title: Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.
abstract: The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.
authors.affiliation: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA.
authors.forename: Vlatka
authors.initials: V
authors.lastname: Matic
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kosowska
authors.forename: Bulent
authors.initials: B
authors.lastname: Bozdogan
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Kathy
authors.initials: K
authors.lastname: Smith
authors.forename: Lois M
authors.initials: LM
authors.lastname: Ednie
authors.forename: Gengrong
authors.initials: G
authors.lastname: Lin
authors.forename: Kim L
authors.initials: KL
authors.lastname: Credito
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Clark
authors.forename: Pamela
authors.initials: P
authors.lastname: McGhee
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Pankuch
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology; D002981:Clindamycin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004917:Erythromycin / Q000494:pharmacology; D005798:Genes, Bacterial; D048628:Ketolides / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; C494136:GW 708408; C494135:GW 773546; D048628:Ketolides; D018942:Macrolides; D002981:Clindamycin; D004917:Erythromycin; D017963:Azithromycin; D017291:Clarithromycin; C106791:telithromycin