cadazolid and Diarrhea

Cadazolid, a novel fluoroquinolone-oxazolidinone antibiotic, exhibits potent in vitro activity against Clostridium difficile, including the epidemic BI/NAP1/027 strain. This multicenter, randomized, double-blind, active reference group, phase 2 study evaluated the efficacy and safety of oral cadazolid in treatment of adult patients with C. difficile infection (CDI). Eligible patients with first occurrence/first recurrence of CDI were randomized 1:1:1:1 to 250, 500, or 1,000 mg cadazolid twice daily (BID) or oral 125 mg vancomycin four times daily (QID) for 10 days. The primary endpoint was clinical cure at test of cure (48 ± 24 h after the end of treatment; modified intent-to-treat population), defined as resolution of diarrhea with no further CDI treatment required. Secondary endpoints included recurrence rate, sustained clinical response (clinical cure without recurrence), and time to diarrhea resolution. Of 84 patients enrolled, 20, 22, 20, and 22 received 250, 500, or 1,000 mg cadazolid BID or 125 mg vancomycin QID, respectively. The primary endpoint was achieved in 76.5% (80% confidence interval [CI], 58.4, 89.3), 80.0% (63.9, 91.0), 68.4% (51.1, 82.5), and 68.2% (52.3, 81.3) of patients, respectively. There was no evidence of a cadazolid dosage-dependent response. Each dosage of cadazolid resulted in a lower recurrence rate than with vancomycin (18.2 to 25.0% versus 50%). Consequently, higher sustained clinical response rates were observed with cadazolid (46.7 to 60.0%) than with vancomycin (33.3%). The times to diarrhea resolution were similar for cadazolid and vancomycin. Cadazolid was well tolerated, with no safety signal observed. The results of this phase 2 study support further clinical development of cadazolid. (This study has been registered in the United States at ClinicalTrials.gov under registration no. NCT01222702 and in Europe with the European Medicines Agency under registration no. EUDRA-CT 2010-020941-29.).

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Diarrhea; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Oxazolidinones; Patient Safety; Recurrence; Vancomycin

Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection.. IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin -10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2).. Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: -1·4 [95% CI -7·2 to 4·3] for modified intention to treat and -4·1 [-9·2 to 1·0] for per protocol; IMPACT 2: -4·7 [-10·7 to 1·3] for modified intention to treat and -4·9 [-10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar.. Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely.. Actelion Pharmaceuticals.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Clostridium Infections; Diarrhea; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Oxazolidinones; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clostridioides difficile; Colony Count, Microbial; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Intestines; Metronidazole; Mice; Microbial Sensitivity Tests; Oxazolidinones; Streptococcal Infections; Treatment Outcome; Vancomycin; Vancomycin Resistance; Vancomycin-Resistant Enterococci

Current treatment options for Clostridium difficile-associated diarrhoea (CDAD) leave a high unmet medical need for new therapies. Cadazolid is a new antibiotic in development for the treatment of CDAD. The objectives of this study were to evaluate its tolerability and pharmacokinetics following single ascending doses (AC-061-101) and multiple ascending doses (AC-061-102).. Single and multiple (twice daily for 10 days) oral doses of cadazolid between 30 mg and 3000 mg, or placebo, were tested in a total of 64 healthy male subjects. Safety assessments were conducted at regular intervals. Blood, urine and faeces were sampled, and cadazolid concentrations were measured.. Cadazolid was well tolerated up to 3000 mg given twice daily for 10 days. The most common adverse event was headache, with no observed relationship between dose or treatment duration and adverse events. Plasma concentrations of cadazolid were low. No plasma concentrations >3.3 ng/mL were observed after single doses or >6.9 ng/mL after 10 days of multiple doses. Food increased the mean C(max) from 0.73 to 1.87 ng/mL and mean AUC(0-t) from 3.13 to 15.69 ng ·h/mL after a single 300 mg dose. The increase in systemic exposure to cadazolid across doses was less than dose-proportional. The mean cumulative faecal recovery was 81.0%-93.5%. Urinary recovery of unchanged compound was <0.015%.. Cadazolid was well tolerated and its systemic exposure was low. The majority of compound was recovered unchanged in the faeces, thus resulting in high concentrations at the site of action (colon).

Topics: Administration, Oral; Aged; Anti-Bacterial Agents; Blood Chemical Analysis; Clostridioides difficile; Diarrhea; Feces; Healthy Volunteers; Humans; Male; Middle Aged; Oxazolidinones; Placebos; Urine