A very interesting clinical case, which was presented by Prof. Köves during the symposium, involved a typical 26-year-old woman with recurrent UTI since the start of her sexual activity. She suffered 3–6 episodes per year and was otherwise in a healthy state. The woman was treated by the general practitioner, urologist and gynaecologist, who usually recommended treatment with various antibiotic classes, viz. quinolones, penicillins and cephalosporins. Interestingly, a proper prophylaxis was never considered for this patient. This was certainly counter to the EAU guideline recommendation, which strongly recommends against treating uncomplicated cystitis with aminopenicillins, cephalosporins, and fluoroquinolones.
The therapeutic options that could be considered in such cases are either the use of especially old antibiotics, as recommended within the scope of the EAU guidelines, or treatment with a non-antibiotic therapy. Of course, the non-antibiotic therapy must be supported by sufficient evidence to show its non-inferiority in providing symptomatic relief relative to the antibiotics recommended in the EAU guideline for the treatment of uncomplicated cystitis. A recommendable approach to this therapeutic regimen could be the use of a phyto-therapeutic product supported by an adequate level of evidence, e.g. a combination of lovage root, centaury herb and rosemary leaves (BNO 1045) .
Prevention strategies which can also lead to a reduction in the number of episodes, as illustrated in this case study, were:
increased fluid intake
vaginal flora regeneration
avoiding various risk factors
self-treatment with non-antibiotic measures
The results presented for this case demonstrated that the measures yielded a reduction in the number of episodes to only 2–3 episodes per year. Despite the limitation of being a case study, the results clearly demonstrated that appropriate treatment of recurrent UTI episodes is mandatory to avoid MDR. Treatment of acute cystitis caused by ESBL-producing bacteria with guideline-recommended therapeutic options, or by using evidence-based symptomatic non-antibiotic treatment, constitutes a plausible approach.
Can we change our practices in relation to treating acute, uncomplicated cystitis?
Worldwide, UTI is one of the most common indications for antimicrobial prescriptions . Due to the rarity of complications, uncomplicated lower UTIs are considered as benign and self-limiting, with the primary goal of achieving a fast symptomatic relief. The symptoms are bothersome and thus have the potential to drastically impair daily activities and reduce the quality of life . Typical symptoms indicative of acute cystitis may present as frequent urination, urgent urination, burning pain during urination, (sensation of) incomplete bladder voiding after urination, pain in the lower abdomen and visible blood in the urine .
Over the past decade, some generally accepted concepts in the field of urology have started to be questioned. For example, the rather harmful effect of treatment of asymptomatic bacteriuria (ABU) in healthy non-pregnant women not facing selected urological procedures  is now accepted and reflected in the guidelines . Furthermore, the bladder environment is no longer believed to be sterile [10, 11].
Recent data now also show that non-antimicrobial treatment may be an appealing therapeutic option and provides an alternative to what is usually first-line antibiotic therapy . But why should we replace antibiotic therapy anyway? Is the patient facing any risk with an alternative? And what options regarding non-antimicrobial therapy can be considered for acute cystitis?
No doubt, appropriate antibiotic therapy has its place in the treatment of UTIs. Unfortunately, treatment also selects for antibiotic resistance in uropathogens and commensal bacteria. Moreover, overuse and misuse hinder antibiotic efficacy in life-threatening events such as urosepsis. Adverse effects of antibiotic use on the gut microbiome and the vaginal flora are generally accepted .
Consequently, evolving practices seek to achieve good symptom control for acute, uncomplicated cystitis, while simultaneously reducing antibiotic use. Women who are affected are increasingly aware of issues associated with over- and misuse of antibiotics and are therefore more willing to delay or even skip antibiotic treatment for acute cystitis. Knottnerus et al.  reported that over a third of women with UTI symptoms were willing to delay antibiotic treatment when they were asked to do so by their general practitioner. Moreover, the majority of these women reported a spontaneous improvement in the symptoms after 1 week.
Prof. Wagenlehner presented four comparative studies showing that initial treatment with a non-steroidal anti-inflammatory drug (NSAID) can reduce the use of antibiotics in women with uncomplicated UTI (Table 1) [14,15,16,17]. Disregarding the pilot trial with small sample size comparing ibuprofen 400 mg TID for 3 days with ciprofloxacin 250 mg BID for 3 days , in the three larger studies ibuprofen 400 mg or 600 mg TID for 3 days compared with fosfomycin trometamol (3 g fosfomycin) single dose or with pivmecillinam 200 mg TID for 3 days, respectively, the NSAID showed inferior results to the results obtained with the antibiotics [14, 16]. The same was true comparing diclofenac 75 mg BID with norfloxacin 400 mg BID for 3 days . But in all three studies there was a marked reduction of antibiotic usage. However, the highest reduction in antibiotic use was seen for the multimodal phytotherapy combination of the three plant combination (BNO 1045), with symptomatic relief being comparable in the phytotherapy and antibiotic groups .
In the four larger studies [4, 14, 16, 17] in the non-antibiotic treatment arm 5–7 cases per study experienced pyelonephritis as comparted to 0–1 case treated with antibiotics.
Warnings from the past: caution to be exercised in the use of antibiotics in uUTI
Prof. Bonkat, who is a private lecturer at the University of Basel and chair of the European Commission for Guidelines for Urological Infections, presented the treatment options for UTI/uUTI according to the current European international (and national) guidelines. Uncomplicated cystitis is limited to non-pregnant women with no known relevant anatomical or functional abnormalities within the urinary tract or comorbidities .
In this particular talk, the warnings from the past were highlighted. The discoverer of penicillin, Alexander Fleming, soon realized not only how useful drugs that have an antibacterial effect are, but also how dangerous a future without them might be, according to his quote “In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism. I hope the evil can be averted” . From our perspective today, Alexander Fleming was foreseeing the problems associated with multidrug-resistant organisms (MDROs), which are resistant to at least one class of antimicrobial agents. The second issue is that more and more large pharmaceutical companies are announcing their withdrawal from antibiotics research (https://www.businessinsider.de/major-pharmaceutical-companies-dropping-antibiotic-projects-superbugs-2018-7?r=US&IR=T). In fact, the antibiotic pipeline is rather narrow, with few or no novel and innovative new antibiotics and antibiotics for the treatment of diseases commonly caused by antibiotic-resistant bacteria, such as UTI (reactgroup.org/news-and-views/news-and-opinions/year-2018/whats-cooking-in-the-antibiotic-pipeline/).
Clinically proven alternatives to antibiotics in the treatment of uUTI
Prof. Wagenlehner reported on the recently published efficacy study which compared the herbal combination BNO 1045 and single-dose fosfomycin (as fosfomycin trometamol = FT) in female patients with acute lower uncomplicated urinary tract infections. BNO 1045 is a coated tablet containing powdered centaury herb (Centaurii herba) 18 mg, lovage root (Levistici radix) 18 mg and rosemary leaves (Rosmarini folium) 18 mg. The randomized, double-blind, multinational Phase III study in 659 women with acute uncomplicated urinary tract infections (AUC) demonstrated that the phytopharmaceutical BNO 1045 is not inferior to antibiotic therapy with single-shot fosfomycin trometamol (FT) in terms of therapeutic success and reduction of symptoms. The three plant combination with its multimodal activity represents a useful symptomatic treatment option. Anti-inflammatory , analgesic , spasmolytic  and anti-adhesive effects  have been demonstrated in various preclinical in vivo and in vitro studies for this unique combination of three medicinal herbs.
Finally, the transfer of these pharmacological effects into clinical benefits is reported in this randomized, controlled, double-blind, double-dummy, multicentre, multinational Phase III study, including 659 women aged 18–70 years with the typical symptoms of newly diagnosed acute uncomplicated cystitis . Patients in the BNO 1045 group received 7 days 2 tablets of BNO 1045 TID plus a single dose of FT-matched placebo and patients in the FT group received a single dose of FT plus 7 days of BNO 1045-matched placebo (= double-dummy design). After the treatment period, there was a 30-day follow-up period. The primary endpoint was the non-inferiority of BNO 1045 versus FT with regard to the need for additional antibiotic therapy during the study period (days 1–38).
83.5% of patients in the BNO 1045 group and 89.8% of patients in the FT group required no additional antibiotic therapy. Thus, the three plant combination was not statistically inferior to the antibiotic FT in the treatment of acute, uncomplicated cystitis with regard to the primary endpoint (Δ = − 6.3%, lower limit of the confidence interval: − 11.99%, p = 0.0014). The symptom decline (measured using the “acute cystitis symptom score”, ACSS  as the sum score for the “typical” symptoms) was comparable in both groups during the study period. The herbal therapy was well tolerated.
Thus, BNO 1045 serves as an evidence-based efficacious substitute to antibiotics for the treatment of acute uncomplicated cystitis in women and helps to reduce the outpatient use of antibiotics to a significant extent. This is of major importance in the context of the antibiotic stewardship strategy, in order to rationalize the wide-spread use of antibiotics and the ensuing danger of antibiotic resistance (who.int/news-room/fact-sheets/detail/antibiotic-resistance).