Non-Antimicrobial Chemically Modified Tetracycline-3 in Humans: Microbial Findings

Tetracyclines are known to promote the overgrowth of Candida species and long-term use has been associated with the selection of tetracycline-resistant bacterial flora. 6 deoxy-6-demethyl-4-dedimethylaminotetracycline (CMT-3; also called COL-3 and Incyclinide in some publications) lacks the C4 dimethylamino group of tetracycline rendering it unable to bind to bacterial ribosomes and inhibit protein synthesis in vitro. Objectives: To determine in vivo if CMT-3 alters the oral flora of humans with chronic periodontitis in a double-blind placebo-controlled clinical trial. Methods: 35 subjects were randomly distributed to receive by oral administration, CMT-3 (10mg q.d; n=18) or visually matched placebo (n=17) capsules daily for 28 days. Subjects were sampled at baseline, week 2, week 4, and week 8. Dental plaque was taken from 2 pockets per patient with endodontic paper-points, placed immediately into anaerobic transport medium, and processed in the laboratory within 2hrs of collection. Dilutions of plaque were plated on a non-selective anaerobic colony count medium (ACCM) and on ACCM containing 4µg/ml doxycycline. Plates were incubated anaerobically for 7days at 37°C and the percentage of doxycycline-resistant CFU's was calculated. Oral mouth-rinse samples were taken and plated on CHROMagar Candida to determine the number of Candida species. Results: 1-way between-subjects ANOVA analysis at each time-point between CMT-3 and Placebo groups determined that the percentage of doxycycline-resistant CFU's and total numbers of Candida species was not statistically different between the two groups (p > 0.05). Conclusion: CMT-3 at 10mg q.d. for 28 days did not select for doxycycline-resistant plaque flora and did not produce an over-growth of oral Candida species. This study was supported by a grant from CollaGenex Pharmaceuticals Inc. Newtown, PA and was conducted at Stony Brook University Hospital GCRC (M01RR10710). The study was approved by the Stony Brook University GAC (03-213-67) and CORIHS (20045260) and the FDA (IND 63,956).