McGee Lesley, Biek Donald, Ge Yigong, Klugman Magderie, du Plessis Mignon, Smith Anthony M, Beall Bernard, Whitney Cynthia G, Klugman Keith P
Emory University, Atlanta, Georgia 30322, USA.
Antimicrob Agents Chemother. 2009 Feb;53(2):552-6. doi: 10.1128/AAC.01324-08. Epub 2008 Nov 17.
Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae. In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of S. pneumoniae. The MICs of ceftaroline and comparators were determined by broth microdilution. In total, 120 U.S. isolates of cefotaxime-resistant (MIC > or = 4 microg/ml) S. pneumoniae were tested along with 18 laboratory-derived R6 strains with known penicillin-binding protein (PBP) mutations. Clinical isolates were characterized by multilocus sequence typing, and the DNAs of selected isolates were sequenced to identify mutations affecting pbp genes. Ceftaroline (MIC(90) = 0.5 microg/ml) had greater in vitro activity than penicillin, cefotaxime, or ceftriaxone (MIC(90) = 8 microg/ml for all comparators) against the set of highly cephalosporin-resistant clinical isolates of S. pneumoniae. Ceftaroline was also more active against the defined R6 PBP mutant strains, which suggests that ceftaroline can overcome common mechanisms of PBP-mediated cephalosporin resistance. These data indicate that ceftaroline has significant potency against S. pneumoniae strains resistant to existing parenteral cephalosporins and support its continued development for the treatment of infections caused by resistant S. pneumoniae strains.
肺炎球菌对广谱头孢菌素的耐药性不断增加，这就需要寻找对这类耐药菌株具有活性的新型药物。头孢洛林是一种目前正处于3期临床开发阶段的肠外头孢菌素，已显示出对包括耐青霉素肺炎链球菌在内的耐药革兰氏阳性菌具有强大的体外活性。在本研究中，评估了头孢洛林对来自疾病控制和预防中心活性细菌核心监测项目的高度耐头孢噻肟肺炎球菌分离株以及实验室衍生的肺炎链球菌头孢菌素耐药突变体的活性。通过肉汤微量稀释法测定头孢洛林和对照药物的最低抑菌浓度（MIC）。总共测试了120株美国耐头孢噻肟（MIC≥4μg/ml）肺炎链球菌分离株以及18株具有已知青霉素结合蛋白（PBP）突变的实验室衍生R6菌株。对临床分离株进行多位点序列分型，并对选定分离株的DNA进行测序以鉴定影响pbp基因的突变。头孢洛林（MIC90 = 0.5μg/ml）对一组高度耐头孢菌素的肺炎链球菌临床分离株的体外活性高于青霉素、头孢噻肟或头孢曲松（所有对照药物的MIC90 = 8μg/ml）。头孢洛林对确定的R6 PBP突变菌株也更具活性，这表明头孢洛林可以克服PBP介导的头孢菌素耐药的常见机制。这些数据表明，头孢洛林对耐现有肠外头孢菌素的肺炎链球菌菌株具有显著的活性，并支持其继续开发用于治疗由耐肺炎链球菌菌株引起的感染。
