Continuous Subcutaneous Delivery of Proline-Rich Antimicrobial Peptide Api137 Provides Superior Efficacy to Intravenous Administration in a Mouse Infection Model
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Media type:
E-Article
Title:
Continuous Subcutaneous Delivery of Proline-Rich Antimicrobial Peptide Api137 Provides Superior Efficacy to Intravenous Administration in a Mouse Infection Model
Description:
Apidaecins are cationic, proline-rich antimicrobial peptides originally isolated fromhoneybees and exhibit high Gram-negative activity by inhibiting bacterial proteintranslation. Pharmacokinetics of apidaecin derivative Api137 was studied usingsingle and multiple intravenous or subcutaneous injections as well as continuoussubcutaneous infusion and correlated to its efficacy in a lethal murine Escherichia coliinfection model. Survival rates of infected CD-1 mice were monitored and Api137 andits metabolites were quantified in plasma of uninfected CD-1 mice and Sprague Dawleyrats using reversed-phase chromatography coupled online to mass spectrometry. Thehighest Api137 plasma levels of 23 mg/L were obtained after a single intravenousinjection of 20 mg/kg body weight, which declined fast over the next 120 min (halflife time < 30 min). In contrast, continuous subcutaneous infusion of a similar dose overan hour (19.2 mg/kg/h) lead to stable plasma levels of ∼6 mg/L, which was above theminimal inhibitory concentration against E. coli ATCC 25922 (4 mg/L). The increasedexposure by continuous subcutaneous administration of Api137 at 19.2 mg/kg/hover 48 h improved efficacy in the murine intraperitoneal sepsis model with survivalrates of 67% over 5 days compared to 33% after intravenous and subcutaneousadministration in different dosing schemes. To the best of our knowledge, continuoussubcutaneous infusion using osmotic pumps was successfully utilized for delivery of anantimicrobial peptide for the first time. Additionally, the potential of apidaecin analogs asnovel antibiotics is demonstrated even in a scenario where the infection site is clearlyseparated from the route of administration.