Wendy Robson

Oral ciprofloxacin or trimethoprim reduces bacteriuria after flexible cystoscopy

To report a large prospective, pragmatic, double‐blind randomized controlled trial to determine whether oral prophylactic antibiotics reduce the risk of bacteriuria after flexible cystoscopy (FC), as up to 10% of patients develop urinary infection afterwards, with significant morbidity and costs for health services.

A CROSSOVER RANDOMIZED TRIAL OF TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION AND OXYBUTYNIN IN PATIENTS WITH DETRUSOR INSTABILITY

PURPOSE Management of idiopathic detrusor instability is difficult in most patients mainly due to the lack of a complete understanding of the pathophysiology. Oxybutynin and transcutaneous electrical nerve stimulation have been used but to our knowledge no direct comparisons have been made. MATERIALS AND METHODS Patients with frequency, urgency, urge incontinence and proved detrusor instability were studied with urodynamics, quality of life instruments, and frequency and volume charts. Patients were randomized to transcutaneous electrical nerve stimulation or oxybutynin. After 6 weeks of treatment, they were reassessed and after a washout of 2 weeks, they were started on the second arm of treatment and reassessed 6 weeks later. RESULTS A total of 13 male and 30 female patients were studied. Functional capacity had increased and number of voids daily had decreased significantly compared with before treatment in both arms (p <0.005). There were significant improvements in symptom specific quality of life measures but no changes were found on the global Short Form 36 (SF-36) quality of life questionnaire. The volume to first desire to void and first unstable contraction had increased significantly with oxybutynin but not with transcutaneous electrical nerve stimulation. Of 23 patients 7 were stabilized with treatment, including 2 with oxybutynin only, 2 with either nerve stimulation or oxybutynin and the remaining 3 with only nerve stimulation. Total bladder capacity did not change significantly with either treatment but patients noticed side effects more commonly with oxybutynin. CONCLUSIONS Both treatments clearly improved subjective parameters. However, only oxybutynin showed significant improvements in objective urodynamic parameters. Transcutaneous electrical nerve stimulation can be used in patients who cannot take oxybutynin. Further studies are needed to show the long-term efficacy and cost analyses of nerve stimulation.

Tolerance of Bacteriuria After Urinary Diversion Is Linked to Antimicrobial Peptide Activity

OBJECTIVES To compare the cationic antimicrobial peptide gene expression profiles and urinary cationic antimicrobial activities of patients after urinary diversion according to their urinary tract infection (UTI) status. Ileal conduit urinary diversion joins the bacterial-tolerant ileal epithelium and intolerant urothelium. After this procedure, one quarter of patients develop repeated symptomatic UTIs. Such development might reflect the altered innate immune mechanisms centered on epithelial expression and urinary activity of cationic antimicrobial peptides, such as defensins. METHODS Ileal and ureteral biopsy specimens from ileal conduit subjects with (n = 18) and without (n = 18) recurrent symptomatic UTIs were assessed for cationic antimicrobial peptide gene expression using quantitative reverse transcriptase polymerase chain reaction. Overnight urine collections were analyzed for antimicrobial activity against a laboratory Escherichia coli strain, and infecting organisms were isolated from individual subjects. RESULTS Overall, the ureteral epithelium showed increased expression of human α-defensin 5 and decreased expression of the human β-defensin 1 after urinary diversion (P < .05). No significant changes were seen for the ileal epithelium. The expression levels of both defensins also did not differ significantly according to UTI status. Urinary cationic activity against infecting bacterial isolates from the individual subjects was significantly greater in those with symptomatic UTI (P < .001), and the activities against the laboratory E. coli strain were similar. CONCLUSIONS The changes in the human β-defensin 1 and human α-defensin 5 expression profiles and the link between symptomatic infection and high urinary antimicrobial activity suggest that innate mechanisms play significant roles in balancing bacterial tolerance and killing after ileal conduit urinary diversion. Future work needs to determine whether these changes can be therapeutically modulated to benefit the patients.

TRANSMISSION OF PENILE CUFF PRESSURE TO THE PENILE URETHRA

PURPOSE We developed a noninvasive method to measure voiding bladder pressure by inflating a penile cuff to interrupt flow. We tested the underlying assumption that cuff pressure is transmitted to the penile urethra. MATERIALS AND METHODS In 35 men we simultaneously recorded penile cuff and urethral pressure during 2 experimental protocols for 6 cuffs of various widths and manufactures. Initially a urethral pressure transducer was placed at the mid point of the cuff and urethral pressure was continuously recorded during cuff inflation. In experiment 2 cuff pressure was set at 120 cm. water and the urethral pressure profile was measured by withdrawing the urethral transducer through the cuff width. RESULTS There was excellent agreement of cuff with urethral pressure over the range of 0 to 200 cm. water for cuffs 37 to 54 mm. wide. Narrower cuffs showed wider variation with less efficient transmission of cuff pressure to the urethral lumen. Similarly maximum pressure in the urethral pressure profile showed best agreement for cuffs 38 and 46 mm. wide. Wider cuffs produced higher and narrower cuffs produced lower transmitted pressure within the urethra. Cuff performance was also related to penile size. Results had good within-subject repeatability. CONCLUSIONS We demonstrated that pressure transmission from cuff to urethra is optimal at a cuff width of 40 to 50 mm. and recommended this width for other investigations of noninvasive bladder pressure measurement.

Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22

Background Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. Methods 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. Results Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62–75%) and 93% negative predictive value (95% CI = 92–95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71–0.79) and 0.72 (95% CI = 0.67–0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88–99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69–74%). Conclusions The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.

Variation in Invasive and Noninvasive Measurements of Isovolumetric Bladder Pressure and Categorization of Obstruction According to Bladder Volume

PURPOSE We developed a noninvasive test that provides an estimate of isovolumetric bladder pressure by measuring the pressure required to interrupt voiding using controlled inflation of a penile cuff. We noted variation in serial measurements obtained during a single void and, therefore, we determined whether this represents variation in detrusor contraction strength, as predicted in previous studies, or measurement error. MATERIALS AND METHODS A total of 36 symptomatic men underwent simultaneous invasive and noninvasive pressure flow studies. Corresponding values of isovolumetric bladder pressure and cuff interruption pressure were recorded at each flow interruption and grouped according to bladder volume to calculate measurement error and bias at various points during a void. Individual variation in the 2 measurements across a range of normalized bladder volumes was then examined using ANOVA. RESULTS Cuff interruption pressure showed a consistent level of accuracy as an estimate of isovolumetric bladder pressure across a range of volumes. There were similar, statistically significant differences in isovolumetric bladder pressure and cuff interruption pressure recorded at specific volume increments with the highest values seen in the mid range and the lowest seen at lower bladder volumes (each p <0.01). When plotting, the maximum recorded value of cuff interruption pressure in each individual on our proposed noninvasive pressure flow nomogram provided the best diagnostic accuracy for obstruction. CONCLUSIONS This study shows that cuff interruption pressure varies in the expected manner with bladder volume and provides a consistent estimate of isovolumetric bladder pressure throughout a void. These data provide important guidance for interpreting noninvasive pressure flow studies and classifying obstruction on the proposed nomogram.

Multisite Evaluation of Noninvasive Bladder Pressure Flow Recording Using the Penile Cuff Device: Assessment of Test-Retest Agreement

PURPOSE We performed a pragmatic study of the penile cuff test, a noninvasive method of categorizing bladder outlet obstruction, at a number of United Kingdom urology centers remote from the originating site. We report the agreement of the test and the subsequent retest using the cuff test in the short term. MATERIALS AND METHODS Men requiring urodynamic investigation for lower urinary tract symptoms were recruited from 6 sites to perform a penile cuff test twice at an interval of approximately 4 weeks. Tests were analyzed by a single interpreter to assess differences in the flow rate, cuff interruption pressure and diagnostic categorization in an individual between the 2 tests due to measurement and physiological error. RESULTS A total of 136 men (69%) performed 2 suitable cuff tests at a median of 20 days (IQR 8-31). The mean +/- SD difference between the 2 tests in the maximum flow rate was 0.2 +/- 3.7 ml per second and in cuff interruption pressure was 4.0 +/- 26 cm H(2)O. Of the men 33% changed diagnostic category on the Newcastle nomogram, while 47% maintained a consistent diagnosis of obstruction or no obstruction. CONCLUSIONS Diagnostic category repeatability was similar to that of conventional urodynamics, although there was greater variability in pressure measurements. This supports widespread routine use of the penile cuff test.

The penile cuff test: A clinically useful non-invasive urodynamic investigation to diagnose men with lower urinary tract symptoms.

Objectives: To summarize the development of a novel non-invasive test to categorize voiding dysfunction in men complaining of lower urinary tract symptoms (LUTS) - the penile cuff test. Methods: The test involves the controlled inflation of a penile cuff during micturition to interrupt voiding and hence estimate isovolumetric bladder pressure (pves.isv). The validity, reliability, and clinical usefulness of the test were determined in a number of studies in men with LUTS. Results: The penile cuff test can be successfully performed in over 90% of men with LUTS. The reading of cuff pressure at flow interruption (pcuff.int) gives a valid and reliable estimate of invasively-measured pves.isv and when combined with the reading for maximum flow rate obtained during the test (Qmax) produces an accurate categorization of bladder outlet obstruction (BOO). Use of this categorization prior to treatment allows improved prediction of outcome from prostatectomy. Conclusion: The penile cuff test fulfils the criteria as a useful clinical measurement technique applicable to the diagnosis and treatment planning of men with LUTS.

Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection

The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFκB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age-matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle.

Interobserver Agreement for Noninvasive Bladder Pressure Flow Recording With Penile Cuff

PURPOSE We assessed variability in interpreting noninvasive measurements of bladder pressure and urine flow between experienced and novice users of the penile cuff. MATERIALS AND METHODS Urodynamicists at 6 sites were asked to use the penile cuff test as part of clinical assessment in 30 men presenting with lower urinary tract symptoms. After a short training period they measured maximum flow rate and cuff interruption pressure from penile cuff test recordings to enable categorization of bladder outlet obstruction using a nomogram. Similar measurements were then made on the same traces by 2 expert observers from the originating center. Interobserver differences were assessed. RESULTS Complete agreement on obstruction categorization was seen in 77% of subjects, which increased to 86% when plots positioned on category boundary lines were allocated to the favored category. The 95% confidence limits of interobserver variability in maximum flow rate and cuff interruption pressure measurements were +/- 1.7 ml per second and +/- 13 cm H(2)O, respectively, although a small number of studies yielded discrepancies between observers that were larger than expected. They arose from complex recordings but were equally likely between experts as between expert and novice. Investigation of the causes suggested in some cases how such discrepancies may be avoided in the future. CONCLUSIONS The excellent level of agreement in measurement and categorization after a short training period suggests that introducing the penile cuff test as part of assessment in men with lower urinary tract symptoms would be straightforward.