Durlobactam in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections: A Systematic Review

Granata, Guido; Taglietti, Fabrizio; Schiavone, Francesco; Petrosillo, Nicola

doi:10.3390/jcm11123258

Cited by 8 publications

(10 citation statements)

References 33 publications

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“…Durlobactam ( 60 ) (ETX2514) + sulbactam ( 61 ) (combination: SUL-DUR, ETX2514SUL; IV) is being developed by Entasis Therapeutics (a subsidiary of Innoviva, Burlingame, CA, USA) and completed a phase-III trial (NCT03894046) for treatment of infections caused by A. baumannii-calcoaceticus (ABC) complex [ 320 – 322 ] in June 2021. In this trial, SUL-DUR demonstrated statistical non-inferiority versus colistin for the primary end point of 28-day all-cause mortality in patients with carbapenem-resistant ABC infections and a significant difference in clinical cure rates, as well as a statistically significant reduction in nephrotoxicity [ 323 ].…”

Section: β-Lactam/β-lactamase Inhibitor (Bl/bli) Combinations Undergo...mentioning

confidence: 99%

Antibiotics in the clinical pipeline as of December 2022

et al. 2023

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The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

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Section: β-Lactam/β-lactamase Inhibitor (Bl/bli) Combinations Undergo...mentioning

confidence: 99%

Antibiotics in the clinical pipeline as of December 2022

et al. 2023

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“…Many nosocomial infections were treatable with medicines; however, the increase in AMR rate has resulted in favoring the use of wide-spectrum antimicrobials in clinical practices, which in turn could lead to antimicrobial selection effects, conversely, this made it challenging to treat AB-infected patients. 46 , 47 …”

Section: Discussionmentioning

confidence: 99%

Genomic Determinants of Pathogenicity and Antimicrobial Resistance of Nosocomial Acinetobacter baumannii Clinical Isolates of Hospitalized Patients (2019–2021) from a Sentinel Hospital in Hangzhou, China

Wei¹,

Chen²,

Anwar³

et al. 2023

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Purpose Acinetobacter baumannii ( A. baumannii or AB) is one of the most opportunistic, nosocomial pathogens threatening public healthcare across countries. A. baumannii has become a primary growing concern due to its exceptional ability to acquire antimicrobial resistance (AMR) to multiple antimicrobial agents which is increasingly reported and more prevalent every year. Therefore, there is an urgent need to evaluate the AMR knowledge of A. baumannii for effective clinical treatment of nosocomial infections. This study aimed to investigate the clinical distribution AMR phenotypes and genotypes, and genomic characteristics of A. baumannii isolates recovered from hospitalized patients of different clinical departments of a sentinel hospital to improve clinical practices. Methods A total of 123 clinical isolates were recovered from hospitalized patients of different clinical departments during 2019–2021 to analyze AMR patterns, and further subjected to whole-genome sequencing (WGS) investigations. Multi-locus sequence typing (MLST), as well as the presence of antimicrobial-resistant genes (ARGs), virulence factor genes (VFGs) and insertion sequences (ISs) were also investigated from WGS data. Results The results highlighted that A. baumannii clinical isolates had shown a high AMR rate, particularly from the intensive care unit (ICU), towards routinely used antimicrobials, ie, β-lactams and fluoroquinolones. ST2 was the most prevalent ST in the clinical isolates, it was strongly associated to the resistance of cephalosporins and carbapenems, with bla OXA-23 and bla OXA-66 being the most frequent determinants; moreover, high carrier rate of VFGs was also observed such as all strains containing the ompA, adeF, pgaC, lpsB , and bfmR genes. Conclusion Acinetobacter baumannii clinical isolates are mostly ST2 with high rates of drug resistance and carrier of virulence factors. Therefore, it requires measurements to control its transmission and infection.

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“…However, in the eleven SUL–DUR-resistant A. baumannii we found Q488K and Y528H mutations in PBP3. To date, reports of SUL–DUR resistance have been rare and resistance is usually attributed to the presence of metallo-β-lactamases, which DUR does not inhibit, or to mutations near the active site of PBP3, the target of sulbactam [ 24 , 25 , 26 ]. Few therapeutic choices are available to treat CR Ab isolates [ 14 , 16 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Durlobactam (DUR), previously called ETX2514, is a non-β-lactam diazabicyclooctane (DBO) inhibitor with activity against Ambler class A, C and D β-lactamases [ 22 , 23 ]. Recently, some studies have shown that sulbactam in combination with durlobactam is active against MDR A. baumannii [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Sulbactam (SUL) is one of the first β-lactamase inhibitors used in combination with ampicillin for the treatment of class A β-lactamase-producing pathogens.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Activity of Sulbactam–Durlobactam against Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates: A Multicentre Report from Italy

et al. 2022

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In the present study, the in vitro activity of the sulbactam–durlobactam (SUL–DUR) combination was evaluated against 141 carbapenem-resistant A. baumannii (CRAb) clinical strains collected from six Italian laboratories. Over half (54.6%) of these isolates were resistant to colistin. The SUL–DUR combination was active against these CRAb isolates with MIC50 and MIC90 values of 0.5 mg/L and 4 mg/L, respectively. Only eleven isolates were resistant to SUL–DUR with MIC values ranging from 8 to 128 mg/L. The SUL–DUR resistant A. baumannii exhibited several antimicrobial resistance genes (ARGs) such as blaOXA-20, blaOXA-58, blaOXA-66, blaADC-25, aac(6′)-Ib3 and aac(6′)-Ib-cr and mutations in gyrA (S81L) and parC (V104I, D105E). However, in these isolates, mutations Q488K and Y528H were found in PBP3. Different determinants were also identified in these CRAb isolates, including adeABC, adeFGH, adeIJK, abeS, abaQ and abaR, which encode multidrug efflux pumps associated with resistance to multiple antibacterial agents. This is the first report on the antimicrobial activity of SUL–DUR against carbapenem-resistant A. baumannii isolates selected from multiple regions in Italy.

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Durlobactam in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections: A Systematic Review

Cited by 8 publications

References 33 publications

Antibiotics in the clinical pipeline as of December 2022

Antibiotics in the clinical pipeline as of December 2022

Genomic Determinants of Pathogenicity and Antimicrobial Resistance of Nosocomial Acinetobacter baumannii Clinical Isolates of Hospitalized Patients (2019–2021) from a Sentinel Hospital in Hangzhou, China

In Vitro Activity of Sulbactam–Durlobactam against Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates: A Multicentre Report from Italy

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