Title: PREVenting infection using Antibiotic Impregnated Long lines (PREVAIL)
Funder: Department of Health and Social Care

Abstract: OVERALL AIM: To determine whether antimicrobial and antifungal impregnated peripherally inserted central venous catheters (AM-PICC) should be introduced across the NHS for very preterm babies. I) RANDOMISED CONTROLLED TRIAL PRIMARY RESEARCH QUESTION: In very preterm babies who require a peripherally inserted central venous catheter (PICC), does antimicrobial and antifungal impregnation of the PICC reduce the time to blood stream infection (BSI)? DESIGN AND SETTING: The study will be a pragmatic, unblinded, 2-arm randomised controlled trial to determine the effectiveness, resource use and cost of antimicrobial (rifampicin) and antifungal (miconazole) impregnated PICC (AM-PICC) compared with standard PICC (S-PICC) for reducing BSI. The setting will be neonatal intensive care units (NICU). TARGET POPULATION: New-born babies who require the narrowest PICC (Premicath 1 French gauge). Premicaths are designed for babies <1kg and almost all participants will be very preterm (<32 weeks of gestation). TECHNOLOGY: Systematic reviews of different types of line impregnation report that antimicrobial-impregnation is one of the most effective options for preventing BSI [1]. No published trials of antimicrobial impregnation have included children and a recently completed trial in paediatric intensive care (CATCH – trial number 08/13/47) is confined to larger minocycline-rifampicin catheters (French gauge 4/5) suitable for larger children. A further trial is needed in preterm babies because the magnitude and mechanism of effect and outcomes differ from previously studied patient groups. First, NICUs have one of the highest rates of BSI of any patient group because preterm babies have immature immunity and skin defences which allow normally benign skin organisms to track internally and externally along the catheter from the insertion site [2]. Second, parenteral nutrition infused in a substantial proportion of babies with PICC increases organism adherence and the development of BSI [3, 4]. Third, the lumens of the lines are far narrower (1 Fr compared with 4/5 Fr in children in CATCH), which may affect bacterial adherence and reduce potential benefits of impregnation. Fourth, the combination of rifampicin and an antifungal – miconazole - has not previously been evaluated in any comparable patient group on in children for efficacy against BSI or emergence of resistant organisms [5, 6]. The occurrence of BSI in very preterm babies is associated with a higher mortality than in more mature children and survivors are at increased risk of long-term neurological impairment, even when BSI is due to skin organisms [7]. We will compare AM-PICC compared with S-PICC (both polyurethane and manufactured by Vygon). Despite availability of a fully licensed AM-PICC, no NICUs in the UK are using this product. This appears to be because of the lack of evidence for benefits in preterm neonates, concerns about antimicrobial resistance, and the additional costs of impregnated PICC. The S-PICC (Premicath) is the most widely used PICC in UK NICUs. Blinding is not possible because brown staining of AM-PICC due to rifampicin cannot be obscured during insertion or whilst in situ. PRIMARY OUTCOMES: Time to BSI based on positive blood culture (including fungal BSI) taken between 24 hours after PICC insertion until 48 hours after removal [8]. A sensitivity analyses for severity will only include positive cultures for skin organisms (e.g. coagulase staphylococci - CONS) if the baby is treated for more than 72 hours with intravenous antimicrobials or dies during treatment. Blood cultures will be taken when clinically indicated according to standard practice. No additional blood will be required. SECONDARY OUTCOMES: Rifampicin resistance in isolates from blood cultures or PICC tips; rate of death before discharge; measures of BSI (rate per 1000 PICC-days, proportion of babies with 1 or more BSI, rate of catheter-related BSI), blood culture frequency; days of antimicrobial exposure; respiratory support or oxygen dependency at 36 weeks postmenstrual age; necrotizing enterocolitis (NEC); time to full milk feeds; duration of parenteral nutrition; time to PICC removal and healthcare resource use and costs up to 6 months post randomisation. Organisms isolated from blood and PICC tips will be routinely tested at local laboratories for rifampicin resistance. Isolates will be retained for further molecular characteristics to track possible transmission events. SAMPLE SIZE: When the sample size in each group is 408, with a total number of BSI required of 79, a 0.050 level two-sided log-rank test for equality of survival curves will have 90% power to detect the difference between a proportion of 0.14 and a proportion of 0.07 (a constant hazard ratio of 2.078). Allowing for a 5% loss to follow-up, a total of 858 participants are required. II) GENERALISABILITY ANALYSES In parallel to the trial, we will conduct analyses of national observational administrative NICU data and infection surveillance data to take into account declining rates of hospital-acquired BSI when generalising the trial findings to benefits for the NHS. Research question: What would the expected rate difference be across NHS NICUs if trial findings are generalised? We will link national neonatal unit administrative data with national BSI surveillance data to determine the expected BSI rate for babies eligible for PICC. These analyses will take into account effects of study involvement on BSI rate and variation between NICUs. Linkage algorithms will enable updating of this national dataset for monitoring BSI trends across NICUs in the NHS and for targeting and monitoring implementation of AM-PICC (if shown to be effective) at specific NICUs. III) COST-EFFECTIVENESS ANALYSES Research questions: What is the cost to the NHS of a BSI in very preterm babies? What is the cost-effectiveness (of AM-PICC vs S-PICC in terms of NHS costs and health benefits in the form of quality adjusted life years - QALYs) over the patient’s expected lifetime based on actual healthcare costs up to 6 months post randomisation and predicted health and social care costs consequent on outcomes? What is the value of further information quantifying the long-term effects of AM-PICC on measures of neurological impairment and mortality up to school age?

Lay abstract: Many babies admitted to intensive care need fluids and medicines given to them through their veins. These are often given through a peripherally inserted central catheter (PICC). A PICC is a very narrow tube placed through the skin of the arm or leg and into a central vein. These lines can stay in place for several weeks, avoiding the need for repeated procedures. The disadvantage of PICC is that infections can develop due to bacteria sticking onto the inside or outside of the tube. These infections can spread making the baby very ill. Affected babies need antimicrobial treatment and often have to stay longer in intensive care. Although infections caused by PICC are uncommon, the long-term consequences of these infections in small babies can be very serious, including damage to the brain and even resulting in death. In adults, it has been shown that when the PICC is coated with an antimicrobial that kills bacteria, the risk of infection can be reduced. A trial is currently investigating antimicrobial lines in children, but no research has been done in preterm new-born babies to find whether antimicrobial PICC are better at preventing infection than the standard PICC that are currently used everywhere in the UK. There are important differences between children and preterm babies that mean that antimicrobial PICC might work differently. First, preterm babies’ veins are much smaller and the PICC is narrower. Second, PICC are often kept in place for much longer (the risk of infection increases over the time a PICC is in place). Third, infections happen more often in preterm babies, as their immune systems and immature skin are not as good at preventing infection. Fourth, the combination of antimicrobials used is different to those tested in studies in children and adults. Finally, the consequences of infection in preterm babies are different and more serious than in older children. The antimicrobial PICC in this study has been licensed for use in babies and, apart from brown coloured tubing, looks exactly the same as PICC used throughout the UK. The antimicrobials are impregnated into the plastic, resulting in high levels of antimicrobials very close to the line, but very low levels in blood. The antimicrobial PICC could reduce serious illness and deaths in preterm babies. Although antimicrobial PICC are more expensive than standard PICC, the NHS may actually save money by preventing infection and all of its related problems. We will also assess whether antimicrobial PICC cause growth of resistant organisms. The only way to accurately test the antimicrobial PICC is to run a comparison with standard PICC. In such a trial, a baby will receive one or other PICC by chance allocation, as though by tossing a coin (known as a randomised controlled trial). 18 neonatal units will take part and 858 babies will participate over 2 years. If a baby in one of these units needs a PICC, they will have a 50-50 chance of being given a standard PICC or an antimicrobial PICC. The study will follow up babies using routine records and will use infection results from samples that need to be taken as part of the baby’s routine clinical care. No additional samples will be taken. The study will be discussed with the parent/legal guardian and the baby will only join if parents agree to participate before the PICC is placed. This trial will help us find out whether antimicrobial PICC can help avoid the serious effects of infection in vulnerable babies.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION