Urinary tract infection (UTI), due to its high prevalence, represents a substantial consumption of healthcare resources and antibiotics, particularly in primary care. Therefore, any strategy that improves its optimisation is welcome. In this issue of the journal, expert physicians from the OPENIN group offer a series of recommendations based on the literature, but above all on their opinion and consensus.1 In this editorial, we aim to provide additional clinical comments, largely grounded in daily clinical practice.
Asymptomatic bacteriuria (ASB) constitutes one of the main causes of antibiotic overtreatment, particularly in primary care. As the experts note,1 screening is not indicated in institutionalised elderly patients but is indicated in pregnancy. Currently, its detection and treatment are limited to urological surgery with mucosal disruption (prostatectomy, transurethral resection of bladder tumour) and in the replacement of nephrostomies and ureteral stents, but not in routine urinary catheter changes.2,3 A primary care antimicrobial stewardship programme (ASP) intervention aimed at avoiding ASB treatment would likely reduce antibiotic overuse in this situation. Recently, an antimicrobial stewardship intervention in primary care demonstrated a 55% reduction in post-treatment urine culture requests following UTI.4 Avoiding urine cultures and treatment of ASB in asymptomatic patients remains a priority, as such practices only increase the risk of adverse effects and antimicrobial resistance.
It is also very pertinent to emphasise the OPENIN group's conclusion that urine culture is not necessary in an institutionalised patient presenting with delirium as the sole symptom,1 since the high rate of ASB (which may reach 50% in women) leads to antibiotic overuse.
We agree with the experts that urine culture is not required in uncomplicated cystitis1 unless recurrent infection is suspected2,3 or the patient has recurrent cystitis. Fosfomycin trometamol (single dose) and nitrofurantoin (5 days) are the antibiotics of choice in acute cystitis,2,5 with preservation of cephalosporins or fluoroquinolones due to the risk of increasing infections by extended-spectrum beta-lactamase (ESBL)-producing organisms. It is important to recall a clinical trial that demonstrated a 12% higher statistically significant clinical cure rate in women treated with nitrofurantoin for 5 days versus single-dose fosfomycin trometamol.6 In a later meta-analysis,7 this difference was not confirmed, but it is important to note that it analysed heterogeneous comparator regimens (different antibiotics and treatment durations) with single-dose fosfomycin trometamol. We consider necessary to evaluate the risk-benefit of a second 3g dose of fosfomycin trometamol at 72h, which could potentially improve cure rates. It seems reasonable in clinical practice to recommend a second dose at day 3, at least in patients with recurrent cystitis or persistent symptoms.
Recurrent UTIs due to relapse (early recurrence) are mainly due to underlying urological pathology, inadequate antibiotic therapy (resistance to the prescribed antibiotic or short course—UTI treated as cystitis when it was actually mildly symptomatic pyelonephritis) and, in men, chronic prostatitis.
Recurrences due to reinfection are a prevalent health problem, predominantly in women. Recurrent UTI (rUTI) is defined as more than 2 distinct episodes in 6 months or 3 in one year. Preventive strategies for rUTI vary considerably in the literature depending on the works selected for analysis. It is important to critically evaluate studies, as most do not assess sexual activity, one of the most relevant risk factors, at least in young womens. This could lead to lack of evidence when a meta-analysis using GRADE methodology does not properly account for recurrence risk factors and study design.
Antibiotic prophylaxis as prevention of rUTI in women is the most extensively studied and probably the most effective prophylactic measure.2,5 Common regimens include fosfomycin trometamol 3g every 7–10 days or daily trimethoprim–sulfamethoxazole 80/400mg. However, other non-antibiotic strategies allow for reduction in antibiotic consumption in a considerable proportion of patients. In menopause, especially in women with a clear association with rUTI onset, application of vaginal oestrogens restores vaginal lactobacilli and is effective in reducing recurrences, being recommended as initial therapy in most guidelines.2,8-10 In women with many rUTIs (8–10 UTIs annually), we usually combine oestrogens with another preventive strategy during the first months,5 since vaginal flora restoration is not immediate and recurrences occur early. Although in patients with a history of breast cancer no increased risk of recurrence has been demonstrated, the American College of Obstetricians and Gynecologists recommends consensus with the referring oncologist.11
With respect to cranberries, clinical practice and guidelines from the European Association of Urology and the American Urological Association establish a weak recommendation in favour of cranberry-derived products to reduce recurrent UTI episodes.5,9,10 Most preparations locally available combine cranberries with another adherence inhibitor: D-mannose. D-mannose, a monosaccharide that inhibits bacterial adhesion via type I fimbriae, has been analysed alone or combined with cranberries, plant extracts, probiotics, among others.12–16 In a randomised, non-blinded trial comparing 2000mg/day of D-mannose with 50mg/day of nitrofurantoin and placebo, including about 100 patients per group, recurrence frequency was significantly lower in the D-mannose (15%) and nitrofurantoin (20%) groups versus placebo (60%).13 Other studies have demonstrated efficacy, so two systematic reviews and meta-analyses consider it a recommended strategy to save antibiotic use14,15 with a relative risk (RR) between 0.23 and 0.34 compared with placebo.14,15 However, a 2022 Cochrane review concluded that the quality of evidence was poor and insufficient regarding preventive efficacy.16 In a recent randomised double-blind placebo-controlled trial (placebo: fructose) including 598 patients with similar baseline rUTIs, D-mannose (2000mg/day) did not significantly reduce recurrences.17 However, the study had three important limitations: (a) nearly 40% of women in both groups were not sexually active, (b) only 53% took D-mannose at least 4 of 7 days per week, and (c) the placebo group had greater antibiotic consumption for any reason. Additionally, more than 60% of women in both groups were postmenopausal. In clinical practice, D-mannose, due to its minimal toxicity, and administered daily with cranberries, works in a considerable proportion of young sexually active women, so we believe it should continue to be used until well-designed randomised studies (balanced for baseline recurrence, sexual activity, antibiotic use and adherence to D-mannose) clarify its true efficacy. It is also true that its high cost is a challenge in daily practice.
Other preventive strategies, such as vaginal lactobacilli (oral administration is ineffective as commented in earlier review1,5,10 or use of vaccines, compared with placebo, show lower efficacy5,10,13 than other strategies, with RR of about 0.65 and 0.69 respectively. Lactobacillus efficacy depends on the strains used and is transient, and vaccines are considered costly and complex to administer (requiring urine collection at infection onset). In a placebo-controlled trial, MV-140 demonstrated superiority,18 but a randomised study with antibiotics is needed to demonstrate at least non-inferiority. Intravesical instillation of glycosaminoglycans (Cystistat®) or avirulent uropathogen strains may be effective5,10 but constitutes a more complex and costly preventive strategy; thus, it should be reserved for patients in whom various earlier strategies, including possible combinations, have failed.
A short course (7 days) of fluoroquinolones (FQ) is sufficient for uncomplicated pyelonephritis. In clinical practice, in patients with prolonged symptoms before diagnosis, delayed response to treatment and/or significant leucocytosis (>25,000–30,000), focal pyelonephritis may be present on radiological study; in this situation, treatment is often extended to 2–3 weeks, using an oral fluoroquinolone when susceptible and response is favourable.
Given the high rates of FQ resistance in our setting, which in our experience were 23% in community-acquired pyelonephritis but exceeded 74% when associated with healthcare exposure,19 FQ are not considered initial empirical therapy for pyelonephritis. Second- or third-generation cephalosporins, aminoglycosides, aztreonam (in allergic patients), piperacillin–tazobactam, or ertapenem (ESBL risk) are recommended in most guidelines.2,5 Since pyelonephritis mortality is low and inadequate empirical therapy has not been shown to affect subsequent patient outcome,19,20 and in our experience mortality was 2.4% when adequate treatment and 2.8% when inadequate, carbapenems should be limited to patients at risk of mortality (primarily septic shock and severe immunosuppression) to avoid future carbapenemase-producing UTI. Other authors have shown that inadequate therapy did not affect evolution even in patients with ESBL pyelonephritis.19 Intravenous fosfomycin may be an initial alternative in patients with ESBL Escherichia coli pyelonephritis, having recently demonstrated efficacy similar to β-lactams or fluoroquinolones.21
Due to high resistance rates to amoxicillin–clavulanate, it is not an adequate treatment for acute bacterial prostatitis (ABP). Guidelines and experts1,3 recommend use of a third-generation cephalosporin or a fluoroquinolone. In patients with septic shock and particularly when there is risk of ESBL or Pseudomonas aeruginosa, an aminoglycoside is recommended. A carbapenem with anti-pseudomonal activity may be an alternative. When evolution is favourable, FQ are recommended due to better prostate tissue penetration, with a duration of 2–3 weeks. In a recent study on ABP,22 risk factors associated with failure were inadequate definitive antibiotic therapy and oral β-lactams or cotrimoxazole; however, a 14-day course was not associated with higher failure rates. Based on these data, we recommend a short 2-week course in cases without risk factors for failure and with a rapid therapeutic response.
As seen in the OPENIN study survey, they agree on providing antibiotic prophylaxis tailored to prior urine culture in urological manipulations that require it; however, this is often logistically difficult.1 An ASP or establishing it as a remunerated objective could perhaps improve results.
With this editorial, we congratulate initiatives based on expert groups such as OPENIN in UTI management and offer our point of view. We consider it necessary to emphasise the need for rational use of diagnostic and therapeutic resources in UTI treatment, considering both daily clinical experience and patient wellbeing. As recently published by a multinational expert group, there are still considerable gaps and needs in the knowledge and diagnostic-therapeutic management of this condition.23 Now we must continue to conduct research in this highly prevalent pathology and disseminate current knowledge through scientific journals, ASP, and continuous education of all professionals involved, primarily from primary care, emergency departments, urology, gynaecology, and infectious diseases.
Conflict of interestI.L. has received honoraria for speaking at educational events from Merck, Shionogi, Pfizer, and Takeda, and has received travel support from Gilead, Merck, Menarini, Shionogi, and Mundipharma for scientific purposes.
