DISCUSSION
Busulfan is an alkylating agent that is commonly used in myeloablative conditioning prior to hematopoietic stem cell transplantation. It has a narrow therapeutic window with adverse consequences of being above or below that window. Toxicity from increased busulfan concentrations causes venoocclusive disease, mucositis, pulmonary toxicity, neurotoxicity and acute graft versus host disease (Andersson et al 2002, Vassal et al 1990). Consequences of subtherapeutic busulfan levels include disease relapse, graft failure and decreased survival (Andersson et al 2002). As such, therapeutic drug monitoring (TDM) is often performed in an attempt to keep patients within this therapeutic window.
Metronidazole is an imidazole antibiotic that is used to treat infections with protozoa, anaerobes and Helicobacter pylori. It is often used to treat or prevent Clostridium difficile infection in hematopoietic stem cell transplant recipient patients as well as in prevention of graft versus host disease (Myers et al 2017, de Castro et al 2016).
In a review of the literature, the effects of metronidazole to decrease busulfan clearance, increase busulfan area under the curve (AUC) and increase the busulfan trough level have previously been described (Nilsson et al 2003, Gulbis et al 2011, de Castro et al 2016, Chung et al 2017, reviewed in Myers et al 2017). The first report was a study of 24 patients receiving three different treatments: 1) busulfan and metronidazole for 4 days, 2) busulfan only for 2 days followed by metronidazole and busulfan for 2 days, and 3) busulfan only for 4 days. The mean busulfan trough levels were increased in the group receiving both busulfan and metronidazole compared to the group receiving busulfan alone. Additionally, the addition of metronidazole at 2 days resulted in a significant increase in busulfan levels (Nilsson et al 2003). The three other reports found in a literature search are case studies. In a 7-year old boy with AML, a test-dose of busulfan was given with TDM. The following day he received metronidazole and the day following that when busulfan was administered the clearance was decreased by 46% (Gulbis et al 2011). Another case report involved a 30 year old male with CML who ended up receiving two test doses of busulfan, one with and one without metronidazole. When metronidazole was present, the busulfan clearance decreased by 38% (de Castro et al 2016). The most recent case report involved a 3-year old girl with ALL who received metronidazole before the third dose of busulfan to treat a Clostridium difficile infection. This resulted in busulfan clearance decreased by 55% (Chung et al 2017).
Once metronidazole is given, the effect is demonstrable within several hours (Nilsson et al 2003, Gulbis et al 2011, Chung et al 2017), and its effect on busulfan clearance was still increasing approximately 12 hours after the final dose of metronidazole in one study (Chung et al 2017). However, the mechanism of this interaction and the longevity of the inhibition after metronidazole discontinuation are not known. Here, we present a case report which suggests that even 80 hours after stopping metronidazole, it still effects the clearance of busulfan. This highlights the importance of therapeutic drug monitoring of busulfan treatment to keep patients in the target therapeutic range.
REFERENCES
Contributed by Megan Zilla, MD, PhD and Raman Venkataramanan, PhD