In vitro activity and beta-lactamase stability of LY163892 (original) (raw)
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Classification of beta-lactamases: groups 1, 2a, 2b, and 2b
Antimicrobial Agents and Chemotherapy, 1989
Information on 3-lactamases has grown rapidly within the past few years, such that it has become difficult to make meaningful comparisons between well-established P-lactamases and those enzymes recently identified. The intention of this review, therefore, is to present a compilation of data that will be useful in establishing a set of unique characteristics for many of the f3-lactamases that have been described in the primary literature (also see reference 14). The criteria used for characterization are discussed elsewhere (13). PARAMETERS In the accompanying tables, the following designations are used. If an enzyme has been named, both the original name and any later assignments are listed in column 1. When major differences were observed between constitutive enzymes from the same species, all the enzymes are listed. Column 2 indicates whether P-lactamase production is chromosomal or plasmid mediated. The plasmid name is included when appropriate. No entry in this column indicates that the mechanism for production has not been designated. The original host for an enzyme is listed with the appropriate strain number, when available. Substrate profiles were compiled by using the following antibiotics: the penicillins benzylpenicillin, ampicillin, carbenicillin, and cloxacillin; the cephalosporins cephaloridine, cephalothin, cefotaxime, and ceftazidime; the monobactam aztreonam; and the carbapenem imipenem. When possible, Vmax values are listed rather than relative rates of hydroly-TABLE 1. Group 1: cephalosporin-hydrolyzing P-lactamases not inhibited by clavulanic acid (CEP-N)a Produc-Relative rate of hydrolysis Ki for inhibition (,uM) * 0.1 mM substrate for cefotaxime and ceftazidime with the cephalosporinase from P. aeruginosa 10662 (73). q From active site sequence of P. aeruginosa 18 S (45). *Similar to S. marcescens GN7647 cephalosporinase (89). Data for GN7647 cephalosporinase of molecular weight 37,000 (89). 'Also K. Bush, unpublished data.
Objective: To study the prevalence of extended-spectrum β-lactamases (ESBLs) among 663 clinical isolates obtained from various parts of India and to study the occurrence of different variants of ESBLs among these isolates. Methods: Phenotypic characterization and susceptibility studies were performed according to the methods described in Clinical and Laboratory Standards Institute guidelines. The occurrence of ESBL variants was analyzed with PCR using the previously reported primers. Results: Among the six hundred sixty three isolates, the identified isolates were Acinetobacter baumannii (72), Escherichia coli (218), Klebsiella pneumoniae (30), Klebsiella oxytoca (63), Pseudomonas aeruginosa (264) and Staphylococcus aureus (16). PCR results revealed that approximately 89.0% of Pseudomonas aeruginosa isolates were positive for ESBL followed by Escherichia coli (85.3%), Klebsiella pneumoniae (76.6%), Klebsiella oxytoca (73.0%), Acinetobacter baumannii (72.2%) and Staphylococcus aureus (31.2%). The overall prevalence of ESBL was 82.5%. The presence of TEM type ESBLs were the predominant (in 186 isolates), followed by SHV (138), OXA (92), CTX-M (65), AmpC (33), KPC (28) and blaZ (5). Of the drugs involved in the study, CSE1034 was found to be the most efficacious against all of ESBL positive clinical isolates showing susceptibility approximately 95.7% with minimal inhibitory concentration values between 0.125 and 8.000 µg/mL for all strains tested. The susceptibilities of penems (meropenem and imipenem and cilastatin) ranged between 83% and 93% for all the isolates. The susceptibilities of other drugs like piperacillin and tazobactam, amoxicillin and clavulanic acid, cefoperazone and sulbactam were <45% for all the isolates. Conclusions: Results of the present study indicated that majority of the isolates was susceptible to CSE1034 and it could be a potent antibacterial agent for the treatment of severe bacterial infections caused by such organisms.
Detection of extended broad-spectrum beta-lactamases inEnterobacteriaceae in four French hospitals
European Journal of Clinical Microbiology & Infectious Diseases, 1989
In 210 strains of Enterobacteriaceae which were isolated in four hospitals and which showed reduced susceptibility to cefotaxime, high synergy was demonstrated between amoxicillin (20/ag) + clavulanate (10/ag) and cefotaxime (30/~g) using a simple doubledisk test. Isoelectric focusing on gel and specific iodometric detection using ceftriaxone identified four extended broad-spectrum ~-lactamases (isoelectric points 7.6, 6.3, 7.0 and 5.9) produced by the strains.
Beta-lactamases and Their Global Health Implications-Two: Resistance Profile and Global Health Risk
Science Journal of Public Health, 2015
Beta-lactamases are enzymes produced by some bacteria, which make them resistant to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins and carbapenems. In this article, global health implications, resistance profile and treatment options were reviewed. Extended-spectrum β-lactamases produced by enterobacteria and methicillinases produced by Staphylococci have been shown to constitute the growing strains of bacteria that confer resistances to all β-lactam agents and many non-β-lactam antimicrobials, including fluoroquinolones. Their continued detection in animal species and food products poses a great challenge to diagnosis and treatment of resulting infections, thus, emanating to serious global health implications. Although a lot of works on β-lactamases have been directed towards the search for molecules which can inhibit these enzymes, the beta-lactamase producting bacteria are not leaving any stone to chance. Investigations targeted at identifying the carriers of these enzymes and intercepting their transmission will help curb the emergence and spread of the βlactamases and their menace to public health.
Microbial Drug Resistance, 2000
An Alicaligenes faecalis (FL-424/98) resistant to expanded-spectrum cephalosporins and aztreonam was isolated from the urine of an inpatient at the Intensive Care Unit of the Várese Hospital (Northern Italy) after antimicrobial chemotherapy with cefazolin, vancomycin, and amikacin. Clavulanic acid restored the activity of expanded-spectrum cephalosporins, suggesting the production of an extended-spectrum /3-lactamase (ESßL). A crude extract of FL-424/98 showed the presence of two /3-lactamase activities focusing at pH 5.3 and 7.6, respectively. The ES/3L activity, purified by means of three Chromatographie steps, was found to correspond to the pi 5.3 enzyme. Determination of kinetic parameters confirmed that the enzyme efficiently hydrolyzed expanded-spectrum cephalosporins and aztreonam. A colony-blot hybridization revealed the presence of ¿topER-related sequences in FL-424/98, and sequencing confirmed the identity of this determinant with WflpER-i> previously detected in Pseudomonas aeruginosa, Acinetobacter, and Salmonella clinical isolates from Turkey. Finding of Waper-i in a species that can be part of the resident human microbiota raises the possibility that it could be an efficient shuttle for spreading of this resistance gene among other opportunistic pathogens that are normally members of the resident microbiota. Kinetic parameters determined for the PER-1 enzyme with some cephalosporin substrates were somewhat different from those previously reported.
Journal of Clinical Microbiology, 2004
Organisms producing CTX-M--lactamases are emerging around the world as a source of resistance to oxyiminocephalosporins such as cefotaxime (CTX). However, the laboratory detection of these strains is not well defined. In this study, a molecular detection assay for the identification of CTX-M--lactamase genes was developed and used to investigate the prevalence of these enzymes among clinical isolates of Escherichia coli and Klebsiella species in the Calgary Health Region during 2000 to 2002. In addition, National Committee for Clinical Laboratory Standards (NCCLS) recommendations were evaluated for the ability to detect isolates with CTX-M extended-spectrum -lactamases (ESBLs). The PCR assay consisted of four primer sets and demonstrated 100% specificity and sensitivity for detecting different groups of CTX-M--lactamases in control strains producing well-characterized ESBLs. Using these primer sets, 175 clinical strains producing ESBLs were examined for the presence of CTX-M enzymes; 24 (14%) were positive for bla CTX-M-1-like genes, 95 (54%) were positive for bla CTX-M-14-like genes, and the remaining 56 (32%) were negative for bla CTX-M genes. Following the NCCLS recommendations for ESBL testing, all of the control and clinical strains were detected when screened with cefpodoxime and when both cefotaxime and ceftazidime with clavulanate were used as confirmation tests.
Clinical Microbiology and Infection, 2008
Strains of Enterobacteriaceae producing an extended spectrum b-lactamase have become a concern in medical bacteriology as regards both antimicrobial treatment and infection control in hospitals. Extended-spectrum b-lactamase (ESBL) detection tests should accurately discriminate between bacteria producing these enzymes and those with other mechanisms of resistance to b-lactams, e.g., broadspectrum b-lactamases, inhibitor-resistant b-lactamases and cephalosporinase overproduction. Several phenotypic detection tests, based on the synergy between a third-generation cephalosporin and clavulanate, have been designed: the double-disk synergy test (DDST), ESBL Etests, and the combination disk method. These tests often need to be refined in order for them to detect an ESBL in some bacterial strains, such as those that also overproduce a cephalosporinase. The sensitivity of the DDST can be improved by reducing the distance between the disks of cephalosporins and clavulanate. The use of cefepime, a fourth-generation cephalosporin that is less rapidly inactivated by cephalosporinase than by ESBL, improves the detection of synergy with clavulanate when there is simultaneous stable hyperproduction of a cephalosporinase; alternatively, the cephalosporinase can be inactivated by performing phenotypic tests on a cloxacillin-containing agar. Some b-lactamases can hydrolyse both third-generation cephalosporins and carbapenems, such as the metallo-b-lactamases, which are not inhibited by clavulanate, but rather by EDTA. The production of an ESBL masked by a metallob-lactamase can be detected by means of double inhibition by EDTA and clavulanate. Since extendedspectrum Ambler class D oxacillinases are weakly inhibited by clavulanate and not inhibited by EDTA, their detection is difficult in the routine laboratory.