Advanced Therapies as Treatments of Gram-negative Infection Following Maxillofacial Surgery

Objective: Multi-drug resistant Gram-negative infections are an important life threatening complication in maxillofacial surgery patients following complex poly-trauma and cancer surgery. Increasing antimicrobial resistance and a dearth of antibiotic discovery means there is an urgent need to improve the efficiency and safety of existing antibiotics. We have developed nanoantibiotic dextrin-colistin conjugates, which, in vitro, exhibit antibacterial activity across a range of Gram-negative bacteria, comparable to Colomycin^®, and reduced toxicity. The objective of this Study was to compare in vivo plasma concentration and toxicity of dextrin-colistin conjugates with colistin sulfate.

Method: Colistin sulphate and dextrin-colistin conjugates (DC1 (1.4 mol% succinoylated 8,000 g/mol dextrin); DC4 (7.2 mol% succinoylated 8,000 g/mol dextrin)) were dissolved in 0.9% w/v sterile saline, filtered (0.22 μm) and injected via the tail vein as a bolus over ~30 s to 2 Sprague-Dawley rats per test item (0.01, 0.05, 0.1, 0.5 mg/kg colistin equiv.). Blood was collected via cannulation (300 μL at 5 and 30 min, 1, 4, 8 and 24 h post-dose), centrifuged to extract plasma, and colistin content assayed by ELISA.

Result: Intravenous administration of dextrin-colistin conjugates led to improved pharmacokinetics of colistin; the blood clearance of dextrin-colistin conjugates was considerably slower (t_1/2α >2 h) than seen for “free” colistin (t_1/2α <1 h). Increasing the degree of dextrin modification by succinoylation further prolonged the blood clearance half-life (t_1/2α >21 h). Escalating dose studies demonstrated a marked reduction in toxicity of conjugates. While administration of 0.5 mg/kg colistin sulfate produced signs of systemic toxicity, equivalent doses of DC1 and DC4 were well tolerated.

Conclusion: The dextrin-colistin conjugates described here exhibit decreased toxicity and prolonged plasma levels of colistin compared to colistin sulfate. These studies demonstrate the considerable advantages that polymer conjugation may offer in the treatment of life-threatening Gram-negative infections in maxillofacial surgery.