Fidaxomicin

Fidaxomicin (Dificlir) is a naturally occurring 18-membered macrocycle (tiacumicin B) that is derived from the fermentation of Dactylosporangium aurantiacum (Drugs in R&D, 2010). Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins (Scott, 2013; Zhanel et al., 2015). The drug product is poorly absorbed and exerts its activity in the gastrointestinal (GI) tract. It is an unsaturated, 18-membered macrocyclic lactone ring with a 7-carbon sugar constituent at carbon 12 and a 6-deoxy sugar at carbon 21 (Figure 88.1). It is structurally related to lipiarmycin, which is thought to act at the early stages of transcription (Sonenshein and Alexander, 1979). It belongs to the class of glycosides with C₅₂H₇₄Cl₂O₁₈ as chemical structure and a molecular weight of 1056 g/mol. In vivo, fidaxomicin is primarily hydrolyzed at the fourth position isobutyryl ester by an unknown esterase to produce its main active metabolite, OP-1118. OP-1118 is a major metabolite of fidaxomicin that also exhibits a narrow spectrum of activity. Par Pharmaceuticals entered into a joint development agreement with Optimer for fidaxomicin (as PAR 101) in May 2005. However, in February 2007, Par returned all marketing rights for the product to Optimer. Optimer was acquired by Cubist Pharmaceuticals in 2013, which was itself acquired by Merck in December 2014. Fidaxomicin was formerly known under various names, including OPT-80 and PAR 101 (Drugs in R&D, 2010). Figure 88.1 Chemical structure of fidaxomicin. https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781315152110/08d8042d-9481-4a8d-8c27-9bd589f6de6b/content/fig88_1.tif" xmlns:xlink="https://www.w3.org/1999/xlink"/>