Beta-lactamases have been classified according to either molecular characteristics or according to their functional properties. The number of unique beta-lactamases now approaches 400, with new enzymes identified on an almost on a weekly basis. Some of these enzymes represent step-wise selection of variants of the common plasmid-encoded TEM, SHV and OXA broad-spectrum beta-lactamases, or the inhibitor-resistant TEM enzymes.
Other plasmid beta-lactamases include variants of chromosomal cephalosporinases; enzymes that apparently originated from an organism that at one time was believed to produce a specific AmpC beta-lactamase.
Multi-drug resistant plasmids are now being disseminated freely among the enterobacteriaceae, resulting in organisms with an accumulation of resistance factors. The appearance of the broad-spectrum carbapenem-hydrolyzing beta-lactamases on plasmids has become most disturbing, as these enzymes appear in organisms that produce other beta-lactamases with even more potent hydrolytic properties. As novel beta-lactamases continue to be recognized, it is proposed that decreased outer membrane permeability may contribute to the selection of a variety of enzymes with lower hydrolytic capabilities.
A multiplicity of factors may act in concert to allow ecologically less fit beta-lactamases to survive in organisms that have decreased susceptibilities to a variety of potent beta-lactam-containing agents.
Among Enterobacteriaceae ESBLs (extended spectrum beta-lactamases) are considered to be one of the most important resistant determinants, especially in Escherichia coli and Klebsiella pneumoniae. These enzymes are often derived from the common TEM, SHV and OXA enzymes, with an important emerging family of ESBLS named CTX-M. Molecular characteristics of these enzymes are delineated on he website from http://www.lahey.org/studies/webt.stm.
Organisms producing these enzymes are garnering special attention by organizations such as NCCLS that have instituted new susceptibility guidelines for testing of putative ESBL-producers in clinical isolates.
Beta-lactamase-related resistance can be approached using multiple therapeutic interventions. Non-beta-lactams, or beta-lactamase-stable beta-lactams, can be used for treatment. However, a frequent approach is to combine a beta-lactamase labile penicillin with a specific beta-lactamase inhibitor for combination therapy. This is particularly effective when the covalent binding of a suicide inhibitor inactivates a beta-lactamase. Beta-lactamase inhibitor combinations were first used in the early 1980s and have proven to be one of the most successful antibiotic regimens for treatment of common infections caused by beta-lactamase-producing Gram-negative bacteria.
Clavulanic acid and other natural product suicide inactivators were identified in the mid 1970s as potent inhibitors of Class A serine beta-lactamases. Clavulanate and the semi-synthetic inhibitors, sulbactam and tazobactam, all have similar mechanisms of inhibition and have been used successfully in combination with penicillins, e.g., clavulanic acid-amoxicillin, sulbactam-ampicillin, and tazobactam-piperacillin.
These combinations inhibit the growth of bacteria producing molecular class A, functional group 2, beta-lactamases, such as the common TEM, SHV and OXA enzymes, beta-lactamases often encoded by plasmids in Gram-negative bacteria. When the inhibitor combinations were first introduced, multiple beta-lactamase production was rare, even in organisms with a plasmid-encoded beta-lactamase.
Today, these plasmids have become much larger with the acquisition of multiple drug determinants, resulting in multidrug resistant Gram-negative rods with as many as five different beta-lactamases, including both serine and metallo-beta-lactamases from multiple functional groups. Because the approved inhibitors do not have useful activity against the Class C chromosomal serine cephalosporinases or the metallo-beta-lactamases that are now appearing more frequently on multidrug resistant plasmids, their utility is becoming more limited.
For the past 25 years, many have tried to identify agents that will inhibit non-class A beta-lactamases. A good example of this is the penem, BRL-42715, that inactivated beta-lactamases from all functional classes. Monobactams, such as aztreonam or Syn 2190, as well as cephem sulfones and other penems, have strong inhibitory activity against class C cephalosporinases with some compounds exhibiting stoichiometric binding in a 1:1 ratio of inhibitor to enzyme.
Non-beta-lactam inhibitors for the serine beta-lactamases include boronic acid derivatives, rhodanines, acyl phosphonates, and alpha-keto-heterocycles. Although many of these can inhibit both Class A and Class C beta-lactamase, a number of these are capable of inhibiting essential mammalian serine proteinases, thus limiting their potential utility as therapeutic agents.
BLIP (beta-lactamase inhibitory protein) analogs and BLIP derivatives have also been described as Class A inhibitors with weak Class C inhibitory activity, but these do not appear to be very drug-like at this point. Potent metallo-beta-lactamase inhibitors, such as picolinic acids, succinic acids and mercaptocarboxylic acids, have been identified, but many of these act as chelating agents with inhibitory activity against nonbacterial metalloenzymes.
Many of these newer inhibitors with broad-spectrum activity are not as potent as the original inactivators, and have not been highly successful in synergistically inhibiting bacterial growth, either alone or in combination with an approved penicillin or cephalosporin. Factors contributing to this lack of useful microbiological activity include the usual issues of penetrability and stability.
However, a more worrisome factor is the prevalence of organisms with high level beta-lactamase production associated with high copy number plasmids or the production of multiple beta-lactamases. Although a highly specific inactivator with broad-spectrum inhibitory activity and good pharmacological properties is highly attractive, this agent currently remains elusive.
■ 기사 요지 = 美 존슨약물연구소 카렌 부쉬 박사가 "제4차 ISAAR"에서 베타락타마제저해제에 대해 발표한 내용.
베타락탐(beta-lactam)계 항생제 내성의 주요 결정인자는 베타락타마제다. 베타락타마제 원인 내성은 비베타락탐항생제로 치료될 수 있지만, 페니실린계 항생제와 특정 베타락타마제저해제의 병용요법이 자주 사용된다.
Clavulanate·sulbactam·tazobactum 등은 모두 비슷한 억제기전을 갖고 있으며, clavulanic acid-amoxicillin, sulbactam-ampicillin, tazobactam-piperacillin 등 페니실린계와의 병용요법도 성공적으로 사용됐다.