Minocycline-EDTA-Ethanol Antimicrobial Catheter Lock Solution Is Highly Effective In Vitro for Eradication of Candida auris Biofilms

INTRODUCTION

The salvage of central lines in the setting of central-line-associated bloodstream infection (CLABSI) can be highly beneficial to patients that require continued vascular access for their medical care. The exchange of catheters at the same insertion site over guidewires in this setting frequently leads to recontamination of the new line and recurrence of the CLABSI. Another alternative is insertion of a fresh catheter at a new insertion site. This may be undesirable for cancer patients and other critically ill patients, because it subjects these patients to anxiety, particularly, for patients with coagulopathies or other adverse events (1).

Candida auris infections have steadily increased in prevalence since first identified in 2009, are frequently resistant to azoles and other classes of systemic antifungals (2), are readily spread through environmental exposure, and have been associated with high mortalities (3, 4). Consequently, catheter lock solutions suitable for salvaging central lines for patients requiring continued vascular access in the setting of C. auris candidemia is desirable.

Two broad-spectrum antimicrobial catheter lock solutions have recently been clinically evaluated for the salvage of vascular catheters in the setting of CLABSI. Saunders et al. evaluated catheter salvage in parenteral nutrition patients using a taurolidine catheter lock solution (5), and Chaftari et al. evaluated catheter salvage in cancer patients using a minocycline-EDTA-ethanol (MEE) catheter lock solution (6). In this in vitro study, we compared the efficacy of these two catheter lock solutions for eradicating biofilms of 10 different strains of C. auris.

Ten strains (AR 0381 to AR 0390) of Candida auris were obtained from the Centers for Disease Control and Prevention (CDC) Antibiotic Resistance Isolate Bank (ARIsolateBank). All isolates have been well characterized by susceptibilities and sequencing (7). Assessments of lock solutions were with a well-established in vitro biofilm eradication model (8, 9). Briefly, silicone discs colonized with 24-h biofilms were exposed to each lock for 60 min. Discs were then sonicated in saline to disrupt biofilms, and all sonicates were quantitatively cultured to assess any remaining viable organisms. Six replicates were run for each test group for each C. auris strain. Pairwise comparisons, using the Mann-Whitney U test, compared MEE with positive controls and taurolidine lock. All tests were two-sided and were considered significant at P values of <0.05. MEE consisted of 0.1% minocycline hydrochloride (Minocin; The Medicines Company, Parsippany, NJ), 3% EDTA (Letco Medical, Decatur, AL), and 25% ethanol (Akorn, Lake Forest, IL). The taurolidine catheter lock solution (TCH) consisted of 1.35% taurolidine (Enzo Life Sciences, Farmingdale, NY), 3.5% disodium citrate (Sigma-Aldrich, St. Louis, MO) and 1,000 IU/ml heparin (Sagent, Schaumburg, IL).

The medians and ranges for recoveries of viable organisms after lock exposure from the 10 C. auris biofilms are presented in Fig. 1. For all C. auris strains, robust biofilms formed for the positive controls. MEE was able to fully eradicate all 10 strains of C. auris biofilms following 60 min of exposure (P = 0.002 compared to control). TCH reduced the concentrations of viable C. auris organisms in all 10 biofilms but was unable to fully eradicate any of the biofilms. The superiority of MEE over TCH was statistically significant for each C. auris strain (P = 0.002).

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FIG 1

Biofilm eradication of Candida auris biofilms after exposure to lock solution. A total of 10 strains of C. auris biofilms were exposed to minocycline plus EDTA plus ethanol (MEE) or taurolidine plus citrate plus heparin (TCH) for 60 min. Quantitative recoveries of viable organisms still remaining in the biofilms were performed. Medians and ranges of the recovered viable organisms for each strain for each treatment group are reported (6 replicates for each group for each strain). MEE fully eradicated all 10 strains of C. auris and was significantly more efficacious than TCH (P = 0.002) for all strains.

Potent complete eradication of biofilms on catheters can help prevent relapses of candidemia from biofilms that retain viable pathogens. Taurolidine is reported to exhibit antimicrobial activity by attacking bacterial and fungal cell wall constituents (10). In a study of parenteral nutrition patients (5), catheter salvage was attempted in patients that had no prior taurolidine catheter lock use as well as in those that experienced breakthrough infections while using taurolidine catheter lock solutions. Salvage was successful in 45% of the pre-taurolidine-use cases and 33% of post-taurolidine-use cases. There were fungemias in both the pre- and post-taurolidine-use groups. In an in vitro study of potency of taurolidine against multiple Candida albicans strains, the MIC₅₀ was found to be 2,048 mg/liter, reflecting weak potency (11). These outcomes are consistent with our findings of partial effectiveness of taurolidine catheter lock solution against all of the C. auris strains tested.

In a previous clinical catheter salvage study, MEE was 100% clinically effective in salvaging central lines for cancer patients with bacterial CLABSIs (6). In vitro studies showed this combination to be synergistically effective against other Candida species (12). Here, we found the MEE combination was also highly effective in eradicating Candida auris biofilms, with significant superiority over taurolidine. Clinical verification of the effectiveness of MEE for salvaging central lines in the setting of C. auris candidemias is warranted.