Primary Outcomes From a Phase 3, Randomized, Double-Blind, Active-Controlled Trial of Surotomycin in Subjects With Clostridium difficile Infection

Abstract

Background.Although the incidence of Clostridium difficile infection (CDI) is increasing, available CDI treatment options are limited in terms of sustained response after treatment. This phase 3 trial assessed the efficacy and safety of surotomycin, a novel bactericidal cyclic lipopeptide, versus oral vancomycin in subjects with CDI.Methods.In this randomized, double-blind, active-controlled, multicenter, international trial, subjects with CDI confirmed by a positive toxin result were randomized to receive surotomycin (250 mg twice daily) or vancomycin (125 mg 4 times daily) orally for 10 days. The primary endpoints were clinical response at end of treatment and evaluation of surotomycin safety. The key secondary endpoints were clinical response over time and sustained clinical response through a 30- to 40-day follow-up period. Clostridium difficile infection recurrence during follow-up and time to diarrhea resolution were also analyzed.Results.In total, 570 subjects were randomized and had confirmed CDI; 290 subjects received surotomycin and 280 subjects received vancomycin. Surotomycin clinical cure rates at end of treatment (surotomycin/vancomycin: 79.0%/83.6%; difference of −4.6%; 95% confidence interval, −11.0 to 1.9]), clinical response over time (stratified log-rank test, P = .832), and sustained clinical response at end of trial (Day 40–50) (60.6%/61.4%; difference of −0.8%; 95% CI, −8.8 to 7.1) in the microbiological modified intent to treat population did not meet noninferiority or superiority criteria versus vancomycin. Both treatments were generally well tolerated.Conclusions.Surotomycin failed to meet the criteria for noninferiority versus vancomycin for the primary and key secondary endpoints in this trial.

More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin

“…Although several resistant mutants were isolated, resistance development is still slower compared to drugs with single protein targets [163]. In contrast to well-characterized compounds like vancomycin, derivatives of daptomycin have not succeeded in making the transition into the clinic yet [12,[164][165][166][167]. This may at least partly be attributed to our limited understanding of its mechanism of action.…”

Current trends in targeted therapy for drug-resistant infections

“…For instance, Daptomycin (Cubicin®) was approved in 2003 for the treatment of skin and bloodstream infections caused by susceptible and methicillin-resistant strains of Staphylococcus aureus (Afacan et al 2012). After that, Surotomycin (CB-315, CB-183315, and MK4261) as one of daptomycin analogs was developed to treat C. difficile-associated diarrhea, but recently, it was failed due to lack of superiority over standard of treatment (Boix et al 2017) (Petrosillo et al 2018). Murepavadin (POL 7080) as cyclic synthetic peptide (14aa) is known as an attractive drug to treat ventilator-associated pneumonia (VAP) and hospitalacquired pneumonia (HAP) caused by Pseudomonas.…”

Microbiologic factors affecting Clostridium difficile recurrence

“…Surotomycin (a cyclic lipopeptide) shows potent antibacterial activity against C. difficile and other Gram-positive bacteria but limited effects on Gram-negative organisms in phase 1 clinical trials and an in vitro gut model [43,44]. However, this did not correlate with improved outcomes in phase 3 studies, and the primary clinical end point of noninferiority to vancomycin was not met (Chesnel et al, 'Impact of surotomycin and vancomycin exposure on gut microbiota and correlation with clinical outcomes from a phase 3 trial of patients with C. difficileeassociated diarrhoea,' paper presented at the 26th European Congress on Clinical Microbiology and Infectious Diseases, 2016) [45,46].…”