Full and Broad-Spectrum In Vivo Eradication of Catheter-Associated Biofilms Using Gentamicin-EDTA Antibiotic Lock Therapy

Abstract

Biofilms that develop on indwelling devices are a major concern in clinical settings. While removal of colonized devices remains the most frequent strategy for avoiding device-related complications, antibiotic lock therapy constitutes an adjunct therapy for catheter-related infection. However, currently used antibiotic lock solutions are not fully effective against biofilms, thus warranting a search for new antibiotic locks. Metal-binding chelators have emerged as potential adjuvants due to their dual anticoagulant/antibiofilm activities, but studies investigating their efficiency were mainly in vitro or else focused on their effects in prevention of infection. To assess the ability of such chelators to eradicate mature biofilms, we used an in vivo model of a totally implantable venous access port inserted in rats and colonized by either Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, or Pseudomonas aeruginosa. We demonstrate that use of tetrasodium EDTA (30 mg/ml) as a supplement to the gentamicin (5 mg/ml) antibiotic lock solution associated with systemic antibiotics completely eradicated Gram-positive and Gramnegative bacterial biofilms developed in totally implantable venous access ports. Gentamicin-EDTA lock was able to eliminate biofilms with a single instillation, thus reducing length of treatment. Moreover, we show that this combination was effective for immunosuppressed rats. Lastly, we demonstrate that a gentamicin-EDTA lock is able to eradicate the biofilm formed by a gentamicin-resistant strain of methicillin-resistant S. aureus. This in vivo study demonstrates the potential of EDTA as an efficient antibiotic adjuvant to eradicate catheter-associated biofilms of major bacterial pathogens and thus provides a promising new lock solution.C entral venous catheters are routinely used to administer medication or fluids to patients admitted to oncology, nephrology, and intensive care units (2, 47, 52). Although these devices greatly improve patient health, their use is often associated with medical complications due to colonization by pathogenic microorganisms (38). This leads to development of complex bacterial or fungal biofilm communities that display strong tolerance toward antimicrobials (15,37,45). Biofilms are difficult to eradicate; moreover, they constitute a potential source of bloodstream infections, a leading cause of health care-associated infections in critically ill patients (29). Currently, there is no fully efficient method for treating catheter-related biofilms aside from traumatic and costly removal of colonized devices (5,11,42,49). However, recent clinical practice guidelines recommended the use of antibiotic lock therapy (ALT) for treatment of uncomplicated long-term catheter-related infections (31). ALT relies on the instillation of highly concentrated antibiotic solutions (up to 1,000 times the MIC) left to dwell in the catheter for 12 to 24 h in order to prevent or eradicate biofilm formation. Although ALT shows a high success rate for coagulase-negative staphyl...

Antimicrobial lock therapy in central-line associated bloodstream infections: a systematic review

“…In an animal study, Chauan et al [22] showed that gentamicin-EDTA lock therapy is active against S. aureus and CoNS biofilms. Fortun et al used this compound as ALT for 14 days, in association with systemic treatment, for gram-negative rod CLABSI.…”

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…Several in vitro and in vivo studies demonstrated the presence of highly tolerant bacterial persisters in biofilms formed by Gram-positive and Gram-negative pathogens (86)(87)(88)(89). Clinical demonstration of the presence of persisters can be inferred from the risk of infection recurrence during biofilm-related infections.…”

“…Using a rat model of biofilm-related infection with a totally implantable venous access port (TIVAP), it was recently shown that the gentamicin-EDTA combination was the most effective lock solution compared to gentamicin alone, EDTA alone, or ethanol (70%) (87,344). Gentamicin-EDTA is therefore a potential lock solution able to cure highly tolerant biofilms and eradicate persistent bacteria, thereby preventing recurrence of Gram-positive as well as Gram-negative bacterial biofilms on TIVAP (344).…”

Evaluation of the removal reasons of totally implantable venous devices in children: a retrospective study

“…In previous studies, the most common infectious agent is reported as S. epidermidis in port catheter related infections 15,25 . Also, coagulase negative staphlococci (S. epidermidis, S. hominis, S. saprophyticus) were reported as the most common microbial organisms 22 .…”