How can we ameliorate irinotecan‐associated diarrhea in children with poor compliance for oral cephalosporin?

To the Editor: Irinotecan-associated diarrhea (IAD) has been a significant problem as reported previously 1. The article by Wagner et al. 2 showed available prevention and treatment strategies to reduce IAD. They concluded that oral cephalosporin prophylaxis is a safe and feasible way to help optimize use of protracted irinotecan. On the other hand, they also mentioned one patient with poor compliance to oral antibiotics who eventually had severe diarrhea. We experienced one patient treated with irinotecan who refused to take oral antibiotics. We treated him with a bile excreting-type of intravenous cephalosporin and successfully controlled the IAD. The patient is a 9-year-old Japanese male, who was diagnosed with stage 4 neuroblastoma. He was treated with intensive chemotherapy, autologous stem cell transplantation, and radiation therapy, but multiple bone relapses were still noted. We treated him with intravenous irinotecan 50 mg/m2 for 5 days and oral temozolomide 150 mg/m2 for 5 days. Before the treatment, informed consent for the treatment was obtained from the parents, and he was also confirmed that he was not homozygous for UGT1A1*polymorphism. After the first course without antibiotics, he experienced grade 2 diarrhea which lasted for 8 days. Then we gave him prophylactic cefpodoxime. He experienced only mild grade 1 diarrhea lasting for a few days of entire course of the treatment, showing that IAD was successfully reduced. We next treated him with high-dose intravenous irinotecan at 180 mg/m2 for 3 days as previously reported 1. In this phase II study, without cephalosporin prophylaxis, severe diarrhea, grade 3–4 was observed as high as 34%. Therefore, we decided to carry out cephalosporin prophylaxis beforehand. We gave him cefpodoxime prophylaxis from 5 days prior to, and until 3 days after, the treatment. He experienced less than grade 2 diarrhea after irinotecan therapy, suggesting the preventive effects of cefpodoxime. High dose irinotecan was thus repeated uneventfully for three courses. During the fourth course, however, he refused to take oral cefpodoxime because of nausea on the third day of the treatment. Maximum dose of granisetron/ondansetron did not clear his symptoms. We gave him intravenous ceftriaxone at 100 mg/kg/day for 3 days after the treatment. He experienced only mild grade 1 diarrhea, showing that adding intravenous ceftriaxone successfully reduced IAD. Ceftriaxone has been shown to be effective in killing the aerobic intestinal bacteria 3, whereas the effects on anaerobic bacteria are minimal compared with cefoperazone, which is a mainly bile-excreting type of antibiotics. As almost half of ceftriaxone is excreted to the intestine, it can eradicate the intestinal bacteria that produces glucuronidase which converts SN-38G to toxic SN-38 2. It is not uncommon for children to refuse to take medication orally. Therefore, it is reasonable to consider a strategy for a non-oral route of cephalosporin prophylaxis. Although further studies with bile excreting-types of antibiotics are needed, intravenous ceftriaxone may be an option to reduce IAD for patients who cannot tolerate oral antibiotics.