scholarly journals beta-Lactamases in laboratory and clinical resistance.

1995 ◽  
Vol 8 (4) ◽  
pp. 557-584 ◽  
Author(s):  
D M Livermore
Keyword(s):  
Bacterial Resistance ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Producer Strain ◽  
Phenotypic Properties ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Clinical Resistance ◽  
Gram Negative Organisms

beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces.

The Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-lactam Antibiotics against Beta-lactamase Producing Strains of Resistant Enterobacterales

2021 ◽  
Author(s):  
Olga Lomovskaya ◽  
Debora Rubio-Aparicio ◽  
Ruslan Tsivkovski ◽  
Jeff Loutit ◽  
Michael Dudley
Keyword(s):  
Broad Spectrum ◽  
Resistance Mechanisms ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Intrinsic Resistance ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
The Impact ◽  
Lactamase Inhibitor

QPX7728 is a cyclic boronate ultra-broad-spectrum beta-lactamase inhibitor, with potent activity against both serine and metallo beta-lactamases. QPX7728 can be delivered systemically by the IV or oral route of administration. Oral β-lactam antibiotics alone or in combination with QPX7728 were evaluated for 1) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728; 2) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams; and 3) in vitro activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes followed by cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten and mecillinam completely reversed beta-lactamase-mediated resistance in cloned beta-lactamases from serine and metallo enzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug-resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of both inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against Enterobacterales that produce serine or metallo beta-lactamases.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

scholarly journals Evaluation of the presence of AmpC (FOX) beta-lactamase gene in clinical strains of Escherichia coli isolated from hospitalized patients in Tabriz, Iran

2021 ◽  
Vol 38 (3) ◽  
pp. 301-304
Author(s):  
Zahra SADEGHI DEYLAMDEH ◽  
Abolfazl JAFARI SALES
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Hospitalized Patients ◽  
Disk Diffusion ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Clinical Strains ◽  
Beta Lactam Antibiotics ◽  
Lactamase Gene

Beta-lactamases are the most common cause of bacterial resistance to beta-lactam antibiotics. AmpC-type beta-lactamases hydrolyze cephalosporins, penicillins, and cephamycins. Therefore, the study aims was to determine antibiotic resistance and to investigate the presence of AmpC beta-lactamase gene in clinical strains of Escherichia coli isolated from hospitalized patients in Tabriz. In this cross-sectional descriptive study, 289 E. coli specimens were collected from clinical specimens. Disk diffusion method and combined disk method were used to determine the phenotype of extended spectrum β-Lactamase producing (ESBLs) strains. Then PCR was used to evaluate the presence of AmpC (FOX) beta-lactamase gene in the strains confirmed in phenotypic tests. Antibiotic resistance was also determined using disk diffusion by the Kibry-Bauer method. A total of 121 isolates were identified as generators of beta-lactamase genes. 72 (59.5 %) isolates producing ESBL and 49 (40.5 %) isolates were identified as AmpC generators. In the PCR test, 31 isolates contained the FOX gene. The highest resistance was related to the antibiotics amoxicillin (76.12%), ceftazidime (70.24%) and nalidixic acid (65.05%). The results indicate an increase in the prevalence of beta-lactamase genes and increased resistance to beta-lactam antibiotics, which can be the result of improper use of antibiotics and not using antibiotic susceptibility tests before starting treatment. Also, using phenotypic and molecular diagnostic methods such as PCR together can be very useful.

scholarly journals In Vitro Activity of the Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Olga Lomovskaya ◽  
Debora Rubio-Aparicio ◽  
Kirk Nelson ◽  
Dongxu Sun ◽  
Ruslan Tsivkovski ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Beta Lactamase ◽  
In Vitro Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactamases ◽  
Lactamase Inhibitor

QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase producing Enterobacterales and Acinetobacter spp. In this study we evaluated the in vitro activity of QPX7728 (8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with varying beta-lactam resistance mechanisms. Seven-hundred-ninety clinical isolates were included in this study; 500 isolates, termed a “representative panel”, were selected to be representative the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data (representative panel). An additional 290 selected isolates (“challenge panel”), that were either non-susceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was >90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in ∼90% and ∼80% of strains, respectively, vs 68-70% for QPX-MEM and QPX-PIP and 63-65% for TOL-TAZ and CAZ-AVI. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ∼70% of strains vs 2-40% for other combinations. Increased efflux and impaired OprD had varying effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varying results according to the beta-lactamase production and other intrinsic resistance mechanisms.

scholarly journals Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ruslan Tsivkovski ◽  
Maxim Totrov ◽  
Olga Lomovskaya
Keyword(s):  
High Efficiency ◽  
Biochemical Characterization ◽  
Molar Ratio ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Content Type ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Class D ◽  
Extended Spectrum Beta Lactamases

ABSTRACT QPX7728 is a new ultrabroad-spectrum inhibitor of serine and metallo-beta-lactamases (MBLs) from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A extended-spectrum beta-lactamases (ESBLs) (50% inhibitory concentration [IC50] range, 1 to 3 nM) and carbapenemases such as KPC (IC50, 2.9 ± 0.4 nM) as well as class C P99 (IC50 of 22 ± 8 nM) with a potency that is comparable to or higher than recently FDA-approved beta-lactamase inhibitors (BLIs) avibactam, relebactam, and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/58, IC50 range, 1 to 2 nM) as well as MBLs such as NDM-1 (IC50, 55 ± 25 nM), VIM-1 (IC50, 14 ± 4 nM), and IMP-1 (IC50, 610 ± 70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high-efficiency k2/K ranging from 6.3 × 104 (for P99) to 9.9 × 105 M−1 s−1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5 to 20 min for OXA carbapenemases from A. baumannii, ∼50 min for OXA-48, and 2 to 3 h for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at a 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on–fast-off kinetics, with Kis of 7.5 ± 2.1 nM, 32 ± 14 nM, and 240 ± 30 nM for VIM-1, NDM-1, and IMP-1, respectively. QPX7728’s ultrabroad spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

scholarly journals Penicillinase Plasmid Australia type in Neisseria Gonorrhoeae Isolated in Poland

2021 ◽  
Author(s):  
Szymon Jerzy Walter de Walthoffen
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Gene Encoding ◽  
Beta Lactamases ◽  
The World ◽  
Lactamase Gene ◽  
Chromosomal Mutations ◽  
First Time

Abstract Purpose. Neisseria gonorrhoeae is an etiological agent of gonorrhea, which continues to be one of the most important public health problems. Currently, the most important problem in treatment is the mechanisms that determine resistance to drugs of the beta-lactam class, which are recommended for the treatment of gonorrhea. Chromosomal mutations are responsible for resistance to ceftriaxone and cefepime. The possibility of mutations in the gene encoding beta-lactamase (blaTEM) in the penicillinase plasmid may also turn out to be a serious threat. Methods. The occurrence of resistance encoded on penicillinase plasmid has been investigated. For this purpose, the susceptibility of bacteria was determined and the gene for resistance to beta-lactams as well as the plasmids themselves was typed. Results. Of the 333 strains tested, 21 (6.3%) had the beta-lactamase gene and produced penicillinase.The results allow to conclude that among the tested strains of N. gonorrhoeae occurred two of the beta-lactamase: TEM-1 and TEM-135. Most of the known penicillinase plasmid types of N. gonorrhoeae were demonstrated: Asian, African, Toronto/Rio plasmids and Australian variant.Conclusions.In the first three years, TEM-1 beta-lactamases dominated in N. gonorrhoeae, which were replaced by TEM-135 in the following years of the study. Not all molecular methods are capable of varying the types of penicillinase plasmids. A particularly noteworthy observation is the fact that the Australia-type of penicillinase plasmid (3270 bp) was identified for the first time in Europe, and the second time in the world.

scholarly journals The outpatient use of beta lactam antibiotics in Montenegro before the introduction of new reform strategy on drug market

2006 ◽  
Vol 134 (5-6) ◽  
pp. 224-228 ◽  
Author(s):  
Natasa Duborija-Kovacevic
Keyword(s):  
Epidemiological Study ◽  
Drug Market ◽  
Developed Countries ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactam Antibiotics ◽  
Reform Strategy

Introduction: The study represents the first investigation of outpatient use of beta lactam antibiotics in Montenegro carried out in accordance with internationally approved methodology (DDD/ATC). Objective: The objective of our study was to establish both the scope and overall use of beta lactam antibiotics, and to assess their compatibility with current pharmacotherapeutic guidelines and their use in developed countries. Methods: The retrospective pharmaco-epidemiological study comprised a 100%-sample of beta lactams that were used in the period prior to introduction of new reform strategy on drug market. Results: Beta lactam antibiotics (J01C, J01D) were the most frequently applied anti-infectives for systemic use (ATC group J) in 2000 (11.3 DDD/1000 inh./day, 61%). Penicillins (J01C) were the most utilized (8.0 DDD/1000 inh./day, 71%). Cephalosporin derivatives (cephalexin and cefaclor) accounted for the remaining 29% (3.3 DDD/1000 inh./day). Aminopenicillins were prevailing among penicillins (85%). Beta lactamase sensitive penicillins were in the second place and approximately accounted for 14%. Conclusion: The results of our study showed that the use of beta lactam antibacterials could be estimated as partially satisfactory. There is a need to make additional efforts with a view of further rationalization.

scholarly journals Promiscuous Enzyme Activity as a Driver of Allo and Iso Convergent Evolution, Lessons from the β-lactamases

2020 ◽  
Author(s):  
Vivek Keshri ◽  
Eric Chabrière ◽  
Lucile Pinault ◽  
Philippe Colson ◽  
Seydina Diene ◽  
...  
Keyword(s):  
Convergent Evolution ◽  
Character State ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Evolutionary Mechanisms ◽  
Beta Lactamases ◽  
Ancestral Sequences ◽  
Two Factors ◽  
Evolution Type

The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. More the evolution of a character is probable more convergent evolution will be witnessed, consequently, convergent evolution could mean that the convergent character evolution result as a combination of these two factors. We investigate this phenomenon by studying the convergent evolution of biochemical functions. We use for the investigation the case of β-lactamases. β-lactamases hydrolyzes β-lactams which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. β-lactamase activity is present in two different superfamilies: the metallo-β-lactamase and the serine β-lactamase superfamily. The mechanism used to hydrolyze the β-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further show that the β-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explaining the promiscuous β-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part, by positive selection as the organisms having β-lactamase activity allows them to resist to organism secreting β-lactams. Indeed a mutation increasing the β-lactamases activity will be selected as the organisms having this activity will have an advantage over the others.

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