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

• A single 3000 mg cadazolid dose in patients with severe Clostridium difficile infection (CDI) was well tolerated.
• Low systemic cadazolid exposure in severe CDI patients.
• High cadazolid faecal concentrations.

Cadazolid is under development as an oral treatment for Clostridium difficile infection (CDI), which is the most common infectious cause of antibiotic-associated diarrhoea. Low systemic cadazolid exposures were previously reported in healthy subjects following both single and multiple oral dosing. The main objective of this study was to investigate systemic cadazolid exposure in patients with severe CDI with potential disrupted lining of the gastrointestinal tract. A single 3000 mg oral dose of cadazolid was administered to six patients with microbiologically-confirmed severe CDI. Plasma and faeces were collected up to 144 h post-dose for determination of cadazolid concentrations. Safety assessments were conducted over the 144-h investigational period. Cadazolid was well tolerated in patients with severe CDI, with no reported drug-related adverse events. Cadazolid systemic exposure following a single 3000 mg oral dose was very low, with a peak plasma concentration (Cmax) of 2.64 ng/mL and an area under the concentration–time curve (AUC0–144) of 125 ng × h/mL. The median peak daily faecal cadazolid concentration was 5675 times the C. difficile MIC90 of 0.25 mg/L. In subjects with severe CDI, cadazolid systemic exposure was very low following a single high oral dose. Cadazolid plasma concentrations were similar in magnitude to those previously reported for healthy subjects, whereas total systemic exposure was ca. 5–6 times higher, but was still low. Peak daily faecal cadazolid concentrations were 5675 times the 0.25 mg/L C. difficile MIC90, and on Day 4 five of the six patients presented a daily faecal cadazolid concentration ≥1651 times the MIC90 [ClinicalTrial.gov ID: NCT02053181].