4k0.7 (4) N.S. 2 . 7 k 1.0 (3) N.S. 1 . 9 11.5 (2) N.S.
5.5 f2.7 (7) 4.4 & 2.7 (4) 2.8f2.5 (2)
6.412.1 (6) N.S. 5.5 2.7 (6) P = 0.06 4.0 f2.6 (3) P = 0.03
N.S. = Not significant.
Although the oral preparation of tobramycin has a slightly unpleasant taste, all patients completed their treatment. No side-effects were noticed and Clostriditrm dificile, or its toxin, was not detected in the endpoint sample. If we consider those patients who presented in their first attack, 10 of 10 patients in the tobramycin group compared with 6 of 10 patients in the placebo group achieved complete symptomatic remission by the endpoint ( P = 0.04).
DISCUSSION It is often difficult both clinically and histologically to distinguish ulcerative colitis from infective colitis9~''in the early stages of the disease. Inflammation is limited to the colon with its abundant microflora, and it is difficult to induce experimental colitis in germ-free animals.' A number of studies have shown that the condition may follow attacks of infective A recent report has shown that 25 % of individuals who return from the tropics with chronic diarrhoea have inflammatory bowel disease.14 These data suggest that an infective agent might be involved in the pathogenesis of ulcerative colitis, but no one pathogenic organism has been regularly identified in the majority of cases of ulcerative colitis. E. coli from patients with ulcerative colitis have been shown to differ qualitatively from those isolated from controls. Cooke demonstrated that E. coli from patients were more likely to produce haemolysin and necrotoxin, and more commonly possessed the ability to dilate rabbit ileal ~ O O P S . ' ~A significant proportion of E. coli from patients with ulcerative colitis has also been found to possess adhesive properties not found in those isolated from controls.'6~17 Higher titres of antibodies to E. coli" and E. coli antibodies that cross-react with the colonic epithelium" have been found in patients with ulcerative colitis. Cellular cytotoxicity to colonic epithelium can be induced in lymphocytes exposed to an E. coli lipopolysaccharide extract." This was one reason why the present study was undertaken using an antibiotic active against Gram-negative organisms and in particular E. coli.
128
D. A. B U R K E et a/.
The aminoglycoside tobramycin was chosen because it is known to be active against Gram-negative organisms that include E. coli, but leaves the majority of anaerobes that form the bulk of the faecal flora intact” and is known to be minimally absorbed from the colon. Furthermore, few coliforms are resistant to tobramycin, and the drug is not routinely used in the community or within our own hospital, thus we were unlikely to encounter bacterial resistance to this drug. The protocol used in the trial was designed to mirror our current practice in the management of ulcerative colitis both with regard to the mode of delivery and the dose of steroid. The endpoint assessment time for out-patients (28 days) was chosen to comply with our routine out-patient review period and the in-patient endpoint (21 days) was chosen to avoid unnecessary hospitalization if patients responded optimally. The results show that patients with ulcerative colitis in relapse, given a weeks oral tobramycin in addition to conventional steroid treatment, did better in the short-term than those given steroids alone. A substantially higher proportion of those who received tobramycin achieved complete symptomatic remission. This achievement was mirrored by that seen with independently assessed histological data. These differences are more relevant when viewed in the context that the improvement was over and above that obtained by conventional steroid therapy, which is itself an effective treatment for this condition. There have been few controlled trials of antibiotic therapy in ulcerative colitis, but antibiotics have often been included in treatment regimens. A similar study with oral vancomycin6did show a trend in favour of the antibiotic-treated group but did not reach statistical significance. The Oxford group5 initially included intravenous tetracycline in their treatment regimen and latterly intravenous metronidazole, until a controlled trial showed that this was of no benefit.4 It is tantalizing to speculate that the better results obtained in the test group are as a result of eliminating E. coli that might be either provoking or aggravating a relapse. More work is needed before this hypothesis can be advanced. It may be that the antibiotic conferred some benefit unrelated to any effect on E. coli. This study shows that the use of an aminoglycoside as an adjunct to conventional steroid therapy improves the clinical outcome in the short-term. Whatever its mechanism of action, the general use of aminoglycosides in ulcerative colitis may improve the short-term outlook of patients with ulcerative colitis. Further independent studies are needed to confirm these observations. ACKNOWLEDGEMENTS
We gratefully acknowledge a research grant from Eli Lilly & Company Limited. We would like to thank the Special Trustees of the General Infirmary, Leeds, for supporting Dr Burke under their Research Scheme, and Mrs Olive Bell for typing the manuscript.
TOBRAMYCIN I N ULCERATIVE COLITIS REFERENCES I Onderdonk A 8, Bartlett J G. Bacteriologi-
cal studies of experimental ulcerative colitis. Am J Clin Nutr 1979;32:258-265. 2 Onderdonk A 8, Hermos J A, Dzink J L, Bartlett J G. Protective effect of metronidazole in experimental ulcerative colitis. Gastroenterology 1978;74:521-6. 3 Van der Waaij D, Cohen B J, Anver M R. Mitigation of experimental inflammatory bowel disease in guinea pigs by selective elimination of aerobic Gram negative intestinal flora. Gastroenterology 1974; 67: 460-72. 4 Chapman
R W, Selby W S, Jewell D P.
Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986; 27: 1210-2.
5 Truelove S C, Jewell D P. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974;i: 1067-70. 6 Dickinson R J, O’Connor H J, Pinder I, Hamilton I, Johnston D, Axon A T R. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985 ; 26: 1380-4. 7 Truelove S C, Witts L J. Cortisone in ulcer-
ative colitis. Final report on a therapeutic trial. Br Med J I955 ; 2:1041-8. 8 Hamilton I, Pinder I F, Dickinson R J, Ruddell W S J, Dixon M F, Axon A T R. A comparison of prednisolone enemas with lowdose oral prednisolone in the treatment of acute distal ulcerative colitis. Dis Col Rect 1984;27:701-2. 9 Tedesco F J, Hardin R D, Harper R N,
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