Why D-mannose may be as efficient as antibiotics in the treatment of acute uncomplicated lower urinary tract infections Preliminary considerations and conclusions from a non-interventional study

Urinary tract infections (UTIs) are very frequent in women and can be caused by a range of pathogens. High recurrence rates and increasing antibiotic resistance of uropathogens make UTIs a severe public health problem. D-mannose is a monosaccharide that can inhibit bacterial adhesion to the urothelium after oral intake. Several clinical studies have shown the efficacy of D-mannose in the prevention of recurrent UTI; these also provided limited evidence for the efficacy of D-mannose in acute therapy. A recent prospective, non-interventional study in female patients with acute cystitis reported good success rates for treatment with D-mannose. Here we present data from a post-hoc analysis of this study to compare the cure rate of D-mannose monotherapy with that of antibiotics. The results show that D-mannose is a promising alternative to antibiotics in the treatment of acute uncomplicated UTIs in women.

epithelial cells by attaching to uroplakin 1a, which consists of glycosylated proteins with mannose molecules as terminal units ( Figure 1A) [20,21]. Since it has been shown in UTI mouse models that FimH is critical for the pathogenesis of E. coli in AUC and is conserved in various E. coli strains [22], this adhesin is considered to be a good target for therapeutic interventions [23]. D-mannose is an epimer of d-glucose with structural similarities to the mannose residues on the urothelium surface or transmembrane proteins such as uroplakin 1a. Thus, adhesion of E. coli via type 1 pili can be inhibited by exogenous D-mannose saturating FimH adhesins ( Figure 1B) [17,18]. This facilitates clearance of the pathogens by the urine flow.

Clinical data for D-mannose in UTI
Several clinical studies have investigated the effects of D-mannose monotherapy in the treatment of AUC and prevention of recurrent UTIs. In a prospective, non-comparative study, Domenici et al. analyzed the efficacy of D-mannose in the treatment of acute uncomplicated UTI and its utility in the management of recurrences in 43 women [18]. The authors observed a significant improvement of most UTI symptoms following administration of 1.5 g D-mannose, twice daily for three days and then once a day for 10 days. Patients were then randomized into two groups, one receiving prophylaxis with Dmannose administered once a day for a week every other month for 6 months, and the other without Dmannose administration. The recurrence rate for women receiving prophylaxis (4.5%) was significantly lower than in the untreated group (33.3%; p = 0.05). The mean time to onset of UTI was 43 days (± 4.1 standard deviations [SD]) in the prophylaxis group, and 28 days (± 5.4 SD) in the other group (p = 0.0001). There were no significant side effects, even during long-term administration [18].
To evaluate the efficacy of D-mannose in the treatment and prophylaxis of rUTIs, Porru et al. performed a randomized cross-over trial including 60 women with acute symptomatic UTI and three or more rUTIs during the preceding 12 months [24]. Patients were randomly assigned to antibiotic treatment with trimethoprim/sulfamethoxazole (TMP-SMZ: 2 x 160 mg/800 mg daily for 5 days) or therapy with Dmannose (3 x 1 g daily for 2 weeks), followed by prophylactic therapy over 5 months with TMP-SMZ (1 x 160 mg/800 mg daily for one week each month) or D-mannose (1 x 1 g daily). In the group treated with D-mannose, a significantly increased mean time to UTI recurrence (200 days) was observed in comparison to the antibiotic group (52.7 days; p < 0.0001) [24].
In a randomized controlled trial, Kranjčec et al. investigated the efficacy of D-mannose in rUTI prevention [25]. After initial antibiotic treatment of AUC, 308 women were randomly divided into three groups receiving daily treatment with 2 g D-mannose, 50 mg nitrofurantoin or no prophylaxis. Recurrence rates were 14.6% in the D-mannose group, 20.4% in the nitrofurantoin group and 60.8% in the group without prophylaxis. The number of rUTIs was significantly higher in the non-prophylaxis group than in both treated groups (p < 0.001). D-mannose significantly reduced the risk of rUTI, which was comparable to that in the nitrofurantoin group. However, the side effects observed in the Dmannose group were significantly lower than in the nitrofurantoin group (p < 0.0001) [25].
An open-label prospective feasibility study by Phe et al. evaluated D-mannose for the prevention of UTIs in 22 patients with multiple sclerosis [26]. The authors showed an association between administration of D-mannose and a significant decrease in the number of monthly proven UTIs. No adverse events were reported in patients with multiple sclerosis who were treated with D-mannose [26].
In 2020, Lenger et al. published a systematic review and meta-analysis of the potential of D-mannose to reduce UTI recurrence in adult women with a history of rUTI and compared its efficacy with that of a placebo or other preventive agents [27]. Comparison of D-mannose with placebo resulted in a pooled relative risk for rUTI of 0.23 (95% confidence interval [CI] 0.14-0.37; heterogeneity = 0%; D-mannose: n = 125, placebo: n = 123). In addition, the pooled relative risk of rUTI comparing D-mannose with preventive antibiotics was 0.39 (95% CI 0.12-1.25; heterogeneity = 88%; D-mannose: n = 163, antibiotics: n = 163) [27]. These data show that D-mannose can provide protection against rUTI with an efficacy similar to that of antibiotics.

Clinical diagnosis and assessment of treatment efficacy in UTIs with a validated measuring instrument
AUC is typically diagnosed based on clinical symptoms, such as a painful or burning sensation when urinating (dysuria) or frequent urination (pollakiuria) in the absence of abnormal vaginal irritation/discharge [2,4,28]. However, the definitions for clinical diagnosis of AUC and assessment of clinical healing after treatment vary widely between clinical studies. The acute cystitis symptom score (ACSS) is derived from a diagnostic questionnaire that measures patient-reported outcomes in women with AUC and assesses the symptoms and their impact on the quality of life [29]. It has been clinically validated in several languages, including German and English (http://www.acss.world/downloads.html). The ACSS has been proven to be suitable for the clinical diagnosis of AUC in women and in monitoring treatment success during and after therapy [30][31][32][33][34]. Furthermore, it has already been used as a "patient-reported outcomes measure" (PROM) in several clinical studies [31,32,[35][36][37][38].
For a clinical diagnosis of AUC, the current guidelines of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend the presence of at least two of four signs or symptoms (i.e. dysuria, urinary frequency, urinary urgency, and suprapubic pain) [40], or a minimum number of symptoms such as urinary frequency, urinary urgency and dysuria, respectively [41]. Thus, the ACSS "typical" domain is compatible with the recommendations of public authorities for AUC diagnosis. The ACSS "typical" domain has also been shown to be comparable in clinical AUC diagnosis with the FDA and EMA proposals [35]. Therefore, the ACSS can be recommended for epidemiological and interventional studies.

Clinical efficacy of D-mannose in the treatment of acute UTI -a non-interventional study
Recently, Wagenlehner et al. assessed the suitability of a D-mannose-containing product as therapy for women with an acute episode of uncomplicated UTI in a multicenter, prospective, non-interventional study (NIS) [42]. The original study evaluated 97 patients who were divided into three groups after completion of the study according to the applied treatment: D-mannose monotherapy, D-mannose in combination with antibiotics, and the combination of D-mannose with other therapeutic measures (most frequently kidney and bladder tea). During the first three days, D-mannose (2 g) was applied three times a day followed by twice daily at days 4 and 5. In the course of the study, patients rated five symptoms as present/absent or on a four-/six-point Likert scale ( Table 1) until they were subjectively free of symptoms, but for a maximum of seven days: 1) burning sensation/pain while urinating, 2) frequency of bladder emptying, 3) small amounts of urine, 4) constant urge to urinate, and 5) change in urine. Healing was defined as relief of burning/pain during urination (score reduction to 0 or 1 on day 7 or on the last day of documentation). A patient was considered to be free of symptoms if burning/pain had a score of "0" or "1", urination frequency was rated as "not more frequent" or "hardly more frequent", and all other symptoms were rated with "0" or "not existing" [42].
After three days, 85.7% of the patients under D-mannose monotherapy were assessed as healed compared to 56.6.% in the group treated with D-mannose and antibiotics and 56.3% in the group combining D-mannose with other measures. On the last day of documentation, healing rates were largely comparable between the subgroups (92.9% vs. 83.0% or 87.5%). Furthermore, the proportion of patients considered as free of symptoms was higher in the monotherapy group (78.6%) than in the groups combining D-mannose with antibiotics (67.9%) or other measures (62.5%) [42].

Transfer of clinical data of the NIS to the ACSS as a validated instrument
For post-hoc data analysis, the clinical symptoms assessed in the NIS were transferred to the "typical" domain of the ACSS ( Table 1). Except for the ACSS item "suprapubic pain", all symptoms investigated in the NIS are also included in the ACSS. In order to balance the overall score range of the NIS (5 items) with that of the ACSS (6 items), the leading AUC symptom "burning/pain during urination" was rated twice for transfer to the ACSS. This approach was required to generate a balanced total score from the NIS-data, which also consisted of 6 item values as in the ACSS. For inclusion in the post-hoc analysis, NIS patients needed to meet the following criteria: (i) AUC diagnosed by a physician, (ii) follow-up examinations after diagnosis and (iii) a summary score of the "typical" domain ≥6 at the beginning of the study (corresponding to the ACSS-based definition of AUC) [36]; this procedure reduced the number of patients who could be evaluated. Based on the above clinical symptoms, the summary score of the "typical" domain was calculated for each patient at each study day, revealing the individual course of the AUC.
Alidjanov et al. defined and evaluated six different thresholds using the ACSS "typical" domain or a combination of the domains "typical" and "quality of life" to specify "clinical cure" during treatment of AUC. In addition, two further thresholds were based on the criteria of the FDA and EMA guidelines. From these eight definitions the following threshold "B" was chosen for our analysis, since its criteria best matched the data available from the NIS: a summary score of "typical" domain ≤4 and "no visible blood in urine" [36]. In addition, the threshold was applied in a modified form (score ≤2 and "no visible blood in urine") to gain a second, more robust estimate for the clinical cure rate. For both estimates, the corresponding 95% CI was determined. The last documented score value of each patient was pursued by "last observation carried forward".

Estimated cure rates from reanalysis of the NIS with D-mannose treatment for acute UTI
Finally, to determine the efficacy of D-mannose in the treatment of AUC, we analyzed two patient groups according to the treatment documented in the patient diaries. One group included patients treated with D-mannose as monotherapy. To increase statistical precision for the efficacy estimates, this cohort was expanded in the second group to further include patients who were taking other measures in addition to D-mannose except antibiotics. After applying the above inclusion criteria (see 6.2), 23 patients treated with D-mannose monotherapy were evaluated with post-hoc analysis. In the second group, 13 patients under D-mannose and additional non-antibiotic measures were added to these 23, making a total of 36 patients analyzed in this group, referred to below as D-mannose and other measures.
In patients treated with D-mannose only, the median of the aligned ACSS "typical domain" (aACSS-TD) had already decreased from 9.0 at baseline to 2.0 on day 3 (Figure 2A). The median aACSS-TD was 0.0 from day 4. Patients treated with D-mannose and other measures showed a clear decrease in the median aACSS-TD from 10.0 before the start of treatment to 3.0 on day 3 ( Figure 2B). The group reached a median score of 0.0 at day 7. Overall, the course of aACSS-TD reduction was similar in both groups.

Figure 2. Median aligned ACSS of "typical domain" (aACSS-TD) over 7 days for patients receiving A) Dmannose monotherapy or B) D-mannose and other measures except antibiotics. Clinical symptoms assessed in
the NIS were transferred to the "typical domain" of the ACSS. The pooled summary score of the treated cohort is shown for each day as a box plot. The red line indicates the median aACSS-TD.
Furthermore, to differentiate the treatment effect for patients with D-mannose monotherapy (n=23) and patients with D-mannose plus other non-antibiotic treatments (n=13), Kaplan-Meier estimates were determined for the course of the aACSS-TD. The probability (p) of reaching an aACSS-TD of zero after day 4, was 0.48 (95% CI 0.21; 0.66) and 0.25 (95% CI 0.0; 0.46) in patients under D-mannose monotherapy compared to D-mannose plus other non-antibiotic treatment, respectively. On day 5, the probabilities were 0.74 (95% CI 0.45; 0.88) and 0.44 (95% CI 0.06; 0.66), respectively. This means comparable results for both treatment groups, with a trend to better results (higher p-values) in the monotherapy group.  1 Score ≤4 and "no visible blood in urine"; 2 Score ≤2 and "no visible blood in urine"

Cure rates of controlled trials --antibiotic treatment of acute UTI
Success rates, odds ratios and/or other risk measures have been published to estimate the effect of antibiotic treatment, mainly in terms of microbiological response. To illustrate and compare these results, simple success rates (healing rates) of the published data were calculated and supplemented with the corresponding 95% CIs as presented below [43].
As the clinical cure or improvement of AUC symptoms during and following treatment becomes increasingly focused on treatment efficacy, the clinical success rate should be evaluated primarily in clinical trials. A systematic review of 19 studies including 3,779 patients in total compared the clinical and microbiological efficacy of single-dose fosfomycin with other antibiotic regimens [46].  [46]. These results showed no clinically significant differences between the microbiological and clinical cure rates and gave comparable results between the different antibiotic groups.
Overall, these analyses reveal comparable clinical cure rates under treatment with fosfomycin, nitrofurantoin and other antibiotics, which are on the same level as estimated for treatment with Dmannose monotherapy by post-hoc analysis of the NIS study (Figure 3).  Table 2). 3 D-mannose and other measures except antibiotics (for numbers see Table 2).

Time-dependent changes of symptoms in AUC patients treated with D-mannose or antibiotics
Besides assessing treatment efficacy as described by cure rate, time to symptom improvement also plays an important role in the patients' quality of life. In order, to compare time to symptom improvement under treatment with D-mannose and antibiotics, we searched for published studies using antibiotics that recorded a clinical summary symptom score in patients with AUC over time. However, the scores were often weighted differently, so that we had to perform some adaptation to achieve comparability between the various studies. The maximum value achievable in each symptom score was set to 100%, and the score values reported were then calculated as the corresponding proportion. The resulting relative (or normalized) daily mean scores were compared between D-mannose (based on aACSS-TD from the post-hoc analysis) and various antibiotic treatments (Table 3) [38,42,[47][48][49][50][51][52]. In addition, we compared the median values from groups receiving antibiotic treatments and mean values of Dmannose monotherapy or D-mannose and other non-antibiotic measures (Figure 4).
The normalized symptom scores of the different treatments in the individual studies were comparable at baseline, with most scores ranging from 46% to 56% also including the two D-mannose groups ( Table  3). At day 3, a distinct decrease in the normalized total symptom scores to 10-25% was observed in all treatment groups considered. After a period of 7-8 days, the normalized total symptom score was lowered to 0-12% in all treatments.
Overall, a clear trend regarding symptom relief over time was found with the various treatments. The normalized symptom score under treatment with D-mannose monotherapy decreased from 51.7% at baseline to 5.6% at day 4, while with D-mannose and other non-antibiotic measures it decreased from 54.5% to 13.9%. Likewise, with D-mannose, the median value derived from all antibiotic treatments decreased from 51% at baseline to 8.2% at day 4. In addition, the time-dependent symptom reduction after 3 days of treatment was similar following D-mannose monotherapy and antibiotic treatments, which again underlines the potential of D-mannose in the treatment of AUC (Figure 4).   Table 3).

Conclusions
Our post-hoc analysis shows that patients using D-mannose as monotherapy achieved very good clinical cure rates, similar to those achieved by patients receiving antibiotic treatments. Furthermore, symptom relief after 3 days of treatment was also comparable between D-mannose monotherapy and antibiotics. These findings are in line with previous studies showing a similar effectiveness of D-mannose to that of antibiotics in UTI prevention. Therefore, D-mannose may be a safe and effective alternative to antibiotics in the treatment of AUC. However, further randomized, controlled trials including a relevant number of patients are necessary, in order to confirm the beneficial effect of D-mannose in AUC.