Livermore D M
Central Public Health Laboratory, London, UK.
J Antimicrob Chemother. 1998 Jun;41 Suppl D:25-41. doi: 10.1093/jac/41.suppl_4.25.
Clinical use of beta-lactams has selected for beta-lactamase-producing organisms. Numerous beta-lactamases are known, and sequencing allows them to be divided into four Classes, A to D, with Classes A and C being the most important. Pharmaceutical chemists have responded to the spread of beta-lactamase-producing organisms by developing stable agents and inhibitors. Stability in penicillins and cephalosporins is achieved by attaching a bulky substituent to the amino group of 6-aminopenicillanic acid or 7-aminocephalosporanic acid, or by replacing the hydrogen on carbon 6 (penicillins) or 7 (cephalosporins) with an alpha-methoxy group. In carbapenems, stability is achieved by incorporation of a simple trans-6-hydroxyethyl group. Beta-lactamase-inhibitory activity occurs in many beta-lactam classes but only clavams and penicillanic acid sulphones have been developed specifically as beta-lactamase inhibitors. These inhibit most Class A and some Class D enzymes but act poorly against Class B and C enzymes. Their success is affected by the amount of enzyme, the permeability of the bacterial cell wall, the partner beta-lactam and the pH. Piperacillin/tazobactam, which combines a good inhibitor of Class A enzymes with a broad-spectrum, easily-protected penicillin, has wide activity against common pathogens, the major exceptions being strains of Enterobacter, Serratia and Citrobacter freundii that produce large amounts of Class C enzymes, and Gram-positive cocci with modified penicillin-binding proteins. Beta-lactamase-stable beta-lactams and inhibitor combinations overcome many existing resistance mechanisms but are themselves selecting new resistances. Few new beta-lactams able to overcome these resistances are advanced in development and consequently the opportunities for control lie mostly in the more prudent use of compounds already available.
β-内酰胺类药物的临床应用筛选出了产β-内酰胺酶的微生物。已知有多种β-内酰胺酶，通过测序可将它们分为A至D四类，其中A类和C类最为重要。药物化学家通过研发稳定型药物和抑制剂来应对产β-内酰胺酶微生物的传播。青霉素类和头孢菌素类的稳定性可通过在6-氨基青霉烷酸或7-氨基头孢烷酸的氨基上连接一个庞大的取代基，或者用α-甲氧基取代6位（青霉素类）或7位（头孢菌素类）的氢来实现。在碳青霉烯类药物中，通过引入一个简单的反式-6-羟乙基基团来实现稳定性。许多β-内酰胺类药物都具有β-内酰胺酶抑制活性，但只有棒酸类和青霉烷酸砜类被专门开发为β-内酰胺酶抑制剂。这些抑制剂可抑制大多数A类和一些D类酶，但对B类和C类酶的作用较弱。它们的效果受酶量、细菌细胞壁通透性、配对的β-内酰胺类药物以及pH值的影响。哌拉西林/他唑巴坦将一种良好的A类酶抑制剂与一种广谱、易于保护的青霉素结合在一起，对常见病原体具有广泛的活性，主要例外是大量产生C类酶的阴沟肠杆菌、沙雷菌属和弗氏柠檬酸杆菌菌株，以及具有修饰青霉素结合蛋白的革兰氏阳性球菌。β-内酰胺酶稳定的β-内酰胺类药物和抑制剂组合克服了许多现有的耐药机制，但它们自身也在筛选出新的耐药性。目前很少有能够克服这些耐药性的新型β-内酰胺类药物进入研发后期，因此控制耐药性的机会主要在于更谨慎地使用现有化合物。
