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Pretreatment With the Protegrin IB-367 Affects Gram-Positive Biofilm and Enhances the Therapeutic Efficacy of Linezolid in Animal Models of Central Venous Catheter Infection

Roberto Ghiselli, MD, PhD^*, Andrea Giacometti, MD, Oscar Cirioni, MD, PhD, Federico Mocchegiani, MD, PhD^*, Carmela Silvestri, PhD, Fiorenza Orlando, PhD, Wojciech Kamysz, PhD, Alberto Licci, MD, PhD, Piotr Nadolski, PhD, Agnese Della Vittoria, MD, PhD, Jerzy ukasiak, PhD, Giorgio Scalise, MD^* and Vittorio Saba, MD

From the ^* Department of General Surgery, I.N.R.C.A. I.R.R.C.S., Università Politecnica delle Marche, Ancona, Italy; Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy; Experimental Animal Models for Aging Units, Research Department, I.N.R.C.A. I.R.R.C.S., Ancona, Italy; and the Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland

Correspondence: Andrea Giacometti, MD, Clinica delle Malattie Infettive, c/o Ospedale Regionale, Via Conca, 71, 60200 Ancona AN Italy. Electronic mail may be sent to anconacmi{at}interfree.it.

Background: Biofilms play an important role in the pathogenesis of several chronic infections and nosocomial infections related to indwelling medical devices. Methods: To assess the efficacy of IB-367 and linezolid (LZD) in the treatment of central venous catheter (CVC) infections using the antibiotic-lock technique, in vitro and in vivo studies were performed. The in vitro antibiotic susceptibility assay for Staphylococcus aureus and Enterococcus faecalis biofilms developed on 96-well polystyrene tissue culture plates was performed to determine the activity of the compounds. Efficacy studies were performed in rat models of Gram-positive CVC infection. Silastic catheters were implanted into the superior cava of adult male Wistar rats. Twenty-four hours after implantation, the catheters were pretreated by filling with IB-367. Thirty minutes later, rats were challenged via the CVC with 1.0 x 10⁶ CFU (colony forming units) of S aureus strain diffuse Smith and clinical isolate of slime-producing E faecalis. Administration of LZD into the CVC at a concentration equal to the minimum bacteriocidal concentration observed using adherent cells or at a much higher concentration (1024 µg/mL) began 24 hours later. Results: Both for S aureus and E faecalis, the killing activities of LZD against adherent bacteria were at least 4-fold to 8-fold lower than that against freely growing cells. For both strains, in IB-367-pretreated wells, LZD strongly increases its activity. The in vivo studies showed that when CVCs were pretreated with IB-367, Gram-positive biofilm bacterial load was further decreased to 10¹ CFU/mL and bacteremia was not detected. Conclusions: IB-367 has potential as an adjunctive agent to LZD in the treatment of Gram-positive biofilm infections such as CVC infections.

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