Bacillus Calmette-Guérin Failure in Patients with Non-Muscle-invasive Urothelial Carcinoma of the Bladder May Be Due to the Urologist's Failure to Detect Urothelial Carcinoma of the Upper Urinary Tract and Urethra

BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.

Stricture of the Afferent Isoperistaltic Tubular Segment: A Late and Rare Cause of Bilateral Dilation of the Upper Urinary Tract After Ileal Bladder Substitution

OBJECTIVE To evaluate the etiology and treatment of bilateral hydronephrosis not responding to bladder substitute drainage after ileal bladder substitution using an afferent isoperistaltic tubular segment. MATERIALS AND METHODS A retrospective analysis was performed of a consecutive series of 739 patients who had undergone bladder substitution from April 1985 to August 2012. RESULTS Of the 739 ileal bladder substitute patients, 10 (1.4%) developed bilateral hydronephrosis unresponsive to complete bladder substitute drainage. The etiology was stenosis of the afferent isoperistaltic tubular segment. The median interval to presentation was 131 months (range 45-192). The incidence of afferent tubular segment stenosis was significantly higher in the 61 ileal bladder substitute patients with recurrent urinary tract infection (9 [15%]) than in the 678 without recurrent urinary tract infection (1 [0.15%]; P <.001). Urine cultures revealed mixed infections (34%), Escherichia coli (18%), Staphylococcus aureus (13%), enterococci (11%), Candida (8%), Klebsiella (8%), and others (8%). Seven patients underwent 10 endourologic interventions, only 1 of which was successful (10%). After failed endourologic treatment, 7 open surgical revisions with resection of the stricture were performed, with all 7 (100%) successful. CONCLUSION Bilateral dilation of the upper urinary tract after ileal orthotopic bladder substitution unresponsive to complete bladder substitute drainage is likely to be caused by stenosis of the afferent isoperistaltic tubular segment. The stenosis occurs almost exclusively in patients with long-lasting, recurrent urinary tract infection and can develop many years after the ileal bladder substitution. Minimally invasive endourologic treatment is usually unsuccessful; however, open surgical revision offers excellent results.

Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis

Abstract Objective To determine whether antibiotic prophylaxis at the time of removal of a urinary catheter reduces the risk of subsequent symptomatic urinary tract infection. Design Systematic review and meta-analysis of studies published before November 2012 identified through PubMed, Embase, Scopus, and the Cochrane Library; conference abstracts for 2006-12 were also reviewed. Inclusion criteria Studies were included if they examined antibiotic prophylaxis administered to prevent symptomatic urinary tract infection after removal of a short term (≤14 days) urinary catheter. Results Seven controlled studies had symptomatic urinary tract infection after catheter removal as an endpoint; six were randomized controlled trials (five published; one in abstract form) and one was a non-randomized controlled intervention study. Five of these seven studies were in surgical patients. Studies were heterogeneous in the type and duration of antimicrobial prophylaxis and the period of observation. Overall, antibiotic prophylaxis was associated with benefit to the patient, with an absolute reduction in risk of urinary tract infection of 5.8% between intervention and control groups. The risk ratio was 0.45 (95% confidence interval 0.28 to 0.72). The number needed to treat to prevent one urinary tract infection was 17 (12 to 30). Conclusions Patients admitted to hospital who undergo short term urinary catheterization might benefit from antimicrobial prophylaxis when the catheter is removed as they experience fewer subsequent urinary tract infections. Potential disadvantages of more widespread antimicrobial prophylaxis (side effects and cost of antibiotics, development of antimicrobial resistance) might be mitigated by the identification of which patients are most likely to benefit from this approach.

High proportion of healthcare-associated urinary tract infection in the absence of prior exposure to urinary catheter: a cross-sectional study

Exposure to urinary catheters is considered the most important risk factor for healthcare-associated urinary tract infection (UTI) and is associated with significant morbidity and substantial extra-costs. In this study, we assessed the impact of urinary catheterisation (UC) on symptomatic healthcare-associated UTI among hospitalized patients.

Characterization of the ebp(fm) pilus-encoding operon of Enterococcus faecium and its role in biofilm formation and virulence in a murine model of urinary tract infection.

We recently identified 15 genes encoding putative surface proteins with features of MSCRAMMs and/or pili in the Enterococcus faecium TX0016 (DO) genome, including four predicted pilus-encoding gene clusters; we also demonstrated that one of these, ebpABC(fm), is transcribed as an operon, that its putative major pilus subunit, EbpC(fm) (also called pilB), is polymerized into high molecular weight complexes, and that it is enriched among clinical E. faecium isolates. Here, we created a deletion of the ebpABC(fm) operon in an endocarditis-derived E. faecium strain (TX82) and showed, by a combination of whole-cell ELISA, flow cytometry, immunoblot and immunogold electron microscopy, that this deletion abolished EbpC(fm) expression and eliminated EbpC(fm)-containing pili from the cell surface. However, transcription of the downstream sortase, bps(fm), was not affected. Importantly, the ebpABC(fm) deletion resulted in significantly reduced biofilm formation (p < 0.0001) and initial adherence (p < 0.0001) versus the wild-type; both were restored by complementing ebpABC(fm) in trans, which also restored cell surface expression of EbpC(fm) and pilus production. Furthermore, the deletion mutant was significantly attenuated in two independent mixed infection mouse urinary tract experiments, i.e., outnumbered by the wild-type in kidneys (p = 0.0003 and < 0.0001, respectively) and urinary bladders (p = 0.0003 and = 0.002). In conclusion, we have shown that the ebpABC(fm) locus encodes pili on the E. faecium TX82 cell surface and provide the first evidence that pili of this emerging pathogen are important for its ability to form biofilm and to cause infection in an ascending UTI model.

Importance of the ebp (endocarditis- and biofilm-associated pilus) locus in the pathogenesis of Enterococcus faecalis ascending urinary tract infection.

BACKGROUND: We recently demonstrated that the ubiquitous Enterococcus faecalis ebp (endocarditis- and biofilm-associated pilus) operon is important for biofilm formation and experimental endocarditis. Here, we assess its role in murine urinary tract infection (UTI) by use of wild-type E. faecalis OG1RF and its nonpiliated, ebpA allelic replacement mutant (TX5475). METHODS: OG1RF and TX5475 were administered transurethrally either at an ~1 : 1 ratio (competition assay) or individually (monoinfection). Kidney pairs and urinary bladders were cultured 48 h after infection. These strains were also tested in a peritonitis model. RESULTS: No differences were observed in the peritonitis model. In mixed UTIs, OG1RF significantly outnumbered TX5475 in kidneys (P=.0033) and bladders (P< or =.0001). More OG1RF colony-forming units were also recovered from the kidneys of monoinfected mice at the 4 inocula tested (P=.015 to P=.049), and 50% infective doses of OG1RF for kidneys and bladder (9.1x10(1) and 3.5x10(3) cfu, respectively) were 2-3 log(10) lower than those of TX5475. Increased tropism for the kidney relative to the bladder was observed for both OG1RF and TX5475. CONCLUSION: The ebp locus, part of the core genome of E. faecalis, contributes to infection in an ascending UTI model and is the first such enterococcal locus shown to be important in this site.

Relative contributions of Enterococcus faecalis OG1RF sortase-encoding genes, srtA and bps (srtC), to biofilm formation and a murine model of urinary tract infection.

Deletion mutants of the two sortase genes of Enterococcus faecalis OG1RF were constructed. srtC (renamed here bps for biofilm and pilus-associated sortase) was previously shown to be necessary for the production of Ebp pili and important for biofilm formation and endocarditis. Here, we report that a srtA deletion mutant showed a small (5%) yet significant (P = 0.037) reduction in biofilm relative to OG1RF, while a DeltasrtA Deltabps double mutant showed a much greater reduction (74% versus OG1RF and 44% versus the Deltabps mutant). In a murine urinary tract infection (UTI), the 50% infective doses of both the DeltasrtA Deltabps and Deltabps mutants were approximately 2 log10 greater than that of OG1RF or the DeltasrtA mutant. Similarly, approximately 2 log10 fewer bacteria were recovered from the kidneys after infection with the Deltabps mutant (P = 0.017) and the DeltasrtA Deltabps double mutant (P = 0.022) compared to wild-type strain OG1RF. In a competition UTI, the Deltabps mutant was slightly, but not significantly, less attenuated than the DeltasrtA Deltabps double mutant. Fluorescence-activated cell sorter analysis with Ebp-specific antibodies confirmed that a minority of OG1RF cells express Ebp pili on their surface in vitro and that Bps has a major role in Ebp pilus biogenesis but also indicated a function for SrtA in surface localization of the pilus subunit protein EbpA. In conclusion, deletion of bps had a major effect on virulence in murine UTIs, as well as biofilm; deletion of srtA from OG1RF had little effect on these phenotypes, but its deletion from a bps mutant had a pronounced effect on biofilm, suggesting that Bps and/or the proteins it anchors may compensate for the loss of some SrtA function(s).

Relative contributions of Enterococcus faecalis OG1RF sortase-encoding genes, srtA and bps (srtC), to biofilm formation and a murine model of urinary tract infection.

Deletion mutants of the two sortase genes of Enterococcus faecalis OG1RF were constructed. srtC (renamed here bps for biofilm and pilus-associated sortase) was previously shown to be necessary for the production of Ebp pili and important for biofilm formation and endocarditis. Here, we report that a srtA deletion mutant showed a small (5%) yet significant (P = 0.037) reduction in biofilm relative to OG1RF, while a DeltasrtA Deltabps double mutant showed a much greater reduction (74% versus OG1RF and 44% versus the Deltabps mutant). In a murine urinary tract infection (UTI), the 50% infective doses of both the DeltasrtA Deltabps and Deltabps mutants were approximately 2 log10 greater than that of OG1RF or the DeltasrtA mutant. Similarly, approximately 2 log10 fewer bacteria were recovered from the kidneys after infection with the Deltabps mutant (P = 0.017) and the DeltasrtA Deltabps double mutant (P = 0.022) compared to wild-type strain OG1RF. In a competition UTI, the Deltabps mutant was slightly, but not significantly, less attenuated than the DeltasrtA Deltabps double mutant. Fluorescence-activated cell sorter analysis with Ebp-specific antibodies confirmed that a minority of OG1RF cells express Ebp pili on their surface in vitro and that Bps has a major role in Ebp pilus biogenesis but also indicated a function for SrtA in surface localization of the pilus subunit protein EbpA. In conclusion, deletion of bps had a major effect on virulence in murine UTIs, as well as biofilm; deletion of srtA from OG1RF had little effect on these phenotypes, but its deletion from a bps mutant had a pronounced effect on biofilm, suggesting that Bps and/or the proteins it anchors may compensate for the loss of some SrtA function(s).

Emergence of methicillin-resistant Staphylococcus pseudintermedius in Switzerland: three cases of urinary tract infections in cats

Methicillin resistance has emerged in clinical isolates of Staphylococcus pseudintermedius from cats in Switzerland. Three cats suffering from urinary tract infections were infected with methicillin-resistant S. pseudintermedius (MRSP). Phenotypic and genotypic characterization of the resistance profile showed that the isolates displayed resistance to all beta-lactams and cephalosporins (blaZ, mecA), fluoroquinolones, tetracyclines [tet(K)], macrolides, lincosamides and streprogramins B [erm(B)], chloramphenicol (catpC221), trimethoprim [dfr(G)] and the aminoglycosides gentamicin [aac(6')-Ie-aph(2')-Ia], kanamycin and neomycin [aph(3')-III] and streptomycin [ant(6)-Ia]. They also harbor the leukocidin gene lukS-I. MRSP represents a new challenge for antibiotic therapy and this zoonotic bacteria may rapidly spread to animals and humans.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER http://www.clinicaltrials.gov; Identifier: NCT02165774.

Urinary tract endometriosis in patients with deep infiltrating endometriosis: prevalence, symptoms, management, and proposal for a new clinical classification

OBJECTIVE To analyze the prevalence of urinary tract endometriosis (UTE) in patients with deep infiltrating endometriosis (DIE) and to define potential criteria for preoperative workup. DESIGN Retrospective study. SETTING University hospital. PATIENT(S) Six hundred ninety-seven patients with endometriosis. INTERVENTION(S) Excision of all endometriotic lesions. MAIN OUTCOME MEASURE(S) Correlation of preoperative features and intraoperative findings in patients with UTE. RESULT(S) Out of 213 patients presenting DIE, 52.6% suffered from UTE. In patients with ureteral endometriosis, symptoms were not specific. Among the patients with bladder endometriosis, 68.8% complained of urinary symptoms compared to 7.9% in the group of patients without UTE. In patients with rectovaginal endometriosis, the probability of ureterolysis showed a linear correlation with the size of the nodule. We found that 3 cm in diameter provided a specific cutoff value for the likelihood of ureteric involvement. CONCLUSION(S) The prevalence of UTE has often been underestimated. Preoperative questioning is important in the search for bladder endometriosis. The size of the nodule is one of the few reliable criteria in preoperative assessment that can suggest ureteric involvement. We propose a classification of ureteral endometriosis that will allow the standardization of terminology and help to compare the outcome of different surgical treatment in randomized studies.

Na(+), K(+), Cl(-), acid-base or H2O homeostasis in children with urinary tract infections: a narrative review.

Guidelines on the diagnosis and management of urinary tract infections in childhood do not address the issue of abnormalities in Na(+), K(+), Cl(-) and acid-base balance. We have conducted a narrative review of the literature with the aim to describe the underlying mechanisms of these abnormalities and to suggest therapeutic maneuvers. Abnormalities in Na(+), K(+), Cl(-) and acid-base balance are common in newborns and infants and uncommon in children of more than 3 years of age. Such abnormalities may result from factitious laboratory results, from signs and symptoms (such as excessive sweating, poor fluid intake, vomiting and passage of loose stools) of the infection itself, from a renal dysfunction, from improper parenteral fluid management or from the prescribed antimicrobials. In addition, two transient renal tubular dysfunctions may occur in infants with infectious renal parenchymal involvement: a reduced capacity to concentrate urine and pseudohypoaldosteronism secondary to renal tubular unresponsiveness to aldosterone that presents with hyponatremia, hyperkalemia and acidosis. In addition to antimicrobials, volume resuscitation with an isotonic solution is required in these children. In secondary pseudohypoaldosteronism, isotonic solutions (such as 0.9 % saline or lactated Ringer) correct not only the volume depletion but also the hyperkalemia and acidosis. In conclusion, our review suggests that in infants with infectious renal parenchymal involvement, non-renal and renal causes concur to cause fluid volume depletion and abnormalities in electrolyte and acid-base balance, most frequently hyponatremia.

Tibial Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review

CONTEXT Tibial nerve stimulation (TNS) is a promising therapy for non-neurogenic lower urinary tract dysfunction and might also be a valuable option for patients with an underlying neurological disorder. OBJECTIVE We systematically reviewed all available evidence on the efficacy and safety of TNS for treating neurogenic lower urinary tract dysfunction (NLUTD). EVIDENCE ACQUISITION The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. EVIDENCE SYNTHESIS After screening 1943 articles, 16 studies (4 randomized controlled trials [RCTs], 9 prospective cohort studies, 2 retrospective case series, and 1 case report) enrolling 469 patients (283 women and 186 men) were included. Five studies reported on acute TNS and 11 on chronic TNS. In acute and chronic TNS, the mean increase of maximum cystometric capacity ranged from 56 to 132mL and from 49 to 150mL, and the mean increase of bladder volume at first detrusor overactivity ranged from 44 to 92mL and from 93 to 121mL, respectively. In acute and chronic TNS, the mean decrease of maximum detrusor pressure during the storage phase ranged from 5 to 15cm H2O and from 4 to 21cm H2O, respectively. In chronic TNS, the mean decrease in number of voids per 24h, in number of leakages per 24h, and in postvoid residual ranged from 3 to 7, from 1 to 4, and from 15 to 55mL, respectively. No TNS-related adverse events have been reported. Risk of bias and confounding was high in most studies. CONCLUSIONS Although preliminary data of RCTs and non-RCTs suggest TNS might be effective and safe for treating NLUTD, the evidence base is poor, derived from small, mostly noncomparative studies with a high risk of bias and confounding. More reliable data from well-designed RCTs are needed to reach definitive conclusions. PATIENT SUMMARY Early data suggest tibial nerve stimulation might be effective and safe for treating neurogenic lower urinary tract dysfunction, but more reliable evidence is required.