scholarly journals Importance of beta-lactamase inhibitor pharmacokinetics in the pharmacodynamics of inhibitor-drug combinations: studies with piperacillin-tazobactam and piperacillin-sulbactam.

1997 ◽  
Vol 41 (4) ◽  
pp. 721-727 ◽  
Author(s):  
P D Lister ◽  
A M Prevan ◽  
C C Sanders
Keyword(s):  
Antibacterial Activity ◽  
Critical Concentration ◽  
Specific Inhibitor ◽  
Logarithmic Phase ◽  
Critical Ratio ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Dosing Regimens ◽  
Lactamase Inhibitor

An in vitro pharmacokinetic model was used to study the pharmacodynamics of piperacillin-tazobactam and piperacillin-sulbactam against gram-negative bacilli producing plasmid-encoded beta-lactamases. Logarithmic-phase cultures were exposed to peak antibiotic concentrations observed in human serum after the administration of intravenous doses of 3 g of piperacillin and 0.375 g of tazobactam or 0.5 g of sulbactam. Piperacillin and inhibitor were either dosed simultaneously or piperacillin was dosed sequentially 0.5 h after dosing with the inhibitor. In studies with all four test strains, the pharmacodynamics observed after simultaneous dosing were similar to those observed with the sequential regimen. Since the ratio between piperacillin and tazobactam was in constant fluctuation after sequential dosing, these data suggest that the pharmacodynamics of the piperacillin-inhibitor combinations were not dependent upon maintenance of a critical ratio between the components. Furthermore, when regrowth was observed, the time at which bacterial counts began to increase was similar between the simultaneous and sequential dosing regimens. Since the pharmacokinetics of the inhibitors were the same for all regimens, these data suggest that the length of time that the antibacterial activity was maintained over the dosing interval with these combinations was dictated by the pharmacokinetics of the beta-lactamase inhibitor in the combination. The antibacterial activity of the combination appeared to be lost when the amount of inhibitor available fell below some critical concentration. This critical concentration varied depending upon the type and amount of enzyme produced, as well as the specific inhibitor used. These results indicate that the antibacterial activity of drug-inhibitor combinations, when dosed at their currently recommended ratios, is more dependent on the pharmacokinetics of the inhibitor than on those of the beta-lactam drug.

scholarly journals Efficacy of ampicillin-sulbactam is not dependent upon maintenance of a critical ratio between components: sulbactam pharmacokinetics in pharmacodynamic interactions.

1996 ◽  
Vol 40 (11) ◽  
pp. 2468-2477 ◽  
Author(s):  
M Alexov ◽  
P D Lister ◽  
C C Sanders
Keyword(s):  
Antibacterial Activity ◽  
Pharmacokinetic Model ◽  
Critical Concentration ◽  
Critical Ratio ◽  
Human Pharmacokinetics ◽  
Immunocompetent Mouse ◽  
E Coli ◽  
Pharmacodynamic Interactions ◽  
Dosing Regimens

An in vitro pharmacokinetic model (IVPM) and a mouse model of lethal bacteremia were used to compare the pharmacodynamics of ampicillin-sulbactam when the two components were dosed simultaneously and in sequence against TEM-1-producing Escherichia coli. The challenge isolates included three strains of E. coli producing various levels of beta-lactamase. Human pharmacokinetics of ampicillin-sulbactam (1.5- and 3.0-g intravenous doses) were simulated in each model, and pharmacodynamic interactions were evaluated over one 6-h dosing interval. Against all three strains, the sequential dosing of sulbactam prior to ampicillin did not alter the pharmacodynamics of these combinations from comparison with results obtained with the simultaneous administration of the two components. Similar pharmacodynamics were observed for the two dosing regimens regardless of the ampicillin-sulbactam dose used or whether the bacteria were treated in an immunocompetent mouse or in the absence of immune defenses in the IVPM. When antibacterial activity was lost and regrowth of the inoculum was observed, viable bacterial counts increased in both the simultaneous and sequential regimens at a point when sulbactam levels fell below a critical concentration. These data suggest that the efficacy of ampicillin-sulbactam is not dependent upon the maintenance of a constant 2:1 ratio for the two components. Rather, the efficacy of ampicillin-sulbactam appears to be dependent upon the maintenance of one or both components above a critical concentration. Furthermore, the pharmacokinetics of sulbactam, specifically, how long sulbactam levels remain above a minimum critical concentration, appears to dictate how long antibacterial activity is maintained with the combination.

A Practical Look at the Clinical Usefulness of the Beta-Lactam/Beta-Lactamase Inhibitor Combinations

1996 ◽  
Vol 30 (10) ◽  
pp. 1130-1140 ◽  
Author(s):  
Susan M. Hart ◽  
Elaine M. Bailey
Keyword(s):  
English Language ◽  
Antimicrobial Agents ◽  
In Vivo Studies ◽  
Patient Specific ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Intraabdominal Infections ◽  
Lactamase Inhibitor

OBJECTIVE: To aid clinicians in developing an approach to the use of intravenous beta-lactam/beta-lactamase inhibitors on a patient-specific basis. To achieve this, the pharmacology, in vitro activity, and clinical use of the intravenous beta-lactam/beta-lactamase inhibitor combinations in the treatment of selected infections seen in hospitalized patients are discussed. DATA IDENTIFICATION: An English-language literature search using MEDLINE (1987–1995); Index Medicus (1987–1995); program and abstracts of the 32nd (1992), 33rd (1993), 34th (1994), and 35th (1995) Interscience Conference on Antimicrobial Agents and Chemotherapy; bibliographic reviews of review articles; and package inserts. STUDY SELECTION: In vitro and in vivo studies on the pharmacokinetics, microbiology, pharmacology, and clinical effectiveness of ampicillin/sulbactam, ticarcillin/clavulanate, and piperacillin/tazobactam were evaluated. DATA SYNTHESIS: Many properties of the beta-lactam/beta-lactamase inhibitor combinations are similar. Differences in dosing, susceptibilities, and clinical applications are important considerations for clinicians. Potential roles for these agents in the clinical setting include pneumonia, intraabdominal infections, and soft tissue infections. A short discussion on susceptibility data interpretation is also presented. CONCLUSIONS: There are important differences among the available beta-lactam/beta-lactamase inhibitor combinations, such as spectra of activity, which need to be considered in choosing an agent for a patient-specific case. These products can be useful alternatives to conventional two- to three-drug regimens in mixed infections such as foot infections in patients with diabetes and hospital-acquired intraabdominal infections.

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.

REVERSION OF ANTIBIOTIC RESISTANCE WITH BETA-LACTAMASE INHIBITOR FROM MEDICINAL PLANTS

2017 ◽  
Vol 10 (10) ◽  
pp. 204
Author(s):  
Sneha Arora ◽  
Shoma Paul Nandi
Keyword(s):  
Antibiotic Resistance ◽  
Medicinal Plants ◽  
Ethyl Acetate ◽  
Ethyl Acetate Extract ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Lactamase Inhibitor

  Objective: Screening of medicinal plants for the presence of beta-lactamase inhibitor identified three plants; Terminalia chebula, Terminalia bellirica, and Ocimum tenuiflorum, extracts of which inhibit beta-lactamase enzyme in vitro. The objective of this study was to evaluate and compare beta-lactamase inhibiting potential of these plant extracts.Methods: Extracts of these plants were prepared with 6 solvents of different polarity. Beta-lactamase inhibition study was performed using antibiotic-resistant bacteria in bioassay and by micro-iodometric assay. Multidrug-resistant clinical strains of Escherichia coli and laboratory strain with plasmid carrying beta-lactamase gene as positive control were used.Results: Our results from bioassay, as well as micro-iodometric assay for enzyme activity, confirmed the presence of beta-lactamase inhibitor in these plant extracts. Among the extracts made by different solvents, hexane and ethyl acetate extract of T. chebula, hexane extract of T. bellirica, and all extracts of O. tenuiflorum except dichloromethane, possessed beta-lactamase inhibitor. Multidrug-resistant clinical isolate of E. coli AIIMS-1 could be reverted by applying 50 μg/μl of extract of all the medicinal plants. The micro-iodometric result showed highest beta-lactamase inhibition with O. tenuiflorum extracts. Comparative evaluation of the O. tenuiflorum extracts with increasing concentration of inhibitor suggests that ethyl acetate extract of O. tenuiflorum contains the highest inhibition potential, which is comparable with clavulanic acid.Conclusion: The results demonstrated that the ethyl acetate extract of O. tenuiflorum contain the highest level of beta-lactamase inhibitor, which in the future can be used as an alternative to synthetic beta-lactamase inhibitors that are presently being used to control beta-lactam antibiotic resistance

scholarly journals In Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance Mechanisms

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Kirk Nelson ◽  
Debora Rubio-Aparicio ◽  
Dongxu Sun ◽  
Michael Dudley ◽  
Olga Lomovskaya
Keyword(s):  
Acquired Resistance ◽  
Fold Increase ◽  
Resistance Mechanisms ◽  
Multiple Resistance ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of meropenem against CRE, with the meropenem MIC90 decreasing from >64 μg/ml to 0.5 μg/ml for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of meropenem against CRE with multiple resistance mechanisms; the reduction in the meropenem MIC90 with QPX7728 (8 μg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, meropenem with QPX7728 was the most potent beta-lactam–BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of meropenem with QPX7728 at 8 μg/ml or lower. The combination of QPX7728 with meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.

Piperacillin/Tazobactam: A New Beta-Lactam/Beta-Lactamase Inhibitor Combination

1995 ◽  
Vol 29 (5) ◽  
pp. 501-514 ◽  
Author(s):  
Lori L Schoonover ◽  
Donna J Occhipinti ◽  
Keith A Rodvold ◽  
Larry H Danziger
Keyword(s):  
Antimicrobial Activity ◽  
Clinical Efficacy ◽  
Clinical Laboratory ◽  
National Committee ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
In Vitro Susceptibility ◽  
Tract Infections ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

Objective: To discuss the antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effect profile of piperacillin/tazobactam, a new beta-lactam/beta-lactamase inhibitor combination. Data Sources: Literature was identified by MEDLINE search of the medical literature, review of selected references, and data provided by the manufacturer. Study Selection: In vitro susceptibility data were surveyed from studies following the methods of the National Committee for Clinical Laboratory Standards. Data evaluating clinical efficacy were selected from all published trials and abstracts. Additional information concerning safety, chemistry, and pharmacokinetics was reviewed. Data Synthesis: The antimicrobial activity of piperacillin is enhanced by addition of tazobactam against gram-positive, gram-negative, and anaerobic bacteria. Tazobactam is active against a broad spectrum of plasmid and chromosomally mediated enzymes and has minimal ability to induce class I chromosomally mediated beta-lactamase enzymes. Piperacillin/tazobactam's expanded activity appears encouraging in the treatment of mixed aerobic and anaerobic infections. Direct comparisons of ticarcillin/clavulanate and piperacillin/tazobactam for the treatment of lower respiratory tract infections showed piperacillin/tazobactam to be clinically superior, and in the treatment of skin and soft tissue infections the 2 agents were comparable. For the treatment of intraabdominal infections, piperacillin/tazobactam was at least as effective as imipenem/cilastatin and clindamycin plus gentamicin. Conclusions: The combination of tazobactam with piperacillin results in an antimicrobial agent with enhanced activity against most beta-lactamase–producing organisms. Preliminary data indicate that piperacillin/tazobactam has proven clinical efficacy in the treatment of a variety of infections, especially polymicrobic infections.

Sign in / Sign up

Export Citation Format

Share Document