Catheter Complications in Cancer Patients Receiving Parenteral Nutrition: Potential for an Effective, Non-Antibiotic, Antimicrobial Catheter Lock Solution Based on Nitroglycerin, Citrate and Ethanol as a Preventative Intervention

Abstract

Background – Patient receiving parenteral nutrition (PN) are at high risk for catheter complications including catheter related infections, catheter occlusions, and venous thrombosis. Several interventions such as antimicrobial lock therapy (ALT) have been used to prevent catheter related infections. However there are currently no ALTs approved for use in the United States, resulting in off-label use of antibiotics, antifungals, or ethanol as ALT. The aims of this dissertation are to synthesize and evaluate the rates of catheter complications, causative organisms, and risk factors in the current literate and in patients receiving PN at a tertiary cancer center. Additionally, in vitro efficacy of microbial biofilm eradication and anti-thrombogenic properties were evaluated for Nitrogylcerin + Citrate + Ethanol (NiCE) ALT. Methods – Three studies were conducted including 1) a systematic review of literature published in Medline, Embase, and CINAHAL between January 2012 to January 2017 regarding rates, risk factors, and/or prevention strategies via ALT for catheter complications among patients receiving PN; 2) a retrospective cohort study among cancer patients receiving inpatient PN between January 2013 and January 2015 at the University of Texas MD Anderson Cancer Center assessing rates of infectious complications, prevalence and time-to-infection of causative pathogens, and identify risk factors for catheter complications among all cases and a random sample of controls; and 3) an in vitro assessment of NiCE evaluating efficacy of eradication of microbial biofilm formed by pathogens commonly associated with catheter related infections. Anti-thrombogenic properties of NiCE compared to standard of care was also assessed. Results – Thirty-seven studies were included in the systematic review. Studies were grouped by definition infection including catheter-related bloodstream infection (CRBSI) and central line associated blood stream infection (CLABSI). Random effects summary rates per 1000 catheter days were 0.8 CRBSI episodes (95% CI 0.21-3.11) and 3.17 CLABSI episodes (95% CI 1.82-5.51). Use of taurolidine or ethanol ALT were efficacious in reducing infection however, several studies has concerns of adverse mechanical complications. Retrospective analyses showed a total of 46 CLABSI cases in 38 of the 1,762 patients that received PN (1.73 episodes/1000 parenteral nutrition days). Gram-positive (37.8%) and yeast (29.7%) were the most common CLABSI pathogens. Non-infectious catheter complications occurred in 38.6% (n=56) of patients included in the sample. Multivariate analysis identified age, GVHD, and history of occlusion in the same catheter, as well as intestinal failure and long-term PN use as significant risk factors for CLABSI and non-infectious complications, respectively. Finally, NiCE showed significant efficacy by complete eradication of common gram-positive, gram-negative, and yeast pathogens embedded in biofilm. When compared to taruolidine + citrate + heparin ALT, NiCE was significantly superior in eradicating both Staphylococcus aureus and Candida glabrata embedded in biofilm. NiCE also showed equivocal anti-thrombogenic properties when compared to heparin standard of care. Conclusions – Patients receiving PN are at risk for both infectious and non-infectious catheter complications. ALT shows promise for prevention of catheter complications, however risks of microbial resistance and mechanical complications make antibiotic/antifungal and ethanol lock not an ideal candidate for universal prophylaxis. Until candidate ALT with less risks is available, a better understanding of risk factors, pathogens, and source of infections will allow clinicians to weigh risks and benefits of available ALTs for targeted infection prevention in higher risk sub-populations. NiCE ALT demonstrates rapid broad-spectrum biofilm eradication as well as effective anticoagulant activity making NiCE a high-quality ALT candidate for clinical assessment