Phytotherapy (BNO 1045) of Acute Lower Uncomplicated Urinary Tract Infection in Women Normalizes Local Host Responses.

INTRODUCTION: Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments. METHODS: Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios. RESULTS: BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively). CONCLUSION: BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.

Bearberry in the treatment of acute uncomplicated cystitis (BRUMI): protocol of a multicentre, randomised double-blind clinical trial.

BACKGROUND: Bearberry (Arctostaphylos uva-ursi) leaf is available as a treatment of uncomplicated cystitis in several European countries. The antimicrobial activity of its extracts and some of its individual constituents has been observed in vitro; however, the efficacy of bearberry compared with standard antimicrobial therapy has not been assessed yet. OBJECTIVE: The objective of the study is to assess the safety and non-inferiority of bearberry as an alternative therapy in the treatment of acute uncomplicated cystitis in comparison with standard antibiotic therapy (fosfomycin). METHODS AND ANALYSIS: This is a randomised controlled double-blinded multicentre trial. Eligible patients will be premenopausal women with a sum score of ≥6 for the typical acute uncomplicated cystitis symptoms (frequency, urgency, painful urination, incomplete emptying, suprapubic pain and visible haematuria) reported on the Acute Cystitis Symptom Score (ACSS) typical domain and pyuria. Patients will be randomly assigned to receive 3 g single dose of fosfomycin powder and two placebo tablets three times a day for 7 days or B a single dose of placebo powder and two tablets containing a dry extract of Uvae ursi folium. At least 504 patients (allocated as 1:1) will need to be enrolled to access non-inferiority with a non-inferiority limit of 14% for the primary endpoint.Improvement of symptoms of uncomplicated cystitis (based on the ACSS score) at day 7 is defined as the primary endpoint, whereas several secondary endpoints such as the number and ratio of patients with bacteriuria at day 7, frequency and severity of side effects; recurrence of urinary tract infection, concurrent use of other over the counter (OTC) medications and food supplements will be determined to elucidate more detailed differences between the groups. The number of recurrences and medications taken for treatment will be monitored for a follow-up period of 90 days (80-100 days). ETHICS AND DISSEMINATION: This study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/4225-1/2021/EKU). The results will be disseminated by publication of peer-reviewed manuscripts. TRIAL REGISTRATION NUMBER: NCT05055544.

Antibiotic therapy of chronic bacterial prostatitis is more effective considering antibiotic susceptibility of all pathogens isolated.

PURPOSE: Because of the insufficient efficacy of the current treatment of chronic bacterial prostatitis (CBP), it is justified to search for a more effective antibiotic therapy (ABT). MATERIALS AND METHODS: This single-centre prospective observational comparative study was conducted in 2012 to 2019 (patients: 60 men with CBP; age: 20-45 y). The clinical examination was performed on admission and at 1, 3, 6, or 12 months. All patients underwent the Meares-Stamey test to obtain expressed prostatic secretion (EPS) and/or post-massage urine (PMU) samples for extended bacteriological examination. The patients were randomly divided into 2 treatment groups (30/30 patients): group I, fluoroquinolones (FQs); group II, a combination of FQs with cephalosporins/macrolides with a treatment duration of 1 month. RESULTS: Patients of both groups had severe symptomatic CBP with an average duration of 4 years. Twenty-three microorganisms (15 aerobes, 9 anaerobes) were identified in PMU. At 3 months follow-up, a positive clinical effect was noted in both groups, which was significant (p<0.05) only in group II concerning NIH-CPSI questionnaire, leukocyturia, prostate volume, maximum urine flow, and decreased pathospermia. At 6 months follow-up, in group II the frequency of Escherichia coli and Enterococcus spp. decreased significantly. In group I aerobes changed only insignificantly from the initial level, but anaerobes increased significantly. In group II the titers of both, aerobes and anaerobes, were significantly lower (p<0.05) at 6 months follow-up as compared to initial values. CONCLUSIONS: ABT targeting all taxa in EPS/PMU is a more effective alternative to standard therapeutic regimens for CBP.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

Postoperative Prevention of Urinary Tract Infections in Patients after Urogynecological Surgeries-Nonantibiotic Herbal (Canephron) versus Antibiotic Prophylaxis (Fosfomycin Trometamol): A Parallel-Group, Randomized, Noninferiority Experimental Trial.

INTRODUCTION AND HYPOTHESIS: Urinary tract infections (UTIs) are one of the most common complications of urogynecological surgeries. The risk of UTIs is increased by the catheterization of the bladder, intraoperative cystoscopy, and urine retention after the procedure. Due to increasing antibiotic resistance, there is a need to search for new methods of postoperative UTI prevention. Canephron is a mixture of century herbs, lovage roots, and rosemary leaves with diuretic, spasmolytic, anti-inflammatory, antibacterial, and nephroprotective properties. The aim of this study is to demonstrate the noninferiority of Canephron versus antibiotic prophylaxis with fosfomycin trometamol (FT), based on the collective results of postoperative urine culture analyses. METHODS: One hundred and twenty-five female patients were randomized into two groups before undergoing urogynecological surgeries, including a control group (n = 67), which received one dose of 3 g of FT the day after the procedure, and a study group (n = 58), which received Canephron three times a day for 14 days, starting the day after the procedure. All the patients were assessed using the Acute Cystitis Symptom Score (ACSS). RESULTS: UTIs were observed in 6.4% of the patients. There was no statistically significant difference between the use of FT and Canephron in terms of UTIs (Chi^2 N-1 = 0.8837; p = ns). Additional factors, such as menopausal status and the type of procedure performed, increased the risk of developing a UTI. Factors such as the body mass index (BMI) and parity had no correlation. CONCLUSIONS: Canephron is noninferior to FT in the prevention of postoperative UTIs. The use of such a phytotherapeutic drug may help to decrease antibiotic consumption, which is closely connected to the growing trend of antibiotic resistance.

Acute Cystitis Symptom Score questionnaire for measuring patient-reported outcomes in women with acute uncomplicated cystitis: Clinical validation as part of a phase III trial comparing antibiotic and nonantibiotic therapy.

PURPOSE: The Acute Cystitis Symptom Score (ACSS) used in a clinical trial comparing the phytodrug Canephron®N (BNO 1045) with an antibacterial agent (fosfomycin trometamol [FT]) in the treatment of acute uncomplicated cystitis (AC) in women was evaluated as a patient-reported outcome measure in a post hoc analysis. MATERIALS AND METHODS: This double-blind, randomized, multicenter, phase III noninferiority trial was performed in 51 centers in Europe. The ACSS questionnaire was used to assess severity and course of symptoms. RESULTS: The post hoc analysis included 325 patients treated with BNO 1045 and 332 patients treated with FT (total of 657 patients). The mean sum-scores of the ACSS-typical domain were comparable between groups on day 1 (BNO 1045: 10.2; FT: 10.1), and then decreased on day 4 (BNO 1045: 5.1; FT: 4.5), at end of treatment on day 8 (BNO 1045: 2.1; FT: 2.1), and at late follow-up on day 38 (BNO 1045: 0.8; FT: 0.9). Predefined thresholds using the scoring system of the ACSS could be established and validated to define "clinical cure." CONCLUSIONS: Evaluating not only antibacterial but also nonantibacterial agents indicated for the treatment of AC in women, clinical criteria for diagnostics, and measures of patient-reported outcomes are more important as main objectives than microbiological criteria. In this post hoc evaluation, we showed that the ACSS questionnaire, validated in several languages, has the potential to be used as a suitable instrument for diagnostics and patient-reported outcomes in well-designed, international, clinical studies investigating different treatment modalities of uncomplicated urinary tract infections.

Effect of a Herbal Therapy on Clinical Symptoms of Acute Lower Uncomplicated Urinary Tract Infections in Women: Secondary Analysis from a Randomized Controlled Trial.

Background: Antibiotics are commonly used as first-line treatment for acute lower uncomplicated urinary tract infections (uUTIs). However, antimicrobial resistance is a growing global problem and efficacious nonantibiotic treatment options are urgently needed. METHODS: A secondary analysis was conducted with data from a randomized, controlled, double-blind trial comparing a fixed combination of extracts of restharrow root, Java tea, and goldenrod herb (Aqualibra®) to placebo in 200 women with acute lower uUTI. Symptom scores reported in the original trial were reanalyzed and adjusted to the definitions of the Acute Cystitis Symptom Score (ACSS). RESULTS: Based on a subgroup of patients with evaluable microbiologic data (n = 122), the decrease of the mean sum-score of three typical ACSS-adjusted symptoms showed significant superiority of the herbal preparation over placebo already after one day of treatment (p = 0.0086); on Day 7, the average difference was -1.9 score points (p < 0.0001). The superior efficacy of the herbal preparation on Day 1 was mainly driven by a difference in response rates of the symptom 'dysuria' (group difference: -29.4%, p = 0.0042). Furthermore, significantly fewer patients in the verum group required antibiotic therapy (15.3% vs. 49.2%, p = 0.0001). These results were confirmed in the intention-to-treat (ITT) population (n = 200). CONCLUSIONS: A fixed combination of extracts of restharrow root, Java tea, and goldenrod herb was superior to placebo regarding symptom relief and prevention of antibiotic use in women with lower uUTI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04032574.

Carbapenem-Containing Combination Antibiotic Therapy against Carbapenem-Resistant Uropathogenic Enterobacteriaceae.

The increasing global prevalence of carbapenem-resistant Enterobacteriaceae (CRE) combined with the decline in effective therapies is a public health care crisis. After respiratory tract infections, urinary tract infections and associated urosepsis are the second most affected by CRE pathogens. By using checkerboard analysis, we tested eight different antibiotics in combination with carbapenems in CAMHB (cation-adjusted Müller-Hinton broth) and artificial urine against seven CRE strains and three susceptible strains. To further determine whether these combinations are also effective in a dynamic model, we have performed growth curves analyses in a dynamic bladder model with three uropathogenic CRE strains. In this model, we simulated the urinary pharmacokinetic after application of 1,000 mg intravenous (i.v.) ertapenem alone or in combination with 500 mg i.v. levofloxacin, 1,000 mg oral rifampin, or 3,000 mg oral fosfomycin. Bacterial growth was measured for 48 h, simulating voiding of the bladder every 3 h. According to the median fractional inhibitory concentration indices (ΣFICIs), the values we found were additive to synergistic results across all tested CRE strains for combinations of carbapenems with colistin sulfate, levofloxacin, fosfomycin, rifampin, and tigecycline in CAMHB and artificial urine. In the dynamic bladder model, all three CRE strains tested showed regrowth after treatment with ertapenem up to 48 h. Regrowth could be prevented by combination with levofloxacin, fosfomycin, or rifampin. Carbapenem-containing combination therapy with fosfomycin or rifampin could be an option for better treatment of urinary tract infections (UTIs) caused by CRE strains. This should be further investigated in clinical studies.

Multidisciplinary approach to prostatitis.

The modern clinical research on prostatitis started with the work of Stamey and coworkers who developed the basic principles we are still using. They established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate and to differentiate the main categories of prostatitis. Such categories with slight modifications are still used according to the NIH classification: acute bacterial prostatitis, chronic bacterial prostatitis, Chronic Pelvic Pain Syndrome (CPPS) and asymptomatic prostatitis. Prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms of benign prostatic hyperplasia and prostatitis. Chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system affecting surrounding neural tissue at molecular, structural and functional levels. Clinical observations suggest that chronic inflammation correlates with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and benign prostatic hyperplasia (BPH) and an history of clinical chronic prostatitis significantly increases the odds for prostate cancer. The NIHNIDDK classification based on the use of the microbiological 4- glasses localization test or simplified 2-glasses test, is currently accepted worldwide. The UPOINT system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments. The UPOINTS algorithm implemented the original UPOINT adding to the urinary domains (U), psycho-social (P), organspecific (O), infection (I), neurological (N), muscle tension and tenderness (T) a further domain related to sexuality (S). In fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality of life of patients with CP/CPPS. Prostatic ultrasound represents the most popular imaging test in the work-up of either acute and chronic prostatitis although no specific hypo-hyperechoic pattern has been clearly associated with chronic bacterial prostatitis and CPPS. Use of a digital-processing software to calculate the extension of prostatic calcification area at ultrasound demonstrated a higher percentage of prostatic calcification in patients with chronic bacterial prostatitis. Multiparametric Magnetic Resonance Imaging (mpMRI) is the current state-of-the art imaging modality in the assessment of patients with prostate cancer although a variety of benign conditions, including inflammation, may mimic prostate cancer and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions. Bacteria can infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. Enterobacteriaceae are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of Enterococci has been reported. Many strains of these uropathogens exhibit the ability to form biofilm and multidrug- resistance. Sexually Transmitted Infections (STI) agents, in particular Chlamydia trachomatis and Mycoplasma genitalium, have been also considered as causative pathogens of chronic bacterial prostatitis. On the contrary the effective role in genital diseases of other "genital mycoplasmas" is still a much debated issue. Sexually Transmitted Infections agents should be investigated by molecular methods in both patient and sexual partner. "Next generation" investigations, such as cytokine analysis, cytological typing of immune cells could help stratifying the immune response. Epigenetic dysregulation of inflammatory factors should be investigated according to systemic and compartment-specific signals. The search for biomarkers should also include evaluation of hormonal pathways, as measurement of estrogen levels in semen. Antimicrobials are the first line agents for the treatment of bacterial prostatitis. The success of antimicrobial treatment depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations in prostate secretion and prostate tissue. Acute bacterial prostatitis can be a serious infection with a potential risk for urosepsis For iInitial treatment of severely ill patients, intravenous administration of high doses of bactericidal antimicrobials, such as broad-spectrum penicillins, third-generation cephalosporins or fluoroquinolones, is recommended in combination with an aminoglycoside. Use of piperacillin-tazobactam and meropenem is justified in presence of multiresistant gramnegative pathogens. The antibiotic treatment of chronic prostatitis is currently based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with chronic bacterial prostatitis. For the treatment of Chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, whereas no differences were observed in microbiological and clinical efficacy between macrolides and tetracyclines for the treatment of infections caused by intracellular pathogens. Aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant prostatitis. Use of alpha-blockers in CP/CPPS patients with urinary symptoms and analgesics +/- non steroidal anti-inflammatory drugs (NSAID), in presence of pain demonstrated a reduction of symptoms reduction and an improvement of quality of life, although long term use of NSAID is limited by side effect profile. However, the multimodal therapeutic regimen by contemporary use of alphablockers, antibiotics and anti-inflammatory showed a better control of prostatitis symptoms than single drug treatment. Novel therapeutic substances for the treatment of pain, such as the cannabinoid anandamide would be highly interesting to test. An alternative for the treatment of chronic prostatitis/chronic pelvic pain syndrome is phytotherapy, as primary therapy or in association with other drugs. Quercetin, pollen extract, extract of Serenoa repens and other mixtures of herbal extracts showed a positive effect on symptoms and quality of life without side effects. The association of CP/CPPS with alterations of intestinal function has been described. Diet has its effects on inflammation by regulation of the composition of intestinal flora and direct action on the intestinal cells (sterile inflammation). Intestinal bacteria (microbiota) interacts with food influencing the metabolic, immune and inflammatory response of the organism. The intestinal microbiota has protective function against pathogenic bacteria, metabolic function by synthesis of vitamins, decomposition of bile acids and production of trophic factors (butyrate), and modulation of the intestinal immune system. The alteration of the microbiota is called "dysbiosis" causing invasive intestinal diseases pathologies (leaky gut syndrome and food intolerances, irritable bowel syndrome or chronic inflammatory bowel diseases) and correlating with numerous systemic diseases including acute and chronic prostatitis. Administration of live probiotics bacteria can be used to regulate the balance if intestinal flora. Sessions of hydrocolontherapy can represent an integration to this therapeutic approach. Finally, microbiological examination of sexual partners can offer supplementary information for treatment.

Transurethral Resection of the Prostate: are We Following the Guidelines? - Outcomes from the Global Prevalence of Infections in Urology (GPIU) Study.

Transurethral resection of the prostate (TURP) is one of the most common urological procedures. With the increasing rate of multiresistant infections including urosepsis, it is essential for all surgeons to adhere to the relevant international guidelines to prevent infectious complications. The aim of this prospective, multinational, multicentre study was to evaluate compliance with recommended infection control measures regarding TURP procedures. The study was performed as a side questionnaire to the annual Global Prevalence Study of Infections in Urology (GPIU) between 2006 and 2009. Patients that had undergone TURP were eligible. Baseline data about hospitals and patients were collected. The questionnaire contained questions regarding preoperative microbiological investigations, catheter care and performance of perioperative antibiotic prophylaxis. A total of 825 men were included from 138 participating centres from Africa, Asia, Europe and South America. Only 50.1% of the patients received perioperative antibiotic prophylaxis with a median duration of 3 days (interquartile range [IQR] = 1-7 days). Preoperative urine culture was taken in 59.2%. The catheter was replaced in 1 week prior to the surgery only in 38.3% of cases. Compliance with the recommended infection control measures regarding TURP were only moderate, despite high grade recommendations in relevant international Guidelines. Stronger guideline adherence is necessary to improve patient care decrease antibiotic consumption in line with antibiotic stewardship in surgical practices.

Should We Always Use Antibiotics after Urodynamic Studies in High-Risk Patients?

AIM: The aim of this observational study was to evaluate the effectiveness of a phytotherapic drug (Canephron N) in preventing urinary tract infection (UTI) in high-risk women undergoing urodynamic studies (UDS). METHODS: The study protocol was approved by the local institutional ethical committee. Adult women with at least one risk factor for acquiring UTI (defined as: age over 70, elevated postvoid residual urine>100 ml, recurrent UTI, pelvic organ prolapse (POP) ≥II in POP-Q scale, and neurogenic bladder) had received after UDS either a single oral dose of fosfomycin trometamol (FT) (3 grams) or a phytodrug containing centaury herb, lovage root, and rosemary leaves (5 ml taken orally three times daily for one week). All patients included in the study had no pyuria according to urine dipstick (nitrite and/or blood and/or leukocyte esterase) and negative urine culture (CFU < 103/ml) before UDS. Urine samples were also tested 7 days after UDS. RESULTS: Seventy-two high-risk participants completed the study. Seven days after urodynamic studies UTI symptoms, pyuria (nitrite and/or blood and/or leukocyte esterase) and bacteriuria with E. coli occurred in two patients (one (2.8%) in the FT and one (2.7%) in the phytodrug group, respectively). No statistical differences in UTI incidence were found between both treatment groups. We did not observe any additional adverse events in both groups. The major disadvantage of prophylaxis with the phytodrug as compared to FT was the necessity of continuing therapy for 7 days. CONCLUSION: Prophylaxis of UTI with a phytodrug (Canephron N) may be considered a good alternative to antibiotic prophylaxis use after UDS in high-risk female patients.

Non-Antibiotic Herbal Therapy (BNO 1045) versus Antibiotic Therapy (Fosfomycin Trometamol) for the Treatment of Acute Lower Uncomplicated Urinary Tract Infections in Women: A Double-Blind, Parallel-Group, Randomized, Multicentre, Non-Inferiority Phase III Trial.

INTRODUCTION: This randomized, controlled, Phase III non-inferiority clinical trial aimed to determine whether herbal therapy with Canephron® N (BNO 1045) is non-inferior to fosfomycin trometamol (FT) in treating acute lower uncomplicated urinary tract infections (uUTIs). MATERIALS AND METHODS: Women aged 18-70 years with typical symptoms of newly diagnosed acute lower uUTIs were randomized to BNO 1045 (n = 325) or FT (n = 334), with corresponding matched placebo. The primary endpoint was the proportion of patients who received additional antibiotics (ABs) to treat uUTIs between Days 1 and 38 ±3. RESULTS: Between Days 1 and 38, 238 (83.5%) patients in the BNO 1045 group and 272 (89.8%) patients in the FT group received no additional ABs. At a 15% non-inferiority margin, BNO 1045 was non-inferior to FT in treating uUTIs (non-AB rate difference: -6.26%; 95% CI -11.99 to -0.53%; 2-sided p = 0.0014). Adverse event rates were similar between groups, with higher rates of gastrointestinal disorders in the FT group and pyelonephritis in the BNO 1045 group. During the trial, no patient died or discontinued due to a treatment-related adverse event. CONCLUSIONS: BNO 1045 has the potential to reduce outpatient use of ABs for uUTIs and thus may have a significant impact on antimicrobial stewardship strategies. TRIAL REGISTRATION: NCT02639520, EudraCT number 2013-004529-99.

Comparison of fosfomycin against fluoroquinolones for transrectal prostate biopsy prophylaxis: an individual patient-data meta-analysis.

PURPOSE: To systematically review and meta-analyse available evidence comparing fosfomycin trometamol (FT) to fluoroquinolone (FQ) prophylaxis to prevent transrectal ultrasound-guided prostate biopsy (TRUSPB) related infectious complications. METHODS: Electronic databases were queried for studies comparing FT to FQ-based TRUSPB prophylaxis. Studies were assessed for comparable outcomes and methodological quality (ROBINS-I modification). The primary outcome measure was the relative odds of overall infectious complications following TRUSPB according to FT/FQ treatment, which was evaluated with meta-analysis. Safety and tolerability were also assessed. The relative odds of infections of different severity [Grade 1, bacteriuria and afebrile urinary tract infection (UTI); Grade 2, bacteraemia, febrile UTI, and urosepsis] according to FT/FQ treatment were also estimated. RESULTS: Five studies, being three prospective randomised trials and two retrospective cohort studies, representing 3112 patients, were included. The relative odds of an infectious complication (OR 0.22, 95% CI 0.09-0.54) or of a more severe (Grade 2) infection (OR 0.13, 95% CI 0.07-0.26) were significantly lower in those receiving FT compared to FQ prophylaxis. A low incidence of medication-related side effects was observed. There were less observed infections due to FQ-resistant pathogens in those receiving FT prophylaxis. CONCLUSIONS: Patients who received FT prophylaxis were less likely than those who received FQ prophylaxis to develop infections overall, as well as severe and resistant infections after TRUSPB. Assessing the performance of FT in other geographic locations or in comparison to targeted prophylaxis based on risk assessment or rectal cultures is desired.

[In-vitro activity of mecillinam against urine isolates of Escherichia coli from outpatient departments in Germany]. / In-vitro-Aktivität von Mecillinam gegen Escherichia coli: Urinisolate von Patienten im niedergelassenen Versorgungsbereich in Deutschland.

National and international guidelines recommend fosfomycin trometamol, nitrofurantoin, nitroxoline, and pivmecillinam as first-line agents for the treatment of acute uncomplicated cystitis. Escherichia coli is by far the leading cause of community-acquired urinary tract infections. Pivmecillinam (X-SYSTO®) is an oral prodrug of mecillinam, a penicillin derivative that was reintroduced to the German market in March 2016. This study aimed to investigate the proportion of mecillinam-resistant strains among E. coli isolates prior to the introduction of X-SYSTO® in Germany.An in-vitro study was carried out to determine the minimal inhibitory concentrations (MICs) of mecillinam against 494 urine isolates of E. coli (including multidrug-resistant strains). Isolates were obtained from outpatients and collected in 25 laboratories between October and December 2013. MIC breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied for classifying the bacterial isolates as mecillinam-susceptible (MIC ≤ 8 mg/l) or resistant (MIC > 8 mg/l).The concentrations of mecillinam needed to inhibit 50 % and 90 % of the test isolates were 1 and 4 mg/l, respectively, for isolates displaying the extended spectrum ß-lactamase phenotype, and 0.25 and 4 mg/l, respectively, for the remaining isolates. Overall, 98 % of the isolates were found to be mecillinam-susceptible (MIC ≤ 8 mg/l), and 2 % were found to be resistant (MIC > 8 mg/l).These findings support the recommendation to regard pivmecillinam as a first-line option for the treatment of acute uncomplicated cystitis.

Antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: fosfomycin trometamol, an attractive alternative.

OBJECTIVE: To compare fosfomycin trometamol (FT) and ciprofloxacin (CIP) for antibiotic prophylaxis in transrectal prostate biopsy (TR-PB). PATIENTS AND METHODS: Data for 1109 patients (mean age 66.7 ± 8.45) who underwent TR-PB between March to September 2015 in seven Italian urological institutions were retrospectively reviewed, of which 632 received FT (Group 1) and 477 received CIP (Group 2) for prophylaxis. We reviewed all urine culture results obtained after the procedure, all adverse drug reactions (ADRs) related to the drug and all febrile and/or symptomatic urinary tract infections (UTIs) occurring within 1 month after TR-PB. The rate of symptomatic UTIs and the rate of ADRs were considered the main outcome measures. RESULTS: In the total study population, 72/1109 (6.5 %) patients experienced symptomatic UTIs and among these 11 (0.9 % of total) had urosepsis. Out of 72, 53 (73.6 %) symptomatic UTIs were caused by fluoroquinolone-resistant strains. Out of 632, 10 (1.6 %) patients in Group 1 and 62/477 (12.9 %) patients in Group 2 had symptomatic UTIs (p < 0.001); in particular, 2/632 (0.3 %) patients in Group 1 and 9/477 (1.8 %) patients in Group 2 had urosepsis (p < 0.001). No differences were reported in terms of adverse events (0.6 vs 0.4 %; p = 0.70). A Charlson comorbidity index ≤1 and type of antimicrobial prophylaxis (FT) were found to be associated with a lower probability of symptomatic UTIs in the multivariate model. CONCLUSIONS: Antibiotic prophylaxis with FT for TR-PB had a lower rate of adverse events and a lower rate of symptomatic UTIs as compared with CIP. Fosfomycin trometamol appears as an attractive alternative prophylactic regimen in prostate biopsies.

Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam, against Uropathogens after Intravenous Administration in Healthy Subjects.

This annex study to a phase 1 study aimed to correlate urinary concentrations and bactericidal titers (UBTs) of BAL30072, a novel siderophore monosulfactam, in healthy subjects in order to evaluate which dosage of BAL30072 should be investigated in a clinical study on complicated urinary tract infection (UTI). Three cohorts of a total of 19 healthy male subjects were included in the add-on study and received the following BAL30072 dosages. The 1st cohort received 1 g once a day (q.d.) intravenously (i.v.) (1 h) on day 1 and 1 g thrice daily (t.i.d.) on day 2, the 2nd cohort received 2 g q.d. i.v. (1 h) on day 1 and 2 g t.i.d. on day 2, and the 3rd cohort received 1 g q.d. i.v. (4-h infusion) on day 8. Urine was collected up to 24 h after drug administration. UBTs were determined for seven Escherichia coli isolates (three wild type [WT], CTX-M-15, TEM-3, TEM-5, NDM-1), two Klebsiella pneumoniae isolates (WT, KPC), one Proteus mirabilis isolate (WT), and two Pseudomonas aeruginosa isolates (WT, VIM-1 plus AmpC). Urine drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median urinary excretions of BAL30072 ranged between 38% and 46% (3 cohorts). The median UBTs after i.v. administration of 1 or 2 g q.d. and after 1 or 2 g t.i.d. showed positive UBTs for 24 h after the lowest dosage (1 g q.d.) for 5 of 7 of the Enterobacteriaceae strains and after the higher dosage of 2 g administered i.v. t.i.d. for all strains tested. After i.v. infusion of 1 g over 4 h, positive UBTs were demonstrated for three E. coli strains for up to 12 h, for the K. pneumoniae (KPC) strain for up to 8 h, and for the P. aeruginosa (VIM-1 plus AmpC) strain for up to only 4 h. The minimal bactericidal concentrations (MBCs) of the E. coli (NDM-1) strain and the K. pneumoniae (WT) strain correlated well between broth and urine but did not correlate well for the two P. aeruginosa strains. BAL30072 exhibits positive UBTs for 24 h even after a dosage of 1 g administered i.v. q.d. for 5 of 7 Enterobacteriaceae strains and after 2 g administered i.v. t.i.d. for all strains except one P. aeruginosa strain (50% of the time). In general, the UBTs correlated well with the MICs of the Enterobacteriaceae but were lower for P. aeruginosa The clinical efficacy with a dosage regimen of BAL30072 of 2 g administered i.v. t.i.d. should be evaluated in the treatment of complicated UTI.

Efficacy and safety of the phytotherapeutic drug Canephron® N in prevention and treatment of urogenital and gestational disease: review of clinical experience in Eastern Europe and Central Asia.

This review evaluates 17 clinical studies from 18 selected publications concerning the safety, tolerability, and additional effects of the phytotherapeutic drug, Canephron® N (CAN, containing the medicinal plants, Centaurium erythraea, Levisticum officinale, and Rosmarinus officinalis) as standard therapy in various clinical settings. Its role in the prophylaxis and treatment of urinary tract infections in adults and in children, therapy and prophylaxis in adult patients with renal stones, treatment and prevention of urinary tract infections and other gestational diseases in pregnancy, and also its safety and tolerability. The dosage was as recommended and over a varying duration. Overall, CAN was shown to be effective in the treatment and prophylaxis of UTI compared with standard therapy, both in adults and children, and there was a reduced number of relapses. Children undergoing surgical correction of vesicoureteral reflux benefited from a prophylactic course of CAN. Ten-day add on therapy increased the rate of spontaneous elimination of kidney stones compared with standard therapy alone and may also have had a positive effect on stone prevention. Pregnant women showed earlier relief of symptoms and normalization of pyuria on additional treatment with the herbal combination. Only one adverse effect was reported (skin rash) in the 3115 patients included in this review. No teratogenic, embryotoxic, or fetotoxic effects, or negative interference with the psychological development or health of children born of mothers treated with the drug were reported. Because some of the studies were not well designed, their statistical significance remains unclear.

[Uncomplicated lower urinary tract infections in females--clinical aspects, aetiology and antimicrobial resistance epidemiology. Results of the ARESC (Antimicrobial Resistance Epidemiological Survey on Cystitis) study in Poland and their implications for empiric therapy]. / Niepowiklane zakazenia dolnych dróg moczowych u kobiet- -obraz kliniczny, etiologia i wrazliwosc na antybiotyki najczestszych patogenów. Wyniki badania Aresc (Antimicrobial Resistance Epidemiological Survey on Cystitis) w Polsce i ich znaczenie w wyborze terapii empirycznej.

UNLABELLED: The Polish results of the international ARESC study are reported concerning clinical aspects, epidemiology, and antimicrobial susceptibility of uropathogens. METHODS: Patients between 18 and 65 years with symptoms of uncomplicated cystitis were consecutively enrolled and investigated clinically including urinalysis and urine culture. Uropathogens were identified and their susceptibility was tested for nine antimicrobials RESULTS: In Poland a total of 212 patients were enrolled and 119 uropathogens from 118 patients were identified. Escherichia coli was the most frequent (90; 75.6%), followed by Staphylococcus saprophyticus (5; 4.2%), Staphylococcus aureus (4; 3.4%), Proteus mirabilis (4; 3.4%), Klebsiella pneumoniae (3; 2.5%), E. coli showed the highest rate of susceptibility to fosfomycin (98.9%) followed by mecillinam (97.8%), nitrofurantoin (92.2%), and ciprofloxacin (92.2%). The lowest rate was found for ampicillin (40.0%) followed by cotrimoxazole (80.0%). For the total spectrum the order was fosfomycin (97.1%), ciprofloxacin (93.1%), and nitrofurantoin (85.2%). The lowest rates were found again for ampicillin (43.2%) and cotrimoxazole (80.7%). CONCLUSIONS: The results indicate that fosfomycin, ciprofloxacin, nitrofurantoin and amoxicillin/clavulanate have preserved their good in vitro activity (> 80%) against both E. coli and the total spectrum of uropathogens.

Fluoroquinolone-macrolide combination therapy for chronic bacterial prostatitis: retrospective analysis of pathogen eradication rates, inflammatory findings and sexual dysfunction.

We previously demonstrated the safety and efficacy of fluoroquinolone-macrolide combination therapy in category II chronic bacterial prostatitis (CBP). The aim of this study is to retrospectively compare the microbiological and clinical findings of two treatment schemes for CBP based on the combination of azithromycin (500 mg, thrice-weekly) with a once-daily 500- or 750-mg dose of ciprofloxacin (Cipro-500 or Cipro-750 cohort, respectively). Combined administration of azithromycin (1500 mg week(-1)) with ciprofloxacin at the rate of 750 mg day(-1) for 4 weeks rather than at 500 mg day(-1) for 6 weeks increased the eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. A significant decrease in pain and voiding signs/symptoms and a significant reduction in inflammatory leukocyte counts and serum prostate-specific antigen (PSA) were sustained throughout an 18-month follow-up period in both groups. Ejaculatory pain, haemospermia and premature ejaculation were significantly attenuated on microbiological eradication in both groups, but the latter subsided more promptly in the Cipro-750 cohort. In total, 59 Cipro-750 patients showed mild-to-severe erectile dysfunction (ED) at baseline, while 22 patients had no ED on microbiological eradication and throughout the follow-up period. In conclusion fluoroquinolone-macrolide therapy resulted in pathogen eradication and CBP symptom attenuation, including pain, voiding disturbances and sexual dysfunction. A once-daily 750-mg dose of ciprofloxacin for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to the 500-mg dose for 6 weeks. Our results are open to further prospective validation.