Selection of Scientific and Clinical Data Prevents biofilm formation Decreases bacteriuria and CAUTI Reduces catheter-related pain and discomfort Prevents blockages Exclusive UK Distributor for UroShield®
Table of Contents Page 1. The Effect of Surface Acoustic Waves on Bacterial Load and 2 Preventing Catheter-Associated Urinary Tract Infections (CAUTI) in Long Term Indwelling Catheters 2. The Effectiveness of UroShield in Reducing Urinary Tract Infections 3 and Patients’ Pain Complaints: Retrospective Data Analysis from Clinical Practice 3. The effectiveness of acoustic energy induced by UroShield® device 5 in the prevention of bacteriuria and the reduction of patient’s complaints related to long-term indwelling urinary catheters 4. Replacement of antibiotic therapy by UroShield® device in subjects 6 with urinary catheter following radical prostatectomy 5. The Use of the UroShield Device in Patients with Indwelling 7 Urinary Catheters 6. Biofilm Prevention By Surface Acoustic Waves: A New Approach To 8 Urinary Tract Infections – A Randomized, Double Blinded Clinical Study 7. Effect of UroShield® on pain and discomfort levels in patients released 10 from the emergency room with urinary catheter due to urine incontinence 8. Effective Prevention of Microbial Biofilm Formation on Medical Devices 11 by Low-Energy Surface Acoustic Waves 9. Surface acoustic waves increase the susceptibility of Pseudomonas 13 aeruginosa biofilms to antibiotic treatment 1
The Effect of Surface Acoustic Waves on Bacterial Load and Preventing Catheter-associated Urinary Tract Infections (CAUTI) in Long Term Indwelling Catheters Shira Markowitz, Jonathan Rosenblum, Martin Goldstein, Hrishikesh P Gadagkar and Leib Litman Medical & Surgical Urology (November 2018) The authors evaluate a novel Surface Acoustic Wave technology and its effect on preventing CAUTI. This is a double-blinded randomized clinical trial of the UroShield™ device. 55 patients, treated with long-term indwelling catheters in a skilled nursing facility in NY, USA, were evaluated. Results show significant difference between the treated group and the placebo group in the number of bacterial Colony Forming Units, as well as a decreased UTI incidence. The effect lasted beyond the time of active treatment. Study Design This randomized double blinded study, of 90 days duration, evaluates the effectiveness and safety of SAW plus standard therapy. Prior to enrollment, the patient must have had an indwelling urinary catheter in place for at least 60 days (including catheter changes). A total of 55 patients were enrolled, 29 of which were treated with SAW plus standard therapy and 26 with standard therapy alone. Study Procedure At baseline the CFUs for all groups both in the catheter and urine assessment were 100K or greater. There was thus no variability between or within groups. The sham control group’s CFU counts in both the catheter and urine assessment, remained at 100K for each subsequent assessment (30, 60, and 90 days). Compared to baseline, the treatment group showed significant improvement at 30 days. There was a statistically and clinically significant reduction in the number of CFU’s in the treatment group as compared to the control group. Mean improvement in treatment vs control was 87.2K CFU, (t (53) 18.1, p<0.001) at thirty days. At 60 days the mean improvement in treatment vs control was 87.5K CFU, (t (53) 18.1, p<0.001). At 90 days the mean improvement in treatment vs control was 79.3K CFU, (t (53) 12.4, p<0.001). After cessation of treatment in the active group at 30 days, there was a minimal increase in CFU count at both 60 and 90 days. In the same group, there was no statistical difference in the decrease of CFU count from 30 to 60 days after treatment, t (28)=1. p= .326, however there was a marginally significant increase in CFU from 60 to 90 days for the active group (28)=1.7 p= 0.09. There were no differences found between the urinary and suprapubic catheters across the three post treatment months F (1,27)=0.87, p=36. Key Outcomes At baseline, every enrolled patient had been treated for infection during the 90 days prior to enrolment. Compared to baseline, the treatment group showed significant statistical and clinical improvement (100%) at 30 days relative to the sham control (73%). There were no reported infections in the Treatment Group while in the control group there were seven reported infections. At 90 days after treatment, the treatment group showed a significantly stronger improvement (89.7%) compared to the sham control (46.2%). There were three reported infections in the treatment group, while in the control group there were fourteen reported infections requiring antimicrobial therapy. At 30 days post-treatment there were no treated infections for both the urinary and suprapubic catheters in the treatment group. At 90 days after treatment, the urinary catheter had fewer treated infections (4.3%) compared to the suprapubic catheter (33.3%). 2
The Effectiveness of UroShield in Reducing Urinary Tract Infections and Patients’ Pain Complaints: Retrospective Data Analysis from Clinical Practice Ksenija da Silva1 *, Alexandra Ibbotson2 , Michaela O’Neill2 1 Faculty of Health and Life Sciences, School of Psychological, Social and Behavioural Sciences, Coventry University, UK; 2 Ideal Medical Solutions, UK Med Surg Urol, Vol. 10 Iss. 6 No: 254, 2021 This evaluation was designed to understand the impact of UroShield ultrasound technology within a “real world” setting, both clinical and social. The key findings reported by the patients included significant improvement across almost all areas measured, including reduced rates of UTIs, catheter blockages, unplanned catheter changes, use of antibiotics and pain. There were also improvements to the participants’ over-all well-being, including reduced levels of worry, improved ability to socialize and increased levels of independence. It is anticipated that the reduced levels of catheter-associated complications reported over the course of this evaluation will result in fewer unplanned hospital admissions and visits required by healthcare professionals. Study Design and Procedure In the framework of the study, a group of 29 NHS (National Health Service) patients were provided with the UroShield device. The participants included in this trial presented a variety of complex diagnoses and multiple underlying health conditions, however the consistent variable was their long-term reliance on indwelling urinary catheters and the presence of recurring CAUTI’s. Over the course of the evaluations both qualitative and quantitative data was collected, to better understand the catheter-associated infections and complications experienced by the patient group both before and after having access to the UroShield device. The real world nature of the study meant that these patients were living with a long term indwelling catheter and cared for in their own homes. No special study arrangements were made, the device was simply clipped onto their existing catheters and data collected on a weekly basis. Following the collection of the data to establish the results of the study, the patients could continue to use UroShield in the daily management of their catheters. Every one of the patients chose to continue using UroShield. Key Outcomes When the baseline reports were compared to the data collected over the course of the evaluation, several statistically significant improvements were reported. Table 1. Descriptive statistics and Wilcoxon test for UroShield parameters over time N Mean SD Z p UTI - base 21 3.24 3.42 -3.179 .001* UTI - end 22 .50 .91 Blockage - base 22 2.59 3.75 -2.755 .006* Blockage - end 22 .36 .90 Cath Change - base 22 2.91 3.57 -3.310 .001* Cath Change - end 22 .32 .48 Pain - base 21 3.30 2.23 -2.395 .017* Pain, end 20 2.60 1.86 *p < .05. 3
The study data reported: • Statistically significant decrease in the number of UTI’s and subsequent need for antibiotic treatment while using UroShield. • Statistically significant reduction in catheter blockages. • Reduced catheter changes. • Reduction in pain and in the use of antibiotics and pain relief medications. There were also improvements to the participants’ over-all well-being, reflected both in their clinical and in their mental and social condition. 4
The effectiveness of acoustic energy induced by the UroShield® device in the prevention of bacteriuria and the reduction of patient’s complaints related to long-term indwelling urinary catheters Károly Nagy, Béla Köves, Márta Jäckel, Péter Tenke Budapest, Hungary. Presented at the Annual Congress of the European Association of Urology in 2011 In case of long-term catheterization, the development of bacteriuria and biofilm formation is inevitable, which can lead to symptomatic urinary tract infections. Microbiological and clinical studies related to short-term catheterization demonstrated that devices attached to catheters, which release lowenergy surface acoustic waves, prevent biofilm formation reducing bacteriuria caused by catheter usage and decrease catheter-related complaints (pain, tenesmus). The aim of the study is to measure the effectiveness of the UroShield® device in the prevention of catheter-associated bacteriuria and in the reduction of catheter-related complaints in patients requiring long-term urinary catheterization. Study Design This is a non-randomized comparative study, involving a total of 27 patients having long-term urinary catheterization, between August 2009 and September 2010. Patients were treated with urinary cathethers, either with or without a UroShield® device. Study Procedure Between August 2009 and September 2010 a total of 27 patients were recruited for the study, 14 of which received a UroShield® device for 8 weeks. The control group consisted of 13 patients that received urinary catheters without UroShield® devices. Urine culture was taken at the time of catheter insertion and every two weeks and general health condition was checked simultaneously. Furthermore, the patients’ catheter-related complaints were documented on a numerical scale of 1 to 10. At the end of the 8th week a small piece of the catheter was sent to electromicroscopy (SEM) to determine the rate of biofilm formation and incrustation. Key outcomes Of the 27 patients recruited, 14 were treated with a UroShield® device for 8 weeks and 13 patients were treated with urinary catheters without a UroShield® device (control group), also for 8 weeks. At the time of catheter insertion and every 2 weeks, urine cultures were taken, and health condition checked. Catheter-related pain was also documented. More than 10×5 CFU/ml of one organism was defined as significant bacteriuria. At the end of week 8, a small piece of the catheter was sent for electromicroscopy to determine the rate of biofilm formation and incrustation. At the end of week 8, significant bacteriuria was detected in 4 patients (33%) in the UroShield® group and in 9 patients (81%) in the control group. No significant biofilm producing P. aeruginosa bacteria were detected in the UroShield® group, whereas, in the control group, the P. aeruginosa bacteria rate was 27%. In the UroShield® group, significant E. coli bacteriuria was half that in the control group. Catheter-related pain scores decreased by 1.6 in the UroShield® group, while increasing by 1.3 in the control group. In patients with at least moderate symptoms (≥3) at baseline, there was a decrease of 2.4 points in the UroShield® group and an increase of 2.0 points in pain scores in the control group. 5
Replacement of antibiotic therapy by UroShield® device in subjects with urinary catheter following radical prostatectomy Dr. Simon Zillich, Dr. Christian Weber, Prof. Uwe Ikinger Urology Department, Salem Medical School, Heidelberg, Germany (2014) The research group demonstrated improved outcomes for patients with urinary catheter following radical prostatectomy that had just one dose of antibiotics given to them, followed by the UroShield SAW treatment, compared to subjects with urinary catheter treated with antibiotics only. Study Design Randomized double-blind study involving 40 patients with urinary catheter after radical prostatectomy, in Heidelberg, Germany. For the duration of the study, the subjects in the treatment group were given a postoperative single dose of Ceftriaxone 2 g and underwent placement of an active UroShield® device on their catheter. The control groups was given a post-operative dose of Ceftriaxone 2 g on days 1 to 3 and trimethoprim 2×200 mg per day until the end of the study duration. Study Procedure 1. Following the radical prostatectomy procedure, both groups were given a single dose of antibiotics treatment. 2. The UroShield® was attached to the urinary catheter and activated in the treatment group only. The antibiotics treatment was continued in the control group. 3. Urine sample was taken for bacterial count (bacteriuria) in both groups. 4. Catheter removal (based on PI decision) in both groups. 5. Urine sample was taken for bacterial count (bacteriuria) in both groups upon study termination. Key Outcomes Of the 40 patients recruited, 20 were randomized to the treatment group and 20 to the control group. The average age was 66.7 and 60.7 years for the treatment group and the control group, respectively. The average catheter days was 8.4 days and 8.3 days for the treatment group and the control group, respectively. In the treatment group, there was 1 case of bacteriuria at the end of the study (bacteriuria rate=5%). In the control group there were 4 cases of bacteriuria at the end of the study (bacteriuria rate=20%). 6
The Use of the UroShield Device in Patients with Indwelling Urinary Catheters Dr. Ofer Shenfeld, Dr. Dagan Haris Shaare Zedek Medical Center, Jerusalem, Israel (2010) This randomized controlled trial showed that the UroShield device, when used as an accessory to the catheter, was effective in reducing pain, discomfort and spasm associated with an indwelling urinary catheter: the severity of pain was reduced by 31%, discomfort by 30% and spasm by 32% in the Treatment Group using the UroShield device, in comparison to the Control Group, without the UroShield device. This difference was found to be statistically significant. Study Design and Objectives An open label, comparative, randomized trial to assess the effectiveness of the UroShield device, when attached to a 14 Fr - 22 Fr siliconized latex urinary catheter, in the therapy of urinary catheter related pain, discomfort and bladder spasm, as well as in the prevention of bacteriuria or UTI and reduction of biofilm. Study Procedure Patients in hospital with an indwelling catheter (more than 24 hours) were recruited into the study and treated with the device for 13 days. The study included 40 patients randomized to one of the two treatment groups in a 2:1 ratio (treatment=27: control=13). Key Outcomes • A reduction in the pain, discomfort and spasm parameters, during all treatment days, was statistically evident in the Treatment group (a two-tailed Student T test was used, p< 0.05) as compared to the Control group: the severity of pain was reduced by 31%, discomfort by 30% and spasm by 32%, when the UroShield accessory was used. • 57% of the patients only from the Treatment group versus 85% of the patients from Control group were given relief medications. However, this outcome is only partially indicative, since such medications are used to relieve not only pain and discomfort associated with an indwelling urinary catheter but also pain associated with invasive surgery treatment. • A notable trend towards reduction of bacteriuria was evident in patients with UroShield. Urine cultures on the 3rd day revealed bacteriuria in only 5.3% of the patients in the Treatment group, compared to 10% in the Control Group. 7
Biofilm Prevention by Surface Acoustic Waves: A New Approach to Urinary Tract Infections – A Randomized, Double Blinded Clinical Study Simon Zillich, Christian Weber, Uwe Ikinger Urology Department, Salem Medical School, Heidelberg, Germany (2008) The potential of a new device, the UroShield® low frequency/low intensity ultrasound system, in preventing biofilm formation on indwelling catheters in subjects requiring urinary catheterization was tested. The main finding of this study is that surface acoustic waves can markedly reduce – or even eliminate – the level of biofilm formation within indwelling catheters while a high rate of biofilm (7 out of 11) can be found in the control group. To the best of our knowledge, this is the first time that such a phenomenon is described in the literature. This approach opens new options for non-pharmacological prevention of urinary tract infections. Study Design This is a randomized, double blinded, sham controlled comparative trial. Independent evaluation of the catheters for biofilm was performed. A sample size of N=22 (11 in each group) was determined to be adequate to demonstrate large differences between the groups, at a significance level of p<0.10. This p-value was used to protect against false negatives, and to increase sensitivity to deviations from equality between the control and active group. Recruitment was continued until a quota of 22 subjects was achieved. A subject who either had a positive urinary culture at baseline or had his catheter removed after less than five days was to be replaced until twenty-two valid subjects had been recruited. Study Procedure The overall plan consisted of the following steps: 1. Subjects were assessed for their eligibility to participate in the study according to the inclusion/exclusion criteria and signed a written informed consent according to Declaration of Helsinki and local regulations. 2. A randomization procedure was performed in order to determine the subject’s study group. 3. The urinary catheter was inserted following the surgical procedure and the UroShield® device was connected to the external segment of the catheter and activated throughout the study period (until catheter withdrawal). Key Outcomes Catheter analysis: Average catheter days were 8.8±2.7 and 9.2±2.2 days for the active and the control groups, respectively (range was 5-13 days). The catheter diameter varied from 14” (French) to 20”. In addition, there were two major types of catheters used in this study: double-lumen and triple-lumen catheters. Triple lumen catheters have a channel for irrigation, which might reduce the likelihood of bacteriuria and biofilm development. Adverse events: One subject within the active group had a Stroke. It was defined as unlikely related to the study device. It should be noted that this subject had a cardiovascular medical history including a previous stroke in the previous year. UroShield® therapy was continued as he recovered from this event. Biofilm formation: SEM analysis by a certified pathologist showed biofilm on seven catheters from the control group while no biofilm was observed in any of the active catheters, neither in the outer or inner lumen of the catheters. 8
Pain medication management: Catheter related urethral pain and bladder spasm were treated with specific medications that were given on per need basis following subject complaints. The treatment group had statistically significant less consumption of these types of analgesics, indicating a reduction in pain levels during the study period. A total of 2 voltaren and 2 spasmex were prescribed for the active group in comparison to a total of 6 voltaren and 12 spasmex prescriptions for the control group, throughout the study. Discussion: It appears that mechanical vibration energy interferes with early events in the biofilm development process, mainly the adhesion of planktonic microorganisms to surfaces. In an era where there is strong interest in curtailing use of antibiotics, using physical measures constitutes a good strategy for the serious clinical problem of biofilm formation. The UroShield® device proved to be safe and well tolerated with no differences in adverse event rate between the groups. Moreover, it appears that the UroShield® reduces pain and spasm levels, and as proven in the treatment group (as compared to the control group), less medication is required to treat these catheter related symptoms. 9
Effect of UroShield® on pain and discomfort levels in patients released from the emergency room with urinary catheter due to urine incontinence I. Appelbaum, T. Zalut, Y. Levy, O. Shenfeld Shaare Zedek Medical Center, Jerusalem, Israel (2008) Urinary catheters carry some risks for the patients. Among them are pain, spasm, discomfort, blocking of the catheter, infection etc. Acoustic energy has the potential to reduce some of these risks. This study tests the effect of UroShield® on pain and discomfort in patients that were released from the ER with urinary catheter. Study Design and Objectives This is an open label treatment study. 10 subjects were recruited to the study. The data was collected via a daily questionnaire using a 1-10 (Numeric Rating) scale. The study is aimed at assessing the effectiveness of the UroShield® in reducing pain and discomfort levels and in improving the well-being of the subject. The UroShield® may be defined as effective if it succeeds in reducing pain, spasm, burning and itching sensation levels of the subject and in improving his well-being. The ability to use it in the home care setting can improve the subject’s tolerance to urinary catheters, consequently improving catheter related injury care. Study Procedures The overall plan for all subjects consists of the following steps: 1. Subjects were assessed for their eligibility to participate in the study according to the inclusions/ exclusions criteria. 2. 24h following discharge from the ER, the UroShield® was attached to the catheter and activated. A basic questionnaire was filled out by the subject. 3. A daily questionnaire was filled out by the subject via phone call. 4. Study termination. Key Outcomes The average age was 63.5 (high – 82, low – 27). All of the subjects received a 14Fr catheter. The average use of the UroShield® was 6.6 days (4-12 days). Results demonstrate a reduction from 6.1 to 1.8, 2.6 to 0.4, 3.7 to 0.2 and 3.7 to 1.0 in pain, itching burning and spasm levels, respectively. Simultaneously, a significant increase from 3.3 to 7.0 was observed in the well-being of the subjects. 10
Effective Prevention of Microbial Biofilm Formation on Medical Devices by Low-Energy Surface Acoustic Waves Zadik Hazan, Jona Zumeris, Harold Jacob, Hanan Raskin, Gera Kratysh, Moshe Vishnia, Naama Dror, Tilda Barliya, Mathilda Mandel, and Gad Lavie Nanovibronix Corporation, Nesher and the Institute of Hematology and Blood Center, Sheba Medical Center, Tel-Hashomer, Israel. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, journal of the American Society of Microbiology (Dec. 2006) Low-energy surface acoustic waves generated from electrically activated piezo elements are shown to effectively prevent microbial biofilm formation on indwelling medical devices. The development of biofilms by four different bacteria and Candida species is prevented when such elastic waves with amplitudes in the nanometer range are applied. Acoustic-wave-activated Foley catheters have all their surfaces vibrating with longitudinal and transversal dispersion vectors homogeneously surrounding the catheter surfaces. The acoustic waves at the surface are repulsive to bacteria and interfere with the initial phases of microbial biofilm development, viz. the docking and attachment of planktonic microorganisms to solid surfaces. The ability to prevent biofilm formation on indwelling devices and catheters can benefit the implanted medical device industry. Study Design and Objectives Indwelling device-related infections constitute a major cause of morbidity and mortality in hospitalized patients. Microbial biofilms readily develop on all types of devices, urinary, endotracheal, intravenous, and other types of catheters and implants inserted into more than 25% of patients during hospitalization. The incidence of bacterial infections in patients with urinary catheters is approximately 5 to 10% per day, with virtually all patients who undergo long-term catheterization (~28 days) becoming infected. The formation of biofilm from planktonic microorganisms results in significantly enhanced resistance to antibiotics. Microbial biofilms also present serious challenges to the immune system. Altogether these properties render biofilms exceedingly difficult to eradicate. The harsh and potentially fatal consequences of microbial biofilm infections generated efforts to prevent their formation, particularly on indwelling medical devices using chemical and mechanical approaches. Catheters coated with hydrogel, silver salts, and antimicrobials have been evaluated; however, they provide minimal reduction in infection incidence. Mechanical approaches to preventing biofilm formation have utilized ultrasonic energy, yet the focus has thus far been on increasing biofilm sensitivity to antibiotics. We devised an innovative approach in which we generate low-energy elastic acoustic waves of practically nonthermal range from electrically activated piezo ceramic elements. The vibration energy is transmitted directly to indwelling medical devices in an integrated unit. Our aim was to achieve dispersion of the acoustic energy on entire surfaces of indwelling medical devices with different consistencies and structures. We analyzed the physical and power requirements for harnessing these waves to prevent microbial attachment and biofilm formation. The findings were consolidated into piezo actuators generating low-power acoustic waves at frequencies ranging from 100 to 300 kHz. The results of studies evaluating the efficacy of these actuators in preventing biofilm formation on indwelling medical devices from several microorganisms, in animal models, are presented. Study Procedure A single piezo actuator was attached to the extracorporeal portion of 10Fr siliconized latex Foley urethral catheter bodies (Unoplast), sterilized with 70% ethanol, and dried. New Zealand White rabbits, 3 to 4 months old and weighing 3.5 to 5.5 kg, were anesthetized with a mixture of 1:1 ketamine (25 mg/ml) and xylazine (20 mg/ml) (0.7 ml/kg of body weight). The perineal region was disinfected with 70% ethanol and antiseptic povidone iodine, the catheters were inserted through the meatus, and the internal balloon was inflated with 3 to 4 ml sterile saline. The rabbits were dressed with a coat-like harness attached to an overhead wire which 11
ran across the top of the cage, enabling limited forward backward movements while preventing the rabbits from pulling out the catheters. A sterile collecting bag was connected to the catheter and replaced daily when urine samples were collected. The extracorporeal portion of the catheter was attached to swing-like devices hanging from the ceiling. These devices allowed free mobility of the catheter with movements of the rabbit and prevented friction with the cage floor, premature catheter detachment, and excessive contamination with feces. Following catheterization, the piezo elements were activated with power from an alternating current source and remained active throughout the full duration of the experiments (7 days in one experiment, up to 8 days in a second experiment, and 9 days in a third experiment). Catheters showing markedly decreased or no urine output for 12 h were unblocked using sterile flexible wires. Urine was collected once daily in a sterile manner from the bag throughout the experiment, serial dilutions were performed in PBS, 100 l was dispersed evenly on blood agar plates (Hylabs, Rehovot, Israel), and bacterial counts were performed after 24 h. Animals that developed bacteriuria of 105 CFU/ml were excluded in accord with Animal Care Committee requirements. Key Outcomes Urine samples were collected daily, the bacterial load was titrated, and time to bacteriuria was determined. Urine samples from rabbits with SAW-treated catheters remained sterile for 5, 7, and 9 days (26 cumulative days of sterile urine) despite the extensive contamination of the perineal area with feces. Furthermore, the bacteriuria that did develop in some rabbits was mostly of low titers, whereas three of four control rabbits developed bacteriuria of >106 CFU/ml within 2 or 3 days and the fourth had a titer of >108 CFU/ml on day 7. The average number of days to development of urinary tract infection, defined as bacteriuria of >105 CFU/ml, was 7.3 ±1.3 days for the SAW-treated animals versus 1.5 ± 0.6 days in the nontreated controls (P < 0.0009 by twotailed Student’s t test; n = 4). At the end of the experiments, the animals were sacrificed, the bladder and urethra were cut open, and the catheters were removed carefully, avoiding disruption of the biofilms. Biofilm content was examined by SEM. Analyses of the internal surfaces of recovered catheters revealed strong inhibition of bacterial biofilm formation on the surfaces of catheters treated with SAW. In contrast, control group catheters were covered with various densities of microbial biofilms despite the shorter durations of catheterization (in two of the animals, the catheters were in place for only 3 or 4 days). Evaluation of the integrity of mucous membranes by histological and ultrastructural analyses in all control and SAW treated animals revealed that the treatment with SAW did not produce any histopathological changes. Furthermore, uroepithelial integrity was found to be less affected by trauma and better conserved in the SAWtreated animals than in the controls. 12
Surface acoustic waves increase the susceptibility of Pseudomonas aeruginosa biofilms to antibiotic treatment Moran Kopel, Elena Degtyar and Ehud Banin The Institute for Nanotechnology and Advanced Materials, Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. Biofouling (August 2011) Bacterial urinary tract infections resulting from prolonged patient catheterization have become a major health problem. One of the major issues is bacterial resistance to antibiotic treatments due to biofilm formation inside the catheters, thus enhancing the search for alternative treatments. In the present study, a device containing a piezo element capable of transmitting low-frequency surface acoustic waves (SAW) onto the indwelling catheter was used. The SAW were able to eradicate biofilm-residing bacteria by >85% when applied simultaneously with an antibiotic in three clinically relevant species, viz. Escherichia coli, Staphylococcus epidermidis and Pseudomonas aeruginosa. Moreover, transcriptome analysis revealed that SAW can alter the transcription pattern of P. aeruginosa, suggesting that this signal can be specifically sensed by the bacterium. Study Description and Design Bacteria thrive in nature in two major physiological states, viz. as free-living (i.e. planktonic) bacteria or in matrixembedded complex structures termed biofilms. Biofilm represents a protected mode of growth that allows bacteria to withstand harsh environmental conditions. The ability of bacteria to colonize virtually any surface and form biofilms has made them a major cause of medical infections. It has been estimated that >65% of the bacterial infections treated in hospitals are caused by bacterial biofilms, most of which are associated with indwelling medical devices. There are two main obstacles towards eradicating biofilm-residing bacteria using antibiotics: the extracellular matrix including polysaccharides, proteins and DNA, and the physiological state of the bacteria, featured by low metabolism. To enhance antibiotic efficacy, researchers have already utilized ultrasonic energy. Invitro studies were mostly aimed at eradication of bacterial biofilms that occurred on implants and utilized sonication baths, having either water or air as the conductor. In invivo studies, the antibiotics were administered systemically and local ultrasound treatment was applied. But these systems are fairly large, require operation of professional staff, they are limited in application time and cannot be utilized with indwelling devices. More recently, a different approach used low-energy acoustic waves, transmitted directly to an indwelling medical device (i.e. urinary catheters) by means of a small portable transmitter. As opposed to previous studies, here low-energy surface acoustic waves (SAW) were spread from an actuator to the entire catheter surface. In the present study the effect of SAW, transmitted directly onto an urinary catheter, on the antibiotic susceptibility of a Pseudomonas aeruginosa biofilm has been further investigated, using a device provided by NanoVibronix Corp. Study Procedure The device constitutes of an electronic driver that sends periodic electrical pulses to an actuator harboring a ceramic piezo element. The frequency of the vibrations generated on the piezo element is 100 kHz+10% and at on/off frequency of 30Hz; the acoustic intensity was 0.4 W cm72 and an amplitude of 2 mm. The acoustic energy on the inner surface of the catheter is 0.3 mW cm72 with a wave amplitude of 0.2–2 nm. In the Epsilometer test experiments, the acoustic intensity and amplitude were preserved through a decrease in actuator energy by 10- fold. E. coli 1313 and P. aeruginosa PAO1 were grown on tryptone soya broth (TSB) medium, while S. epidermidis was grown on TSB supplemented with 0.2% glucose. For flow cell experiments 10% TSB medium supplemented with 0.2% casamino acids was used. All bacteria were grown at 37ºC for indicated times. The experimental system was composed of a medium container connected through silicon tubes to a 10 cm long Foley catheter segment (16Ch/Fr5/10ml/2cc, standard Latex, Siliconized). Catheters were incubated with 1 ml of 1.5 6 108 bacteria ml 71 of inoculum for 1 h. Following the incubation the medium flow was initiated and 13
sustained by a peristaltic pump at flow rate of 10 ml h71 for 48 h at 378C. At this point the indicated treatment was applied. For antibiotic treatment 25 mg ml 71 gentamicin were administered. For a combined treatment or SAW alone the actuator was activated and incubation was prolonged for an additional 24 h. At the end of the experiment biofilm cells were removed from the catheter and the bacteria were plated and counted. Key Outcomes Acoustic vibrations have already been demonstrated to have the ability to prevent biofilm formation, and this is supported also by the present results. The present study has additionally demonstrated that a combined SAW and antibiotic treatment is capable of effectively treating biofilm of several clinically relevant bacterial species, such as P. aeruginosa, S. epidermis and E. coli. It seems that certain types of antibiotics are capable of better penetration through biofilm in the presence of ultrasound. This enhanced penetration is also true for nutrients and oxygen causing a change in the bacterial metabolic state. Confocal images clearly show that there is increased eradication of bacteria inside the biofilm in such circumstances. This is evidently due to better antibiotic penetration, to the bacterial metabolic state or to a physiological change inflicted by the acoustic energy. Most likely it is the combination of all of the above that leads to the observed effect. 14
The Effect of Surface Acoustic Waves on Bacterial Load and Preventing Catheter – Associated Urinary Tract Infections (CAUTI) in Long Term Indwelling Catheters • Statistically significant reduction in CFU: >100,000 to 10,000 CFU or less (25/29) in the treatment group. • At 30 days - No reported infections in the treatment group vs. 27% symptomatic treated infections in control group. • At 90 days – 10% reported infections in the treatment group vs. 54% symptomatic treated infections in control group. The Effectiveness of UroShield in Reducing Urinary Tract Infections and Patients’ Pain Complaints: Retrospective Data Analysis from Clinical Practice • Statistically significant decrease in the number of UTI’s and subsequent need for antibiotic treatment while using UroShield. • Statistically significant reduction in catheter blockages. • Reduced catheter changes. • Reduction in pain and in the use of antibiotics and pain relief medications. Effective Prevention of Microbial Biofilm Formation on Medical Devices by Low-Energy Surface Acoustic Waves • Low-energy surface acoustic waves from electrically activated piezo elements were shown to effectively prevent microbial biofilm formation on indwelling medical devices. • The development of biofilms by four different bacteria and Candida species is prevented when such elastic waves with amplitudes in the nanometer range are applied. • Acoustic-wave-activated Foley catheters have all their surfaces vibrating with longitudinal and transversal dispersion vectors homogeneously surrounding the catheter surfaces. The acoustic waves at the surface are repulsive to bacteria and interfere with the docking and attachment of planktonic microorganisms to solid surfaces that constitute the initial phases of microbial biofilm development. Surface acoustic waves (SAW) increase the susceptibility of Pseudomonas aeruginosa biofilms to antibiotic treatment • SAW was clearly demonstrated to enhance antimicrobial activity. The SAW effect may be enhancement of the diffusion through the biofilm or through the cell membrane. • It was also demonstrated that a combined SAW and antibiotic treatment is capable of effectively treating biofilm of several clinically relevant bacterial species, such as P. aeruginosa, S. epidermis and E. coli. The effectiveness of acoustic energy induced by UroShield in the prevention of bacteriuria and the reduction of patients’ complaints related to long-term indwelling urinary catheters • At the end of week 8, significant bacteriuria detected in 4 patients (33%) in the UroShield group vs. 9 patients (81%) in the control group. • No significant biofilm producing P. aeruginosa bacteria detected in the UroShield group, while P. aeruginosa bacteria rate was 27% in the control group. In the UroShield group, significant E. coli bacteriuria was half that in the control group. • Catheter-related pain scores decreased by 1.6 in the UroShield group, while they increased by 1.3 in the control group. Exclusive UK Distributor for UroShield® For more information about UroShield®, please scan the QR code, visit https://peakmedical.co.uk/uroshield or call Freephone 0800 652 0424 www.peakmedical.co.uk