Antibacterials Developed to Target a Single Organism: Mechanisms and Frequencies of Reduced Susceptibility to the Novel Anti-Clostridium difficileCompounds Fidaxomicin and LFF571

Abstract

Clostridium difficile is the most common cause of antibacterial-associated diarrhea. Clear clinical presentation and rapid diagnostics enable targeted therapy for C. difficile infection (CDI) to start quickly. CDI treatment includes metronidazole and vancomycin (VAN). Despite decades of use for CDI, no clinically meaningful resistance to either agent has emerged. Fidaxomicin (FDX), an RNA polymerase inhibitor, is also approved to treat CDI. Mutants with reduced susceptibility to FDX have been selected in vitro by single and multistep methods. Strains with elevated FDX minimum inhibitory concentrations (MICs) were also identified from FDX-treated patients in clinical trials. LFF571 is an exploratory agent that inhibits EF-Tu. In a proof-of-concept study, LFF571 was safe and effective for treating CDI. Spontaneous mutants with reduced susceptibility to LFF571 were selected in vitro in a single step, but not via serial passage. Although there are several agents in development for treatment of CDI, this review summarizes the frequencies and mechanisms of C. difficile mutants displaying reduced susceptibility to FDX or LFF71.

Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study

“…The same survey identified a single strain of C. difficile from a patient with recurrence with a fidaxomicin MIC of 16 mg/L; however, the relatedness of the pre-and post-treatment strains was not determined [11], and the association of resistance with drug exposure cannot be made definitively [21]. Schwanbeck et al described fidaxomicin resistance (MIC > 64 mg/L), associated with a V1143D mutation in rpoB, in a single clinical C. difficile isolate of 50 isolates tested [19]; however, the fitness burden imposed by the mutation was higher when generated in vitro [13,19] than observed in the clinical isolate [19]. In the light of high fidaxomicin gut concentrations, the significance of this is unclear but highlights the need for further monitoring.…”

Novel Antimicrobials for the Treatment of Clostridium difficile Infection

“…LFF571 is a novel semi-synthetic cyclic lipopeptide antibiotic derived from a natural metabolite produced by the actinomycete Planobisporarosea ( 75 , 76 ). It belongs to a new class of thiopeptide antibiotics and acts disrupting bacterial protein synthesis by inhibiting the elongation factor Tu (EF-Tu), a bacterial factor involved in peptide synthesis ( 75 – 78 ).…”

Narrow-spectrum antibacterial agents

“…56 C. difficile is a spore forming bacterium, which makes it difficult to remove from surfaces and enables it to spread rapidly. 57 Despite receiving high-dose extended duration treatment with multiple antibiotics, typically metronidazole and vancomycin, up to 65% of patients that become colonized by C. difficile suffer a relapse, an outcome that is correlated with the presence of a low-diversity microbiome. 10 Additionally, treatment with both oral vancomycin and metronidazole has been associated with colonization of the gut by vancomycin resistant Enterococcus faecium (VRE).…”