<i>In Vivo</i>
            Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing
            <i>Klebsiella pneumoniae</i>
            Infection

Weiss, Jason; Pulse, Mark; Nguyen, Phung M.; Growcott, Ellena

doi:10.1128/aac.02214-18

Cited by 9 publications

(8 citation statements)

References 18 publications

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“…In summary, these data demonstrate that variations in the zinc content of commercially available caMHB significantly influence MBL AST and the development of zinc-limited media using EDTA. As evidence of carbapenem efficacy against MBLharboring Enterobacteriaceae in animal infection models continues to mount (14,37,38), a harmonized consensus on the appropriate amount of zinc that culture media should contain will be paramount to optimizing current antimicrobial agents and the development of novel therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Variability in Zinc Concentration among Mueller-Hinton Broth Brands: Impact on Antimicrobial Susceptibility Testing of Metallo-β-Lactamase-Producing Enterobacteriaceae

et al. 2020

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Zinc concentrations have been found to vary among different manufacturers of cation adjusted Mueller-Hinton broth (caMHB). Herein, we evaluated the impact of utilizing different brands and lots of commercially available caMHB on antimicrobial susceptibility of metallo-β-lactamase (MBL)-harboring Enterobacteriaceae, and to evaluate the addition of EDTA to caMHB as a means to achieve zinc-limited media. Fifteen clinical Enterobacteriaceae isolates (NDM, n=7; VIM, n=3; IMP, n=2; KPC, n=3) and 9 different commercial lots from 3 caMHB manufacturers (Becton-Dickinson, Oxoid, and Sigma-Aldrich) were utilized. Zinc-limited media was prepared by addition of EDTA at concentrations ranging from 3 to 300 μg/mL. Meropenem MICs were determined in triplicate in each lot of conventional caMHB and zinc-limited media by broth microdilution. Zinc concentration was determined in each lot of conventional caMHB by inductively coupled plasma mass spectrometry. Up to 8-fold differences were observed in meropenem MICs between the commercial lots resulting in varying classifications of susceptibility among MBL-harboring isolates. Mean zinc concentrations were highest among conventional Becton-Dickinson caMHB, relative to Oxoid and Sigma-Aldrich broth. Among MBL-harboring isolates, the impact of EDTA on MICs was dependent on the lot, correlating with initial zinc availability (i.e., less MIC reduction with higher initial zinc concentration) while MICs to KPC-harboring isolates were unchanged. In summary, zinc variability was observed among commercial lots of caMHB resulting in different classification of susceptibility among MBL-harboring Enterobacteriaceae. Addition of EDTA concentrations ≥30 μg/mL were sufficient to provide a zinc-limited media, resulting in MICs that reflect in vivo meropenem activity.

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Section: Discussionmentioning

confidence: 99%

Variability in Zinc Concentration among Mueller-Hinton Broth Brands: Impact on Antimicrobial Susceptibility Testing of Metallo-β-Lactamase-Producing Enterobacteriaceae

et al. 2020

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“…coli and K. pneumoniae strains, including strains expressing KPC and NDM carbapenemases (9, 10). Using this model, it was determined that the predominant PK/pharmacodynamic (PD) parameter associated with antibacterial efficacy of LYS228 was the percentage of the dosing interval that free drug concentrations remained above the MIC of the infecting organism (% T >MIC ) (9, 10).…”

Section: Discussionmentioning

confidence: 99%

“…LYS228 is a monobactam antibiotic, which kills bacteria by inhibiting cell wall synthesis through covalent modification of the active-site serine of penicillin binding protein 3 (7, 8). LYS228 is active in vitro and in vivo against Enterobacteriaceae (9, 10). LYS228 is stable to most serine-β-lactamases (SBLs) and all metallo-β-lactamases (MBLs) profiled to date and has demonstrated activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates (MIC 90 , 1 μg/ml) (11).…”

Section: Introductionmentioning

confidence: 99%

A First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy Volunteers

Boysen‐Osborn

Stachulski

Sun

et al. 2019

Antimicrob Agents Chemother

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Infections caused by antibiotic-resistant Gram-negative bacteria expressing extended-spectrum β-lactamases and carbapenemases are a growing global problem resulting in increased morbidity and mortality with limited treatment options. LYS228 is a novel intravenous monobactam antibiotic targeting penicillin binding protein 3 with potent activity against Enterobacteriaceae, including multidrug-resistant clinical isolates expressing serine and metallo-β-lactamases. In this study, we evaluated the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of LYS228 in healthy volunteers. LYS228 was safe: no serious adverse events were reported. Adverse events, with the exception of catheter-related events, occurred sporadically, with similar incidences between LYS228 and placebo groups. No apparent adverse event-dose relationship was identified. LYS228 was not associated with any clinically significant dose-related hematologic, hepatic, or renal laboratory abnormalities. The most frequently observed adverse events were local injection site reactions, noted in 91.7% and 75.0% of subjects administered multiple doses of LYS228 and placebo, respectively. LYS228 demonstrated pharmacokinetic properties consistent with those of other β-lactam antibiotics, with systemic exposures slightly greater than dose proportional, short terminal half-lives (between 1.0 and 1.6 h) with no significant accumulation, and rapid clearance predominantly through urinary excretion.

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“…Weiss et al confirmed its in vivo efficacy using a neutropenic mice thigh infection model caused by NDM-1 positive K. pneumoniae. In brief, 24-h log 10 CFU/thigh for LYS228 (90 mg/kg q4 h) was significantly lower than that for no drug therapy (Weiss et al, 2019). No study on its antibacterial activity against MBL-producing P. aeruginosa or A. baumannii was found.…”

Section: Lysmentioning

confidence: 90%

Drug development concerning metallo-β-lactamases in gram-negative bacteria

et al. 2022

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β-Lactams have been a clinical focus since their emergence and indeed act as a powerful tool to combat severe bacterial infections, but their effectiveness is threatened by drug resistance in bacteria, primarily by the production of serine- and metallo-β-lactamases. Although once of less clinical relevance, metallo-β-lactamases are now increasingly threatening. The rapid dissemination of resistance mediated by metallo-β-lactamases poses an increasing challenge to public health worldwide and comprises most existing antibacterial chemotherapies. Regrettably, there have been no clinically available inhibitors of metallo-β-lactamases until now. To cope with this unique challenge, researchers are exploring multidimensional strategies to combat metallo-β-lactamases. Several studies have been conducted to develop new drug candidates or calibrate already available drugs against metallo-β-lactamases. To provide an overview of this field and inspire more researchers to explore it further, we outline some promising candidates targeting metallo-β-lactamase producers, with a focus on Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Promising candidates in this review are composed of new antibacterial drugs, non-antibacterial drugs, antimicrobial peptides, natural products, and zinc chelators, as well as their combinations with existing antibiotics. This review may provide ideas and insight for others to explore candidate metallo-β-lactamases as well as promote the improvement of existing data to obtain further convincing evidence.

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In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection

Cited by 9 publications

References 18 publications

Variability in Zinc Concentration among Mueller-Hinton Broth Brands: Impact on Antimicrobial Susceptibility Testing of Metallo-β-Lactamase-Producing Enterobacteriaceae

Variability in Zinc Concentration among Mueller-Hinton Broth Brands: Impact on Antimicrobial Susceptibility Testing of Metallo-β-Lactamase-Producing Enterobacteriaceae

A First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy Volunteers

Drug development concerning metallo-β-lactamases in gram-negative bacteria

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