两种新型大环内酯类药物GW 773546和GW 708408与红霉素、阿奇霉素、克拉霉素、克林霉素和泰利霉素相比的抗肺炎球菌活性。
Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.
作者信息
Matic Vlatka, Kosowska Klaudia, Bozdogan Bulent, Kelly Linda M, Smith Kathy, Ednie Lois M, Lin Gengrong, Credito Kim L, Clark Catherine L, McGhee Pamela, Pankuch Glenn A, Jacobs Michael R, Appelbaum Peter C
机构信息
Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA.
出版信息
Antimicrob Agents Chemother. 2004 Nov;48(11):4103-12. doi: 10.1128/AAC.48.11.4103-4112.2004.
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.
GW 773546、GW 708408和泰利霉素对164株大环内酯类敏感肺炎球菌和161株大环内酯类耐药肺炎球菌的最低抑菌浓度（MIC）较低。GW 773546、GW 708408和泰利霉素对大环内酯类耐药菌株的MIC相似，与菌株的耐药基因型无关。克林霉素对除携带erm(B)的菌株和一株有23S rRNA突变的菌株外的所有大环内酯类耐药菌株均有活性。GW 773546、GW 708408和泰利霉素在其MIC的两倍浓度下，作用24小时后对12株菌株中的7至8株具有杀菌作用。12株菌株在低于MIC浓度下连续传代产生了54个突变体，其中29个在L4或L22蛋白或23S rRNA序列上发生了变化。在大环内酯类敏感菌株中，在克林霉素、GW 773546、红霉素、阿奇霉素和克拉霉素存在下传代后耐药突变体产生得最快，而在GW 708408和泰利霉素存在下传代后产生得最慢。仅在红霉素、阿奇霉素、克拉霉素和克林霉素存在下，从敏感亲本中筛选出MIC≥0.5μg/ml的菌株；36个来自敏感亲本菌株的耐药克隆在L4或L22蛋白或23S rRNA序列上发生了变化。在红霉素和阿奇霉素存在下传代后，没有mef(E)菌株产生耐药克隆。在两株mef(E)菌株中用GW 773546、GW 708408、泰利霉素和克林霉素进行筛选，并未使红霉素、阿奇霉素和克拉霉素的MIC升高超过两倍。在为大环内酯类耐药性而筛选的18个突变体中，有15个的核糖体蛋白（L4或L22）或23S rRNA序列没有变化；3个突变体在L22蛋白序列上发生了变化。GW 773546、GW 708408和泰利霉素筛选出的克隆的MIC为0.03至＞2.0μg/ml。单步研究显示，对于大环内酯类敏感菌株，GW 773546、GW 708408和泰利霉素的突变频率＜5.0×10⁻¹⁰至3.5×10⁻⁷，对于耐药菌株为1.1×10⁻⁷至＞4.3×10⁻³。GW 773546、GW 708408和泰利霉素的抗生素后效应为2.4至9.8小时。
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