Universidad de Buenos Aires, Junin, Ciudad Autónoma de Buenos Aires, Argentina.
Curr Pharm Des. 2013;19(2):164-208.
Early after the introduction of the first (narrow spectrum) penicillins into clinical use, penicillinase-producing staphylococci replaced (worldwide) the previously susceptible microorganisms. Similarly, the extensive use of broad-spectrum, orally administered β- lactams (like ampicillin, amoxicillin or cefalexin) provided a favorable scenario for the selection of gram-negative microorganisms producing broad spectrum β-lactamases almost 45 years ago. These microorganisms could be controlled by the introduction of the so called "extended spectrum cephalosporins". However, overuse of these drugs resulted, after a few years, in the emergence of extended-spectrum β-lactamases (ESBLs) through point mutations in the existing broad-spectrum β-lactamases, such as TEM and SHV enzymes. Overuse of extended-spectrum β-lactams also gave rise to chromosomal mutations in regulatory genes which resulted in the overproduction of chromosomal AmpC genes, and, in other regions of the world, in the explosive emergence of other ESBL families, like the CTX-Ms. Carbapenems remained active on microorganisms harboring these extended-spectrum β-lactamases, while both carbapenems and fourth generation cephalosporins remained active towards those with derepressed (or the more recent plasmidic) AmpCs. However, microorganisms countered this assault by the emergence of the so called carbapenemases (both serine- and metallo- enzymes) which, in some cases, are actually capable of hydrolyzing almost all β-lactams including the carbapenems. Although all these enzyme families (some of them represented by hundreds of members) are for sure pre-dating the antibiotic era in environmental and clinically significant microorganisms, it was the misuse of these antibiotics that drove their evolution. This paper describes in detail each major class of β-lactamase including epidemiology, genetic, and biochemical evaluations.
早在第一代（窄谱）青霉素引入临床应用后，产青霉素酶的葡萄球菌就取代了（全球范围内）以前敏感的微生物。同样，广泛使用口服广谱β-内酰胺类药物（如氨苄西林、阿莫西林或头孢氨苄），为近 45 年前产生广谱β-内酰胺酶的革兰氏阴性微生物的选择提供了有利条件。这些微生物可以通过引入所谓的“扩展谱头孢菌素”来控制。然而，这些药物的过度使用导致几年后，在现有的广谱β-内酰胺酶（如 TEM 和 SHV 酶）中发生点突变，产生了超广谱β-内酰胺酶（ESBLs）。扩展谱β-内酰胺类药物的过度使用也导致了调节基因中的染色体突变，导致染色体 AmpC 基因的过度产生，并且在世界其他地区，其他 ESBL 家族（如 CTX-Ms）也突然出现。碳青霉烯类药物对携带这些扩展谱β-内酰胺酶的微生物仍然有效，而碳青霉烯类药物和第四代头孢菌素类药物对那些失活（或最近的质粒）AmpC 的微生物仍然有效。然而，微生物通过出现所谓的碳青霉烯酶（包括丝氨酸和金属酶）来对抗这种攻击，在某些情况下，这些酶实际上能够水解几乎所有的β-内酰胺类药物，包括碳青霉烯类药物。虽然所有这些酶家族（其中一些由数百个成员组成）肯定在环境和临床上有意义的微生物中早于抗生素时代，但正是这些抗生素的滥用推动了它们的进化。本文详细描述了每一类β-内酰胺酶，包括流行病学、遗传和生化评价。
