Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

2020 ◽  
Vol 63 (24) ◽  
pp. 15802-15820
Author(s):  
David T. Davies ◽  
Simon Leiris ◽  
Magdalena Zalacain ◽  
Nicolas Sprynski ◽  
Jérôme Castandet ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

scholarly journals In Vitro Activity of the Ultra-Broad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Meropenem against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Kirk Nelson ◽  
Debora Rubio-Aparicio ◽  
Ruslan Tsivkovski ◽  
Dongxu Sun ◽  
Maxim Totrov ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Wide Distribution ◽  
Clinical Isolates ◽  
Beta Lactamase ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Substrate Inhibitor ◽  
Lactamase Inhibitor

ABSTRACT QPX7728 is a recently discovered ultra-broad-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 beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

scholarly journals Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections

2019 ◽  
Vol 63 (6) ◽  
pp. 2789-2801 ◽  
Author(s):  
Bin Liu ◽  
Robert E. Lee Trout ◽  
Guo-Hua Chu ◽  
Daniel McGarry ◽  
Randy W. Jackson ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Infections ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii

2017 ◽  
Vol 2 (9) ◽  
Author(s):  
Thomas F. Durand-Réville ◽  
Satenig Guler ◽  
Janelle Comita-Prevoir ◽  
Brendan Chen ◽  
Neil Bifulco ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Lactamase Inhibitor

scholarly journals Activity of the β-Lactamase Inhibitor LN-1-255 against Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Juan Carlos Vázquez-Ucha ◽  
María Maneiro ◽  
Marta Martínez-Guitián ◽  
John Buynak ◽  
Christopher R. Bethel ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Kinetics Parameters ◽  
Clinical Issue ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Continued Use ◽  
Global Threat ◽  
Lactamase Inhibitor

ABSTRACT The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in Acinetobacter baumannii, including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant A. baumannii infections. However, the spread of OXA carbapenemases is compromising the continued use of these antimicrobials. In response to this clinical issue, it is necessary and urgent to design and develop new specific inhibitors with efficacy against these enzymes. The aim of this work was to characterize the inhibitory activity of LN-1-255 (a 6-alkylidene-2-substituted penicillin sulfone) and compare it to that of two established inhibitors (avibactam and tazobactam) against the most relevant enzymes of each group of class D carbapenemases in A. baumannii. The β-lactamase inhibitor LN-1-255 demonstrated excellent microbiological synergy and inhibition kinetics parameters against all tested CHDLs and a significantly higher activity than tazobactam and avibactam. A combination of carbapenems and LN-1-255 was effective against A. baumannii class D carbapenemases. Docking assays confirmed the affinity of LN-1-255 for the active site of these enzymes. LN-1-255 represents a potential new β-lactamase inhibitor that may have a significant role in eradicating infections caused by A. baumannii isolates carrying CHDLs.

scholarly journals Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Sarah M. McLeod ◽  
Adam B. Shapiro ◽  
Samir H. Moussa ◽  
Michele Johnstone ◽  
Robert E. McLaughlin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Broad Spectrum ◽  
Active Site ◽  
Stringent Response ◽  
Clinical Isolates ◽  
The Novel ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Sensitive Isolate ◽  
Lactamase Inhibitor

ABSTRACTThe novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistantAcinetobacter baumannii. The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10−10to <9.0 × 10−10at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to β-lactamase inhibition, ETX2514 may enhance sulbactam activity inA. baumanniivia inhibition of PBP2.

scholarly journals Impact of an antimicrobial stewardship programme on reducing broad-spectrum antibiotic use and its effect on carbapenem-resistant Acinetobacter baumannii (CRAb) in hospitals in Jordan

2020 ◽  
Author(s):  
Dawood Yusef ◽  
Wail A Hayajneh ◽  
Ali Bani Issa ◽  
Rami Haddad ◽  
Sayer Al-Azzam ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antimicrobial Stewardship ◽  
Broad Spectrum ◽  
Antibiotic Use ◽  
Broad Spectrum Antibiotic ◽  
Carbapenem Resistant ◽  
Restriction Policy ◽  
Prior Approval ◽  
Tertiary Teaching ◽  
The Impact

Abstract Objectives To evaluate the impact of an antimicrobial stewardship programme (ASP) on reducing broad-spectrum antibiotic use and its effect on carbapenem-resistant Acinetobacter baumannii (CRAb) in hospitalized patients. Methods The study was a retrospective, ecological assessment in a tertiary teaching hospital over 6 years (January 2014 to December 2019). The intervention involved the implementation of an ASP in February 2018, which remains in effect today. This ASP consists of several components, including education, antibiotic guidelines, antibiotic restriction policy with prior approval, audit of compliance to the restriction policy and feedback. Restricted antibiotics were imipenem/cilastatin, ertapenem, meropenem, vancomycin, teicoplanin, tigecycline, colistin, amikacin, piperacillin/tazobactam, levofloxacin and ciprofloxacin. The intervention was evaluated by time-series methods. Results Statistically significant decreases in the level of antibiotic use, after the introduction of the ASP, were observed for the following antibiotics: imipenem/cilastatin (P = 0.0008), all carbapenems (P = 0.0001), vancomycin (P = 0.0006), colistin (P = 0.0016) and third-generation cephalosporins (P = 0.0004). A statistically significant decrease in the slope, after the introduction of the ASP, for ertapenem (P = 0.0044) and ciprofloxacin (P = 0.0117) was observed. For piperacillin/tazobactam, there was a significant increasing trend (P = 0.0208) before the introduction of the ASP. However, this increased trend was halted post-introduction of the ASP (P = 0.4574). The introduction of the ASP was associated with a significant impact on reducing the levels of CRAb (P = 0.0237). Conclusions The introduced antimicrobial stewardship interventions contributed to a reduction in the use of several broad-spectrum antibiotics, reversed the trends of increasing use of other antibiotics and were associated with a significant reduction in CRAb.

Uncertainty in evaluating treatment outcomes in carbapenem-resistant Acinetobacter baumannii infections

2021 ◽  
Author(s):  
Jessica Howard-Anderson ◽  
David van Duin
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Outcomes ◽  
Controlled Trials ◽  
Careful Evaluation ◽  
Treatment Regimens ◽  
Randomized Controlled ◽  
Carbapenem Resistant ◽  
The Impact ◽  
Lactamase Inhibitor

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are challenging to treat and associated with poor clinical outcomes. In this issue, sulbactam-durlobactam, a novel β-lactam-β-lactamase inhibitor, was used with cefiderocol to successfully treat CRAB pneumonia. While this report and in vitro data are encouraging, determining the impact of treatment regimens on clinical outcomes after CRAB infections is not straightforward. Therefore, careful evaluation in pathogen-directed randomized controlled trials is needed to determine the optimal treatment of CRAB infections.

In vitro activity of sulbactam/durlobactam against global isolates of carbapenem-resistant Acinetobacter baumannii

2020 ◽  
Vol 75 (9) ◽  
pp. 2616-2621 ◽  
Author(s):  
Harald Seifert ◽  
Carina Müller ◽  
Danuta Stefanik ◽  
Paul G Higgins ◽  
Alita Miller ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
The Novel ◽  
In Vitro Activity ◽  
Carbapenem Resistant ◽  
Excellent Activity ◽  
Acinetobacter Spp ◽  
Lactamase Inhibitor

Abstract Objectives To evaluate the activity of the novel broad-spectrum serine β-lactamase inhibitor durlobactam (ETX2514) combined with sulbactam against global isolates of carbapenem-resistant Acinetobacter baumannii with defined carbapenem resistance mechanisms compared with reference antimicrobials with known activity against Acinetobacter spp. Methods The susceptibility of 246 carbapenem-resistant non-duplicate A. baumannii isolates to sulbactam/durlobactam, amikacin, colistin, imipenem/sulbactam/durlobactam, imipenem, meropenem, minocycline and sulbactam was tested using broth microdilution. Isolates were obtained from various body sites from patients in 37 countries and from six world regions between 2012 and 2016. Identification of carbapenem resistance mechanisms and assignment to A. baumannii clonal lineages was based on WGS. Results Sulbactam/durlobactam showed excellent activity comparable to colistin but superior to amikacin, minocycline and sulbactam. The sulbactam/durlobactam MIC50/90 values were 1/4 and 2/4 mg/L and the colistin MIC50/90 values were 0.5 and 1 mg/L, respectively. Comparatively, amikacin, minocycline and sulbactam MIC50/90 values were 256/≥512, 2/16 and 16/64 mg/L, respectively. Conclusions Sulbactam/durlobactam had excellent in vitro potency against A. baumannii isolates, including those that were resistant to imipenem/meropenem, amikacin, minocycline and colistin, compared with other compounds. Sulbactam/durlobactam has the potential to become a useful addition to the limited armamentarium of drugs that can be used to treat this problem pathogen.

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