Current therapies for Clostridium difficile infection (CDI) are encumbered by treatment failures and recurrences. Due to its high in vitro activity against C. difficile but low activity against the typical intestinal flora, minimal absorption, and durable cure in the hamster model of C. difficile infection, OPT-80 was considered for clinical development as a therapy for CDI. This trial consisted of two phases. Four single oral doses of OPT-80 (100, 200, 300, and 450 mg) were administered in a crossover manner to 16 healthy volunteers in a doubleblind, placebo-controlled phase 1A study; a 1-to 2-week washout interval separated the treatments. In the double-blind phase 1B study, 24 healthy subjects were randomized to receive OPT-80 (150, 300, or 450 mg) or placebo for 10 days. In both studies, OPT-80's safety and tolerability were evaluated and the concentrations of OPT-80 and its primary metabolite (OP-1118) in plasma and feces were determined. OPT-80 levels in the urine were also analyzed for the phase 1A study. In both the single-dose and the multiple-dose studies, OPT-80 was well tolerated by all subjects in all dose groups. Maximal plasma concentrations were near or below the limit of quantification (5 ng/ml) across the dose range; urine concentrations were below the detection limit. The fecal total recovery of OPT-80 plus its major metabolite, OP-1118, approximated 100%. The tolerability, high fecal concentration, and low systemic exposure data from these studies support the further clinical development of OPT-80 as an oral therapy for CDI.Clostridium difficile-associated diarrhea (CDAD) is a significant problem in hospitals and long-term care facilities and in the community. Clostridium difficile is the most common cause of nosocomial diarrhea in developed countries (7,12,17). The organism accounts for approximately 20% of cases of antibiotic-associated diarrhea and the majority of cases of antibioticassociated colitis (2, 6, 10, 18). The rising incidence of CDAD has been attributed to the frequent prescription of broadspectrum antibiotics to hospitalized patients (4).OPT-80 is a naturally occurring 18-member macrocycle derived from fermentation (8, 16). The antimicrobial activity of OPT-80 versus anaerobic species including C. difficile has been examined (1, 3, 5, 9). OPT-80 displays a narrow antimicrobial spectrum with excellent activity against many clostridia including C. difficile and moderate activity against certain gram-positive cocci. It is inactive against gram-negative organisms and Candida spp. In an experiment in which 110 genetically distinct strains of C. difficile were tested, the MIC at which 90% of isolates tested were inhibited (MIC 90 ) was 0.125 g/ml, translating to 4-and 16-fold-better potencies than those of metronidazole and vancomycin, respectively, against this species: MIC 90 values of metronidazole and vancomycin for this panel of organisms were 0.5 and 2.0 g/ml, respectively (7a). Furthermore, OPT-80 is bactericidal, with a minimum bactericidal concentration against C. difficile...