scholarly journals AAI101, a Novel β-Lactamase Inhibitor: Microbiological and Enzymatic Profiling

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S375-S375 ◽  
Author(s):  
Krisztina M Papp-Wallace ◽  
Christopher R Bethel ◽  
Melissa D Barnes ◽  
Joseph D Rutter ◽  
Magdalena A Taracila ◽  
...  
Keyword(s):  
Inactivation Kinetics ◽  
Phase 2 ◽  
Broth Microdilution ◽  
E Coli ◽  
Steady State Inactivation ◽  
Enzymatic Profiling ◽  
Kinetics Of ◽  
Lactamase Inhibitor ◽  
Phase 2 Clinical Trials ◽  
Research Grant

Abstract Background AAI101 is a novel β-lactamase inhibitor (BLI), active against ESBLs and other β-lactamases. AAI101 combined with cefepime (FEP) is in Phase 2 clinical trials. The objective of this study was to determine differences between AAI101 and tazobactam in their inhibition of selected β-lactamases of clinical relevance. Methods Isogenic E. coli strains expressing single clinically relevant β-lactamases were tested for susceptibility (broth microdilution MIC) to FEP, FEP/AAI101 and piperacillin-tazobactam (P/T). Periplasmic β-lactamase extracts from selected strains then were used to determine IC50s for AAI101 and for tazobactam. β-Lactamases with low IC50s for AAI101 were purified, and steady-state inactivation kinetics determined for AAI101 and for tazobactam. Results AAI101 restored activity of FEP against E. coli strains producing defined β-lactamases, and FEP/AAI101 was more potent than P/T (Table). Conclusion Addition of AAI101 enhances cefepime activity vs. a selected array of β-lactamases expressed in E. coli in an isogenic Background. The inhibitory kinetics of β-lactamases by AAI101 compared with those of tazobactam indicate different mechanisms of β-lactamase inhibition. Disclosures K. M. Papp-Wallace, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Merck: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant M. R. Jacobs, Allecra: Grant Investigator, Research grant Roche: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant; R. A. Bonomo, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Wockhardt: Grant Investigator, Research grant Merck: Grant Investigator, Research grant Roche: Grant Investigator, Research grant GSK: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant

scholarly journals Reclaiming the Efficacy of β-Lactam–β-Lactamase Inhibitor Combinations: Avibactam Restores the Susceptibility of CMY-2-Producing Escherichia coli to Ceftazidime

2014 ◽  
Vol 58 (8) ◽  
pp. 4290-4297 ◽  
Author(s):  
Krisztina M. Papp-Wallace ◽  
Marisa L. Winkler ◽  
Julian A. Gatta ◽  
Magdalena A. Taracila ◽  
Sujatha Chilakala ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Rate Constant ◽  
Clinical Isolates ◽  
Inactivation Kinetics ◽  
Content Type ◽  
E Coli ◽  
Cephalosporin Resistance ◽  
Molecular Modeling Studies ◽  
Kinetics Of ◽  
Lactamase Inhibitor

ABSTRACTCMY-2 is a plasmid-encoded Ambler class C cephalosporinase that is widely disseminated inEnterobacteriaceaeand is responsible for expanded-spectrum cephalosporin resistance. As a result of resistance to both ceftazidime and β-lactamase inhibitors in strains carryingblaCMY, novel β-lactam–β-lactamase inhibitor combinations are sought to combat this significant threat to β-lactam therapy. Avibactam is a bridged diazabicyclo [3.2.1]octanone non-β-lactam β-lactamase inhibitor in clinical development that reversibly inactivates serine β-lactamases. To define the spectrum of activity of ceftazidime-avibactam, we tested the susceptibilities ofEscherichia coliclinical isolates that carryblaCMY-2orblaCMY-69and investigated the inactivation kinetics of CMY-2. Our analysis showed that CMY-2-containing clinical isolates ofE. coliwere highly susceptible to ceftazidime-avibactam (MIC90, ≤0.5 mg/liter); in comparison, ceftazidime had a MIC90of >128 mg/liter. More importantly, avibactam was an extremely potent inhibitor of CMY-2 β-lactamase, as demonstrated by a second-order onset of acylation rate constant (k2/K) of (4.9 ± 0.5) × 104M−1s−1and the off-rate constant (koff) of (3.7 ± 0.4) ×10−4s−1. Analysis of the reaction of avibactam with CMY-2 using mass spectrometry to capture reaction intermediates revealed that the CMY-2–avibactam acyl-enzyme complex was stable for as long as 24 h. Molecular modeling studies raise the hypothesis that a series of successive hydrogen-bonding interactions occur as avibactam proceeds through the reaction coordinate with CMY-2 (e.g., T316, G317, S318, T319, S343, N346, and R349). Our findings support the microbiological and biochemical efficacy of ceftazidime-avibactam againstE. colicontaining plasmid-borne CMY-2 and CMY-69.

scholarly journals 166. Activity of a Novel β-lactamase Inhibitor QPX7728 Combined With β-lactams Against st258 klebsiella Pneumoniae and st131 escherchia Coli Isolates Producing β-lactamases

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S212-S213
Author(s):  
Mariana Castanheira ◽  
Jill Lindley ◽  
Timothy B Doyle ◽  
Andrew P Davis ◽  
Olga Lomovskaya
Keyword(s):  
Multidrug Resistant ◽  
Chemical Diversity ◽  
Sequencing Analysis ◽  
E Coli ◽  
Escherchia Coli ◽  
Global Spread ◽  
Encoding Genes ◽  
Center Research ◽  
Lactamase Inhibitor ◽  
Research Grant

Abstract Background ST258 K. pneumoniae and ST131 E. coli clones are considered vectors for the global spread of multidrug resistance. We evaluated the activity of β-lactams in combination with QPX7728, a novel β-lactamase inhibitor active against all β-lactamase classes, against a collection of 210 isolates belonging to these clones collected from a worldwide surveillance study. Methods A total of 118 ST258 K. pneumoniae and 92 ST131 E. coli (single loci variant also included) were susceptibility tested by reference broth microdilution against various β-lactams ± QPX7728 and comparator agents. All isolates were screened for β-lactamases using whole genome sequencing analysis. Results All β-lactam agents had limited activity against 118 ST258 K. pneumoniae (1.7–7.6% susceptible). Among these, 104 carried carbapenemase-encoding genes: 66 KPC variants, 20 NDM and 17 OXA-48-like. One isolate carried 2 carbapenemases. The addition of QPX7728 at 4 mg/L or 8 mg/L lowered the MICs for cefepime (MIC50/90, 0.25/1 mg/L and MIC50/90, 0.12/0.5 mg/L), ceftolozane (MIC50/90, 0.5/ > 32 mg/L and MIC50/90, 0.25/16 mg/L), ertapenem (MIC50/90, 0.12/2 mg/L and MIC50/90, 0.06/0.5 mg/L), and meropenem (MIC50/90, 0.06/0.5 mg/L and MIC50/90, 0.03/0.12 mg/L; Table). QPX7728 at 4 mg/L reduced the ceftibuten (MIC50/90, 0.25/8 mg/L) or tebipenem (MIC50/90, 0.12/2 mg/L) MICs for ST258 isolates. E. coli ST131 carried mainly CTX-M variant (85 isolates), but 6 isolates harbored carbapenemases. Carbapenems were the only β-lactams displaying > 80.0% activity against ST131 E. coli, followed by piperacillin-tazobactam (79.3% susceptible). Only 5.4%and 41.3% ST131 isolates were susceptible to cefepime and ceftibuten, respectively. MIC50/MIC90 values for these agents with QPX7728 were ≤ 0.015/≤ 0.015 mg/L for cefepime and ≤ 0.015/0.06 mg/L for ceftolozane with the inhibitor at 8 mg/L and ≤ 0.015/0.03 mg/L for ceftibuten with the inhibitor at 4 mg/L. Conclusion QPX7728 lowered the MICs for all agents tested to clinically achievable levels when tested against isolates multidrug resistant belonging to important clones responsible to the dissemination of KPC, CTX variants, and metallo-β-lactamases. The development of this broad β-lactamase inhibitor should be pursued. Table 1 Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Jill Lindley, Allergan (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Olga Lomovskaya, PhD, Qpex Biopharma (Employee)

scholarly journals Activity of the Novel Extended-spectrum β-Lactamase Inhibitor AAI101 in Combination with Cefepime Towards a Challenge Panel of Acinetobacter baumannii

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S366-S367 ◽  
Author(s):  
Ian Morrissey ◽  
Sophie Magnet ◽  
Stephen Hawser ◽  
Stuart Shapiro ◽  
Harald Seifert ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Isolates ◽  
The Novel ◽  
Phase 2 ◽  
Broth Microdilution ◽  
Highly Active ◽  
Southern Us ◽  
Extended Spectrum ◽  
Broad Array ◽  
Lactamase Inhibitor

Abstract Background AAI101 is a novel extended-spectrum β-lactamase inhibitor (BLI), active against ESBLs and a broad array of other BLs. AAI101 in combination with cefepime (FEP) is in Phase 2 development. Infections caused by A. baumannii, a pathogen endemic to the southern US and other global regions, are very challenging to treat, and often require combination therapy. This study examined the activity of FEP/AAI101 against a challenge set of A. baumannii clinical isolates enriched with OXA carbapenemase producers. Methods BLs in A. baumannii were identified by genotyping. Broth microdilution MICs and susceptibilities were obtained following CLSI methods and breakpoints (BPs), except for ceftazidime-avibactam (CAZ/AVI) where FDA P. aeruginosa BPs were used. CLSI FEP BPs were used for FEP/AAI101. Results All OXA-51 producers had the ISAba1 promoter. MIC90 data and % susceptibilities (%S) for FEP/AAI101 and comparators are shown in the Table: FEP/AAI101 was highly active against meropenem-susceptible (MPMs) isolates. FEP/AAI101 (AAI101 fixed at 8 µg/ml) covered 67% of OXA-51 and 53% of OXA-58 strains. Lower susceptibilities were obtained for OXA-23 and OXA-24/40 producers. FEP/AAI101 was the most active β-lactam product. Colistin (COL) was the only agent with consistently high activity against all A. baumannii isolates. Conclusion FEP/AAI101 was the most potent β-lactam product tested against clinical isolates of A. baumannii producing OXA-51 and OXA-58 β-lactamases. Infections by this difficult pathogen often require combination therapy, of which FEP-AAI101 may be a component. Disclosures S. Shapiro, Allecra: Employee, Salary

Inactivation of Escherichia coli by Ultrasound Combined with Nisin

2018 ◽  
Vol 81 (6) ◽  
pp. 993-1000 ◽  
Author(s):  
ZUWEN WANG ◽  
XIUFANG BI ◽  
RUI XIANG ◽  
LIYI CHEN ◽  
XIAOPING FENG ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Synergistic Effect ◽  
Linear Models ◽  
Treatment Time ◽  
Nutrient Broth ◽  
Inactivation Kinetics ◽  
Growth Phases ◽  
E Coli ◽  
Kinetics Of ◽  
Inactivation Effect

ABSTRACT The aim of this study was to investigate the inactivation of nonpathogenic Escherichia coli in nutrient broth and milk through the use of either ultrasound (US) alone or US combined with nisin (US + nisin) treatments. The E. coli cells were treated at 0 to 55°C, 242.04 to 968.16 W/cm2 for 0 to 15 min. The results showed that the inactivation of E. coli by US and US + nisin increased when the temperature, US power density, and treatment time were increased. The inactivation kinetics of E. coli in nutrient broth by US and US + nisin both conformed to linear models. The largest reductions of 2.89 and 2.93 log cycles by US and US + nisin, respectively, were achieved at 968.16 W/cm2 and at 25°C for 15 min. The suspension media of the E. coli cells influenced the inactivation effect of US, while the growth phases of E. coli cells did not affect their resistance to US. Under all experiment conditions of this study, the differences between US and US + nisin in their respective inactivation effects on E. coli were not obvious. The results suggested that nisin had either no effect at all or a weak synergistic effect with US and that the E. coli cells were inactivated mainly by US, thus indicating that the inactivation of E. coli by US is an “all or nothing” event.

Viability of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes in Yellow Fat Spreads as Affected by Storage Temperature

2003 ◽  
Vol 66 (4) ◽  
pp. 549-558 ◽  
Author(s):  
SARAH L. HOLLIDAY ◽  
LARRY R. BEUCHAT
Keyword(s):  
Escherichia Coli ◽  
Listeria Monocytogenes ◽  
Storage Temperature ◽  
Salt Content ◽  
Inactivation Kinetics ◽  
Escherichia Coli O157 ◽  
E Coli ◽  
Inhibition Of Growth ◽  
Time Required ◽  
Kinetics Of

A study was conducted to characterize the survival and inactivation kinetics of a five-serotype mixture of Salmonella (6.23 to 6.55 log10 CFU per 3.5-ml or 4-g sample), a five-strain mixture of Escherichia coli O157:H7 (5.36 to 6.14 log10 CFU per 3.5-ml or 4-g sample), and a six-strain mixture of Listeria monocytogenes (5.91 to 6.18 log10 CFU per 3.5-ml or 4-g sample) inoculated into seven yellow fat spreads (one margarine, one butter-margarine blend, and five dairy and nondairy spreads and toppings) after formulation and processing and stored at 4.4, 10, and 21°C for up to 94 days. Neither Salmonella nor E. coli O157:H7 grew in any of the test products. The time required for the elimination of each pathogen depended on the product and the storage temperature. Death was more rapid at 21°C than at 4.4 or 10°C. Depending on the product, the time required for the elimination of viable cells at 21°C ranged from 5 to 7 days to >94 days for Salmonella, from 3 to 5 days to 28 to 42 days for E. coli O157:H7, and from 10 to 14 days to >94 days for L. monocytogenes. Death was most rapid in a water-continuous spray product (pH 3.66, 4.12% salt) and least rapid in a butter-margarine blend (pH 6.66, 1.88% salt). E. coli O157:H7 died more rapidly than did Salmonella or L. monocytogenes regardless of storage temperature. Salmonella survived longer in high-fat (≥61%) products than in products with lower fat contents. The inhibition of growth is attributed to factors such as acidic pH, salt content, the presence of preservatives, emulsion characteristics, and nutrient deprivation. L. monocytogenes did not grow in six of the test products, but its population increased between 42 and 63 days in a butter-margarine blend stored at 10°C and between 3 and 7 days when the blend was stored at 21°C. On the basis of the experimental parameters examined in this study, traditional margarine and spreads not containing butter are not “potentially hazardous foods” in that they do not support the growth of Salmonella, E. coli O157:H7, or L. monocytogenes.

Correction to: Ultraviolet-C Light Inactivation Kinetics of E. coli on Bologna Beef Packaged in Plastic Films

2017 ◽  
Vol 10 (12) ◽  
pp. 2269-2269
Author(s):  
Tarek R. Abdussamad ◽  
Barbara A. Rasco ◽  
Shyam S. Sablani
Keyword(s):  
Inactivation Kinetics ◽  
Plastic Films ◽  
E Coli ◽  
Ultraviolet C ◽  
Kinetics Of

scholarly journals Disinfection of Escherichia coli and Pseudomonas aeruginosa by copper in water

2016 ◽  
Vol 14 (3) ◽  
pp. 424-432 ◽  
Author(s):  
Andrew M. Armstrong ◽  
Mark D. Sobsey ◽  
Lisa M. Casanova
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Enteric Bacteria ◽  
Inactivation Kinetics ◽  
Log10 Reduction ◽  
E Coli ◽  
Piped Water ◽  
Ionic Copper ◽  
Household Water ◽  
Kinetics Of

When households lack access to continuous piped water, water storage in the home creates opportunities for contamination. Storage in copper vessels has been shown to reduce microbes, but inactivation kinetics of enteric bacteria in water by copper alone needs to be understood. This work characterized inactivation kinetics of Escherichia coli and Pseudomonas aeruginosa by dissolved ionic copper in water. Reductions of E. coli and P. aeruginosa increase with increasing dose. At 0.3 mg/L, there was a 2.5 log10 reduction of E. coli within 6 hours. At 1 and 3 mg/L, the detection limit was reached between 3 and 6 hours; maximum reduction measured was 8.5 log10. For P. aeruginosa, at 6 hours there was 1 log10 reduction at 0.3 mg/L, 3.0 log10 at 1 mg/L, and 3.6 log10 at 3 mg/L. There was no significant decline in copper concentration. Copper inactivates bacteria under controlled conditions at doses between 0.3 and 1 mg/L. E. coli was inactivated more rapidly than P. aeruginosa. Copper at 1 mg/L can achieve 99.9% inactivation of P. aeruginosa and 99.9999997% inactivation of E. coli over 6 hours, making it a candidate treatment for stored household water.

Ultraviolet inactivation of bacteria and model viruses in coconut water using a collimated beam system

2019 ◽  
Vol 25 (7) ◽  
pp. 562-572 ◽  
Author(s):  
Manreet S Bhullar ◽  
Ankit Patras ◽  
Agnes Kilonzo-Nthenge ◽  
Bharat Pokharel ◽  
Michael Sasges
Keyword(s):  
Pathogenic Bacteria ◽  
Microbial Inactivation ◽  
Coconut Water ◽  
Inactivation Kinetics ◽  
E Coli ◽  
Log Reduction ◽  
Ultraviolet C ◽  
Log Linear ◽  
Kinetics Of ◽  
Collimated Beam

This study investigated the effect of ultraviolet-C irradiation on the inactivation of microorganisms in coconut water, a highly opaque liquid food (1.01 ± 0.018 absorption coefficient). Ultraviolet-C inactivation kinetics of two bacteriophages (MS2, T1UV) and three surrogate bacteria ( Escherichia coli, Salmonella Typhimurium, Listeria monocytogenes) in 0.1% (w/v) peptone and coconut water were investigated. Ultraviolet-C irradiation at 254 nm was applied to stirred samples, using a collimated beam device. A series of known ultraviolet-C doses (0–40 mJ cm−2) were applied for ultraviolet-C treatment except for MS2 where higher doses were delivered (100 mJ cm−2). Inactivation levels of all organisms were proportional to ultraviolet-C dose. At the highest dose of 40 mJ cm−2, three surrogates of pathogenic bacteria were inactivated by more than 5-log10 (p < 0.05) in 0.1% (w/v) peptone and coconut water. Results showed that ultraviolet-C irradiation effectively inactivated bacteriophage and surrogate bacteria in highly opaque coconut water. The log reduction kinetics of microorganisms followed log-linear and exponential models with higher R2 (>0.95) and low root mean square error values. The D10 values of 3, 5.48, and 4.58 mJ cm−2 were obtained from the inactivation of E. coli, S. Typhimurium, and L. monocytogenes, respectively. Models for predicting log reduction as a function of ultraviolet-C irradiation dose were found to be significant (p < 0.05). Fluid optics were the key controlling parameters for efficient microbial inactivation. Therefore, the ultraviolet-C dose must be calculated not only from the incident ultraviolet-C intensity but must also consider the attenuation in the samples. The results from this study imply that adequate log reduction of vegetative cells and model viruses is achievable in coconut water and suggested significant potential for ultraviolet-C treatment of other liquid foods.

Ultraviolet-C Light Inactivation Kinetics of E. coli on Bologna Beef Packaged in Plastic Films

2015 ◽  
Vol 8 (6) ◽  
pp. 1267-1280 ◽  
Author(s):  
Abdussamad R. Tarek ◽  
Barbara. A. Rasco ◽  
Shyam S. Sablani
Keyword(s):  
Inactivation Kinetics ◽  
Plastic Films ◽  
E Coli ◽  
Ultraviolet C ◽  
Kinetics Of

Inactivation kinetics of indicator microorganisms during urea treatment for sanitizing finished compost from composting toilet

2016 ◽  
Vol 6 (2) ◽  
pp. 269-275 ◽  
Author(s):  
Seyram K. Sossou ◽  
Mariam Sou/Dakoure ◽  
Yacouba Konate ◽  
Amadou H. Maiga ◽  
Naoyuki Funamizu
Keyword(s):  
Treatment Time ◽  
Urea Concentration ◽  
Inactivation Rate ◽  
Inactivation Kinetics ◽  
Kinetics Parameters ◽  
Urea Treatment ◽  
Indicator Microorganisms ◽  
E Coli ◽  
Kinetics Of ◽  
Linear Reduction

This study aimed at estimating the sanitizing effectiveness of urea treatment by studying the inactivation kinetics of selected indicator microorganisms. Finished composts from a composting toilet were inoculated with indicator microorganisms and subjected to different urea concentrations (0.5–2% w/w) and temperatures (22, 32 and 42°C). The inactivation kinetics parameters were determined in relation to pH, ammonia content and temperature during treatment time. The results show that urea addition to compost enhanced inactivation of microorganisms. The decline in number of E. coli and Enterococus followed a linear reduction, while that of Ascaris lumbricoides eggs followed a linear reduction plus shoulder. The inactivation rate constants of all microorganisms tested were positively correlated to the increase of NH3(aq) concentration and temperature. The relationship between the inactivation rate of microorganisms, ammonia through urea concentration and temperature were established. Therefore, the best decimal decay of E. coli, Enterococus and A. lumbricoides eggs occurred with 2% w/w urea concentration at 42°C within 0.9, 1.1 and 1.4 days, respectively. E. coli was the most sensitive microorganism to urea treatment, while Enterococcus and A. lumbricoides eggs showed resistance, especially at lower temperatures. Urea treatment has proved to be an efficient option for safe reuse of compost from composting toilets.

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