Antimicrobial resistance: the example of Staphylococcus aureus.
Antimicrobial resistance: the example of Staphylococcus aureus.
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DOI：
10.1172/jci18535
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发表时间：
2003-05
期刊：
影响因子：
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通讯作者：
F. Lowy
中科院分区：
文献类型：
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作者：
F. Lowy
20世纪70年代初，医生们最终被迫放弃了他们的信念，即考虑到大量有效的抗菌剂，几乎所有的细菌感染都是可以治疗的。金黄色葡萄球菌、肺炎链球菌、铜绿假单胞菌和结核分枝杆菌等病原体对多种抗生素产生抗药性，动摇了他们的乐观情绪。抗菌剂耐药性日益增强的细菌物种的演变源于多种因素，包括抗菌剂的广泛使用，有时是不适当的使用，这些药物在动物饲料中作为生长促进剂的广泛使用，以及随着区域和国际旅行的增加，抗菌剂抗药性细菌相对容易跨越地理障碍(1-3)。具有讽刺意味的是，这种细菌逐渐变得更具耐药性的趋势，恰逢人们对抗菌素耐药性的分子机制的了解急剧增加的时期。不幸的是，尽管这种洞察力导致了新的药物靶点的确定，但它还没有产生有效的新的化疗药物。这一悖论与过去十年抗病毒(尤其是抗逆转录病毒)治疗取得的巨大进步形成了鲜明对比，在过去十年中，一些新发现的分子靶点导致了临床有效的治疗药物。没有任何地方比革兰氏阳性细菌肺炎球菌、肠球菌和葡萄球菌更令人担忧。多药耐药现在是这些病原体中的常态。金黄色葡萄球菌可能是最令人担忧的病原体，因为它的内在毒力，它能够引起各种威胁生命的感染，以及它适应不同环境条件的能力(4，5)。尽管有有效的抗菌剂，金黄色葡萄球菌菌血症的死亡率仍保持在20-40%左右(6)。金黄色葡萄球菌现在是医院感染的主要总原因，随着越来越多的患者在医院外接受治疗，这是社区日益关注的问题(7，8)。来自全国各地重症监护病房的金黄色葡萄球菌分离株和世界各地的血培养分离株对更多的抗菌剂产生越来越大的抗药性(4，8)。不可避免的是，用来治疗这些常常危及生命的感染的有效杀菌抗生素越来越少(图(图1)1)。随着新抗生素的引入，葡萄球菌已经开发出有效的机制来中和它们(表(表11))。图1国家医院感染监测系统中重症监护病房金黄色葡萄球菌感染情况。数据包括1987年至1997年的感染总人数。对分离出的菌株进行了对以下抗菌剂的敏感性测试：庆大霉素，...表1金黄色葡萄球菌对抗菌剂的抗药性机制最近的报道显示，金黄色葡萄球菌对万古霉素具有中等或完全抗药性，预示着一个化疗时代，针对这种微生物的有效杀菌抗生素可能不再容易获得(9，10)。本文将重点介绍金黄色葡萄球菌对抗生素的耐药性。它将回顾耐药菌株的历史演变、它们的传播、对选定抗生素的耐药性的分子机制，以及在开发替代药物靶点或治疗或预防干预的新方法方面的进展。
In the early 1970s, physicians were finally forced to abandon their belief that, given the vast array of effective antimicrobial agents, virtually all bacterial infections were treatable. Their optimism was shaken by the emergence of resistance to multiple antibiotics among such pathogens as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The evolution of increasingly antimicrobial-resistant bacterial species stems from a multitude of factors that includes the widespread and sometimes inappropriate use of antimicrobials, the extensive use of these agents as growth enhancers in animal feed, and, with the increase in regional and international travel, the relative ease with which antimicrobial-resistant bacteria cross geographic barriers (1–3). The irony of this trend toward progressively more resistant bacteria is that it coincides with a period of dramatically increased understanding of the molecular mechanisms of antimicrobial resistance. Unfortunately, while this insight has resulted in the identification of novel drug targets, it has not yet resulted in effective new chemotherapeutic agents. This paradox stands in sharp contrast to the dramatic progress made in antiviral (notably antiretroviral) therapy in the past ten years, where a number of newly discovered molecular targets have resulted in clinically effective therapeutic agents. Nowhere has this issue been of greater concern than with the Gram-positive bacteria pneumococci, enterococci, and staphylococci. Multidrug resistance is now the norm among these pathogens. S. aureus is perhaps the pathogen of greatest concern because of its intrinsic virulence, its ability to cause a diverse array of life-threatening infections, and its capacity to adapt to different environmental conditions (4, 5). The mortality of S. aureus bacteremia remains approximately 20–40% despite the availability of effective antimicrobials (6). S. aureus is now the leading overall cause of nosocomial infections and, as more patients are treated outside the hospital setting, is an increasing concern in the community (7, 8). S. aureus isolates from intensive care units across the country and from blood culture isolates worldwide are increasingly resistant to a greater number of antimicrobial agents (4, 8). Inevitably this has left fewer effective bactericidal antibiotics to treat these often life-threatening infections (Figure (Figure1).1). As rapidly as new antibiotics are introduced, staphylococci have developed efficient mechanisms to neutralize them (Table (Table11). Figure 1 S. aureus infections in intensive care units in the National Nosocomial Infections Surveillance System. Data include the total number of infections from 1987 to 1997. Isolates were tested for sensitivity to the following antimicrobial agents: gentamicin, ... Table 1 Mechanisms of S. aureus resistance to antimicrobialsA Recent reports of S. aureus isolates with intermediate or complete resistance to vancomycin portend a chemotherapeutic era in which effective bactericidal antibiotics against this organism may no longer be readily available (9, 10). This review will focus on the emergence of antimicrobial resistance in S. aureus. It will review the historical evolution of resistant strains, their spread, the molecular mechanisms of resistance for selected antibiotics, and progress toward the development of alternative drug targets or novel approaches for therapeutic or prophylactic intervention.