Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection

Abstract

C lostridium difficile infection (CDI), the main cause of nosocomial infectious diarrhea, results from the growth of toxinproducing C. difficile in the colon following disruption of the normal enteric microbiota, usually as a consequence of antibiotic therapy (1). The frequency and severity of CDI have risen over the past decade, with associated increases in morbidity and mortality, especially among the elderly (2, 3). The increase in CDI has been attributed, at least in part, to the epidemic C. difficile BI/NAP1/027 strain, first reported in 2005 (1, 4). Current treatment of CDI includes metronidazole, vancomycin, or fidaxomicin, with cure rates of approximately 86 to 95% (5-7); however, 15 to 40% of patients experience recurrence following clinical cure (6-9). Reducing recurrence rates, together with improving outcomes for those severely affected by CDI, remains a substantial unmet medical need.Cadazolid is a novel, nonabsorbable antibiotic that acts by inhibiting bacterial protein synthesis. In vitro, cadazolid demonstrates potent activity against C. difficile, including the BI/NAP1/ 027 strain, with a low propensity for resistance development (10)(11)(12)(13). In cultures of toxigenic C. difficile, cadazolid strongly inhibits de novo formation of toxins A and B, the main virulence factors of C. difficile, and prevents in vitro C. difficile spore formation at sub-growth-inhibitory concentrations (11). In healthy male patients, single and twice-daily (BID) ascending oral doses of 30 to 3,000 mg cadazolid resulted in very low systemic exposure, with the majority of cadazolid being excreted unchanged in the feces (14). In a human gut model, cadazolid demonstrated narrowspectrum activity, eliminating CDI while having a very limited impact on the normal gut microbiota (15), which, together with preventing the formation of C. difficile spores, may indicate that cadazolid has the potential to reduce CDI recurrence.Here, we report the results of a phase 2 study investigating the efficacy and safety of three oral dosages of cadazolid, with vancomycin as an active reference, in patients with CDI.

U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin

“…This surveillance forms a baseline for future comparisons as fidaxomicin use becomes more common and other new agents are introduced for the treatment of C. difficile-associated disease (34,35).…”

Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection

“…In healthy subjects following a single 3000 mg oral cadazolid dose, the majority of the oral dose (94%) was recovered as unchanged drug in the faeces [11]. Cadazolid doses of 250, 500 and 1000 mg twice daily for 10 days were effective in the treatment of patients with CDI [12]. Clinical cure rates were similar to vancomycin while having lower recurrence rates, resulting in higher sustained cure rates [12].…”

“…Cadazolid has previously been shown to be well tolerated in healthy subjects and subjects with CDI [11,12]. In both populations, very low cadazolid systemic exposures were observed following both single and multiple oral doses [11].…”

“…Cadazolid doses of 250, 500 and 1000 mg twice daily for 10 days were effective in the treatment of patients with CDI [12]. Clinical cure rates were similar to vancomycin while having lower recurrence rates, resulting in higher sustained cure rates [12]. Cadazolid is now in phase 3 clinical development.…”

Cadazolid Does Not Promote Intestinal Colonization of Vancomycin-Resistant Enterococci in Mice

“…CDZ exhibited potent in vitro activity not only against C. difficile clinical isolates but also against VRE (MIC 90 , 2 g/ml) (12, 13), while having a limited impact on bacteria of the normal gut microflora in the in vitro human gut model (14). Recently, a phase 2 trial in CDAD showed clinical cure rates with CDZ treatment similar to those with VAN treatment, while having lower recurrence rates, resulting in higher sustained cure rates (15).…”