Ridinilazole—a novel antibiotic for treatment of Clostridium difficile infection

Clostridium difficile (C. difficile) infection has become a major health problem worldwide and is considered to be one of the most common hospital-acquired (nosocomial) infections with increasing incidence and severity (1). In Germany, the number of C. difficile infections (CDI) increased from 7 to 39 reported cases per 100,000 hospitalized patients between 2000 and 2004, with yet another doubling of numbers between 2004 and 2006 (2). The recent rise has been associated with the spread of hyper-virulent strains of the bacteria such as the NAP1/ribotype 027 strain (3). The disease is primarily associated with prior broad-spectrum antibiotic therapy causing a disruption of the normal gut microbiota; leading to an overgrowth of C. difficile bacteria (4). Therefore, prudent use of antibiotics by antibiotic stewardship is central in preventing CDI. C. difficile is a Gram-positive, spore-forming, non-invasive bacterium, which is usually transmitted via the faecal-oral route. The spectrum of clinical manifestations of CDIs ranges from asymptomatic colonization of the gut to more severe disease manifestations by toxigenic strains. The release of the toxins A (enterotoxin) and B (cytotoxin) results in a disruption of the colonic mucosal interface; with symptoms ranging from mild secretory diarrhoea to the full clinical presentation of pseudomembranous colitis with typical endoscopic findings. In severe cases, the progression of the disease can lead to complications such as toxic megacolon, perforation of the gut and potentially fatal sepsis (5). As a key clinical issue, CDIs are associated with high rates of recurrence, affecting up to one-third of patients, after completing initial therapy. Risk factors for recurrence of CDI include gastric acid suppression by proton pump inhibitor therapy, gastrointestinal tract surgery, underlying immunosuppression (malignancy, cirrhosis, chemotherapy, immunosuppressive therapy), as well as older age (>65 years) of affected patients (6-11). Recurrent infections are associated with an increased risk of further episodes of infection, which become more difficult to treat. Subsequent repeated hospitalisations and antibiotic therapies inevitably lead to a higher financial burden on the healthcare system (12,13).

Treatment options are limited to three antibiotics, these being metronidazole, vancomycin and fidaxomicin. Metronidazole and vancomycin, the standard options of treatment for decades, are associated with disruption of the gut microbiota that might trigger recurrence of disease (14). Fidaxomicin has a narrower spectrum of activity, with lower rates of disease recurrence (15). However, its wider application has been hindered by financial considerations (9). Although fidaxomicin lowers the rates of recurrence and subsequently the costs of treating relapses, its regular use would increase total costs of treatment over time (16). Additional therapeutic approaches for the prevention of CDI relapses have been evaluated, including the adjunct use of probiotics and transplantation of faecal microbiota. However, so far, there are limited data to recommend the use of probiotics routinely (17). Faecal microbiota transplantation has been shown to reduce the rate of recurrence of CDIs, especially in patients who had multiple relapses. However, further work is needed to address remaining issues such as the route of administration (duodenal, colonic, packaged in capsules for oral application) and how to determine eligibility for treatment (18,19). Additional investigations evaluate the oral administration of non-toxigenic C. difficile strains to compete with toxigenic strains (20).

Other approaches include the development of vaccines or antibodies. The administration of the fully human monoclonal antibody bezlotoxumab against C. difficile toxin B, in addition to antibiotic therapy, has been shown to decrease recurrence rates of CDI substantially (21). It is noteworthy that the use of vaccines and antibodies for treatment does not contribute to an increased risk of antibiotic resistance. However, resistance of C. difficile to the available antibiotics has been reported rarely in the literature, despite their widespread use (22).

Ridinilazole is a novel, narrow-spectrum antibiotic, which has been developed for the treatment of CDI (23). An earlier study has shown that this drug causes minimal disruption of the normal gut microbiota (24). Vickers and colleagues report the results of a phase 2 study of ridinilazole, in which the safety and efficacy of the new drug was compared to vancomycin in patients with CDI (25). Accordingly, 100 patients were randomly assigned to receive a ten-day course of either ridinilazole (200 mg orally twice daily) or vancomycin (125 mg four times daily). Patients in the ridinilazole group also received two doses of placebo daily in order to maintain the same dosing schedule. Patients recruited to the study were confirmed to have CDI by detection of toxin in the stool. Sixty-nine patients (36 treated with ridinilazole and 33 treated with vancomycin) were included in the primary analysis of efficacy. The clinical response rates were defined as a composite endpoint of cure at the end of treatment and no recurrence for 30 days after treatment. Ridinilazole was shown to be significantly more effective than vancomycin regarding the endpoint of sustained clinical responses (66.7% for ridinilazole vs. 42.4% for vancomycin). The cure rate for ridinilazole also met the pre-specified endpoint of non-inferiority at the end of treatment compared with vancomycin (77.8% for ridinilazole vs. 68.7% for vancomycin). Recurrent infections were seen in 14.3% of patients treated with ridinilazole and in 34.8% of patients treated with vancomycin. The rates of adverse events were similar in both treatment groups. Adverse events were reported in 82% (41 of 50) of patients receiving ridinilazole, compared with 80% (40 of 50) of patients receiving vancomycin. No adverse events that required treatment to be discontinued were seen in the ridinilazole group. However, safety assessments are limited because of the relatively small number of patients. Further limitations of the trial included over-representation of younger patients recruited to the study. Additionally, only 14% of patients in the ridinilazole group and 18% in the vancomycin group had severe disease and few of the participants in the trial had a history of previous episodes of CDI (10% in the ridinilazole group and 8% in the vancomycin group). Also, it remains unclear, why only 64% (21/33) of the sites in this multicentre study recruited patients to the trial. Furthermore, future studies designed to compare the clinical response rates of ridinilazole with those of fidaxomicin, might yield additional insights.

In summary, due to the still limited effectiveness of available therapies for CDI, and despite considerable advances in the field, further development of innovative treatment options is needed. The promising results of this phase 2 study of the new drug ridinilazole definitely warrant further clinical assessment in patients with CDI.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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