At least one fourth of these patients will have a recurrence within a year [2], and 22 % will have recurrent urinary tract infections (RUTIs). Infections are considered recurrent when patients have three or more culture-documented infections in a year or two or more in 6 months [5].

The European Association of Urology defines a significant bacteriuria as≥10³ uropathogens/ml of midstream urine in acute uncomplicated cystitis in women, ≥ 10⁴ uropathogens/ml of midstream urine in acute uncomplicated pyelonephritis in women, ≥ 10⁵ uropathogens/ml of midstream urine in women, or≥10⁴ uropathogens/ml of midstream urine in men (or in straight catheter urine in women) with complicated UTI (in a suprapubic bladder puncture specimen, any count of bacteria is relevant) [6].

On average, each episode of acute UTI in premenopausal women is associated with 6.1 days of symptoms, 2.4 days of school or work absenteeism, and 0.4 days in bed [1]. Besides the clinical impact on the health and quality of life, RUTIs have a great economic impact. An annual cost of US$2.5 billion is estimated in the USA [5]. Bacteriuria is found in 2–3 % of women 15–24 years of age, 20 % in women 65–80 years of age, and 25–50 % in women greater than 80 years of age [7]. The population of women greater than 65 years of age in the USA is projected to double between 2000 and 2030 [8]. Therefore, it could be anticipated that UTIs will increase in the upcoming years. Aside from being common in the community, 2 % of the hospitalized patients acquire UTIs. In the 1980s, nosocomial infections accounted for more than 500,000 per year [9, 10].

Continuous prophylaxis with antibiotics is the recommended initial therapy for RUTIs. Sulfamethoxazole/trimethoprim (SMX/TMP) for a period of 6 months is the most commonly recommended option [11]. However, the continuous use of antibiotics is not free of risk. Multiresistance of the bacteria to antibiotics is widely increasing, which creates the dramatic situation that more than 40 % of the bacterial strains are resistant to available antibiotics in some regions of the world. An added problem is the high incidence of adverse reactions associated with the use of antibiotics and other chemotherapeutics.

Therefore, it is reasonable to consider other preventive strategies such as those that reinforce the natural mechanisms of pathogen defense.

Bacterial preparations have been used to prevent RUTIs. Lettgen [18] reported the use of an oral bacterial lysate of 10⁹E. coli compared with the use of nitrofurantoin as a prophylaxis of RUTIs in girls, showing that the efficacy of the long-term administration of this bacterial lysate was comparable to that of nitrofurantoin. Bauer et al. [19] reported in 2002 a meta-analysis performed on five studies of an oral bacterial lysate of 10⁹E. coli compared to placebo in double-blind studies in patients with UTI (601 women), showing superiority of this treatment over placebo, with a confidence interval of 0.64-0.72. The drug was well tolerated and patient compliance was excellent in all studies. The same authors reported in 2005 [20] a double-blind, placebo-controlled study in 454 women using the same product. Patients were treated with 1 capsule (active or placebo) per day for 90 days, 3 months without treatment, then the first 10 days in months 7, 8, and 9 and were followed up during 12 months. The authors reported a 34 % reduction of UTIs in patients treated with the bacterial lysate when compared to placebo. In our study, patients were treated for a period of 3 months and showed a reduction of 75, 86, and 77 % at 3, 9, and 15 months when compared with conventional antibiotic prophylaxis, not to placebo. This high difference in the clinical benefit could be explained by the form in which the antigen is delivered (lysate or whole inactivated bacteria) and the route of administration (orally swallowed or sublingual).

Purified components from bacteria selectively activate Toll-like receptors (TLR), leading to shared and unique responses in innate immune cells, whereas whole non-lysate bacteria contain agonists for multiple TLR and induce a common macrophage activation program [21] eliciting a more potent and robust response [22], because the innate immune response to whole bacteria is a consequence of the cumulative activation of TLR [23].

These products act through the mucosal immune system. This local system contributes almost 80 % of all immunocytes. These cells are accumulated in, or in transit between, various mucosa-associated lymphoid tissues (MALT), which together form the largest mammalian lymphoid organ system [24] and are considered as the “common mucosal immune system” whereby immunocytes activated at one site disseminate immunity to remote mucosal tissues, although there is a significant degree of compartmentalization linking specific mucosal inductive sites with particular effector sites [24]. Oral immunization (swallowed) may induce substantial immune responses in the small intestine (strongest in the proximal segment), ascending colon, and mammary and salivary glands, but it is relatively inefficient at evoking response in the distal segments of the large intestines, tonsils, or female genital tract mucosa [25–27]. However, sublingual and nasal mucosa can serve as an inductive site for generating a broad spectrum of mucosal and systemic immune responses, including also the respiratory and genitourinary tracts [24, 28] with a high degree of efficacy and persistence of the immune response [29]. Sublingual administration of immunogens such as cholera toxin and ovalbumin induces systemic humoral dose-dependent immune responses [28], mucosal antibody responses [28], and an immune-stimulating effect on CD4+ T helper cell responses to bacteria [30].

The number of UTIs increases after the 3 months of treatment with Uromune®, being more pronounced from the 9th month of observation. This observation highlights the need for a more prolonged treatment or for starting a new period of 3-month treatment. In a pilot trial using a similar immunostimulant, with a different bacterial composition because it focused on preventing recurrent respiratory tract infections, the treatment period was of 6 months’ duration and had a clinical effect for a minimum period of 12 months [30].

An important finding, not described previously, is the trend of developing UTIs and the presence of UC+ by means of the regression analysis. The corresponding slopes in group A are much flatter than those of group B, indicating that the trend to develop UTIs and to have UC+ is much more meaningful in group B and showing that for one UTI in group A there are more than four UTIs in group B and for one UC+ in group A there are more than seven in group B.

The decrease in the number of UTIs implies an important decrease in antibiotic consumption. This approach is in line with the recommendations of health authorities, because the use of this immunostimulant agrees with the need for new treatment alternatives, non-antimicrobial treatments (vaccines) against bacterial diseases and diseases that may precipitate secondary bacterial diseases [31–35].

This study demonstrates the effectiveness of a bacterial preparation administered through the sublingual route. We acknowledge that because this study is retrospective, it does not provide deeper and more accurate outcomes as could be obtained in a prospective explanatory double-blind placebo-controlled trial conducted under clinical experimental conditions. However, the data collected from clinical histories of patients provide clinically valuable information of the patients treated under “real-life” conditions.

However, we believe that further prospective double-blind, placebo-controlled, randomized clinical trials are needed to establish more accurately the clinical impact (severity of episodes of UTI, quality of life, associated economic costs) of these bacterial immune stimulants in patients with RUTIs, although the Note of Clarification on Paragraph 29 added by the World Medical Association General Assembly to the Declaration of Helsinki [36] states that care must be taken in using a placebo-controlled trial and that this methodology should only be used in the absence of an existing proven therapy.