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.
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 10(6) 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 microg/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 10(1) 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.
Ghiselli
Roberto
R
Department of General Surgery, I.N.R.C.A. I.R.R.C.S., Università Politecnica delle Marche, Ancona, Italy.
Giacometti
Andrea
A
Cirioni
Oscar
O
Mocchegiani
Federico
F
Silvestri
Carmela
C
Orlando
Fiorenza
F
Kamysz
Wojciech
W
Licci
Alberto
A
Nadolski
Piotr
P
Della Vittoria
Agnese
A
Łukasiak
Jerzy
J
Scalise
Giorgio
G
Saba
Vittorio
V
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002405:Catheterization, Central Venous / Q000009:adverse effects; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects / Q000502:physiology; D016908:Gram-Positive Bacterial Infections / Q000517:prevention & control*; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D000081:Acetamides; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D023303:Oxazolidinones; D010455:Peptides; D000069349:Linezolid; C119872:antimicrobial peptide IB-367