Background Parenteral nutrition (PN) is an intravenous (IV) therapy that provides all nutrients required when a patient requires supplementary feeding due to problems with the gastrointestinal tract. It may or may not contain intravenous fat emulsions (IVFE). PN needs to be administered via a large vein, through a central venous access device (CVAD), as the osmolarity of the infusate would damage smaller veins. PN is delivered as a continuous infusion through tubing called an intravenous administration set (IVAS) which connects to the CVAD. Although PN is a life-saving therapy, it can be associated with adverse events, particularly bloodstream infections (BSI) associated with the CVAD, which have a substantial morbidity and mortality impact. Infection control precautions for CVADs and IVASs used to deliver PN containing IVFE are more rigid than for solutions not containing IVFE. Guidelines recommend replacing the IVAS and bag containing PN with IVFE every 24 hours and that PN be administered on a dedicated lumen, whereas solutions not containing IVFE need to be replaced every four to seven days and infusions can be delivered simultaneously through the same lumen unless there are compatibility issues. It is recognised by the infection control, vascular access and PN guidelines that these recommendations for PN containing IVFE are based on low levels of evidence. Aims and objectives The overarching aim of this research was to assess the influence of PN on microorganism growth and infection risk in patients with a CVAD. There were three objectives to guide the three research phases: (1) to measure and compare the growth of microorganisms commonly associated with catheter-related infection (CRI) in a variety of PN and non-PN (control) solutions; (2) to develop a dynamic laboratory model of IVAS that simulated the clinical environment and investigated the effect of duration of IVAS use for PN containing IVFE on microorganism growth; and (3) to explore associations between PN containing IVFE and solutions not containing IVFE, CVAD and IVAS practices, and patient risk factors with CRI outcomes in a clinical population. Methods This research was guided by the Cancer Institute New South Wales (NSW) Model of Translational Research: a bench-to-bedside approach, which enabled a mixed methods design to be employed to address the aims and objectives in the three phases using in vitro, ex vivo/simulation and secondary analysis of a large dataset from a randomised controlled trial (RCT). Two systematic reviews were undertaken, the first of which compared the rates of catheter-related bloodstream infections (CRBSIs) in patients with CVADs who received PN versus those who did not receive PN, and described the microorganisms that colonised the blood and CVADs in both groups. The second systematic review reported the comparative rates of CRBSI in patients with CVADs who received PN on a dedicated lumen compared to those who had PN administered through a multi-lumen CVAD. In Phase 1, laboratory experiments compared the growth of several microorganisms known to cause CRIs in a controlled environment in a variety of PN and non-PN solutions. In Phase 2, an IVAS laboratory simulation model was developed and tested to investigate the safety of extending the duration of IVAS use up to seven days. Finally, in Phase 3, a secondary analysis of a large dataset from an RCT involving 807 patients with CVADs in a tertiary hospital compared infection outcomes for the 180 (22%) patients who received PN containing IVFE with those who did not. Results Systematic reviews The first review concluded that the data published to date were not sufficient to establish whether patients who receive PN are more at risk of developing CRBSI than those who do not. The second review suggested that there was no difference in rates of CRBSI when PN is administered through a dedicated lumen or a multi-lumen catheter. The results of these systematic reviews critiqued and synthesised knowledge to date and confirmed that the topic warranted further investigation. Phase 1 The Phase 1 results showed that the five microorganisms tested were able to replicate in nine out of the 10 solutions tested, which represented components and combinations of PN and non-PN control solutions. All microorganisms tested, except for Staphylococcus aureus, were non-viable in 50% glucose. Candida albicans has the potential to double in all the solutions tested within 24 hours, with the exception of 50% glucose, where cell death occurred within four hours, and 0.9% sodium chloride, where there was a 1.5-fold increase. C. albicans demonstrated a 30-fold growth increase in all in-one PN when compared to the inoculum at 24 hours. Similarly, Synthamin with electrolytes showed a 20-fold growth at 24 hours. The observation that Synthamin with electrolytes and 50% glucose, which had a 9-fold increase, did not show similar growth supports the role that 50% glucose plays in inhibiting microorganism growth. In contrast to these findings, none of the species showed greater than a 2-fold growth over the inoculum when grown in all-in-one PN. However, for S. aureus, and Pseudomonas aeruginosa, 4-fold growth at 24 hours was observed in IVFE. Phase 1 confirmed that most IV solutions have the potential to support the growth of microorganisms after being contaminated, although, generally, the microorganisms tested reproduced more rapidly in all-in-one PN and IVFE. Phase 2 As in Phase 1, the IVAS model developed in Phase 2 identified differences in the effect of PN containing IVFE and other IV solutions on microorganism growth. The IVAS model simulated seven days continuous administration of all-in-one PN, IVFE and 0.9% sodium chloride. C. albicans was consistently recovered 48 hours after inoculation in both the all-in-one PN and IVFE experiments. C. albicans did not reproduce effectively in 0.9% sodium chloride in the IVAS model. S. aureus survived only in IVFE up to three days. S. epidermidis did not survive in the IVAS model in any fluid. These results suggest that this model is effective for investigating C. albicans touch contamination and can now be used to test the effect of different plastics, IVAS components or solutions on C. albicans survival in the setting. However, modification will be required to assess other microorganisms. In this study, we deliberately chose microorganism contamination rates that are likely to occur in hospitals. Clearly this was too low for consistent recovery. To be useable, the number of these bacteria used to seed the model for these organisms will need to be increased. Phase 3 Of the 807 patients studied, three-quarters (589/807; 73%) were recruited from the haematology and haematopoietic stem cell transplant unit, followed by surgical (90/807; 11%), trauma and burns (61/807; 8%), medical (44/807; 5%) and oncology (23/807; 3%). More primary BSIs occurred in the IVFE group (46/180; 26%) than in the no-IVFE group (98/627; 16%). However, when primary BSI was assigned as either a central lineassociated bloodstream infection (CLABSI) or a mucosal barrier injury laboratoryconfirmed bloodstream infection (MBI-LCBI), the incidence of CLABSI was similar in IVFE and no-IVFE patient groups (15/180; 8% IVFE vs 57/627; 9% no-IVFE; p = 0.88). Expressed as rates per 1,000 CVAD days, this was 5.21 (no-IVFE) and 3.25 (IVFE) (incidence rate ratio [IRR] 0.62; 95% CI 0.33 to 1.12; p = 0.097). Kaplan-Meier curves showed survival from CLABSI was significantly superior in the IVFE group (log rank p = 0.011). The incidence of MBI-LCBI was significantly different between groups (7% no-IVFE; 17% IVFE, p < 0.001), occurring at 3.74 and 6.72 per 1,000 CVAD-days no- IVFE and IVFE groups respectively (IRR 1.79; 95% CI 1.09 to 2.93; p = 0.016). Survival from MBI-LCBI was not significantly different between groups (log rank p = 0.614). Conclusion Phase 1 provided important data that established that most IV solutions, the exception being 50% glucose, have the potential to support the growth of microorganisms after being contaminated, although, generally, the microorganisms tested reproduced more rapidly in all-in-one PN and IVFE. Phase 2 developed an IVAS model that simulated seven days continuous administration of all-in-one PN, IVFE and 0.9% sodium chloride. As with the results of Phase 1, C. albicans was consistently recovered after inoculation in both the all-in-one PN and IVFE experiments. None of the microorganisms reproduced effectively in 0.9% sodium chloride in the IVAS model. This finding supports daily IVAS replacement for PN containing IVFE as recommended by clinical practice guidelines. However, less than 2% (3/180) of positive blood cultures in Phase 3 were caused by Candida. Additionally, the Phase 3 findings provide compelling and previously unrecognised evidence that patients receiving PN containing IVFE are not at increased risk of CLABSI compared to patients not receiving PN. In fact, once MBI-LCBI cases were removed and survival analysis was performed, CLABSI was significantly lower in the PN containing IVFE group. This finding is incongruent with previous research suggesting PN is an independent risk factor for CRIs. This study classified primary BSIs as either CLABSI or MBI-LCBI. This research is the first to explore the effect of the MBI-LCBI classification by grouping patients into those who received PN containing IVFE and those who did not. This thesis has made an important contribution in uncovering and understanding the role of haematogenous seeding from the gastrointestinal tract in the pathogenesis of CRI in patients receiving PN containing IVFE.