<i>In Vivo</i>
            Pharmacodynamic Profile of EVER206, a Novel Polymyxin Antimicrobial, against Gram-Negative Bacteria in the Murine Thigh Infection Model

Gill, Christian M; Nicolau, David P.

doi:10.1128/aac.01738-22

Cited by 1 publication

(1 citation statement)

References 27 publications

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“…A previous report evaluated SPR206 in murine thigh infections against MDR K. pneumonia, P. aeruginosa, and E. coli infections, but not A. baumannii 40 ; and our study highlights the need to further investigate the effects of SPR206 on A. baumannii as well as the potential use of SPR206 in other infection models. The in vivo observations from our work in the murine pulmonary and wound infection models point to the potential clinical indications of SPR206 for the treatment of HAP/VAP and SSTI/ABSSSIs caused by XDR and MDR gram-negative infections.…”

Section: Discussionmentioning

confidence: 61%

The polymyxin SPR206 remediates gram-negative infections in vivo

Fitzgerald,

Castellanos,

Escatte

et al. 2023

Preprint

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ESKAPEE pathogens (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli), particularly the gram-negative species, are a problematic group of bacteria associated with nosocomial infections in susceptible patients. These infections are often further complicated by multidrug-resistant (MDR) strains and a lack of treatment options. While the pipeline of new antibiotics is nothing short of thin when it comes to gram-negative activity, one promising molecule is SPR206. SPR206 is a novel polymyxin antibiotic, a nonapeptide designed to overcome the nephrotoxicity associated with other members of this drug class. As intended, SPR206 was found to be safe with no severe adverse events in a Phase 1, single ascending dose/multiple ascending dose clinical trial. SPR206 has in vitro activity against almost all gram-negative species, and we confirmed this activity in minimal inhibitory concentration assays against unique diversity sets of bacterial isolates. Additionally, bactericidal activity was observed in time-kill assays, which is expected for polymyxins. Subsequently, we evaluated the safety and efficacy of SPR206 in three separate in vivo models: Galleria mellonella and two murine models, a pulmonary model and a wound model. In G. mellonella and in the mouse pulmonary model, SPR206 provided almost 100% survival in treated animal groups when compared to untreated control groups. With wound infection, SPR206 significantly reduced bacterial burden and decreased time to heal compared to untreated groups. With wound infection, SPR206 significantly reduced bacterial burden and decreased time to heal compared to untreated groups. These results suggest SPR206 is a potent antibiotic with MDR gram-negative activity that could have expanded clinical indications to include skin and soft tissue infection and hospital-acquired pneumonia.

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Section: Discussionmentioning

confidence: 61%