Expanding the armamentarium for the treatment of Clostridium difficile infection
Authors: Simon D Goldenberg
Journal: The Lancet Infectious Diseases (2017)

In The Lancet Infectious Diseases, Richard Vickers and colleagues1Vickers RJ Tillotson GS Nathan R et al.Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study.Lancet Infect Dis. 2017; (published online April 28)http://dx.doi.org/10.1016/S1473-3099(17)30235-9Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar report results of a phase 2 study of ridinilazole, a promising new drug for the treatment of Clostridium difficile infection. Although efforts to improve infection control practices and antimicrobial stewardship have led to significant reductions in some countries,2Dingle KE Didelot X Quan TP et al.Effects of control interventions on Clostridium difficile infection in England: an observational study.Lancet Infect Dis. 2017; 17: 411-421Summary Full Text Full Text PDF PubMed Scopus (216) Google Scholar C difficile infection remains a substantial problem worldwide. All-cause 30-day mortality associated with C difficile infection has been reported to be in the region of 9–38%.3Mitchell BG Gardner A Mortality and Clostridium difficile: a review.Antimicrob Resis Infect Control. 2012; 1: 20Crossref PubMed Google Scholar, 4Van Kleef E Green N Goldenberg SD et al.Excess length of stay and mortality due to Clostridium difficile infection: a multi-state modelling approach.J Hosp Infect. 2014; 88: 213-217Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Furthermore, cases are associated with excess length of hospital stay of approximately 7 days (and 12 days in severe cases).3Mitchell BG Gardner A Mortality and Clostridium difficile: a review.Antimicrob Resis Infect Control. 2012; 1: 20Crossref PubMed Google Scholar C difficile infection usually occurs following disruption of the intestinal microbiota resulting from exposure to antibiotics. The risk of C difficile infection increases by up to six times during antibiotic therapy and in the month thereafter.5Hensgens MP Goorhuis A Dekkers OM Kuijper EJ Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics.J Antimicrob Chemother. 2012; 67: 742-748Crossref PubMed Scopus (261) Google Scholar, 6Thomas C Stevenson M Riley TV Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review.J Antimicrob Chemother. 2003; 51: 1339-1350Crossref PubMed Scopus (254) Google Scholar Risk of disease recurrence within 8 weeks of treatment of an initial episode is estimated to be approximately 15–25%; for those with more than one previous recurrence, the risk of further recurrences increases to 40–65%.7Abou Chakra CN Pepin J Sirard S Valiquette L Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.PLoS One. 2014; 9: e98400Crossref PubMed Scopus (167) Google Scholar, 8Kelly CP Can we identify patients at high risk of recurrent Clostridium difficile infection?.Clin Microbiol Infect. 2012; 18: 21-27Summary Full Text Full Text PDF PubMed Scopus (244) Google Scholar Recurrences have been associated with impaired immune responses to C difficile toxins together with disturbance of the indigenous colonic microbiota. Continued use of antibiotics, as well as numerous other factors such as concomitant anti-ulcer medication and older age (particularly those older than 65 years) are well recognised risk factors for recurrence.7Abou Chakra CN Pepin J Sirard S Valiquette L Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.PLoS One. 2014; 9: e98400Crossref PubMed Scopus (167) Google Scholar Management of such patients is challenging and places substantial demand on health-care resources. For several decades the only available drugs to treat C difficile infection were metronidazole and vancomycin. Concerns over emerging resistance and worsening clinical outcomes have resulted in a shift away from the use of metronidazole, even for non-severe cases.9Barkin JA Sussman DA Fifadara N Barkin JS Clostridium difficile infection and patient-specific antimicrobial resistance testing reveals a high metronidazole resistance rate.Dig Dis Sci. 2017; 62: 1035-1042Crossref PubMed Scopus (23) Google Scholar, 10Stevens WV Nelson RE Schwab-Daughterty EM et al.Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection.JAMA Intern Med. 2017; 177: 546-553Crossref PubMed Scopus (112) Google Scholar Fidaxomicin was licensed in the European Union and USA in 2011. Its use has led to significant reductions in recurrences compared with the use of vancomycin, particularly when it is not restricted to highly selected cases.11Goldenberg SD Brown S Edwards L et al.The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations.Eur J Clin Microbiol Infect Dis. 2016; 35: 251-259Crossref PubMed Scopus (38) Google Scholar Despite its effectiveness for all C difficile infections, fidaxomicin is generally used to treat a first recurrence; this decision is probably driven by the greater cost of the drug compared with vancomycin. However, this strategy could be short-sighted since the costs of managing recurrent episodes can be severe.12Shah DN Aitken SL Barragan LF et al.Economic burden of primary compared with recurrent Clostridium difficile infection in hospitalized patients: a prospective cohort study.J Hosp Infect. 2016; 93: 286-289Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar Because of the limited number of effective antimicrobials available to treat C difficile infection, the development of new drugs is vital. An ideal agent would be bactericidal against vegetative cells, inhibit spore and toxin production, have targeted activity against C difficile while sparing indigenous gut flora, be poorly absorbed from the gastrointestinal tract, and be well tolerated. Ridinilazole appears to have many of these attributes, making it a good candidate for further development. The main outcome measure reported by Vickers and colleagues1Vickers RJ Tillotson GS Nathan R et al.Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study.Lancet Infect Dis. 2017; (published online April 28)http://dx.doi.org/10.1016/S1473-3099(17)30235-9Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar was sustained clinical response. This is a combined endpoint that measures cure at the end of treatment (resolution of symptoms with three or fewer unformed bowel movements over a 24-h period) and an absence of recurrence in the 30 days after treatment. 24 (66·7%) of 36 patients in the ridinilazole group had a sustained clinical response compared with 14 (42·4%) of 33 patients in the vancomycin group, showing statistical superiority in the modified intention-to-treat analysis. Subgroup analysis of this outcome measure showed that ridinilazole performed better than vancomycin in patients older than 75 years, those with markers of severe disease, those with one or more episodes of C difficile infection, and those requiring concomitant antibiotics, although the differences were not all statistically significant because of the low numbers. Recurrence of infection occurred in four (14·3%) of 28 ridinilazole-treated participants versus eight (34·8%) of 23 vancomycin-treated participants. The study was somewhat limited by the inclusion of patients who were slightly younger than those who might be expected to be seen in everyday clinical practice (most patients were younger than 65 years). Similarly, only 10% in the ridinilazole group and 8% in the vancomycin group had a previous episode of C difficile infection, and just 14% in the ridinilazole group and 18% in the vancomycin group had severe disease. Furthermore, it is unclear why some of the centres were not able to recruit to the study (only 21 of 33 [64%] sites recruited patients). Discounting these shortcomings, it is rare for a study of an antimicrobial to show statistical superiority over the standard of care. The main advantage of ridinilazole and other new drugs such as fidaxomicin and bezlotoxumab appears to be related to the reduction or prevention of recurrence. Therefore, the development of bedside tools that can be used in real time to predict accurately the risk of recurrent C difficile infection could be helpful. These tools could help to optimise treatment for those at risk of severe, complicated, or recurrent infection at the early stages of disease and drive improvement in a range of clinical outcomes. I have received grants and personal fees from Astellas, personal fees from BD, Luminex, Abbott, Orion Diagnostics, Qiagen, MSD, and DNA electronics, and non-financial support from Eurobiotix CIC, outside the submitted work. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority studyRidinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted. Full-Text PDF Open Access