Life‐threatening Clostridium difficile‐associated diarrhea induced by paclitaxel‐carboplatin combination chemotherapy

Abstract

Diarrhea has been reported in 10% of patients undergoing antineoplastic chemotherapy (1). Infectious colitis contributes to diarrhea in some chemotherapy-induced cases, and the most common etiologic agent is Clostridium difficile. Prior antibiotic use is considered the most important risk factor in the development of C. difficile-associated diarrhea (CDAD). However, CDAD can occur in the absence of antibiotic use and the association between antineoplastic therapy and CDAD has recently become evident. Meanwhile, the risk of paclitaxel in CDAD is not well defined. Among fifty patients with gynecologic malignancies treated with standard-dose paclitaxel-carboplatin combination chemotherapy (paclitaxel, 180 mg/m2; carboplatin, AUC 5) at our institution, one patient (2%) developed life-threatening CDAD. A 50 year-old woman with post-surgical stage IIIc endometrial cancer of the uterine corpus underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymph node sampling. Cefmetazole (2 g/day) and clindamycin (1.2 g/day) were given for 5 days for postoperative coverage. Postoperative recovery was uncomplicated and she had no episode of diarrhea following recovery. Four weeks after operation, she received the first cycle of paclitaxel-carboplatin combination chemotherapy. Since she developed loose stools on day 5, we prescribed loperamide and drip-infusion according to the guideline for chemotherapy-induced diarrhea. However, she had abrupt onset of severe diarrhea on day 9, and fell into severe dehydration and acute renal insufficiency (urine volume, 12 ml/hr). Biochemistry revealed azotemia (BUN, 50 mg/dl; creatinine, 1.52 mg/dl), serum electrolyte imbalance (Na, 127 mEq/l; K, 1.8 mEq/1), and hypoalbuminemia (1.8 g/dl). She was intensively managed with total parenteral nutrition, and octreotide (Sandostatin, 300 μg/day) was added according to the guideline. Octreotide was so effective that the number of episodes of diarrhea decreased remarkably. Notwithstanding, her condition continued to deteriorate for 4 days. On day 14, she presented typical features of pseudomembranous colitis with massive bloody and watery stool and fever. An abdominal X-ray demonstrated toxic dilatation. Oral vancomycin was started (1 g/day for 14 days), and octreotide were discontinued. We did not perform a colonoscopy or biopsy because of the obvious need to avoid the risk of perforation. Severe myelosuppression also appeared; the nadir of WBC count: 1500/mm3 on day 17, the nadir of platelet count: 8000/mm3 on day 11. Stool culture obtained on day 9 revealed C. difficile (105/ml) on day 17. She was discharged with complete resolution of clinical findings 38 days after the beginning of intensive care. Kamthan et al. (1) reported a 5.7% incidence of CDAD in patients with chemotherapy-related gastrointestinal toxicity in the absence of recent antimicrobial therapy. Anand and Glatt (2) found several antineoplastic agents including cisplatin to be associated with C. difficile infection. In phase II studies evaluating paclitaxel, Millward et al. reported the incidence of diarrhea to be 20% (3). Although the question of whether paclitaxel is a risk factor of C. difficile colitis remains unanswered, Husain et al. (4) estimated the risk of C. difficile colitis to be 2.2% in patients receiving standard-dose paclitaxel-based chemotherapy. Paclitaxel can cause extensive intestinal inflammatory changes (5) and may have an antimicrobial-like effect on the enteric bacteria like other antineoplastic agents, potentiating the growth of C. difficile (1). Furthermore, C. difficile cytotoxin can cause mucosal damage leading to pseudomembranous colitis. Thus, paclitaxel-based chemotherapy may induce severe CDAD. Patients with chemotherapy-induced neutropenia like our case may manifest more severe symptoms than those without neutropenia. Furthermore, potent anti-diarrheal agents such as octreotide should not be used for cases of chemotherapy-induced diarrhea with fever or bloody stool, suspecting infectious colitis. These agents may enhance the effect of C. difficile toxin resulting in clinical deterioration. Our observation suggested that CDAD might be a potentially severe complication in paclitaxel-based chemotherapy, especially when accompanied by prior antibiotic use and/or neutropenia.