A tolerability and patient acceptability pilot study of a novel antimicrobial urinary catheter for long‐term use

We have developed a novel antimicrobial urinary catheter (AUC) impregnated with rifampicin, triclosan, and sparfloxacin and demonstrated that it has long‐term (∼84 days) protection against bacterial colonization in vitro. This study aimed to assess the safety and patient acceptability of this device in long‐term catheter users.

received the nitrofurantoin-coated catheter experienced greater discomfort than with the control catheter. 2 Therefore, there is no commercially available anti-CAUTI technology for those who require catheterisation for over 28 days.
We have previously developed a silicone urinary catheters impregnated, not coated, with rifampicin, sparfloxacin, and triclosan and demonstrated seven to 12 weeks of protective activity against colonization by major uropathogens, including multi-drug resistant strains. 3 The long-term duration of activity is conferred by the migration of the antimicrobials through the silicone to the intraluminal, extraluminal and balloon surfaces. Particularly, in light of the discomfort experienced with the nitrofurantoin-coated catheter, this study aims to understand primarily the tolerability of this novel antimicrobial urinary catheter (AUC) in the target patient population. Specifically, this was determined by the rate of adverse events (AEs) attributable to the antimicrobials or the antimicrobial impregnation process. Other secondary outcomes included patient acceptability, trial withdrawal, severity of AEs, time to occurrence of AEs, microbial colonization of the AUC. The trial was not intended to determine efficacy in reducing CAUTI, but instead to determine in human participants for the first time, the tolerability and acceptability of a novel antimicrobialimpregnated catheter for long-term use.

| Patient and public involvement
Lay members who were either long term catheter users or carers were recruited to a research management committee to meet several times yearly to review the trial protocol, trial progress, and trial results. All travel expenses were covered and lay members received payment for attendance.

| Manufacture of trial devices
Two-hundred and five all-silicone, two-way urinary catheters in sizes 12-20Ch standard and female lengths were impregnated according to a previously published method. [3][4][5] Briefly, with any plastic ports and connectors removed, and catheters were immersed in a chloroform solution containing 0.2% w/v rifampicin (Sigma-Aldrich, St. Louis, MO), 1.0% w/v triclosan (Irgacare MP, BASF) and 1.0% sparfloxacin (Sigma-Aldrich) for 1 h. The catheters were removed and the chloroform was left to evaporate off under constant air flow for at least 12 h. Surface residues were removed by rinsing in ethanol and the catheters left to dry. The catheters were packaged in individual plastic sleeves within Tyvek packaging with a clear front and opaque back. The catheters were sterilized by ethylene oxide and removal of ethylene oxide residuals was verified by gas chromatography by a Varian gas chromatograph using a 10 volt detector and 1 µL injection volume.
Chloroform removal was verified by gas-chromatography-mass spectrometry in which catheter segments were immersed in acetone to extract the chloroform. Analysis was carried out using a JEOL AccuTOF GCX (Jeol Ltd., Tokyo, Japan) mass spectrometer and an Agilent 7890B (Agilent Technologies Inc., Berkshire, UK) gas chromatograph. An extended ion current trace at 82.9 mass to charge ratio (m/z) was used to detect chlorine isotopes.
High-performance liquid chromatography (HPLC) was employed to verify antimicrobial contents of the manufactured trial catheters. Please see Supporting Information Method S1 for the full method of drug content analysis. Briefly, the antimicrobials were extracted in chloroform, resolubilized in methanol, and analyzed by an Agilent 1100 HPLC machine with a variable wavelength UV detection (Agilent Technologies Inc).

| Participants and setting
Adults (age 16 years or greater) who were catheterized with a long-term indwelling urinary catheter and who required another long-term indwelling urinary catheter were initially considered for inclusion. Please see Table 1 for the full inclusion and exclusion criteria. Participants were recruited from the community and hospital settings through letters of invitation and screening as participants came through Urology clinics

| Study design
This single-centre, non-randomized trial with the aim of evaluating the safety of a CE-marked medical device with modifications was carried out between November, 2016 and February, 2018. Eligible participants who provided informed consent were catheterized with the AUC (trial catheter) at their next scheduled catheter change date. They were catheterized with the AUC for their normal catheterization length, which ranged from 28 to 84 days. Participants were interviewed by telephone at 24, 48, and 72 h post-catheterization and then once weekly for the rest of the trial duration. The original catheter and trial catheter were collected upon removal for laboratory analysis.
The primary outcome measure was the rate of adverse events (AE) attributable to the antimicrobials or the impregnation process. All AEs were recorded in the case report and a score of severity and a score of relatedness to the AUC was given to each adverse event by the research nurse and adjudicated by the principal investigator. AEs were detected by patient self-reporting during the telephone interview and followed up by a review of the patient's notes. Relationship causality was classified as unrelated, unlikely, possible, probable, or definite according to the algorithm given by the World Health Organization. 6 Further classification grouped AEs as non-serious or serious. An AE was classified as serious (SAE) if it was fatal, life threatening, resulted in hospitalization or prolonged hospitalization or resulted in persistent or significant disability or incapacity.
Secondary outcome measures included time to occurrence of adverse events, patient acceptability which was captured by the telephone interviews, whether the trial device was removed before the planned end date of the trial (trial withdrawal), and microorganism colonization of trial and original catheters.

| Laboratory analysis of removed catheters
Catheters were analyzed within 24 h of removal. The balloon was separated from the lumen using a sterile scalpel and placed into a sterile Universal container and covered with phosphate buffered saline (PBS). The remaining ports on the catheter were also removed with a sterile scalpel and discarded. The remaining luminal tubing was filled with 1-2 mL of PBS, clamped using sterile, straight-jawed surgical clamps, and placed in a sterile container. The balloon and lumen components were sonicated for 5 min at 30 kHz to detach the bacteria into the surrounding PBS. The luminal tubing ends were cleaned with an alcoholic pre-injection swab and the lumen sonicate was drained into a sterile Bijou bottle (Sterilin). The balloon and lumen sonicates were plated onto cysteine-lactose electrolyte-deficient medium (Oxoid), and incubated overnight at 37°C. If culture-positive, the colonies were quantified and general microbiological identification performed. If culture-negative the plates were incubated for a further 24 h.

| Statistical analysis
Data were analyzed and graphs were prepared using Graph-Pad Prism 7.01 (GraphPad Software Inc., LaJolla CA).

| Participant demographics
Thirty participants were recruited and were catheterized with the AUC. Please see Figure 1 for a STROBE flow diagram of recruitment and participation. The majority of participants were male and except for one patient were catheterized urethrally ( Table 2). The mean duration of catheterization with the trial catheter was 56.03 days with a range of 1-84 days. There were a total of 1681 days of participants catheterized with the AUC.

| Primary outcome: Safety
Eighty-four adverse events were reported by participants (0-11 AEs per participant). The majority (72.62%) of AEs were "unrelated" or "unlikely" to be related to the antimicrobial impregnation process. The AEs considered to be "possibly" related to the AUC (26.19%) included blockage of the Significantly impaired sensation of the bladder and/or urethra catheter, CAUTI episodes, and stinging after catheterization as these are AEs associated with all urinary catheterization ( Table 3). The exception to this was one participant who experienced increased stinging following catheterization that the participant had not experienced with previous catheters. This AE was classified as "probably" related to antimicrobial impregnation of the catheters due to the noticeable difference between the AUC and the normal catheters. The stinging subsided within 48 h and the participant then went on to consider the AUC no different from their normal catheter. Patient medical history was recorded at baseline and eight participants had a history of frequent CAUTIs. Four participants each experienced one CAUTI while using the AUC. This provided a preliminary indication as to the potential efficacy of the AUC, but will need further systematic investigation.

| Secondary outcome: Severity of AEs
None of the AEs with any relationship to antimicrobial impregnation of the catheters was considered serious or severe as seen in Table 3. All SAEs were determined to be "unrelated" to antimicrobial impregnation of the urinary catheters. The participants were not withdrawn from the trial as a result of the SAEs and there were no restrictions on treatments received.

| Secondary outcome: time to occurrence of AEs
There was no difference between time to AE in the AE causality relationship groups (P = 0.5252. Log rank test).

| Secondary outcome: Patient acceptability
A total of 82.14% of participants rated the AUC as no different or better than their previous catheters and 89.3% of participants reported the same amount of pain or less pain from the AUC at the last recorded interview (Table 4).
A full thematic analysis of the free responses can be found as Supporting Information Table S1. At the last interview, three patients reported reduced infections, six commented on increased comfort, three wanted to keep the AUC for longer, and two wanted to have a second AUC. Impacts on mental health included getting better quality of sleep due to less need to empty the bladder via a valve and increased confidence in their catheter not becoming infected.

| Secondary outcome: Trial withdrawal
Nine of the 30 participants ended the trial earlier than expected. Seven were withdrawn because of catheter expulsion, a burst balloon, or balloon deflation. Bladder stones were confirmed for the patient who had a burst balloon. One catheter was changed by a district nurse due to concerns that it may have been pulled out of position. The remaining two participants voluntarily ended the trial early, both due to what they felt was a shorter catheter length. However, both had received standard length catheters, which were 400 mm in length. No catheters were removed over safety concerns.

| Secondary outcome: Colonization of original and trial catheters
Twenty-nine of the 30 original and 28 of the 30 AUCs were collected. The three lost catheters fell out in the community and could not be retrieved. The original catheters and AUCs were matched (n = 27 pairs) and there were significantly fewer (P = 0.0088, two-tailed t-test) species of microorganisms attached to the AUC balloons compared to the matched control catheter. The pairs were well matched for the duration of catheterization (P = 0.8428, two-tailed t-test).
The lumens of two trial catheters were culture-negative and no lumens of original catheters were culture-negative.
One possible concern at the start of the study was that eradication of organisms sensitive to the activity of the AUC would allow replacement by other organisms. However, this was not seen in the catheter analyses. For example, E. faecalis is not sensitive to the activity of the AUC yet there was no overgrowth of E. faecalis in the AUCs. In fact, five fewer AUC balloons and two fewer lumens contained E. faecalis compared to the control catheters. In general, the presence of all groups of organisms was reduced in the AUCs, with the exception of Pseudmonas spp. in which there were two more AUC lumens colonized with Pseudomonas spp. compared to the control catheters. The main limitation of this analysis is that the numbers are small and future studies will be needed to monitor the colonizing microorganism populations. It is important to emphasize that, though reduction in CAUTI was mentioned by three participants in the free comments (Supporting Information Table S1), this trial was not designed to quantify efficacy.

| DISCUSSION
Antimicrobial urinary catheters were produced and validated for use in this study, which is the first human trial of this device. 84 AEs in 30 participants across 1681 catheterization days were recorded, and of those only one was identified as being "probably" related to antimicrobial impregnation. This event was worse stinging than usual at catheterization and it resolved within 48 h. The safety profile of the AUC appears favorable. Patient acceptability was positive with 82% of participants rating the AUC as "no different" or better than their previous urinary catheters. Of the remaining 18% (5 participants) responding "a bit worse," two felt that their trial catheter was too short, despite it being of identical length to their standard catheter; one changed the type of drainage device and experienced disconnections; one experienced increased urinary urgency, and one experienced pain on passing urine using a catheter valve.
Microbiological analysis of the participant's original and trial catheters demonstrated a significant reduction of the number of species attached to the balloon of the AUCs. Importantly, the use of the AUC did not increase the prevalence of MDR organisms or increase the prevalence of microorganisms that are non-susceptible to the activity of the AUC.
The CATHETER trial was a multi-centre randomized controlled trial of anti-septic (silver-alloy and nitrofurazone coated) catheters for short-term use. Patients receiving experimental catheters reported increased discomfort following catheterization (silver catheter 28.7%, nitrofural catheter 38.9%) and this was a motivation for our obtaining data on safety and patient acceptability before undertaking larger studies. Our findings regarding comfort and acceptability compared very favorably with these. Haematuria and septicaemia were two recorded significant clinical events included in the CATHETER trial. 7 Haematuria and blockage of the catheter due to a blood clot were recorded during this trial, but there were alternative reasons for the presence of blood such as taking aspirin and the presence of an enlarged prostate which is a recognized cause of haematuria. 8 During adjudication of AE causality, as haematuria was not present without other predisposing factors and was no worse than previous episodes, the episodes were determined as "possibly" related as it is related to catheterization but not necessarily catheterization with the AUC. The ESCALE trial, a trial of silver-alloy catheters in spinal cord injury patients, reported more AEs possibly  related to catheterization with the experimental catheters compared to standard catheters, including itching which was not reported in the control group. 9 Other AEs captured by the ESCALE trial included haematuria, rash, blockage, and suprapubic pain. 9 Rash related to catheterization and suprapubic pain were not reported by patients in our AUC safety trial. Blockage was reported during this trial. Other unique AEs reported here included the sensation of needing to void, burning at the beginning and end of passing urine using a catheter valve, difficulty connecting the catheter bag to the catheter, and the catheter drainage system "pushing off" the catheter connection. While these were mild events and mostly associated with the catheter drainage systems, they were still reported by participants as part of their catheter management. The base silicone urinary catheters that were impregnated with antimicrobials may have been from a different manufacturer than their normal catheter, which could have affected what the catheter user perceives as "normal" for their catheter.
Although the follow-up was short, any AEs relating to the composition of the catheter material are likely to have manifested in the time period studied. Further studies will confirm long-term tolerability as well as clinical efficacy and will benefit from a control arm for comparison. Other limitations include that this was an unblinded study and this may have introduced an element of bias of the participant's in reporting. Although multi-centre trials provide a better generalisability of the results and therefore increased external validity, the participants represented many health conditions and were managed throughout several districts once catheterized with the trial catheter. Therefore, they were managed as standard according to their local policies and guidelines, which were not influenced by the clinical trial.
In this trial participants were excluded if they not did have sensation in the urethra and/or bladder as they would be unable to self-report some symptoms and also for their safety. If the AUC were to cause irritation, allergy, or discomfort both the participant and research team would be unaware. This by extension excluded patients with spinal cord injury or cauda equina syndrome. Likewise, many patients with impaired cognitive capacity may require a urinary catheter but were not eligible to participate due to the possible inability to self-report new symptoms or adhere to the telephone interview schedule. These exclusion criteria were put in place to protect patients and to preserve the accuracy of the data collected. They will be included in a further randomized controlled trial of efficacy.

| CONCLUSIONS
The AUC has an advantageous safety profile and was an acceptable alternative catheter to the majority of trial participants. Information gained from this trial will support future regulatory applications for commercialization and larger randomized controlled studies of efficacy of the AUC. 9. Bonfill X, Rigau D, Esteban-Fuertes M, et al. Efficacy and safety of urinary catheters with silver alloy coating in patients with spinal cord injury: a multicentric pragmatic randomized controlled trial. The ESCALE trial. Spine J. Nov 2017;17:1650-1657.

SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article.