SAN FRANCISCO – Those desperate for new treatments for Clostridium difficile infection may want to keep an eye on the experimental oral antibiotic cadazolid, which looked promising in an early-phase trial, according to Daniela Baldoni, Pharm.D.
Cadazolid produced low systemic exposure with high concentrations at the desired site – the colon – and was well tolerated in 64 healthy men who received up to 3,000 mg b.i.d. for 10 days, she reported in a poster presentation at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Dr. Baldoni is employed by Actelion Pharmaceuticals, the company that is developing cadazolid.
The study randomized nonsmoking men to either the drug (single or multiple doses of cadazolid) or placebo. All subjects remained in the clinic for observation for 120 hours after the last dose.
In the single-dose group, 30 fasting subjects received a single dose of 30, 100, 300, 1,000, or 3,000 mg cadazolid and 10 subjects received matching placebo. After a wash-out period of 8-15 days, the six subjects who had taken 300 mg received a second dose of 300 mg after eating instead of after fasting. In the multiple-dose group, 18 subjects took 300, 1,000, or 3,000 mg of cadazolid twice a day and 6 received matching placebo for 10 days.
Taking cadazolid with food appeared to increase the rate and extent of drug absorption by two- to fivefold. Blood samples showed low systemic exposure after single or multiple doses, with a minor, twofold increase in cadazolid in plasma after 10 days for all doses in the twice-a-day group, Dr. Baldoni reported at the meeting, sponsored by the American Society for Microbiology.
Negligible recovery of unchanged cadazolid in urine samples and the fact that most of the dose was recovered in feces suggests that treatment produced high concentrations at the colon. In fecal samples collected during days 6 and 10 of treatment, the mean cumulative recovery of unchanged cadazolid in feces was between 87% and 94%.
There were no significant changes in vital signs, ECG results, or laboratory parameters compared with baseline measurements, and no drug-related serious adverse events. All subjects completed the study except one man in the 100-mg single-dose subgroup who withdrew consent for reasons unrelated to adverse events.
The dose or duration of treatment did not seem to affect the number of adverse events.
In the single-dose group, 8 of 30 subjects on cadazolid (27%) and 4 of 10 on placebo (40%) reported adverse events, most commonly headache and diarrhea. Four subjects on cadazolid (13%) and two on placebo (20%) reported headache, and three subjects on cadazolid (10%) and one on placebo (10%) reported diarrhea.
In the twice-a-day dosing group, 7 of 18 subjects on cadazolid (39%) and 1 of 6 subjects on placebo (17%) reported adverse events, most commonly headache in 5 subjects on cadazolid (28%) and 1 subject on placebo (17%).
Subjects were aged 45-60 years and had a body mass index of 18-32 kg/m2.
C. difficile is the most common cause of antibiotic-associated infectious diarrhea, especially among the elderly. The mainstays of treating C. difficile–associated infection, metronidazole or vancomycin, fail in approximately 20%-45% of patients.
Cadazolid is in the oxazolidinone class of antibiotics. Its mechanism of action consists mainly of bacterial protein-synthesis inhibition.
Dr. Baldoni and most of her coinvestigators are employees of Actelion Pharmaceuticals, which funded the study.