Potential therapeutic role of histatin derivative P-113D in experimental rat models of Pseudomonas aeruginosa sepsis

Background. Morbidity and mortality from Pseudomonas aeruginosa sepsis remain high despite the availability of antibiotics to which the microorganism is sensitive. Methods. The in vitro activity of histatin derivative P-113D was investigated against Pseudomonas aeruginosa. In addition, its in vivo efficacy was studied in 3 rat models of infection: intraperitoneal injection of 1 mg of P. aeruginosa 10 lipopolysachharide, intraperitoneal injection of 2 x 10(10) cfu of P. aeruginosa ATCC 27853, and intra-abdominal sepsis induced by cecal ligation and puncture. Rats received isotonic sodium chloride solution parenterally ( control groups), 1 mg of P-113D/kg of body weight, 1 mg of polymyxin B/kg of body weight, or 20 mg of imipenem/kg of body weight. Main outcomes measured were abdominal exudate and plasma bacterial growth, plasma concentrations of endotoxin and tumor necrosis factor (TNF)-alpha, and lethality. Results. The in vivo studies showed that all compounds reduced lethality, when compared with results for the control group. Overall, P-113D exhibited a slightly lower antimicrobial activity than did imipenem, even though P-113D achieved a substantial decrease in plasma concentrations of endotoxin and TNF-alpha, compared with the imipenem. No statistically significant differences for antimicrobial and antiendotoxin activities were noted between P-113D and polymyxin B. Discussion. These results provide evidence for double antiendotoxin and antimicrobial activity for P-113D and point to its potential use for the treatment of severe infections.