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

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.