The effects of Cernitin® on inflammatory parameters and benign prostatic hyperplasia: An in vitro study.

The pollen extract Cernitin® is widely used for treatment of benign prostatic hyperplasia (BPH) and non-bacterial chronin prostatitis. However, little is known about the underlying molecular mechanisms to explain the clinical effects of Cernitin®. In this study, we sought to investigate the cellular mechanisms by which Cernitin® induces its effects on human prostatic cell lines BPH-1 and WPMY-1 and primary human peripheral blood mononuclear cells (hPBMCs) in vitro. We examined the effects of Cernitin® formulas T60 and GBX on the protein expression, proliferation, and cytokines production. Results revealed that Cernitin® upregulated antiinflammatory cytokine interleukin (IL)-10 and its receptors IL-10RA and IL-10B in addition to the upregulation of tumour necrosis factor-related apoptosis-inducing ligand in hPBMC. Interestingly, the levels of proinflammatory cytokines IL-6 and IL-8 were also increased. Furthermore, Cernitin® had significantly increased the level of IL-10 in BPH-1 and WPMY-1 cells. The level of IL-6 was also significantly increased in these cells although both T60 and GBX inhibited STAT-3 phosphorylation. Moreover, Cernitin® formulas had significantly reduced androgen receptor and prostate-specific antigen protein expression in stromal cells (p < .05). Treatment with GBX and T60 had significantly inhibited proliferation of BPH (p < .001) and stromal cells (p < .05), in a dose-dependent manner. Taken together, treatment with Cernitin® showed to regulate cytokines level in both prostatic cell lines and hPBMCs and it was associated with decreased androgen receptor and prostate-specific antigen levels WPMY-1 cells.

Tailored perioperative antimicrobial prophylaxis in urological surgery: myth or reality?

PURPOSE OF REVIEW: The controversies surrounding perioperative antimicrobial prophylaxis (AMP) are about the use and especially misuse of antibiotics. The overall lack of evidence to facilitate a rational perioperative AMP policy in urological surgery and the postoperative infectious complications remain a challenge. Therefore, a basic tool to aid decision-making would be useful. A model based on the patients' risk factors, the level of contamination and grading of surgical procedures is discussed. RECENT FINDINGS: A series of studies have shown that infectious complications and healthcare-associated infections remain consistently at an average of 10%, with a great variation in frequency dependent on the patients' preoperative status and the type, severity and contamination level of the surgical procedure. Preoperative patient assessment and preparation are key factors for well tolerated surgery and recovery. Adherence to the guidelines appears to reduce both the prescription of antimicrobials and the total costs without risking the patient outcome. Several studies of a series of interventions such as cystoscopy, endoscopic stone surgery and selected clean-contaminated interventions give support to the model. Bacteriuria, upgrading the patient to the contaminated level, requires preoperative control. SUMMARY: The discussed model assists the urologists in decision-making on perioperative AMP and contributes to a responsible use of antibiotics.

Antimicrobial resistance in urosepsis: outcomes from the multinational, multicenter global prevalence of infections in urology (GPIU) study 2003-2013.

OBJECTIVE: Primary objective was to identify the (1) relationship of clinical severity of urosepsis with the pathogen spectrum and resistance and (2) appropriateness of using the pathogen spectrum and resistance rates of health-care-associated urinary tract infections (HAUTI) as representative of urosepsis. The secondary objective was to provide an overview of the pathogens and their resistance profile in patients with urosepsis. POPULATION AND METHODS: A point prevalence study carried out in 70 countries (2003-2013). Population studied included; 408 individuals with microbiologically proven urosepsis, 1606 individuals with microbiological proof of HAUTI and 27,542 individuals hospitalised in urology wards. Main outcomes are pathogens and resistance identified in HAUTIs and urosepsis including its clinical severity. A statistical model that included demographic factors (study year, geographical location, hospital setting) was used for analysis. RESULTS: Amongst urology practices, the prevalence of microbiologically proven HAUTI and urosepsis was 5.8 and 1.5 %, respectively. Frequent pathogens in urosepsis were E. coli (43 %), Enterococcus spp. (11 %), P. aeruginosa (10 %) and Klebsiella spp. (10 %). Resistance to commonly prescribed antibiotics was high and rates ranged from 8 % (imipenem) to 62 % (aminopenicillin/ß lactamase inhibitors); 45 % of Enterobacteriaceae and 21 % of P. aeruginosa were multidrug-resistant. Resistance rates in urosepsis were higher than in other clinical diagnosis of HAUTI (Likelihood ratio <0.05). CONCLUSIONS: It is not appropriate to use the pathogen spectrum and resistance rates of other HAUTIs as representative of urosepsis to decide on empirical treatment of urosepsis. Resistance rates in urosepsis are high, and precautions should be made to avoid further increase.

Preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures.

PURPOSE: To assess the patient and identify the risk factors for infectious complications in conjunction with urological procedures and suggest a model for classification of the procedures. METHOD: Review of literature, critical analysis of data and tentative model for reducing infectious complications. RESULTS: Risk factors are bound to the patient and to the procedure itself and are associated with the environment where the healthcare is provided. Assuming a clean environment and sterile operation field, a five-level assessment ladder related to the patient and type of surgery is useful, considering: (1) the ASA score, (2) the general risk factors, (3) the individual endogenous and exogenous risk factors, (4) the class of surgery and the potential bacterial contamination burden and (5) the level of severity and difficulty of the surgical intervention. A cumulative approach will identify the level of risk for each patient and define preventive measures, such as the type of antibiotic prophylaxis or therapeutic measures before surgery. There are data suggesting that the higher the ASA score, the higher is the risk of infectious complication. Age, dysfunction of the immune system, hypo-albuminaemia/malnutrition and overweight, uncontrolled blood glucose level and smoking are independent general risk factors, whilst bacteriuria, indwelling catheter treatment, urinary tract stone disease, urinary tract obstruction and a history of urogenital infection are specific urological risk factors. There is inconclusive evidence for most other reported risk factors. The level of contamination of the surgical field is of utmost importance as are the procedure-related factors, and the sum of these have to be reflected on for the subsequent perioperative management of the patient. CONCLUSIONS: It is essential to identify and control risk factors to minimize infectious complications in conjunction with urological procedures. Our knowledge is limited and clinical research and quality registries analysing risk factors must be undertaken. We propose a working basis for assessment of patients' risk factors and classification of urological procedures.

Update on biofilm infections in the urinary tract.

PURPOSE: Biofilm infections have a major role in implants or devices placed in the human body. As part of the endourological development, a great variety of foreign bodies have been designed, and with the increasing number of biomaterial devices used in urology, biofilm formation and device infection is an issue of growing importance. METHODS: A literature search was performed in the Medline database regarding biofilm formation and the role of biofilms in urogenital infections using the following items in different combinations: "biofilm," "urinary tract infection," "bacteriuria," "catheter," "stent," and "encrustation." The studies were graded using the Oxford Centre for Evidence-based Medicine classification. RESULTS: The authors present an update on the mechanism of biofilm formation in the urinary tract with special emphasis on the role of biofilms in lower and upper urinary tract infections, as well as on biofilm formation on foreign bodies, such as catheters, ureteral stents, stones, implants, and artificial urinary sphincters. The authors also summarize the different methods developed to prevent biofilm formation on urinary foreign bodies. CONCLUSIONS: Several different approaches are being investigated for preventing biofilm formation, and some promising results have been obtained. However, an ideal method has not been developed. Future researches have to aim at identifying effective mechanisms for controlling biofilm formation and to develop antimicrobial agents effective against bacteria in biofilms.

Role of hexaminolevulinate-guided fluorescence cystoscopy in bladder cancer: critical analysis of the latest data and European guidance.

OBJECTIVE: Hexaminolevulinate (HAL) is an optical imaging agent used with fluorescence cystoscopy (FC) for the detection of non-muscle-invasive bladder cancer (NMIBC). Guidelines from the European Association of Urology (EAU) and a recent, more detailed European expert consensus statement agree that HAL-FC has a role in improving detection of NMIBC and provide recommendations on situations for its use. Since the publication of the EAU guidelines and the European consensus statement, new evidence on the efficacy of HAL-FC in reducing recurrence of NMIBC, compared with white light cystoscopy (WLC), have been published. MATERIAL AND METHODS: To consider whether these new trials have an impact on the expert guidelines and on clinical practice (e.g. supporting existing recommendations or providing evidence for a change or expansion of practice), a group of bladder cancer experts from Denmark, Finland, Norway and Sweden met to address the following questions: What is the relevance of the new data on HAL-FC for clinical practice in managing NMIBC? What impact do the new data have on European guidelines? How could HAL-FC be used in clinical practice? and What further information on HAL-FC is required to optimize the management of NMIBC? RESULTS AND CONCLUSIONS: This article reports the outcomes of the discussion at the Nordic expert panel meeting, concluding that, in line with European guidance, HAL-FC has an important role in the initial detection of NMIBC and for follow-up of patients to assess tumour recurrence after WLC. It provides practical advice, with an algorithm on the use of this diagnostic procedure for urologists managing NMIBC.

Experimental in vivo model to evaluate the impact of Cernitin™ on pain response on induced chronic bladder inflammation.

OBJECTIVE: Inflammation of the urinary bladder may cause burdensome pain also called bladder pain syndrome (BPS). A limitation in understanding BPS pathophysiology is the lack of appropriate preclinical model. Previously published clinical and preclinical studies revealed positive impact of Cernitin™ on pain relief in chronic prostatitis. The objective of this study was to evaluate the effects of Cernitin™ on induced inflammation of the urinary bladder in rats. We also sought to identify biomarkers which might play a role in the management of BPS. MATERIALS AND METHODS: Cystitis was induced by injection of cyclophosphamide (CYP) in female rats. Thereafter, animals were randomly divided into four treatment groups and two control groups. Evaluation of pain scores was assessed by von Frey assay. Expression of pain- and pro-inflammatory biomarkers was determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. RESULTS: Treatments with Cernitin™ displayed significant anti-nociceptive effects on CYP-induced visceral pain (p < .01). In contrast, vehicle-treated animals showed high pain score even at the lowest force. Furthermore, results of ELISA showed that Cernitin™-treated animals had significantly reduced levels of COX-2 (T60, p < .01; GBX, p < .05) in bladder tissue homogenate. Immunohistochemical (IHC) staining of bladder tissues showed that Cernitin™-treated animals exhibited less CD45-positive cells, while massive CD45-positive cells infiltration was detected in vehicle-treated animals. IHC also revealed lower SP and PGD2 expression levels in Cernitin™-treated tissues. CONCLUSIONS: Cernitin™ components reduced pain score and inflammatory marker COX-2. Our findings suggest a potential therapeutic role for Cernitin™ in the management of BPS.

Community-onset urosepsis: incidence and risk factors for 30-day mortality - a retrospective cohort study.

BACKGROUND: Urosepsis is a life-threatening condition that needs to be addressed without delay. Two critical issues in its management are: (1) Appropriate empirical antibiotic therapy, considering the patients general condition, comorbidity, and the pathogen expected; and (2) Timing of imaging to identify obstruction requiring decompression. OBJECTIVES: To identify risk factors associated with 30-day mortality in patients with urosepsis. METHODS: From a cohort of 1,605 community-onset bloodstream infections (CO-BSI), 282 patients with urosepsis were identified in a Swedish county 2019-2020. Risk factors for mortality with crude and adjusted odds ratios were analysed using logistic regression. RESULTS: Urosepsis was found in 18% (n = 282) of all CO-BSIs. The 30-day all-cause mortality was 14% (n = 38). After multivariable analysis, radiologically detected urinary tract disorder was the predominant risk factor for mortality (OR = 4.63, 95% CI = 1.47-14.56), followed by microbiologically inappropriate empirical antibiotic therapy (OR = 4.19, 95% CI = 1.41-12.48). Time to radiological diagnosis and decompression of obstruction for source control were also important prognostic factors for survival. Interestingly, 15% of blood cultures showed gram-positive species associated with a high 30-day mortality rate of 33%. CONCLUSION: The 30-day all-cause mortality from urosepsis was 14%. The two main risk factors for mortality were hydronephrosis caused by obstructive stone in the ureter and inappropriate empirical antibiotic therapy. Therefore, early detection of any urinary tract disorder by imaging followed by source control as required, and antibiotic coverage of both gram-negative pathogens and gram-positive species such as E. faecalis to optimise management, is likely to improve survival in patients with urosepsis.

Antimicrobial Stewardship: What We All Just Need to Know.

CONTEXT: Microbial resistance to antibiotics is increasing while antimicrobials are limited. Responsible use is necessary. OBJECTIVE: Describe the present acquisitions of antimicrobial stewardship programmes (ASPs) in general and in urology. EVIDENCE SYNTHESIS: Well-designed ASPs have an impact on reducing treatment duration, shortening intravenous treatment in favour of oral targeted therapy, and reducing the total antibiotic prescription. Moreover, the hospital length of stay can potentially be reduced without hazard for the patient. CONCLUSIONS: It is recommended to set up an ASP for education and feedback as standard in urological practice. The exact design of the ASP should be tailored to regional prerequisites.

Asymptomatic Bacteriuria is Harmless and Even Protective: Don't Treat if You Don't Have a Very Specific Reason.

Symptom-free bacterial colonization of the lower urinary tract in an otherwise healthy individual was long misunderstood. Our current understanding is based on solid research proving that asymptomatic bacteriuria (ABU) is harmless and even protective against symptomatic urinary tract infection episodes. Thus, ABU should not be treated in patients with the exception of before endosurgery and, until we have accumulated more knowledge, in pregnant women.

Can routine outpatient follow-up of patients with bladder cancer be improved? A multicenter prospective observational assessment of blue light flexible cystoscopy and fulguration.

BACKGROUND: The aim of this prospective cohort study was to determine the feasibility of incorporating blue light flexible cystoscopy (BLFC) and biopsy/fulguration into routine outpatient follow-up of non-muscle invasive bladder cancer patients. METHODS: The study included patients with non-muscle-invasive bladder cancer (NMIBC) who were scheduled for routine follow-up. Hexaminolevulinate was instilled in the outpatient department, and the bladder was examined under white light and then with BLFC. Biopsies were taken from all suspicious lesions. Small tumors and suspicious lesions were fulgurated on site; patients with larger lesions were referred to the operating room for resection. RESULTS: The study included 69 patients, with a mean age of 70 years (range 33-89 years) and a mean duration since NMIBC diagnosis of 8 years. Most patients had high-grade cancer at initial diagnosis (52/69) and were at high risk of recurrence (48/69). Two patients per hour could be assessed using outpatient BLFC. Preparation and instillation of hexaminolevulinate took less than 10 minutes per patient, and patients had an additional waiting time of 45-60 minutes following instillation, while the hexaminolevulinate solution was retained in the bladder before examination. Eleven patients had histologically confirmed tumors that were identified using both white light flexible cystoscopy and BLFC. An additional three patients had tumors that were identified by BLFC only: two with Ta tumors and one with carcinoma in situ. Of the 14 patients with confirmed tumors, 11 could be managed on site with fulguration, whereas three were referred to the operating room. No adverse events attributable to BLFC were reported. CONCLUSION: Routine outpatient management of patients with NMIBC using BLFC and on-site biopsy/fulguration is feasible, despite the additional time required for hexaminolevulinate instillation, and appears to allow early detection of recurrent lesions, which can be fulgurated without the need for hospitalization.

Catheter-associated urinary tract infections and other infections in patients hospitalized for acute stroke: A prospective cohort study of two different silicone catheters.

OBJECTIVE: Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection. The primary aim of this study was to investigate whether the use of a silicone catheter coated with an ultrathin layer of a combination of the noble metals gold, palladium and silver (BIP™-silicone catheter) could reduce the incidence of CAUTI and antibiotic prescription compared with a standard silicone catheter in a cohort of acute neurological patients suffering primarily from stroke. At the same time, all infectious events requiring prescription of an antimicrobial agent were registered and are reported. MATERIALS AND METHODS: The study was designed as a crossover cohort study enrolling men and women aged over 18 years, requiring emergency management for stroke including the insertion of an indwelling catheter. Data on patient characteristics, urinary tract infections (UTIs), other infectious events and all antibiotic prescriptions were recorded prospectively. RESULTS: The patients' characteristics differed in the two centres in terms of age but not in diagnosis distribution. UTIs were recorded in 78 (24.2%) of the patients, ahead of pulmonary tract infections (n = 65; 20.2%). There was no difference in terms of CAUTI in the two catheter groups, even in subgroups with catheter treatment for 1 week or less. The patients with a diagnosed UTI required 3.5 more days of hospitalization than those without a UTI. CONCLUSION: CAUTIs were the most frequent healthcare-associated infections, slightly ahead of pulmonary tract infections. No advantages of the coated catheter could be found in this cohort of critically ill patients.

Contemporary Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

CONTEXT: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that causes severe symptoms, bother, and quality-of-life impact in the 8.2% of men who are believed to be affected. Research suggests a complex pathophysiology underlying this syndrome that is mirrored by its heterogeneous clinical presentation. Management of patients diagnosed with CP/CPPS has always been a formidable task in clinical practice. Due to its enigmatic etiology, a plethora of clinical trials failed to identify an efficient monotherapy. OBJECTIVE: A comprehensive review of published randomized controlled trials (RCTs) on the treatment of CP/CPPS and practical best evidence recommendations for management. EVIDENCE ACQUISITION: Medline and the Cochrane database were screened for RCTs on the treatment of CP/CPPS from 1998 to December 2014, using the National Institutes of Health Chronic Prostatitis Symptom Index as an objective outcome measure. Published data in concert with expert opinion were used to formulate a practical best evidence statement for the management of CP/CPPS. EVIDENCE SYNTHESIS: Twenty-eight RCTs identified were eligible for this review and presented. Trials evaluating antibiotics, α-blockers, anti-inflammatory and immune-modulating substances, hormonal agents, phytotherapeutics, neuromodulatory drugs, agents that modify bladder function, and physical treatment options failed to reveal a clear therapeutic benefit. With its multifactorial pathophysiology and its various clinical presentations, the management of CP/CPPS demands a phenotypic-directed approach addressing the individual clinical profile of each patient. Different categorization algorithms have been proposed. First studies applying the UPOINTs classification system provided promising results. Introducing three index patients with CP/CPPS, we present practical best evidence recommendations for management. CONCLUSIONS: Our current understanding of the pathophysiology underlying CP/CPPS resulting in this highly variable syndrome does not speak in favor of a monotherapy for management. No efficient monotherapeutic option is available. The best evidence-based management of CP/CPPS strongly suggests a multimodal therapeutic approach addressing the individual clinical phenotypic profile. PATIENT SUMMARY: Chronic prostatitis/chronic pelvic pain syndrome presents a variable syndrome. Successful management of this condition is challenging. It appears that a tailored treatment strategy addressing individual patient characteristics is more effective than one single therapy.

Grey Zones in the Field of Urinary Tract Infections.

Urinary tract infections are a very common clinical problem with various knowledge gaps requiring urgent attention in areas including pathophysiology, diagnosis, antibiotic resistance, and prophylaxis. These grey zones preclude optimal management of urologic patients.

How to Use Antimicrobial Prophylaxis in Urological Procedures.

A revision of clinical practice in terms of antimicrobial prophylaxis is urgently needed starting from: (1) obtaining information about local pathogen profiles and antimicrobial resistance, (2) evaluating all patient-related risk factors for the development of infectious complications, (3) and prescribing antimicrobials according to the principles of the European Association of Urology guidelines.

Asymptomatic Bacteriuria in Clinical Urological Practice: Preoperative Control of Bacteriuria and Management of Recurrent UTI.

Asymptomatic bacteriuria (ABU) is a common clinical condition that often leads to unnecessary antimicrobial use. The reduction of antibiotic overuse for ABU is consequently an important issue for antimicrobial stewardship and to reduce the emergence of multidrug resistant strains. There are two issues in everyday urological practice that require special attention: the role of ABU in pre-operative prophylaxis and in women affected by recurrent urinary tract infections (rUTIs). Nowadays, this is the time to think over our practice and change our way of thinking. Here, we aimed to summarize the current literature knowledge in terms of ABU management in patients undergoing urological surgery and in patients with rUTIs. In the last years, the approach to patient with ABU has changed totally. Prior to all surgical procedures that do not enter the urinary tract, ABU is generally not considered as a risk factor, and screening and treatment are not considered necessary. On the other hand, in the case of all procedures entering the urinary tract, ABU should be treated in line with the results of a urine culture obtained before the procedure. In patients affected by rUTIs, ABU can even have a protective role in preventing symptomatic recurrence, particularly when Enterococcus faecalis (E. faecalis) has been isolated.

Controversies in antibiotic prophylaxis in urology.

Antibiotic prophylaxis in urologic surgery remains controversial. However, progress has been made and some of the controversies have been answered. Firstly, it is important to underline that urologic diagnostic and therapeutic procedures can induce surgical site infections (SSIs), bacteriuria, pyelonephritis and septicaemia in a substantial number of patients, too great to be neglected. Secondly, as patients are different and have various risk factors, a careful assessment of the patient and its individual risk is crucial. Thirdly, the same procedure may be totally different from one individual to another and they can rarely be grouped as standard procedures. A floating level of invasiveness is followed by a variation of the risk of infection. Fourthly, the pathogens and their susceptibility pattern vary extensively in Europe so that no clear-cut recommendations as for the choice of antibiotics can be given. Basic principles of antibiotic prophylaxis in terms of timing, mode of administration and length of regiment apply for urologic interventions. Thus, clean operations will usually not require antimicrobial prophylaxis except for those including the implant of a prosthetic device, while clean-contaminated will benefit from preventive antimicrobials. It is the task of the urologists to carefully assess each individual patient and procedure to opt for an optimal prophylaxis.

The nested variant of urothelial carcinoma: a rare but important bladder neoplasm with aggressive behavior. Three case reports and a review of the literature.

OBJECTIVE: To describe our experience with the nested variant of urothelial carcinoma (UC-NV) of the bladder, by characterization of the clinical picture and the prognostic implications of this rare form of bladder neoplasm. MATERIALS AND METHODS: Three cases of UC-NV of the bladder treated in our institutions were revised and data compared with previously published case-reports. RESULTS: Three patients presented with advanced muscle-invasive UC-NV, of which two had lymph node metastasis at cystoprostatectomy. The histopathology in the latter two cases showed the same picture in the lymph node metastasis as in the primary tumor with nests of tumor cells with mild-moderate atypia. In all three cases the tumor involved a ureteric orifice or the bladder neck. CONCLUSION: UC-NV is a rare but important histopathologic entity. It has a poor prognosis. At early stage, tumors might be difficult to differentiate from benign conditions and awareness of the condition is of outermost importance.