Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial.
Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial.
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DOI：
10.1371/journal.pmed.1000377
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发表时间：
2010-12-14
期刊：
影响因子：
15.8
通讯作者：
Keenan JD
中科院分区：
文献类型：
--
作者：
Skalet AH;Cevallos V;Ayele B;Gebre T;Zhou Z;Jorgensen JH;Zerihun M;Habte D;Assefa Y;Emerson PM;Gaynor BD;Porco TC;Lietman TM;Keenan JD
Jeremy Keenan及其同事报告说，在埃塞俄比亚进行的一项集群随机临床试验中，随机接受阿奇霉素治疗的社区中，鼻咽肺炎球菌对大环内酯类药物的耐药性明显高于未接受治疗的对照组。人们普遍认为，广泛使用抗生素会导致社区抗生素耐药性，尽管这一点很难在社区随机临床试验中得到证明。在这项研究中，我们采用随机临床试验设计来评估接受大规模阿奇霉素治疗沙眼的社区与未接受治疗的对照组相比，大环内酯类药物耐药性是否更高。在埃塞俄比亚进行的沙眼控制的整群随机试验中，12个社区在0、3、6和9个月时随机接受1-10岁儿童的大规模阿奇霉素治疗。12个对照社区被随机分配，在研究结束前不接受抗生素治疗。在基线和第12个月随机选择治疗组和对照组的儿童收集鼻咽拭子。对拭子分离的肺炎链球菌进行抗生素药敏试验。在治疗组中，所有监测儿童中阿奇霉素耐药性的平均患病率从基线时的3.6%（95%可信区间[CI] 0.8%-8.9%）增加到第12个月时的46.9% (37.5%-57.5%)（p = 0.003）。对照组12个月时阿奇霉素耐药率为9.2% (95% CI 6.7%-13.3%)，显著低于治疗组（p<0.0001）。1年时，对照组中有0.8%（95%可信区间为0%-4.2%）的分离株出现青霉素耐药，而在基线或1年时，儿童治疗组中没有分离株出现青霉素耐药。该集群随机临床试验表明，与未经治疗的对照社区相比，随机接受阿奇霉素强化治疗的社区鼻咽肺炎球菌对大环内酯类药物的耐药性明显更高。大量发放阿奇霉素的频率比目前世界卫生组织沙眼项目建议的要高。在这种情况下，阿奇霉素的使用没有选择对青霉素的耐药性，青霉素仍然是肺炎球菌感染的首选药物。www.ClinicalTrials.gov NCT00322972请参见文章后面的编辑总结1928年，亚历山大·弗莱明发现了青霉素，这是第一种抗生素（一种杀死细菌的药物）。到20世纪40年代初，科学家们已经能够制造出大量的青霉素，在接下来的几十年里，科学家们又发现了其他几类强效抗生素。例如，红霉素——第一种大环内酯类抗生素——是在20世纪50年代早期开发出来的。有一段时间，细菌和它们引起的疾病似乎已经被打败了。但是细菌很快就会对抗生素产生抗药性。在抗生素的“选择压力”下，细菌在DNA中获得了随机变化，使它们能够在抗生素的存在下生存，而不是非耐药细菌。更重要的是，细菌可以在它们之间传递抗生素抗性基因。如今，抗生素耐药性是一个主要的公共卫生问题。在临床使用中，几乎所有类型的致病细菌都对一种或多种抗生素产生了耐药性，多重耐药细菌正在医院和社区中引起潜在致命疾病的爆发。虽然流行病学研究（对人群中疾病的原因、分布和控制的调查）表明抗生素使用与人群中抗生素耐药性之间存在相关性，但这些研究不能证明抗生素使用实际上导致抗生素耐药性。可能是使用更多抗生素的人有其他特征，增加了他们产生抗生素耐药性的机会（所谓的“混杂”）。抗生素使用与抗生素耐药性之间的因果关系只能通过随机对照试验来确定。在此类试验中，随机选择个体组以避免混淆，给予不同的治疗，并比较不同组的结果。在这里，研究人员进行了一项随机临床试验，以评估阿奇霉素治疗沙眼的社区是否比未治疗的社区对大环内酯类药物的耐药性更高。阿奇霉素是一种红霉素衍生物，用于治疗常见的细菌感染，如由肺炎链球菌引起的中耳感染。沙眼是世界上最主要的致盲传染病，由沙眼衣原体引起。世界卫生组织的消除沙眼战略包括每年对高危社区进行阿奇霉素治疗。在这项聚类随机试验（一项随机分配人群而非个体进行不同治疗的研究）中，12个埃塞俄比亚社区的1-10岁儿童在0、3、6和9个月时接受了大规模阿奇霉素治疗，而12个对照社区仅在12个月时接受抗生素治疗。研究人员从随机选择的0和12个月大的接受治疗的儿童和随机选择的12个月大的对照组儿童中提取了鼻咽（鼻子和喉咙）拭子。他们从拭子中分离出肺炎链球菌，并对分离物进行抗生素敏感性测试。70%-80%接受检测的儿童的鼻子或喉咙中都有肺炎链球菌。在治疗组中，3.6%的监测儿童在0个月时携带阿奇霉素耐药肺炎链球菌，而46.9%的儿童在12个月时携带阿奇霉素耐药肺炎链球菌，这在统计学上有显著增加。在12个月时，未治疗组中仅有9.2%的监测儿童携带阿奇霉素耐药肺炎链球菌，明显低于治疗组。重要的是，在0个月或12个月时从接受治疗的儿童中获得的任何肺炎链球菌分离株均未对青霉素产生耐药性；从对照儿童中获得1株青霉素耐药分离株。这些结果表明，在接受阿奇霉素强化治疗的社区中，鼻咽肺炎链球菌对大环内酯类药物的耐药性高于未接受治疗的社区。因此，他们支持这样一种观点，即频繁使用抗生素会导致人群产生抗生素耐药性。尽管该研究是在鼻咽部肺炎链球菌携带率较高的埃塞俄比亚社区进行的，但这一发现可能可推广到其他环境。重要的是，这些发现与目前的沙眼控制活动无关，这些活动使用较少的抗生素治疗，并且不太可能选择阿奇霉素耐药性。青霉素耐药性通常是肺炎链球菌感染的一线治疗方法，没有任何增加，这也令人放心。然而，尽管这些发现表明大规模阿奇霉素治疗沙眼的益处大于任何潜在的不良影响，但它们仍然强调了继续监测大规模抗生素分布的次要影响的重要性。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.1000377访问这些网站。“细菌和药物”网站提供有关抗生素耐药性的信息和其他资源的链接，美国国家过敏和传染病研究所提供有关抗生素耐药性和肺炎链球菌（肺炎球菌疾病）引起的疾病的信息，美国疾病控制和预防中心也有关于抗生素耐药性的信息（英文和西班牙文），世界卫生组织有关于抗生素全球威胁的信息关于这篇论文中描述的试验的更多信息可以在ClinicalTrials.gov上找到
Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities. It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities. In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year. This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections. www.ClinicalTrials.gov NCT00322972 Please see later in the article for the Editors' Summary In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, scientists were able to make large quantities of penicillin and, in the following decades, several other classes of powerful antibiotics were discovered. For example, erythromycin—the first macrolide antibiotic—was developed in the early 1950s. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly become resistant to antibiotics. Under the “selective pressure” of an antibiotic, bacteria that have acquired a random change in their DNA that allows them to survive in the antibiotic's presence outgrow nonresistant bacteria. What's more, bacteria can transfer antibiotic resistance genes between themselves. Nowadays, antibiotic resistance is a major public health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use and multi-drug resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community. Although epidemiological studies (investigations of the causes, distribution, and control of disease in population) show a correlation between antibiotic use and antibiotic resistance in populations, such studies cannot prove that antibiotic use actually causes antibiotic resistance. It could be that the people who use more antibiotics share other characteristics that increase their chance of developing antibiotic resistance (so-called “confounding”). A causal link between antibiotic use and the development of antibiotic resistance can only be established by doing a randomized controlled trial. In such trials, groups of individuals are chosen at random to avoid confounding, given different treatments, and outcomes in the different groups compared. Here, the researchers undertake a randomized clinical trial to assess whether macrolide resistance is higher in communities treated with azithromycin for trachoma than in untreated communities. Azithromycin—an erythromycin derivative—is used to treat common bacterial infections such as middle ear infections caused by Streptococcus pneumoniae. Trachoma—the world's leading infectious cause of blindness—is caused by Chlamydia trachomatis. The World Health Organization's trachoma elimination strategy includes annual azithromycin treatment of at-risk communities. In this cluster-randomized trial (a study that randomly assigns groups of people rather than individuals to different treatments), 12 Ethiopian communities received mass azithromycin treatment of children aged 1–10 years old at 0, 3, 6, and 9 months, and 12 control communities received the antibiotic only at 12 months. The researchers took nasopharyngeal (nose and throat) swabs from randomly selected treated children at 0 and 12 months and from randomly selected control children at 12 months. They isolated S. pneumoniae from the swabs and tested the isolates for antibiotic susceptibility. 70%–80% of the children tested had S. pneumoniae in their nose or throat. In the treated group, 3.6% of monitored children were carrying azithromycin-resistant S. pneumoniae at 0 months, whereas 46.9% were doing so at 12 months—a statistically significant increase. Only 9.2% of the monitored children in the untreated group were carrying azithromycin-resistant S. pneumoniae at 12 months, a significantly lower prevalence than in the treated group. Importantly, there was no resistance to penicillin in any S. pneumoniae isolates obtained from the treated children at 0 or 12 months; one penicillin-resistant isolate was obtained from the control children. These findings indicate that macrolide resistance is higher in nasopharyngeal S. pneumoniae in communities receiving intensive azithromycin treatment than in untreated communities. Thus, they support the idea that frequent antibiotic use selects for antibiotic resistance in populations. Although the study was undertaken in Ethiopian communities with high rates of nasopharyngeal S. pneumoniae carriage, this finding is likely to be generalizable to other settings. Importantly, these findings have no bearing on current trachoma control activities, which use less frequent antibiotic treatments and are less likely to select for azithromycin resistance. The lack of any increase in penicillin resistance, which is usually the first-line therapy for S. pneumoniae infections, is also reassuring. However, although these findings suggest that the benefits of mass azithromycin treatment for trachoma outweigh any potential adverse affects, they nonetheless highlight the importance of continued monitoring for the secondary effects of mass antibiotic distributions. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000377. The Bugs and Drugs website provides information about antibiotic resistance and links to other resources The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on diseases caused by S. pneumoniae (pneumococcal diseases) The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish) The World Health Organization has information about the global threat of antimicrobial resistance and about trachoma (in several languages) More information about the trial described in this paper is available on ClinicalTrials.gov
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影响因子：
9.4
作者：
Farrell, DJ;Morrissey, I;Felmingham, D
通讯作者：
Felmingham, D
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6.4
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11.8
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5.2
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11.8
作者：
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