Extended-spectrum beta-lactamases

Extended-spectrum beta-lactamases (ESBLs) were discovered in Europe in the early 1980s after widespread use of broad-spectrum antibiotics. They are largely derivatives of 3 progenitor beta-lactamases that confer resistance to ampicillin in gram-negative bacteria and are now carried on plasmids. Substitutions at the active enzyme site of these progenitor enzymes at single or multiple amino sites have resulted in altered substrate affinities for ESBLs. Depending on the location of the substitution, susceptibility to broad-spectrum antibiotics is variably diminished. ESBLs are most commonly found in Klebsiella species and Escherichia coli, but also in other bacteria including Pseudomonas, Salmonella, Proteus, and Enterobacter species. The discovery of ESBLs in hospital and nursing-home outbreaks and their ability to be transferred to other bacterial species makes management and treatment of ESBLs of great medical concern.This article provides a review of ESBLs and their impact on patient care.     

Extended-spectrum beta-lactamases

Extended-spectrum beta-lactamases, most commonly found in Klebsiella pneumoniae and Escherichia coli, have increased markedly in the past decade, particularly in the intensive care unit setting. The problem has been significant in the United States but is even more prevalent in parts of Latin America and Asia. These plasmid-mediated beta-lactamases confer resistance to broad-spectrum beta-lactam antibiotics, including third- and fourth-generation cephalosporins, aztreonam, and extended-spectrum penicillins. Other resistances, such as aminoglycoside resistance and trimethoprim/sulfamethoxazole resistance, are often cotransferred on the same plasmid. Fluoroquinolone resistance is often associated, resulting in an organism that is resistant to most of the usual antimicrobial options. Although carbapenems are currently considered the drugs of choice for these pathogens, widespread use of these agents may lead to other resistance problems. Due to limited therapeutic options, prevention and control measures are important. Traditional infection control measures, such as contact precautions, are recommended to prevent spread in intensive care units. In addition, because this type of antimicrobial resistance appears to be particularly influenced by antibiotic utilization, antibiotic control measures may also be a very important intervention in limiting the spread of extended-spectrum beta-lactamases.     

Extended-spectrum beta-lactamases

Extended-spectrum beta lactamase (ESBL) producing gram-negative bacilli are a growing concern, especially because the species of organisms producing these enzymes are increasing. Bacteria possessing these enzymes are resistant to third-generation cephalosporins--antimicrobial agents important for inpatient therapy. These resistant organisms are clinically important because they result in increased morbidity and mortality. Additionally, some laboratories may have difficulty detecting ESBL-producing organisms. These and other issues are discussed in this article.     

Extended-spectrum beta-lactamases: the European experience

Extended-spectrum beta-lactamases mediate resistance to cephalosporin antibiotics and were first discovered in Europe in the early 1980s. They have become a widespread problem, particularly in Klebsiella pneumoniae, but increasingly in non-typhoid Salmonella species. Traditionally, extended-spectrum beta-lactamases have been derivatives of TEM and SHV parent enzymes. The last year, however, has seen an explosion of developments in extended-spectrum beta-lactamases of non-TEM, non-SHV lineage in Europe. The CTX-M type extended-spectrum beta-lactamases have become particularly widespread. At the same time, European clinical microbiology laboratories have become more aware of the pressing need for detection methods given increasing awareness of the lack of reliability of cephalosporins in the treatment of extended-spectrum beta-lactamase producers.     

Extended-spectrum beta-lactamases: a challenge for clinical microbiologists and infection control specialists

Since first reported in Europe in the early 1980s, extended-spectrum beta-lactamases (ESBLs) have spread worldwide. When producing these broad-spectrum plasmid-encoded enzymes, organisms become highly effective at inactivating penicillins, most cephalosporins, and aztreonam. Mainly produced by Klebsiella spp, ESBLs have been isolated worldwide in different species, most of them belonging to the Enterobacteriaceae. ESBL-producing bacteria can appear as in vitro susceptible to beta-lactams by conventional laboratory methods, making the laboratory diagnosis problematic. Once detected, all beta-lactams except carbapenem and beta-lactamase inhibitor compounds should be reported as resistant. In addition, organisms harboring ESBLs are frequently resistant to other antibiotic classes, such as fluoroquinolones and aminoglycosides. Because of the very limited remaining alternatives for treatment and ESBLs significant prevalence worldwide, infection control remains the best way to deal with this bacterial resistance mechanism.     

Extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory, therapy, and infection control

Extended-spectrum beta-lactamase (ESBL) producing gram-negative bacilli are a growing concern in human medicine today. When producing these enzymes, organisms (mostly K. pneumoniae and E. coli) become highly efficient at inactivating the newer third-generation cephaloporins (such as cefotaxime, ceftazidime, and ceftriaxone). In addition, ESBL-producing bacteria are frequently resistant to many classes of non-beta-lactam antibiotics, resulting in difficult-to-treat infections. This review gives an introduction into the topic and is focused on various aspects of ESBLs; it covers the current epidemiology, the problems of ESBL detection and the clinical relevance of infections caused by ESBL-producing organisms. Therapeutic options and potential strategies for dealing with this growing problem are also discussed in this article.     

beta-lactamases in bacteroides.

Bacteroides fragilis is responsible for most anaerobic infections in man. Most isolates of B. fragilis show resistance to beta-lactam antibiotics. This resistance might be due to beta-lactamase production or permeability barrier in the cell wall. B. fragilis produce beta-lactamase with mainly cephalosporinase activity. Other Bacteroides species such as B. clostridiformis, B. melaninogenicus and B. oralis also produce beta-lactamase but with different biochemical characteristics.     

Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern

The medical community relies on clinical expertise and published guidelines to assist physicians with choices in empirical therapy for system-based infectious syndromes, such as community-acquired pneumonia and urinary-tract infections (UTIs). From the late 1990s, multidrug-resistant Enterobacteriaceae (mostly Escherichia coli) that produce extended-spectrum beta lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of UTIs. Recent reports have also described ESBL-producing E coli as a cause of bloodstream infections associated with these community-onset UTIs. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Thus, more rapid diagnostic testing of ESBL-producing bacteria and the possible modification of guidelines for community-onset bacteraemia associated with UTIs are required.     

迎接β-内酰胺酶的挑战

细菌对β内酰胺类抗生素的耐药可通过下列三种机制:(1)外膜渗透力下降和主动泵出。(2)靶位点青霉素结合蛋白(ＰＢＰｓ)的改变。(3)产生β内酰胺酶(ＢＬＡ)。ＰＢＰ的改变是革兰阳性菌耐β内酰胺类抗生素的最主要的机制,而在革兰阴性菌中ＢＬＡ是最普遍的。染色体型ＢＬＡ在抗生素应用以前就已存在于细菌中,而β内酰胺类抗生素的广泛使用大量选择出产酶株,它包括染色体介导和质粒介导的酶。在近半个世纪中,每一个新β内酰胺类抗生素的上市,都会选择出相对应的新突变的产ＢＬＡ株。目前文献报道的ＢＬＡ已达190多种[1]。当前最佳的分类法是Ｂ…     

Plasmid-mediated beta-lactamases among aminoglycoside resistant gram-negative bacilli

Plasmid-mediated beta-lactamases were characterized by DNA hybridization in 371 aminoglycoside resistant gram-negative bacilli with known aminoglycoside resistance mechanism. Positive hybridization was detected in 50% to a TEM-1 probe, in 2% to a SHV-1 probe, and in 3% to both probes simultaneously. No hybridization was obtained to OXA-1, OXA-2, PSE-1/PSE-4/CARB-3 or PSE-2 beta-lactamase probes. TEM-1 beta-lactamase occurred simultaneously in 82% of strains showing the AAC(3)-V type of aminoglycoside resistance mechanism. Using isoelectric focusing as a control method, we found potentially plasmid-encoded beta-lactamases, other than TEM-1 and SHV-1, at various pIs in 13% of 288 randomly selected strains. The pIs of these strains or strains showing positive hybridizations did not fit to pIs of recently characterized plasmid-mediated enzymes against third-generation cephalosporins (e.g. CTX-1). In addition, the strains did not show resistance to cefotaxime or ceftazidime. According to the in vitro susceptibility data ceftazidime and cefotaxime were active against most of the aminoglycoside resistant strains studied. In contrast, the activity of piperacillin was much lower than that of the cephalosporins tested.     

beta-lactamases and R-plasmids of Haemophilus influenzae.

The emergence of resistance to ampicillin and other antibiotics in Haemophilus influenzae has been a relatively recent event. In contrast, drug resistance has been rampant in the Enterobacteriaceae for many years. Ampicillin-resistance in H. influenzae is almost invariably attributable to possession of the TEM (Type III a)beta-lactamase. As is common in other bacteria the gene specifying this enzyme is plasmid-borne in Haemophilus. Some ampicillin-resistant strains of H. influenzae can transfer the TEM beta-lactamase gene to other strains of Haemophilus, to Escherichia coli and to Pseudomonas aeruginosa. The features of such transfer are unusual and lead for example, to the induction of adenine requirement in recipient strains of P. aeruginosa. Crypticity measurements of beta-lactamase activity show that in comparison to P. aeruginosa or E. coli, the outer membrane of H. influenzae affords only a weak penetration barrier to beta-lactam antibiotics. This may have consequences for the stability and distribution of beta-lactamase production in Haemophilus spp. which are discussed. A comparison of the molecular properties of R-plasmids determining a variety of resistances and carried by strains of H. influenzae isolated in diverse geographical locations has revealed unexpected homologies. A series of such plasmids of similar molecular weights (about 30 X 10(6)) differ substantially only in the transposable resistance genes that they carry. A model based on these findings is presented to explain the acquisition of ampicillin- and other resistances by Haemophilus.     

Detection of plasmid-mediated class C beta-lactamases.

Plasmid-mediated class C beta-lactamases are reported from Enterobacteriaceae with increasing frequency. They likely originate from chromosomal AmpC of certain Gram-negative bacterial species and subsequently are mobilized onto transmissible plasmids. There are reports of unfavorable clinical outcomes in patients infected with these organisms and treated with broad-spectrum cephalosporins. However, unlike class A extended-spectrum beta-lactamases (ESBLs), no screening and confirmatory tests have been uniformly established for strains that produce class C beta-lactamases. Reduced susceptibility to cefoxitin is a sensitive but not specific indicator of class C beta-lactamase production. Simple confirmatory tests including tests using boronic acid compounds as specific class C beta-lactamase inhibitors have recently been developed. Their utilization will enable clinical microbiology laboratories to report those strains producing plasmid-mediated class C beta-lactamases as being resistant to all broad-spectrum cephalosporins, thus allowing physicians to prescribe appropriate antimicrobial therapy.     

革兰阴性杆菌产AmpC酶及超广谱β-内酰胺酶的研究

为探讨临床分离的对第三代头孢菌素耐药的革兰阴性杆菌AmpCβ－内酰胺酶（AmpC)和超广谱β－内酰胺酶（ESBLs)的分布情况，采用头孢西丁三维试验检测AmpC酶，纸片确证试验和头孢曲松三维试验检测ESBLs。结果显示，227株革兰阴性杆菌中产AmpC酶者97株（占42．6％），产ESBLs者38株（占16．7％）。提示AmpC酶和ESBLs是导致革兰阴性杆菌耐药的两类主要酶。AmpC酶和ESBLs的单克隆抗体有望为这类细菌感染的免疫生物治疗提供新方法。