title: CEM-101 activity against Gram-positive organisms.
abstract: The in vitro activity of CEM-101, a new fluoroketolide, was determined against Gram-positive organisms with various macrolide susceptibility profiles. Experiments for determination of the MICs and minimum bactericidal concentrations (MBCs), timed killing, single-step and multistep mutation rates, the erythromycin induction of resistance, postantibiotic effect (PAE), and drug interactions were performed for CEM-101; and the results were compared to those obtained with telithromycin, macrolides, and lincosamides. The MBCs of CEM-101 remained lower overall than those of telithromycin, and CEM-101 displayed a 2-fold greater potency than the ketolide. Timed-killing curve testing showed that CEM-101 had greater bactericidal activity than telithromycin (a >or=3-log(10)-CFU/ml decrease in the initial inoculum at 24 h) against the staphylococcal isolates tested. The propensity of CEM-101 to cause resistance was low, as determined from the rates of resistance determined in single-step mutational studies (<10(-8) or 10(-9)). In multipassaging studies, mutants of two strains (both of which were USA300 isolates) resistant to CEM-101 emerged. That number was comparable to the number resistant to clindamycin but less than the number resistant to telithromycin. Erythromycin induced CEM-101 resistance in Staphylococcus aureus and Streptococcus pneumoniae, similar to telithromycin; however, in seven of eight beta-hemolytic streptococci, CEM-101 resistance induction was not observed. CEM-101 showed a significant concentration- and exposure-dependent PAE against the strains tested, with the values ranging from 2.3 to 6.1 h for Gram-positive organisms (these times were longer than those for telithromycin). No antagonism was found in synergy analyses, with enhanced inhibition being most noted for combinations with CEM-101 and ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole. Overall, this new antimicrobial agent (CEM-101) showed good antimicrobial characteristics compared with those of the agents in its class and exhibited measured parameter values similar or superior to those of utilized comparators, indicating that CEM-101 warrants further clinical evaluation.
authors.affiliation: JMI Laboratories, North Liberty, IA 52317, USA.
authors.forename: Leah N
authors.initials: LN
authors.lastname: Woosley
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004917:Erythromycin / Q000494:pharmacology; D005839:Gentamicins / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D048628:Ketolides / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D048628:Ketolides; D018942:Macrolides; D014230:Triazoles; D004917:Erythromycin; D014640:Vancomycin; D002443:Ceftriaxone; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D017963:Azithromycin; C547755:solithromycin; D015242:Ofloxacin; D017291:Clarithromycin; C106791:telithromycin