110
introduction of cyclosporin has yielded. For example, in First and colleagues’ report it was mandatory for patients given ketoconazole to make two or three clinic visits per week for cyclosporin dose adjustment;1 of the 17 patients treated with the combination had to discontinue ketoconazole because of gastrointestinal side-effects; and 2 patients had rejections, probably related to ketoconazole, which were successfully treated with a 10-day course of OKT3 (cost, without inpatient charges, about US$4000 each). Without a controlled trial, taking into account both the medical and the financial consequences, the prescription of a systematic drug interaction between cyclosporin and ketoconazole cannot be recommended. If First and colleagues wish to pursue their therapeutic strategy it might be worthwhile to reduce the liver’s capacity to metabolise another drug of their triple therapy
(azathioprine) by adding allopurinol.9
toxin from the stools in all of five consecutive patients following bacteriotherapy strongly suggests a therapeutic effect of the approach. Furthermore, faecal bacteria grown on seven media were examined before bacteriotherapy and at follow-up. The suggestion that we selected strains at random from the subset of organisms that happened to grow well on brain-heart infusion medium is a misinterpretation of our paper, and the lack of consistence with previous work in animals referred to by Wilson is of questionable relevance for the interpretation of studies in man. We cannot at present help Wilson to determine the function of the remainder of the human flora, but, again, the importance of species differences cannot be overestimated. Department of Clinical Microbiology, Rigshospitalet, Statens Seruminstitut, DK-2100 Copenhagen Ø, Denmark
M. TVEDE
Section of
Gastroenterology, Department of Medicine G, Bispebjerg Hospital, Copenhagen
Transplant Service, University of California, Moffitt Hospital,
F. J. FREY
San Francisco, CA 94143, USA
1. Odds FO, Webster CE. Effects of azole antifungals m vitro on host/parasite interactions relevant to candida infections. J Antimcrob Chemother 1988; 22 173-81. 2. Senior DS, Shaw JT. In vitro effects of fluconazole (UK-19,858) and ketoconazole on mouse lymphocyte proliferation and on Candida blastospore destruction by human polymorphonuclear leukocytes. Int J Immunopharmacol 1988; 10: 169-73. 3. Zurcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of prednisolone. Clin Pharmacol Ther 1989; 45: 366-72. 4. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol Clin Pharmacol Ther 1987; 42: 465-70 5. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy. Gastroenterology 1984; 86: 503-13. 6. European Dialysis and Transplant Association. Combined report on regular dialysis and transplantation in Europe. Proc EDTA-ERA 1985; 21: 2-68. 7. Frey FJ, Schaad HJ, Renner EL, Horber FF, Frey BM, Preisig R. Impaired liver function in stable renal allograft recipients. Hepatology 1989; 9: 606-13. 8. Showstack J, Katz P, Amend W, et al. The effect of cyclosporine on the use of hospital resources for kidney transplantation. N Engl J Med 1989; 321: 1086-92. 9. Elion GB, Callahan S, Nathan H, Bieber S, Rundles BW, Hitching GH. Potenuation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem Pharmacol 1963; 12: 85-93.
Bacteriotherapy for Clostridium difficile diarrhoea SIR,-Dr Seal and colleagues (Sept 2, p 558) agree that replacing normal colonic flora by bacteriotherapyl-3 is more logical than repeated prescribing of antibiotics for diarrhoea due to toxigenic Clostridium difficile, which occurs mainly because of a loss of normal resistance to colonisation in the gastrointestinal tract from antibiotic use. They have previously attempted oral bacteriotherapy,l because it was assumed to be less traumatic and to carry lower risk of septicaemia than our rectal route of administration.4 We question the view that the oral route is preferable, because it is dubious whether mainly non-spore forming bacteria would survive the low pH in the stomach, unless the stomach is bypassed with a duodenal tube. It is well established that the upper intestine is rarely colonised with bacteria, especially normally occurring colonic bacteria. Why therefore is the risk of enteritis and septicaemia by the oral route emphasised? We re-established normal faecal flora by giving bacteria indigenous to the human colon, instead of by providing a temporary flora that discourages growth of toxigenic C difficile, later to be replaced by a normal faecal flora. Before bacteriotherapy the inflammation caused by C difficile was treated by vancomycin for one week. The reasons for selecting physiological concentrations of ten bacteria (that inhibited C difficile growth in vitro’) instead of a single strain were that our patients harboured no Bacteroides spp-predominantly among gut bacteria in adults-and that we could not predict which strain would prevent or stop the diarrhoeas. Dr Wilson (Nov 4 p 1096) argues that the small number of patients and the uncontrolled study design make our experiment "less than conclusive". We agree that placebo-controlled trials are necesary to prove clinical efficacy. However, findings can be clinical rather than statistically significant; statistical significance only specifies the probability that an observed difference could have been produced by chance.’ Thus, the prompt loss of C difficile and its
J. RASK-MADSEN
SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of non-toxigenic strain. Eur J Clin Microbiol 1987, 6: 51-53. 2. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with lactobacillus GG. Lancet 1987; ii: 1519. 3. Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, Van Belle G. A clinical trial to test the ability of Saccharomyces boulardii to prevent antibiotic associated diarrhoea. Microecol Ther (in press). 4. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea is six patients. Lancet 1989; ii: 1156-60. 5. Launtsen K, Rask-Madsen J. Review: clinical trials in peptic ulcer disease—problems of methodology and interpretation. Ailment Pharmacol Ther 1987; 1:91-123. 1. Seal DV, Borrielo
Surgery for biliary atresia SIR,-Your editorial (Sept 9, p 597) states that surgical modifications to Roux-en-Y loops in the surgical management of biliary atresia "show no great benefit ... Transplantation is not compromised by a previous portoenterostomy provided that complex loops and enterostomies are avoided". We continue to exteriorise the biliary conduit in biliary atresia patients because of the very real danger of bile shutdown early on after the Kasai operation. Our concept of the sequence of post-surgical events is that after hilar duct transection, bile drains from the open ends of the microscopic communicating ducts; an autoanastomosis occurs between intrahepatic duct epithelium and the coated intestinal mucosa, a process that takes about six weeks. During this interval, the transected microscopic ducts are prone to inflammatory closure. The foregoing is not simply of hypothetical interest, but clarifies the early postoperative jeopardy the infant is in because of the precarious nature of bile drainage. If the bilioenteric conduit is exteriorised, inflammatory closure is manifest by a precipitous decline in bile output (both in quantity and quality), an event occurring in about one-third of our 131 patients in Denver.’ Immediate institution of steroid therapy often reverses the process, presumably by its anti-inflammatory action. If steroid therapy fails and diminution of bile flow proceeds to complete cessation, the chances for re-establishment of biliary drainage by prompt reoperation are good (14 of 18 patients in our series). The liability to biliary shutdown remains until an epithelialmucosal anastomosis takes place. Thus, the major advantage of conduit exteriorisation is the immediate recognition of impending operative failure and its abortion by summary medical and surgical manoeuvres. Without exteriorisation the surgeon would not be aware of a fall-off in bile output and miss the opportunity to reverse it. Bile output might very well cease and the patient would be written off as a "failed Kasai"-that is, one that never worked in the first place. These advantages apply only to the first 2-3 months after operation, and all our conduits are promptly closed after this period. This is a minor procedure so transplantation, if needed subsequently, is not compromised. JOHN R. LILLY Children’s Hospital, Denver, Colorado 80218, USA 1.
F. M. KARRER
Lilly JR, Karrer FM, Hall RJ, et al. The surgery of biliary atresia. Arm Surg 1989; 210: 289-96.
introduction of cyclosporin has yielded. For example, in First and colleagues’ report it was mandatory for patients given ketoconazole to make two or three clinic visits per week for cyclosporin dose adjustment;1 of the 17 patients treated with the combination had to discontinue ketoconazole because of gastrointestinal side-effects; and 2 patients had rejections, probably related to ketoconazole, which were successfully treated with a 10-day course of OKT3 (cost, without inpatient charges, about US$4000 each). Without a controlled trial, taking into account both the medical and the financial consequences, the prescription of a systematic drug interaction between cyclosporin and ketoconazole cannot be recommended. If First and colleagues wish to pursue their therapeutic strategy it might be worthwhile to reduce the liver’s capacity to metabolise another drug of their triple therapy
(azathioprine) by adding allopurinol.9
toxin from the stools in all of five consecutive patients following bacteriotherapy strongly suggests a therapeutic effect of the approach. Furthermore, faecal bacteria grown on seven media were examined before bacteriotherapy and at follow-up. The suggestion that we selected strains at random from the subset of organisms that happened to grow well on brain-heart infusion medium is a misinterpretation of our paper, and the lack of consistence with previous work in animals referred to by Wilson is of questionable relevance for the interpretation of studies in man. We cannot at present help Wilson to determine the function of the remainder of the human flora, but, again, the importance of species differences cannot be overestimated. Department of Clinical Microbiology, Rigshospitalet, Statens Seruminstitut, DK-2100 Copenhagen Ø, Denmark
M. TVEDE
Section of
Gastroenterology, Department of Medicine G, Bispebjerg Hospital, Copenhagen
Transplant Service, University of California, Moffitt Hospital,
F. J. FREY
San Francisco, CA 94143, USA
1. Odds FO, Webster CE. Effects of azole antifungals m vitro on host/parasite interactions relevant to candida infections. J Antimcrob Chemother 1988; 22 173-81. 2. Senior DS, Shaw JT. In vitro effects of fluconazole (UK-19,858) and ketoconazole on mouse lymphocyte proliferation and on Candida blastospore destruction by human polymorphonuclear leukocytes. Int J Immunopharmacol 1988; 10: 169-73. 3. Zurcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of prednisolone. Clin Pharmacol Ther 1989; 45: 366-72. 4. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol Clin Pharmacol Ther 1987; 42: 465-70 5. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy. Gastroenterology 1984; 86: 503-13. 6. European Dialysis and Transplant Association. Combined report on regular dialysis and transplantation in Europe. Proc EDTA-ERA 1985; 21: 2-68. 7. Frey FJ, Schaad HJ, Renner EL, Horber FF, Frey BM, Preisig R. Impaired liver function in stable renal allograft recipients. Hepatology 1989; 9: 606-13. 8. Showstack J, Katz P, Amend W, et al. The effect of cyclosporine on the use of hospital resources for kidney transplantation. N Engl J Med 1989; 321: 1086-92. 9. Elion GB, Callahan S, Nathan H, Bieber S, Rundles BW, Hitching GH. Potenuation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem Pharmacol 1963; 12: 85-93.
Bacteriotherapy for Clostridium difficile diarrhoea SIR,-Dr Seal and colleagues (Sept 2, p 558) agree that replacing normal colonic flora by bacteriotherapyl-3 is more logical than repeated prescribing of antibiotics for diarrhoea due to toxigenic Clostridium difficile, which occurs mainly because of a loss of normal resistance to colonisation in the gastrointestinal tract from antibiotic use. They have previously attempted oral bacteriotherapy,l because it was assumed to be less traumatic and to carry lower risk of septicaemia than our rectal route of administration.4 We question the view that the oral route is preferable, because it is dubious whether mainly non-spore forming bacteria would survive the low pH in the stomach, unless the stomach is bypassed with a duodenal tube. It is well established that the upper intestine is rarely colonised with bacteria, especially normally occurring colonic bacteria. Why therefore is the risk of enteritis and septicaemia by the oral route emphasised? We re-established normal faecal flora by giving bacteria indigenous to the human colon, instead of by providing a temporary flora that discourages growth of toxigenic C difficile, later to be replaced by a normal faecal flora. Before bacteriotherapy the inflammation caused by C difficile was treated by vancomycin for one week. The reasons for selecting physiological concentrations of ten bacteria (that inhibited C difficile growth in vitro’) instead of a single strain were that our patients harboured no Bacteroides spp-predominantly among gut bacteria in adults-and that we could not predict which strain would prevent or stop the diarrhoeas. Dr Wilson (Nov 4 p 1096) argues that the small number of patients and the uncontrolled study design make our experiment "less than conclusive". We agree that placebo-controlled trials are necesary to prove clinical efficacy. However, findings can be clinical rather than statistically significant; statistical significance only specifies the probability that an observed difference could have been produced by chance.’ Thus, the prompt loss of C difficile and its
J. RASK-MADSEN
SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of non-toxigenic strain. Eur J Clin Microbiol 1987, 6: 51-53. 2. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with lactobacillus GG. Lancet 1987; ii: 1519. 3. Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, Van Belle G. A clinical trial to test the ability of Saccharomyces boulardii to prevent antibiotic associated diarrhoea. Microecol Ther (in press). 4. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea is six patients. Lancet 1989; ii: 1156-60. 5. Launtsen K, Rask-Madsen J. Review: clinical trials in peptic ulcer disease—problems of methodology and interpretation. Ailment Pharmacol Ther 1987; 1:91-123. 1. Seal DV, Borrielo
Surgery for biliary atresia SIR,-Your editorial (Sept 9, p 597) states that surgical modifications to Roux-en-Y loops in the surgical management of biliary atresia "show no great benefit ... Transplantation is not compromised by a previous portoenterostomy provided that complex loops and enterostomies are avoided". We continue to exteriorise the biliary conduit in biliary atresia patients because of the very real danger of bile shutdown early on after the Kasai operation. Our concept of the sequence of post-surgical events is that after hilar duct transection, bile drains from the open ends of the microscopic communicating ducts; an autoanastomosis occurs between intrahepatic duct epithelium and the coated intestinal mucosa, a process that takes about six weeks. During this interval, the transected microscopic ducts are prone to inflammatory closure. The foregoing is not simply of hypothetical interest, but clarifies the early postoperative jeopardy the infant is in because of the precarious nature of bile drainage. If the bilioenteric conduit is exteriorised, inflammatory closure is manifest by a precipitous decline in bile output (both in quantity and quality), an event occurring in about one-third of our 131 patients in Denver.’ Immediate institution of steroid therapy often reverses the process, presumably by its anti-inflammatory action. If steroid therapy fails and diminution of bile flow proceeds to complete cessation, the chances for re-establishment of biliary drainage by prompt reoperation are good (14 of 18 patients in our series). The liability to biliary shutdown remains until an epithelialmucosal anastomosis takes place. Thus, the major advantage of conduit exteriorisation is the immediate recognition of impending operative failure and its abortion by summary medical and surgical manoeuvres. Without exteriorisation the surgeon would not be aware of a fall-off in bile output and miss the opportunity to reverse it. Bile output might very well cease and the patient would be written off as a "failed Kasai"-that is, one that never worked in the first place. These advantages apply only to the first 2-3 months after operation, and all our conduits are promptly closed after this period. This is a minor procedure so transplantation, if needed subsequently, is not compromised. JOHN R. LILLY Children’s Hospital, Denver, Colorado 80218, USA 1.
F. M. KARRER
Lilly JR, Karrer FM, Hall RJ, et al. The surgery of biliary atresia. Arm Surg 1989; 210: 289-96.
