1st Medical Clinic Cologne City Hospital Cologne Germany
Sir,
Differential diagnosis of diarrhoea in diabetic patients with combined pancreas and renal transplantation comprises infectious causes, the existence of diabetic enteropathy, diarrhoea due to antibiotic therapy or pre-existing antibiotic therapy. In addition, transplant-associated causes have to be excluded, such as immunosuppressive overdose and CMV-virus infection. We describe the case of a patient with diarrhoea due to Clostridium difficile toxin possibly induced by mycophenolate mofetil treatment.
Case.
A 37-year-old woman with diabetes type I was admitted to the Cologne City Hospital with diarrhoea lasting 2 weeks. The frequency of diarrhoea was 15 times a day. She had received a combined pancreas and renal transplantation at the same hospital 1 year previously. Both organs worked well. Immunosuppressive therapy consisted of tacrolimus and mycophenolate mofetil. Since the date of transplantation, motion was reported to occur once or twice a day.
Medical history showed no hint for a nutritive intoxication, no bloody bowel movement, no journey had been undertaken within the previous weeks, nor had immunosuppressive therapy been changed in the previous days. The patient had not received any antibiotic therapy during the previous months. The initial triple therapy consisted of tacrolimus, mycophenolate mofetil and prednisone, the latter having been ended 6 weeks before admittance. Trough levels for tacrolimus were measured within the range of 6.110.0 ng/ml without any change of the symptoms. No disturbance of electrolytes such as hypercalcaemia could be found. Renal and pancreatic perfusion were found to be good on ultrasonography. Renal and pancreatic function were stable (creatinine levels 1.4 mg/dl) with pancreatic enzymes in the normal range as well as normal glucose levels.
Systemic inflammation parameters were not elevated (leucocytes 4.2/nl, CRP 8.1 mg/l, BSG 10/20). CMV pp 65 and CMV-IgM from the blood as well as CMV-PCR from urine were negative. Stool probes were analysed for bacteria and found to be negative for Salmonella, Shigella, Yersinia, Campylobacter coli or Jejuni. However, C. difficile toxin A and B was found to be present. Diarrhoea stopped after discontinuation of mycophenolate mofetil therapy and administration of oral vancomycine.
Comment.
Mycophenolate mofetil is a powerful immunosuppressive drug used in organ transplantation. It is rapidly metabolized to its active component mycophenolic acid (MPA) in the intestine and in the blood [1,2]. MPA reversibly inhibits the ionosin monophosphate dehydrogenase (IMPDH) [3]. IMPDH exists in two isoforms: the constitutively active type I and the inducible type II, which is significantly more susceptible to MPA [4]. IMPDH is responsible for the de novo synthesis of guanosine. As this is important for B and T lymphocytes, MPA inhibits the proliferation of both of these cells [5].
Mycophenolate mofetil is a fermentation product of several Penicillium species [6] isolated by Gosio [7] one century ago (1896), who noted its antibacterial properties [8,9]. Later, several studies have described antibacterial [9,10] and antifungal [10,11] effects of the drug. Studies showed it to have an effect against specific pathogenic agents as Leishmania tropica, Eimeria tenella, Candida albicans as well as Pneumocystis carinii [8]. In three large controlled trials of mycophenolate mofetil for organ transplantation with 499 patients in the US [12], 503 in Europe [13] and 150 in a collaborative study [14], the incidence of P. carinii-pneumonitis was higher in those patients without MMF treatment leading to the conclusion that it is an effective drug against P. carinii [8].
The second immunosuppressive agent, tacrolimus (FK506), is a fermentation product of Streptomyces tsukubaensis with a macrolide-like structure, which might also have antibiotic side-effects. On the other hand, tacrolimus has already been applied in the field of transplantation for several years and no cases of tacrolimus-induced pseudomembraneous colitis have been reported so far.
We therefore conclude that MMF-treatment may have an antibacterial effect on the physiological intestinal flora followed by an overwhelming growth of C. difficile and the appearance of a pseudomembraneous colitis as normally known in correlation with antibiotic treatment.
References