scholarly journals Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

2021 ◽  
Vol 12 ◽  
Author(s):  
Adam B. Shapiro ◽  
Samir H. Moussa ◽  
Sarah M. McLeod ◽  
Thomas Durand-Réville ◽  
Alita A. Miller
Keyword(s):  
First Generation ◽  
Multidrug Resistant ◽  
Class A ◽  
Carbapenem Resistant ◽  
Medical Need ◽  
Spectrum Activity ◽  
Resistant Strains ◽  
Direct Acting ◽  
Lactamase Inhibitor ◽  
Broad Spectrum Activity

Durlobactam is a new member of the diazabicyclooctane class of β-lactamase inhibitors with broad spectrum activity against Ambler class A, C, and D serine β-lactamases. Sulbactam is a first generation β-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam’s ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. This sulbactam-durlobactam combination is currently in late-stage development for the treatment of Acinectobacter infections, including those caused by carbapenem-resistant isolates, for which there is a high unmet medical need. The following mini-review summarizes the molecular drivers of efficacy of this combination against this troublesome pathogen, with an emphasis on the biochemical features of each partner.

scholarly journals In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

2010 ◽  
Vol 54 (6) ◽  
pp. 2291-2302 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre
Keyword(s):  
Multidrug Resistant ◽  
Unusual Property ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
High Affinity ◽  
Class A ◽  
Carbapenem Resistant ◽  
Lactam Antibiotic ◽  
Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

scholarly journals 694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S314-S314
Author(s):  
Alita Miller ◽  
Sarah McLeod ◽  
Tarun Mathur ◽  
Ian Morrissey
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Package Insert ◽  
Multidrug Resistant ◽  
Antibiotic Resistant ◽  
Carbapenem Resistant ◽  
In Vitro Antibacterial Activity ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India. Methods A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert. Results As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR. Conclusion The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii. Disclosures All authors: No reported disclosures.

scholarly journals 1370. Cefepime/VNRX-5133 Broad-Spectrum Activity Is Maintained Against Emerging KPC- and PDC-Variants in Multidrug-Resistant K. pneumoniae and P. aeruginosa

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S419-S420 ◽  
Author(s):  
Denis Daigle ◽  
Jodie Hamrick ◽  
Cassandra Chatwin ◽  
Natalia Kurepina ◽  
Barry N Kreiswirth ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Clinical Isolates ◽  
Research Support ◽  
Class A ◽  
Highly Active ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Abstract Background VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) currently in clinical development with cefepime to treat multidrug-resistant (MDR) infections caused by ESBL- and carbapenemase-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA). VNRX-5133 has direct inhibitory activity against serine-active site β-lactamases (Ser-BL) and emerging VIM/NDM metallo-β-lactamases (MBL). We show herein that cefepime/VNRX-5133 is highly active against MDR-K. pneumoniae and P. aeruginosa clinical isolates producing BL-variants evolved during therapy that compromise activity of ceftazidime/avibactam and ceftolozane/tazobactam. Methods Susceptibility testing was performed according to CLSI methods with cefepime, ceftolozane, and ceftazidime alone or in combination with VNRX-5133, avibactam, or tazobactam, respectively, fixed at 4 mg/L. Five clinical isolates of K. pneumoniae producing KPC variants impacting ceftazidime/avibactam and five clinical isolates of P. aeruginosa producing Pseudomonas-derived cephalosporinase variants impacting ceftolozane/tazobactam activity were collected in 2016 and 2017, respectively, from United States and Spanish hospitals. All other clinical isolates of Enterobacteriaceae and P. aeruginosa (n = 40) were collected in 2016. Results Cefepime/VNRX-5133 was highly active against five ceftazidime/avibactam-resistant K. pneumoniae clinical isolates producing KPC variants with MIC ranging from 0.5 to 4 mg/L relative to ceftazidime/avibactam MIC range of 16 to >128 mg/L. Cefepime/VNRX-5133 was also active against all five clinical isolates of ceftolozane/tazobactam-resistant P. aeruginosa, where 4/5 isolates had MIC of 4–8 mg/L relative to ceftolozane/tazobactam MIC range of 32–128 mg/L. The elevated cefepime/VNRX-5133 MIC (16 mg/L) in the remaining P. aeruginosa isolate was not due to the PDC-221 variant, as an engineered strain of P. aeruginosa producing this enzyme had a cefepime/VNRX-5133 MIC of 1 mg/L. Conclusion VNRX-5133 is a potent BLI possessing a unique broad spectrum of activity, including Class A, C, and D Ser-BLs, clinically evolving variants of Ser-BLs (e.g., KPC, PDC) and emerging VIM/NDM-type MBLs. Cefepime/VNRX-5133 is highly active against emerging multidrug-resistant Enterobacteriaceae and P. aeruginosa. Disclosures D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. J. Hamrick, VenatoRx Pharmaceuticals Inc.: Employee, Salary. C. Chatwin, VenatoRx Pharmaceuticals Inc.: Employee, Salary. N. Kurepina, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. B. N. Kreiswirth, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. R. K. Shields, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. A. Oliver, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. C. J. Clancy, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. M. H. Nguyen, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee, Salary. L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary.

Delafloxacin activity against Staphylococcus aureus with reduced susceptibility or resistance to methicillin, vancomycin, daptomycin or linezolid

2020 ◽  
Vol 75 (9) ◽  
pp. 2605-2608
Author(s):  
Louis D Saravolatz ◽  
Joan M Pawlak ◽  
Corinne Wegner
Keyword(s):  
Staphylococcus Aureus ◽  
Good Activity ◽  
Limited Data ◽  
Skin Structure ◽  
Spectrum Activity ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Gram Negative Organisms ◽  
Susceptibility Rate ◽  
Broad Spectrum Activity

Abstract Background Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by MRSA. There are limited data available against MRSA blood isolates (MRSABIs), vancomycin-intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin-non-susceptible strains (DNSSA) and linezolid-resistant Staphylococcus aureus (LRSA). Methods Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin and linezolid was determined against 110 MRSABIs, 15 VRSA, 35 VISA, 40 DNSSA and 6 LRSA. Microdilution testing using CAMHB was used to determine MIC according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics. PCR testing for molecular markers was performed. Results Delafloxacin demonstrated activity against MRSABIs with an MIC90 of 1 mg/L and 68% susceptibility. Against the other groups the MIC90 and susceptibility were 1 mg/L and 40%, respectively, for VISA, 4 mg/L and 7% for VRSA and 1 mg/L and 38% for DNSSA. None of the LRSA isolates was susceptible to delafloxacin. Delafloxacin was active against 94% of MRSA blood isolates that were genotype SCC IVa. For MRSABIs with a levofloxacin MIC ≥8 mg/L (55/110), suggesting multiple mutations in the QRDR, delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate. Conclusions Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA and DNSSA, and demonstrates good activity against blood isolates most commonly found in the community.

scholarly journals 1588. Delafloxacin Activity Against Staphylococcus aureus with Reduced Susceptibility or Resistance to Methicillin, Vancomycin, Daptomycin, or Linezolid

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S579-S580
Author(s):  
Louis D Saravolatz ◽  
Joan Pawlak
Keyword(s):  
Antimicrobial Agents ◽  
Minimal Bactericidal Concentration ◽  
Limited Data ◽  
Methicillin Resistant ◽  
Mueller Hinton ◽  
Spectrum Activity ◽  
Resistant Strains ◽  
Gram Negative Organisms ◽  
Mueller Hinton Broth ◽  
Broad Spectrum Activity

Abstract Background Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by methicillin-resistant S. aureus. There is limited data available against methicillin-resistant S. aureus blood isolates (MRSABI), vancomycin intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin non-susceptible strains (DNSSA) and linezolid-resistant S. aureus (LRSA). Methods Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin, ceftaroline, and linezolid was determined against recent (2016–2018) MRSABI (110), VRSA (15), VISA (35), DNSSA (40), and LRSA (6). Broth microdilution testing using Mueller–Hinton broth was used to determine minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics. Results Antimicrobial MIC90 expressed in mg/L and (% susceptible) None of the LRSA were susceptible to delafloxacin or levofloxacin. All strains that were susceptible to the antimicrobial agents above had an MBC that was the same as the MIC or one dilution greater except for linezolid which demonstrated an MBC that was more than eight-fold greater than the MIC. For MRSABI isolates with a levofloxacin MIC ≥ 8 mg/L (55/110) suggesting multiple mutations in the quinolone-resistant determining region, the delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate. Conclusion Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA, and DNSSA. Disclosures All authors: No reported disclosures.

Alkoxyphenylthiazoles with broad-spectrum activity against multidrug-resistant gram-positive bacterial pathogens

2018 ◽  
Vol 152 ◽  
pp. 318-328 ◽  
Author(s):  
Moustafa ElAwamy ◽  
Haroon Mohammad ◽  
Abdelrahman Hussien ◽  
Nader S. Abutaleb ◽  
Mohamed Hagras ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Pathogens ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

scholarly journals Fighting Antibiotic-Resistant Klebsiella pneumoniae with “Sweet” Immune Targets

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Roberto Adamo ◽  
Immaculada Margarit
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Therapeutic Approaches ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Surface Polysaccharides ◽  
Resistant Strains ◽  
Murine Monoclonal Antibodies

ABSTRACT Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago-Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen.

scholarly journals Synergistic Activity of Colistin-Containing Combinations against Colistin-ResistantEnterobacteriaceae

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Alejandro Pironti ◽  
James E. Kirby
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Bacterial Outer Membrane ◽  
Time Kill ◽  
Synergistic Combinations

ABSTRACTResistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistantEnterobacteriaceae(CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistantEnterobacteriaceaeisolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

scholarly journals Comprehensive Genome Analysis of Carbapenem-Resistant Strains of Raoultella Species, an Emerging Multidrug-Resistant Bacterium in Hospitals

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Xiao Yu ◽  
Beiwen Zheng ◽  
Jing Zhang ◽  
Hao Xu ◽  
Tingting Xiao ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antibiotic Resistance Genes ◽  
Genomic Analysis ◽  
Multidrug Resistant ◽  
Control Measures ◽  
Carbapenem Resistant ◽  
Multidrug Resistant Bacterium ◽  
The World ◽  
Resistant Strains

ABSTRACT We report the characterization of six carbapenem-resistant Raoultella spp. (CRRS) in our hospital and a genomic analysis of 58 publicly available isolates. CRRS isolates are sporadically identified around the world, and different transposons carrying carbapenemases were the resistant mechanisms. Mobile genetic elements play an important role in acquiring antibiotic resistance genes from the hospital. An improved understanding of these transposon and targeted control measures will be very valuable to prevent CRRS dissemination.

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