Introduction

Urinary tract infection (UTI) is an infection of the urinary system that could affect the kidneys, the ureters, the bladder and the urethra. The pathogen that could cause UTIs in the urogenital tract and the bladder is Escherichia coli (E. coli) in approximately 53% of cases. Many people develop a single episode in their life (50% of them are female), and approximately 15% to 25% of adults and children suffer from chronic symptomatic UTIs, namely recurrent, persistent, re-infected or relapsed UTIs. Compared to men, women have a higher likelihood of developing a urinary tract infection (UTI). At present, available remedies and interventions for UTI include administering antibiotics, methenamine hippurate salts, topical estrogens, urine alkalisers, dietary supplements, and implementing modifications in lifestyle and behavior. In clinical practice, many patients do not respond to standard antibiotic treatments producing important patient burden and high cost to healthcare systems [1]. Escalating bacterial resistance to traditional antibiotics and limited efforts in developing new antibiotics require the identification of novel therapies.

The concept of “disarming” bacteria, rather than outright killing them, was first proposed in the 1980s. This approach has since driven extensive research in both structural biology and clinical settings, in contrast to other small molecule strategies that aim to prevent bacterial binding to urothelial cells [2, 3].

In UTI prevention, D-mannose utilized for N-glycosylation and glycerophospholipid anchor synthesis is derived from the enzymatic stereospecific interconversion of glucose rather than dietary intake various healthcare products in the European Union and the United States, including food supplements, contain alpha-D-mannose [4]. It was introduced to the European market in 2015 as a Class IIa medical device. The Borderline and Classification Medical Devices Expert Group identified D-mannose as a borderline product in their 2019 manual, excluding it from their list [5].

The criterion for establishing the regulatory framework in which a product may fall starts from the definition and identification of the mechanism by which it performs its main action [6]. A very relevant documentation supporting the discussion is the Guidance on Borderline Between Medical Devices and Medicinal Products Under MDR (MDCG 2022–5), in which the definition of medical device derives from the Art. 2 of the 2017/745 MDR regulation [7]. By this definition, for medical devices, the main action for intended use must not act in or on the human body by pharmacological, immunological or metabolic means, although it can be supported by one of these. However, the definitions of pharmacological, immunological or metabolic action are not always unique: distinction between mechanism of action and related actions in the organism could be unclear. The quality and nature of mechanism of action and intended use can be helpful aspects [6, 8].

The expert panel’s objective was to examine the role of alpha-D-mannose as a medicinal product or medical device in its interaction with E. coli bacteria, and their systematic review methodology adds further value compared to previous publications [4].

Materials and Methods

Delphi Panel

The consensus was structured according to the modified Delphi panel method [14].

The expert group was formed representing the key expertise with a specific interest in the topic: key opinion leaders were covering different fields to include in the discussion the point of view of the physicians preventing UTIs in their everyday life (urologists) and of the pharmacologists/biotechnologists for their deep knowledge of the different interactions leading to therapeutic action. The point of view of professionals with thorough expertise in the regulatory process of medicinal products and medical devices was also integrated. The panel consisted of representatives from various European nations, and their collective median h-index ranged from 38 to 74 with a value of 48 [range: 38–74].

A Likert scale, graded from 1 to 7, was employed to gauge opinions, with 1 signifying no concurrence and 7 indicating complete agreement. Agreement was defined by a threshold of 6, whereas a score of 5 was considered indicative of indecision [15].

Prisma Research

Prisma 2020 expanded checklist and flow diagram were used as appropriate to systematic reviews of studies that evaluate the effects of health interventions [16]. All studies (in vitro and in vivo) explicitly related to the mechanism of action of D-mannose in the binding of E. coli preventing UTI were included. All abstracts were included. All other articles considered relevant by the panel, as far as the regulatory and pharmacological point of view, guidelines and directives, including papers from references were manually retrieved. Research papers that lacked abstracts, studies that investigated the clinical efficacy of D-mannose, studies that focused on pathogens other than E. coli, and abstracts written in languages that necessitated translation, such as Russian, Bulgarian, and Japanese, were omitted from consideration.

The PubMed database was searched out on 10th October 2022. MESH research was implemented (“Urinary Tract Infections/drug therapy”[Mesh] OR “Urinary Tract Infections/etiology”[Mesh] OR “Urinary Tract Infections/immunology”[Mesh] OR “Urinary Tract Infections/metabolism”[Mesh] OR ”Urinary Tract Infections/microbiology”[Mesh] OR “Urinary Tract Infections/physiology”[Mesh] OR “Urinary Tract Infections/physiopathology”[Mesh] OR “Urinary Tract Infections/prevention and control”[Mesh] OR ”Urinary Tract Infections/therapy”[Mesh])) AND “Mannose”[Mesh]). A search without MESH was also implemented ((D-mannose [Title/Abstract]) AND (urinary tract infection*[Title/Abstract]). No limits were set on timeframe and languages.

Articles were manually retrieved. Three external reviewers (SL, LP, SG) screened each record and each report retrieved (title/abstract). Multiple reviewers (FS, MG, BE) worked independently at each stage of screening and an email process was used to resolve disagreements between screeners.

Data collection process was manually performed by three reviewers (SL, SG, LP) who independently worked. Synthesis methods included all the included studies which were qualitatively tabulated according to the study type (in vitro, in vivo, review) and main results relevant to describe the nature of the interaction between D-mannose and E. coli. Since the review does not regard clinical outcomes assessment, no risk of bias and no aggregated data could be estimated and synthesis of qualitative has been consulted [17, 18].

Statements Drafting

The research question has been discussed based on the Medical Device Coordination Group (MDCG) 2022–5 guidelines (Fig. 2) [7] and art. 2 of the regulation 2017/745 (MDR) [19]Footnote 1 and available evidence on the mechanism of action of D-mannose for UTI prevention.

Figure 2
figure 2

Flowchart for Determining if a Product Fulfils the Definition of a Medical Device (MDCG 2002–5) [7].

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Results

Prisma Results

A total of 33 articles were retrieved (Fig. 3). Studies characteristics, results of individual studies and synthesis are reported in the supplement materials.

Figure 3
figure 3

PRISMA Flowchart of the Selection Process of Articles that Fulfilled the Criteria.

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Delphi Panel Results

Following a kick-off virtual meeting, a series of 17 statements were sent to the panelists via email. During Round I, experts were allowed to provide comments and suggest rephrasing or additional items. During Round 2, the statements that did not meet consensus after the first round were rephrased according to panellists’ comments: one statement was cancelled. During a final teleconference (29th November 2022), statements which had not reached a consensus after Round II were discussed and reviewed for the merit of inclusion and statements that had already reached a consensus were reviewed, discussed and validated: 3 statements were merged. In the end, 13 statements were drafted, 4 of which regarding definitions and the remaining specifically regarding alfa-D-mannose. Statements are reported in Table 1.

Table 1 Statements Regarding Definitions and Alpha-D-Mannose Interactions: Related Delphi Panel Votes.
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The two-domain structures of FimH allows the type 1 pilus to bind by a catch-bond mechanism. The catch-bond in FimH is biphasic: under moderate force (such as during urination) FimH binds to ligands with higher affinity. In reality, the application of moderate mechanical flow force prompts the dissociation of the FimHLD and FimHPL subunits, resulting in a switch of the lectin domain from a state of low affinity to one of high affinity, up to 1000-fold greater.

FimH’s comparatively feeble affinity in static conditions favors the invasion of UPEC along the urinary tract, while its high affinity under moderate flow conditions (i.e., during urination) allows UPEC to be retained in the urinary tract. This phenomenon can be attributed to the dynamic interplay between flow-induced mechanical forces and the molecular structure of FimH.

The panel concluded that, on the basis of the definitions, the mechanism of D-mannose does not involve a metabolic or immunological action while there is an uncertainty regarding the possibility of a pharmacological action.

As a matter of fact, D-mannose interacts with a cellular component present in the user’s body (the bacterial adhesin) and prevents a pathological process (i.e. the bacterial adhesion and infection). Regardless of whether D-mannose activates an intracellular pathway in bacteria or not, its mechanism of action involves preventing bacterial binding to uroepithelial cells. As a result, the bacteria are subsequently eliminated through urine without any interaction with human tissue. From this prevention effect derives the well-established prevention clinical effect [54,55,56,57].

Uncertainty regards the features of the interaction between D-mannose and the bacterial adhesin and if they delineate a classical ligand-receptor interaction. On one side, the interaction is due to multiple bonds between specific atoms of D-mannose and specific aminoacids residues in a specific binding region of the adhesin. On the other side, such an interaction does not result in specific changes of the conformation of the bacterial protein and there is no activation of intracellular pathways important for the intended effect. From a regulatory perspective, the implications of this result, based initial assumptions, drives to the possible classification of alpha-D-mannose as a medical device.

Discussion

From a regulatory perspective, the fact that the pharmacological action is uncertain (as for the panel votes), drives toward the classification of D-mannose as a medical device. An interaction between the product and the bacteria within the body occurs, it is reversible and dose-dependent, but its nature is inert because it does not induce a direct response activating or inhibiting body processes or restoring, correcting, or modifying the physiological functions in the human being. Moreover, it must be considered that the action of D-mannose takes place, even if inside the bladder, outside the epithelium on bacteria that have not yet invaded the urothelial tissue. Hence, the modus operandi of this substance is not aimed towards the host’s anatomical components, but rather towards extrinsic structures, specifically bacteria, that exist outside of the host’s tissues.

Indeed, according to the EU jurisprudence [58, 59], products inducing a physiological effect cannot be automatically classified as medicinal products “by function” if the pharmacological, immunological, or metabolic effect is not demonstrated based on established scientific knowledge. Evidence does not demonstrate alpha-D-mannose pharmacological, immunological or metabolic action. Furthermore, the MEDDEV 2.1/3 rev.3 [24] and the updated version MDCG 2022–5 [7] define the pharmacological mode of action including two sequential steps: the interaction and the signal transduction pathway. The interaction by itself is not sufficient to determine the therapeutic effect [8].

The topic of borderline products is presently a subject of lively and ongoing debate within the scientific community, reflecting the nuanced complexities of this area of inquiry. The MDCG 2022–5 guidelines are the current instrument used to discuss the borderline nature of products. Using them in this research orientated the discussion toward a conservative hypothesis on the nature of the interaction between alpha-D-mannose and E. coli, being the guidelines the unique official document which introduces a specific definition of pharmacological effect. However, the guidelines do not have legal value and debate is ongoing in the scientific community around their completeness in the definitions provided. Nevertheless, regulatory considerations remain valid because guidelines include the MDR medical device definition.

Furthermore, Art. 2 related to medicinal products, included in the directive 2001/83/CE of the EU Parliament dated 6 November 2001- modified by the rule dated 31 March 2004, 2004/27/CE – does not apply to products whose functional quality of medicinal is not scientifically proven, although it cannot be excluded [21, 60]. In other words, in presence of scientific evidence providing a complete demonstration of alfa-D-mannose as a medicinal product, it remains possible its classification as a medical device.

A very recent European Court sentence [61] Judgment of the 7th Court Directive 93/42/EEC 19th January 2023, declared that “when the main mode of action of a product have not been scientifically establish, this product cannot meet either the definition of the notion of medical device..nor to that of medicine by function…” Taking into account the above, this could also be applied to alfa-D-mannose. As a consequence, as in the previous red yeast rice [58], “the national courts must assess “on a case-by-case basis, whether the conditions relating to the definition of the concept of “medicinal product by presentation” within the meaning of the Directive 2001/83 and amendments are satisfied.”

Conclusions

The regulatory framework is constantly changing. New regulations and legal judgments can add further consideration. A request pending at the European Court will answer to the specific case of a medicinal product with insufficient evidence of the drug and its regulatory classification. The judgment of the Court (Fourth Chamber) 3 October 2013, reports the fact that each Member State can have a different regulatory classification for the same product (medicinal product or medical device), demonstrating that there is not a unique opinion on classifications but, mostly, that it is not even required [62].

Ultimately, it is unlikely that additional chemical evidence will emerge regarding the interaction between E. coli and natural products such as alpha-D-mannose, given the low affinity of the interaction. Research efforts are instead focused on synthetic mannosides and their potential for preventing urinary tract infections.