Abstract
BackgroundThe recent rise and spread of carbapenem-resistant pathogens pose an urgent threat to public health and has fueled the search for new therapies. Localized delivery of topical antibiotics is an alternative for the treatment of infected wounds caused by drug-resistant pathogens. In this study, we aimed to develop antimicrobial-loaded hydrogels for topical treatment of wound infections in a murine skin wound infection.ResultsPaenipeptin analogue 1, a linear lipopeptide, potentiated clarithromycin against multidrug-resistant Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae. Enzymatically-crosslinked gelatin hydrogels were developed to encapsulate paenipeptin analogue 1 and clarithromycin. The encapsulated antimicrobials were gradually released from hydrogels during incubation, reaching 75.43 and 53.66% for paenipeptin and clarithromycin, respectively, at 24 h. The antimicrobial-loaded hydrogels containing paenipeptin and clarithromycin synergistically resulted in 5-log reduction in carbapenem-resistant A. baumannii within 6 h in vitro. Moreover, the antimicrobial-loaded hydrogels reduced 3.6- and 2.5-log of carbapenem-resistant A. baumannii when treated at 4 or 20 h post infection, respectively, in a murine skin wound infection.ConclusionsEnzymatically-crosslinked gelatin hydrogels loaded with paenipeptin analogue 1 and clarithromycin exhibited potent therapeutic efficacy against carbapenem-resistant A. baumannii in murine skin wound infection.
Highlights
The recent rise and spread of carbapenem-resistant pathogens pose an urgent threat to public health and has fueled the search for new therapies
We previously reported that paenipeptin analogues potentiated clarithromycin and rifampicin against 10 carbapenem-resistant pathogens, including five isolates of A. baumannii and five isolates of Klebsiella pneumoniae [16]
Paenipeptin failed to increase the activity of clarithromycin against P. aeruginosa
Summary
The recent rise and spread of carbapenem-resistant pathogens pose an urgent threat to public health and has fueled the search for new therapies. Localized delivery of topical antibiotics is an alternative for the treatment of infected wounds caused by drug-resistant pathogens. Bacterial infections caused by carbapenem-resistant pathogens are difficult to treat and have been recognized as an urgent threat [1, 2]. It was estimated that carbapenem-resistant Acinetobacter caused 8500 cases of infections and 700 deaths in the United States in 2017 [3]. Localized delivery of topical antibiotics is an alternative to systemic antibiotics for the treatment of infected wounds [7]. The lipopeptide antibiotic colistin was encapsulated in glycol chitosanbased hydrogels for the treatment of infection in mice. The localized release of colistin from hydrogels exhibited potent activity against Pseudomonas aeruginosa in the in vivo animal “burn” infection model [8]. Topically delivered moxifloxacin reduced P. aeruginosa and Staphylococcus aureus wound infections and prompted wound healing [9]
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