In Vitro Assessment of the Antimicrobial Efficacy of Optimized Nitroglycerin-Citrate-Ethanol as a Nonantibiotic, Antimicrobial Catheter Lock Solution for Prevention of Central Line-Associated Bloodstream Infections

Abstract

cThe rapid, broad-spectrum, biofilm-eradicating activity of the combination of 0.01% nitroglycerin, 7% citrate, and 20% ethanol and its potential as a nonantibiotic, antimicrobial catheter lock solution (ACLS) were previously reported. Here, a nitroglycerincitrate-ethanol (NiCE) ACLS optimized for clinical assessment was developed by reducing the nitroglycerin and citrate concentrations and increasing the ethanol concentration. Biofilm-eradicating activity was sustained when the ethanol concentration was increased from 20 to 22% which fully compensated for reducing the citrate concentration from 7% to 4% as well as the nitroglycerin concentration from 0.01% to 0.0015% or 0. C entral line-associated bloodstream infections (CLABSIs) pose a significant public health problem in the United States. More than 7 million patients require central venous access each year, resulting in an estimated 250,000 CLABSIs, approximately 30,000 attributable deaths (1), and substantial treatment costs of at least $45,000 per infection (2). The majority of CLABSIs occur in chronically catheterized patients, such as cancer, hemodialysis, or critical care patients. Long-term catheters, such as central venous catheters (CVCs), peripherally inserted central catheters (PICCs), ports, and dialysis catheters, are susceptible to internal colonization of the catheter lumens due to repeated catheter manipulation and infusions. Biofilm formation on the catheter surfaces can serve as the primary source of CLABSI and can be highly resistant to eradication by systemic antibiotic therapy. Several bundled measures have been proposed for both treatment and prevention of CLABSIs, most of which center around reducing and preventing colonization at the skin insertion site or at connections (3). While bundles have been shown to decrease the risk of CLABSI in short-term CVCs (Ͻ30 days of dwell time), approximately 90% of CLABSIs in longer-term catheters are luminally sourced (4, 5). While antimicrobial coatings exist that do cover luminal surfaces, the duration of protection is limited to only a few weeks (6). Because disinfecting antimicrobial catheter lock solutions (ACLSs) can be repetitively instilled, they have emerged as another approach to prevent luminally sourced CLABSIs.Antimicrobial lock therapy solutions for preventing CLABSI have been reported to include prophylactic applications of antibiotics, antifungals, or antiseptics such as ethanol (EtOH) (7,8). The development of microbial resistance is of great concern with prophylactic antibiotic ACLSs (9). Alternatively, high-concentration antiseptic ethanol ACLSs have been studied. An ACLS consisting of 70% ethanol was not effective in decreasing intraluminal CLABSI and was associated with adverse events such as dizziness (10). Ethanol ACLSs with concentrations of greater than 30% have also been associated with clotting, transient dizziness, and compromising catheter integrity in polyurethane catheters (11). Use of ethanol locks with ethanol concentrations greater than 28% has been further advised ...

A Novel Nonantibiotic Nitroglycerin-Based Catheter Lock Solution for Prevention of Intraluminal Central Venous Catheter Infections in Cancer Patients

“…These data are consistent with our previous data showing anticoagulant activity of NiCE equivalent to that of heparin, with the distinction of better antimicrobial activity with NiCE (17). This activity is related to the role that each component of NiCE plays.…”

“…Furthermore, this combination was found to be superior to taurolidine in eradicating resistant organisms such as vancomycin-intermediate Staphylococcus aureus (VISA) and Candida glabrata (17). Hence, the clinical results of this study demonstrating that NiCE completely prevented the occurrence of CLABSI are consistent with the high efficacy of NiCE demonstrated in our in vitro model in completely eradicating these organisms in a biofilm colonization model within 2 h (17).…”

“…Our group was the first to show that subpharmacological concentrations of nitroglycerin (NTG) are synergistic with 4% citrate and 22% ethanol. This triple-combination NiCE lock, which is a combination of subpharmacological concentrations of FDAapproved injectable agents, is capable of eradicating all resistant bacteria in addition to various Candida species in biofilms (17,18).…”

“…Recent in vitro studies of a nonantibiotic, heparin-free solution containing nitroglycerin (NTG) in combination with ethanol and citrate demonstrated a broad spectrum of antimicrobial efficacy and an ability to eradicate biofilm formation as well as an anticoagulant activity similar to that of heparin (17,18).…”

Nephrologists Hate the Dialysis Catheters: A Systemic Review of Dialysis Catheter Associated Infective Endocarditis

“…The suggested measures include antibiotic lock therapy with varying concentrations of solutions like antibiotics [9], ethanol [10], and nitroglycerin [10]. The consensus is to remove the infected line unless an extenuating circumstance prevents removing the line.…”