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.

scholarly journals Five-Year Longitudinal Assessment (2008 to 2012) of E-101 Solution Activity against Clinical Target and Antimicrobial-Resistant Pathogens

2014 ◽  
Vol 58 (8) ◽  
pp. 4911-4914 ◽  
Author(s):  
Gerald A. Denys ◽  
Chris M. Pillar ◽  
Daniel F. Sahm ◽  
Peter O'Hanley ◽  
Jackson T. Stephens
Keyword(s):  
Broad Spectrum ◽  
Susceptibility Testing ◽  
Bacterial Species ◽  
Clinical Isolates ◽  
Longitudinal Assessment ◽  
Gram Negative ◽  
Spectrum Activity ◽  
Eskape Pathogens ◽  
Negative Target ◽  
Broad Spectrum Activity

ABSTRACTThis study summarizes the topical E-101 solution susceptibility testing results for 760 Gram-positive and Gram-negative target pathogens collected from 75 U.S. sites between 2008 and 2012 and 103 ESKAPE pathogens. E-101 solution maintained potent activity against all bacterial species studied for each year tested, with MICs ranging from <0.008 to 0.25 μg porcine myeloperoxidase (pMPO)/ml. These results confirm that E-101 solution retains its potent broad-spectrum activity against U.S. clinical isolates and organisms with challenging resistance phenotypes.

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 Olorofim Susceptibility Testing of 1,423 Danish Mold Isolates Obtained in 2018-2019 Confirms Uniform and Broad-Spectrum Activity

2020 ◽  
Vol 65 (1) ◽  
pp. e01527-20
Author(s):  
Karen Marie Thyssen Astvad ◽  
Karin Meinike Jørgensen ◽  
Rasmus Krøger Hare ◽  
Raluca Datcu ◽  
Maiken Cavling Arendrup
Keyword(s):  
Broad Spectrum ◽  
Susceptibility Testing ◽  
Population Data ◽  
Dihydroorotate Dehydrogenase ◽  
Content Type ◽  
Species Complexes ◽  
Upper Limits ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

ABSTRACTOlorofim is a novel antifungal drug in phase 2 trials. It has shown promising in vitro activity against various molds, except for Mucorales. Initially, we observed a broad range of EUCAST MICs for Aspergillus fumigatus. Here, we explored the MIC variability in more detail and prospectively investigated the susceptibility of contemporary clinical mold isolates, as population data are needed for future epidemiological cutoff (ECOFF) settings. Fifteen A. fumigatus isolates previously found with low/medium/high MICs (≤0.002 to 0.25 mg/liter) were tested repeatedly and EUCAST MICs read in a blinded fashion by three observers. pyrE, encoding the olorofim target enzyme dihydroorotate dehydrogenase (DHODH), was sequenced. A total of 1,423 mold isolates (10 Aspergillus species complexes [including 1,032 A. fumigatus isolates] and 105 other mold/dermatophyte isolates) were examined. Olorofim susceptibility (modal MIC, MIC50, MIC90, and wild-type upper limits [WT-ULs] [species complexes with ≥15 isolates]) was determined and compared to that of four comparators. MICs (mg/liter) were within two 2-fold dilutions (0.016 to 0.03) for 473/476 determinations. The MIC range spanned four dilutions (0.008 to 0.06). No significant pyrE mutations were found. Modal MIC/WT-UL97.5 (mg/liter) values were 0.03/0.06 (A. terreus and A. flavus), 0.06/0.125 (A. fumigatus and Trichophyton rubrum), and 0.06/0.25 (A. niger and A. nidulans). The MIC range for Scedosporium spp. was 0.008 to 0.25. Olorofim susceptibility was similar for azole-resistant and -susceptible isolates of A. fumigatus but reduced for A. montevidensis and A. chevalieri (MICs of >1). With experience, olorofim susceptibility testing is robust. The testing of isolates from our center showed uniform and broad-spectrum activity. Single-center WT-ULs are suggested.

scholarly journals In VitroAntimicrobial Activity of Razupenem (SMP-601, PTZ601) against Anaerobic Bacteria

2011 ◽  
Vol 55 (5) ◽  
pp. 2398-2402 ◽  
Author(s):  
Chau Minh Tran ◽  
Kaori Tanaka ◽  
Yuka Yamagishi ◽  
Takatsugu Goto ◽  
Hiroshige Mikamo ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Anaerobic Bacteria ◽  
Clinical Isolates ◽  
Strong Activity ◽  
Content Type ◽  
Spectrum Activity ◽  
Reference Strains ◽  
Gram Positive Cocci ◽  
Broad Spectrum Activity

ABSTRACTWe evaluated thein vitroantianaerobic activity of razupenem (SMP-601, PTZ601), a new parenterally administered carbapenem, against 70 reference strains and 323 clinical isolates. Razupenem exhibited broad-spectrum activity against anaerobes, inhibiting most of the reference strains when used at a concentration of ≤1 μg/ml. Furthermore, it exhibited strong activity, comparable to those of other carbapenems (meropenem and doripenem), against clinically isolated non-fragilis Bacteroidesspp. (MIC90s of 2 μg/ml), with MIC90values of 0.06, 0.03, and 0.5 μg/ml againstPrevotellaspp.,Porphyromonasspp., andFusobacteriumspp., respectively. Clinical isolates of anaerobic Gram-positive cocci,Eggerthellaspp., andClostridiumspp. were highly susceptible to razupenem (MIC90s, 0.03 to 1 μg/ml).

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.

Broad-spectrum activity of a novel antibiotic peptide against multidrug-resistant veterinary isolates

2013 ◽  
Vol 198 (2) ◽  
pp. 534-537 ◽  
Author(s):  
Clotilde Silvia Cabassi ◽  
Simone Taddei ◽  
Sandro Cavirani ◽  
Maria Cristina Baroni ◽  
Paolo Sansoni ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Multidrug Resistant ◽  
Spectrum Activity ◽  
Antibiotic Peptide ◽  
Broad Spectrum Activity

scholarly journals In Vitro Profiling of Ceftaroline against a Collection of Recent Bacterial Clinical Isolates from across the United States

2008 ◽  
Vol 52 (9) ◽  
pp. 3398-3407 ◽  
Author(s):  
Yigong Ge ◽  
Donald Biek ◽  
George H. Talbot ◽  
Daniel F. Sahm
Keyword(s):  
United States ◽  
The United States ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Hospital Acquired Infections ◽  
Spectrum Activity ◽  
Hospital Acquired ◽  
Broad Spectrum Activity

ABSTRACT This study evaluated the in vitro activity of ceftaroline, a novel cephalosporin with broad-spectrum activity against gram-negative and -positive pathogens, against 4,151 recent clinical isolates collected in the United States. Ceftaroline was very potent against bacteria found in community- and hospital-acquired infections, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and common Enterobacteriaceae spp.

scholarly journals 1293. Sulbactam-durlobactam is active against recent, multi-drug resistant Acinetobacter baumannii clinical isolates from the Middle East

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S662-S662
Author(s):  
Alita Miller ◽  
Sarah McLeod ◽  
Samir Moussa ◽  
Meredith Hackel
Keyword(s):  
Antibacterial Activity ◽  
Middle East ◽  
Acinetobacter Baumannii ◽  
United Arab Emirates ◽  
Blood Stream ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Surveillance Systems ◽  
Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of &gt;3600 isolates from 2012-2017, the MIC90 of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region. Methods 190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available. Results This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC90 from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of &gt; 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes. Conclusion SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections. Disclosures Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)

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