Susceptibilities of Penicillin- and Erythromycin-Susceptible and -Resistant Pneumococci to HMR 3647 (RU 66647), a New Ketolide, Compared with Susceptibilities to 17 Other Agents

Abstract

Susceptibility of 230 penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, was tested by agar dilution, and results were compared with those of erythromycin, azithromycin, clarithromycin, roxithromycin, rokitamycin, clindamycin, pristinamycin, ciprofloxacin, sparfloxacin, trimethoprim-sulfamethoxazole, doxycycline, chloramphenicol, cefuroxime, ceftriaxone, imipenem, and vancomycin. HMR 3647 was very active against all strains tested, with MICs at which 90% of the strains were inhibited (MIC90s) of 0.03 μg/ml for erythromycin-susceptible strains (MICs, ≤0.25 μg/ml) and 0.25 μg/ml for erythromycin-resistant strains (MICs, ≥1.0 μg/ml). All other macrolides yielded MIC90s of 0.03 to 0.25 and >64.0 μg/ml for erythromycin-susceptible and -resistant strains, respectively. The MICs of clindamycin for 51 of 100 (51%) erythromycin-resistant strains were ≤0.125 μg/ml. The MICs of pristinamycin for all strains were ≤1.0 μg/ml. The MIC90s of ciprofloxacin and sparfloxacin were 4.0 and 0.5 μg/ml, respectively, and were unaffected by penicillin or erythromycin susceptibility. Vancomycin and imipenem inhibited all strains at ≤1.0 μg/ml. The MICs of cefuroxime and cefotaxime rose with those of penicillin G. The MICs of trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol were variable but were generally higher in penicillin- and erythromycin-resistant strains. HMR 3647 had the best kill kinetics of all macrolides tested against 11 erythromycin-susceptible and -resistant strains, with uniform bactericidal activity (99.9% killing) after 24 h at two times the MIC and 99% killing of all strains at two times the MIC after 12 h for all strains. Pristinamycin showed more rapid killing at 2 to 6 h, with 99.9% killing of 10 of 11 strains after 24 h at two times the MIC. Other macrolides showed significant activity, relative to the MIC, against erythromycin-susceptible strains only.

Efficacy and Tolerability of Once-Daily Telithromycin Compared with High-Dose Amoxicillin for Treatment of Community-Acquired Pneumonia

“…Current treatment recommendations for CAP vary across countries, including either ␤-lactams at high dose, macrolides or new quinolones [1,[25][26][27]. However, macrolide resistance is increasing [28] and pneumococci resistant to fluoroquinolones are also starting to emerge, a development that appears to be a result of the selective pressure from increasing use of these agents [29,30].Telithromycin is active against erythromycin-resistant S. pneumoniae [16] and represents an alternative to fluoroquinolones in those situations in which they are prescribed as first-line therapy.…”

“…Telithromycin, the first member of a new family of antimicrobials -the ketolides -has been developed specifically to provide optimal therapy for the treatment of respiratory tract infections (RTIs) such as CAP [12].This agent is highly active against common, atypical and intracellular pathogens associated with CAP, including drug-resistant strains [13][14][15][16][17][18][19][20]. The pharmacokinetic profile of oral telithromycin supports a convenient once-daily dosage regimen, with drug concentrations in plasma and bronchopulmonary tissues and fluids consistently exceeding the MIC for common respiratory pathogens at a dose of 800 mg once daily [21,22].…”

Superiority of 11,12 Carbonate Macrolide Antibiotics as Inhibitors of Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

“…1. The ketolide compounds, with the 3-cladinose sugar substituted with a keto group, have recently shown promise as a third generation of novel and broadly effective antibiotics [8,16,17]. Replacement of the sugar with the ketone has generated a class of compounds that will not induce expression of the 23S rRNA methyltransferase activity leading to macrolide resistance [2,18].…”

Evaluation of telithromycin against Streptococcus pneumoniae with ribosomal mutations utilizing in vitro time–kill methodology

“…Previously conducted time-kill studies with telithromycin have demonstrated the agent's bactericidal activity against S. pneumoniae with a variety of phenotypic profiles, including resistance both to ␤-lactams and macrolides [3,4]. Moreover, these studies demonstrated that this activity was irrespective of the genotypic resistance profile (e.g.…”