"Catheter replacement in catheter-associated urinary tract infection: current state of evidence ".

PURPOSE: Catheter associated urinary tract infection (CAUTI) is the most common healthcare associated infection. A significant knowledge gap exists regarding the necessity of catheter replacement as part of CAUTI treatment. Current guidelines recommend replacement for faster recovery and to prevent recurrences, but adherence is low. In this systematic review, we aimed to assess the available evidence regarding catheter replacement for CAUTI. MATERIALS AND METHODS: Eligible studies investigated the effect of catheter replacement in CAUTI on clinical outcomes and/or recurrence rates, irrespective of catheter type or setting. We searched electronic literature databases from inception to October 15th, 2023. Information was extracted regarding setting, eligibility criteria, definition of CAUTI, timing of replacement, and outcomes. RESULTS: Of the 257 identified studies, four were considered relevant and included. Two were randomized controlled trials (RCT) and two were observational studies. One RCT showed higher rates of clinical recovery and lower recurrence rates in the replacement group, while results of the other RCT favoured retainment, with a lower recurrence rate in the retainment group, although longer antimicrobial treatment in this group. Two observational studies were inconclusive. CONCLUSIONS: Current guidelines rely heavily on recommendations from a single study, emphasizing the need for further research. The burden of catheter replacement, including patient discomfort and resource impact, warrants careful consideration. A randomized trial is essential to provide more evidence on the effect of catheter replacement on clinical outcomes including CAUTI recurrence.

Diagnostic accuracy of urine biomarkers for urinary tract infection in older women: a case-control study.

OBJECTIVES: Urinary tract infection (UTI) is common among older women. However, diagnosis is challenging because of frequent chronic lower urinary tract symptoms, cognitive impairment, and a high prevalence of asymptomatic bacteriuria (ASB). Current urine diagnostics lack specificity, leading to unnecessary treatment and antimicrobial resistance. This study aimed to evaluate the diagnostic accuracy of 12 urine biomarkers for diagnosing UTI in older women. METHODS: In this case-control study, cases were women ≥65 years with ≥2 new-onset lower urinary tract symptoms, pyuria, and one uropathogen ≥104 CFU/mL. Controls were asymptomatic and classified as ASB (one uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Urine biomarker concentrations were measured through liquid chromatography-mass spectrometry and ELISA. Diagnostic accuracy parameters of individual biomarkers and a biomarker model were derived from receiver operating characteristic curves. RESULTS: We included 162 community-dwelling and institutionalized older women. Five urine inflammatory biomarkers demonstrated high discriminative ability (area under the curve ≥0.80): interleukin 6, azurocidin, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinases 2, and C-X-C motif chemokine 9. Azurocidin exhibited the highest diagnostic accuracy (sensitivity 86% [95% CI 75%-93%] and specificity 89% [95% CI 82%-94%] at 16.7 ng/mmol creatinine). A combined biomarker and pyuria model showed improved diagnostic accuracy in patients with UTI and ASB, compared with pyuria alone. DISCUSSION: We identified several urine biomarkers that accurately differentiated older women with UTI from asymptomatic women, including ASB. These findings represent a potential advancement towards improved diagnostics for UTI in older women and warrant validation in a diverse population.

Intravesical aminoglycoside instillations as prophylaxis for recurrent urinary tract infection: patient satisfaction, long-term safety and efficacy.

Background: Recurrent urinary tract infections (UTIs) are common, especially in women. When oral antimicrobial prophylaxis is ineffective or not possible due to allergies or antimicrobial resistance, intravesical aminoglycoside instillations (IAIs) are a non-systemic alternative. Objectives: To assess treatment satisfaction, long-term safety and efficacy of IAIs for recurrent UTI. Methods: We conducted a cohort study using data collected between January 2013 and June 2022 at the Leiden University Medical Center. Adult patients with recurrent UTI who received prophylactic IAI were eligible for inclusion. Treatment satisfaction was assessed through a survey. Data on serum aminoglycoside concentrations, cystoscopy results and number of recurrences were obtained through chart review. Number of recurrences and UTI characteristics were compared between patients on and off IAI using Poisson and logistic mixed effects models. Results: Forty-four patients were included (median follow-up time 976 days) and 323 UTIs occurred during follow-up. Overall treatment satisfaction was high (median 79.2/100). All but one patient had undetectable serum aminoglycoside levels and no malignancies were found on follow-up cystoscopy. IAI increased the time to first recurrence (102 days versus 36 days, P = 0.02), reduced the number of recurrences (rate ratio 0.75, 95% CI 0.56-0.99, P = 0.04) and the necessity for systemic antibiotics (OR 0.33, 95% CI 0.13-0.86, P = 0.02). Conclusions: In patients with recurrent UTI, IAI was associated with high treatment satisfaction, and was found to be a safe and effective alternative to oral antimicrobial prophylaxis.

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer.

More effective therapy for patients with either muscle-invasive or high-risk non-muscle-invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose-dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient-derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.

Initial report on distribution of ß3-adrenoceptor in the human female urethra.

INTRODUCTION: Past research has demonstrated that the urethral tonus is mainly under sympathetic control. Since 5 years, a beta 3-adrenoceptor (ADRB3) agonist is available in the treatment of overactive bladder syndrome. The presence of ADRB3 within the human urethra has not been demonstrated to date. Presence of ADRB3 in the urethra could influence urethral tonus. The aim of this study is to investigate the presence of ADRB3 in the human female urethra. MATERIAL AND METHODS: We performed anatomical studies in five female specimens. Three specimens were obtained from the body donation program, two from female patients with muscle-invasive bladder cancer, where radical resection of bladder and urethra was performed. The urethra up till the bladder neck was separated from the rest of the bladder and freshly obtained for this study. For demonstrating ADRB3 expression, we used rabbit polyclonal anti-human ADRB3 LS-A4198. RESULTS: Expression of ADBR3 was demonstrated in the epithelial layer of all urethral parts, except at the level of the meatus. The level of ADRB3 expression was highest in the mid urethra. There was no direct contact between ADRB3 and nerve tissue. ADRB3 expression was also demonstrated in the stratified muscle layer at the level of the external urethral sphincter. CONCLUSIONS: This is the first study to demonstrate the expression of ADRB3 in the human female urethra. There is an absence of a direct connection between ADRB3 and nerve tissue.

An ex vivo Tissue Culture Model for the Assessment of Individualized Drug Responses in Prostate and Bladder Cancer.

Urological malignancies, including prostate and bladder carcinoma, represent a major clinical problem due to the frequent occurrence of therapy resistance and the formation of incurable distant metastases. As a result, there is an urgent need for versatile and predictive disease models for the assessment of the individualized drug response in urological malignancies. Compound testing on ex vivo cultured patient-derived tumor tissues could represent a promising approach. In this study, we have optimized an ex vivo culture system of explanted human prostate and bladder tumors derived from clinical specimens and human cancer cell lines xenografted in mice. The explanted and cultured tumor slices remained viable and tissue architecture could be maintained for up to 10 days of culture. Treatment of ex vivo cultured human prostate and bladder cancer tissues with docetaxel and gemcitabine, respectively, resulted in a dose-dependent anti-tumor response. The dose-dependent decrease in tumor cells upon administration of the chemotherapeutic agents was preceded by an induction of apoptosis. The implementation and optimization of the tissue slice technology may facilitate the assessment of anti-tumor efficacies of existing and candidate pharmacological agents in the complex multicellular neoplastic tissues from prostate and bladder cancer patients. Our model represents a versatile "near-patient" tool to determine tumor-targeted and/or stroma-mediated anti-neoplastic responses, thus contributing to the field of personalized therapeutics.

Injectable Bulking Agent to Treat Postprostatectomy Urinary Incontinence: A Safety and Effectiveness Pilot Study.

OBJECTIVES: To evaluate the safety and effectiveness of the injectable bulking agent Opsys® (Promedon, Cordoba, Argentina) for treating minimal postprostatectomy stress urinary incontinence (SUI). PATIENTS AND METHODS: Single-centre, pilot study on ten male patients with SUI, < 30 g urine loss/ 24 h, more than 1 year after radical prostatectomy. Patients were treated by endoscopic transurethral injections of bulking agent in the presphincteric zone of the urethral submucosa. The results were evaluated using a pad weight test to quantify the differences in urine loss at 1, 3, and 6 months after intervention. Subsequently, the results of treatment were also evaluated by International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), Incontinence Impact Questionnaire (IIQ-7), Urogenital Distress Inventory Short Form (UDI-6-SF), and the Patient Global Impression of Improvement (PGI-I) at 1, 3, and 6 months after intervention. RESULTS: The primary outcome was the absolute result of the 24-hour pad weight test after treatment. Treatment success was defined as <3 g urine loss/24 h, improvement as ≥50% decrease in urine loss/ 24h, failure as <50% decrease in urine loss/24 h, or worsening of urine loss. Success was demonstrated in one, improvement in one, and failure in eight patients one month after treatment. One patient improved and 9 failed 3 and 6 months after treatment. The median 24-hour pad weight test was higher at all three moments of follow-up (1, 3, and 6 months after treatment). The median 24-hour pad weight test was before treatment 17.3g (6.4-20.9) and 1, 3, and 6 months after treatment, respectively, 40.3g (5.9-130.6) p= 0.038, 38.3g (18.3-202.1) p= 0.014, 55.0g (16.5-314.6) p= 0.028. The ICIQ-SF was significantly higher at 3 and 6 months, respectively 15.0 (12.0-18.5) p= 0.007 and 16.0 (12.5-17.5) p=0.012 versus 10.0 (9.0-12.0) before injection. No significant differences were found between IIQ-7, UDI-6-SF, and PGI-I before and after injection. Complications occurred in four patients: two patients reported spontaneously resolved haematuria and two patients reported urinary frequency. All complications were classified as Clavien-Dindo 1. CONCLUSION: Injection therapy with Opsys® bulking agent is not an effective treatment option for male SUI after radical prostatectomy. It is not a safe treatment option, due to worsening urine loss after treatment.

The ultimate radiochemical nightmare: upon radio-iodination of Botulinum neurotoxin A, the introduced iodine atom itself seems to be fatal for the bioactivity of this macromolecule.

BACKGROUND: Botulinum neurotoxin A (BoNT-A) is a highly neurotoxic drug and frequently used in patients. Knowledge on the optimal way of administration of BoNT-A and its subsequent distribution is still rather limited. An accurate method for monitoring these processes might be the use of radiolabelled BoNT-A. In this paper, we report our feasibility study on labelling BoNT-A with high-dose iodine-125 ((125)I) via IODOGEN-coated BoNT-A method. METHODS: Using cetuximab as model substrate for BoNT-A, a miniaturization of the IODOGEN-coated mAb method was developed with special attention to the minimum required amount of the oxidant IODOGEN, while the amount of substrate, reaction volume and reaction time were downsized. Labelling efficiency and radiochemical purity were determined by TLC, integrity by SDS-PAGE and HPLC and immunoreactivity by cell-binding assay. BoNT-A (50 µg) was labelled with (125)I by coating with 2.5 µg IODOGEN, in a total reaction volume of 250 µL and a reaction time of 90 s. (125)I-BoNT-A was purified by size exclusion chromatography (PD10 column) using ascorbic acid solution (5 mg/ml, pH = 5) as eluent. Quality analysis of (125)I-BoNT-A was performed by an in vitro bladder strip model, an electrochemiluminescence assay and an Endopep assay. RESULTS: Cetuximab (50 µg) labelling with (125)I (15 to 150 MBq) resulted in a labelling efficiency of 70% to 80%, a radiochemical purity of >99%, an immunoreactivity of >95% and a retained integrity on SDS; HPLC analysis revealed partly affected integrity when 110 to 150 MBq (125)I was used, i.e. when the averaged I/mAb molar ratio exceeded 3. Addition of HEPES (20 mM) and lactose (1.25%) (lyophilized BoNT-A contains HEPES and lactose) decreased the labelling efficiency to 44% to 54%. BoNT-A (50 µg) labelling with (125)I (97.2 to 98.3 MBq) resulted in labelling efficiency of 51% to 52% with a radiochemical purity >98.5%, a specific activity of 150.5 to 152.9 MBq/nmol and an I/BoNT-A molar ratio of 1.86 to 1.90. The in vitro bladder strip model showed no bioactivity of (125)I-BoNT-A when compared to unlabelled BoNT-A. The electrochemiluminescence and Endopep assay demonstrated around 10% and 15% bioactivity of (125)I-BoNT-A compared to unlabelled BoNT-A, respectively. The remaining bioactivity correlates within the Poisson distribution with the amount of BoNT-A molecules that does not bear an iodine atom. CONCLUSIONS: BoNT-A was successfully radio-iodinated with an activity high enough to enable in vivo measurement of nanograms of BoNT-A, which could be used in studying optimization of administration techniques of BoNT-A. The bioactivity of a BoNT-A molecule is, however, lost upon the introduction of an iodine atom into the tyrosine moiety of this sensitive molecule.

Development of an in vitro model to measure bioactivity of botulinum neurotoxin A in rat bladder muscle strips.

BACKGROUND: Botulinum toxin A (BoNT-A) is a new treatment modality in various causes of bladder dysfunction; like neurogenic detrusor overactivity and overactive bladder. The best technique of administrating BoNT-A in patients is unknown. A validated in vitro model could be used to investigate newer intravesical administration techniques of BoNT-A. In this study, we describe the development and validation of in vitro model to measure inhibitory effects of BoNT-A on bladder strip contractions. METHODS: Rat bladder strips were mounted in organ baths filled with Krebs' solution. The strips were stimulated chemically (80 mM potassium chloride, 1 µM carbachol) and electrically (Electrical Field Stimulation (EFS) 100 shocks, 50 V, 20 Hz, every 3 minutes). The viability of the strips was measured by carbachol stimulation at the beginning and at the end of the experiments. The strips were incubated in various concentrations of BoNT-A (0.03, 0.2, 0.3 nM). Controls were incubated in Krebs' solution only. The inhibition of strip contraction induced by EFS was measured. These measurements were statistically analyzed with a log-logistic model representing diffusion. RESULTS: All strips remained viable during the experiments. Inhibition of strip contraction was observed after incubation with 0.3 nM BoNT-A. The measurements fitted to a log-logistic model describing diffusion of BoNT-A in the bladder strip. The parameters of the log-logistic model representing diffusion were significant for 0.3 nM BoNT-A. Incubation with 0.2 nM BoNT-A showed insignificant results for 2 out of 3 runs. Incubation with 0.03 nM BoNT-A did not result in significant inhibition of strip contractions. CONCLUSIONS: An in vitro model was developed and validated in which the inhibitory effect of low concentrations of BoNT-A on bladder strip contractions can be measured.