Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection

Urinary tract infections (UTIs) are the most common bacterial infections in the outpatient setting and occur mainly in women. Over 40% of women experience acute cystitis during their lifetime and 25% of young women without underlying abnormalities have a recurrence within 6 months. First-line treatment relies on short-course antimicrobials, but repeated antibiotic use alters vaginal and gastrointestinal microbiota and promotes multidrug-resistant (MDR) organisms, worsening public health and economic burden. Recurrent UTIs (rUTIs) are defined as ≥2 symptomatic episodes within 6 months or ≥3 within a year, most often as reinfections. Up to 80% of UTIs are caused by Escherichia coli. Female anatomy, sexual activity, spermicide use, and postmenopausal estrogen deficiency increase susceptibility. The purpose of this review is to synthesize current understanding of uropathogen pathogenicity—especially UPEC virulence and intracellular persistence—and to discuss non-antibiotic antivirulence and host-directed strategies to prevent rUTIs and reduce antibiotic reliance.

The review outlines how commensal organisms acquire virulence via horizontal gene transfer to become uropathogens, with UPEC the predominant cause of uncomplicated UTIs. UPEC serogroups (e.g., O1, O2, O4, O6, O7, O16, O18, O75) and phylogroups (B2, D) are described. Key virulence factors include adhesins (type 1, P, Dr, S/F1C fimbriae) for urothelial attachment and invasion; toxins (α-hemolysin, CNF-1; autotransporters SAT and VAT) that drive exfoliation, apoptosis, and barrier disruption; iron acquisition systems (siderophores yersiniabactin, salmochelin, enterobactin, aerobactin); and flagella for ascending infection. UPEC adapts by invading urothelial cells, forming intracellular bacterial communities and biofilms that increase persistence and antibiotic tolerance. Intracellular survival strategies involve cytochrome bd-mediated respiration to counter host apoptosis, siderophore-mediated iron scavenging, zinc transporters for metal homeostasis and oxidative stress relief, and toxin-mediated cytotoxicity for nutrient access. Host defenses include TLR4-mediated inflammation (IL-1β, IL-6, IL-8), neutrophil recruitment, urothelial apoptosis/exfoliation, antimicrobial peptides (e.g., cathelicidin, defensins), and nutrient sequestration (lipocalin-2 against enterobactin, calprotectin for zinc/manganese). The urinary microbiome is not sterile; >100 species have been identified. In women, Lactobacillus predominance supports low pH and pathogen inhibition; reductions associate with rUTIs and incontinence. Gardnerella overgrowth can trigger re-emergence of latent UPEC reservoirs and is linked to pyelonephritis risk. MDR uropathogens are rising (25–54% of isolates in recent decades). Mechanisms include biofilm formation, stress responses, horizontal gene transfer, efflux pump regulation (marA, AcrAB-TolC), and other resistance-associated genes (rapA, yafQ, ymgB, yhcQ).

This is a narrative review synthesizing mechanistic studies, preclinical models, randomized controlled trials, meta-analyses, and clinical guidelines to summarize UPEC pathogenic mechanisms and evaluate non-antibiotic preventive and therapeutic options for rUTIs. No explicit systematic search strategy or formal risk-of-bias assessment is described.

- Epidemiology and burden: >40% of women experience UTI; ~30% develop rUTI within 6 months. Up to 80% of UTIs are due to E. coli. MDR uropathogens comprise an estimated 25–54% of isolates in recent decades. - Pathogenesis: UPEC uses adhesins (type 1, P, Dr, S/F1C fimbriae), toxins (α-hemolysin, CNF-1, SAT, VAT), siderophores (yersiniabactin, salmochelin, enterobactin, aerobactin), and flagella to colonize, invade, and persist within urothelial cells via intracellular bacterial communities and biofilms. Intracellular survival leverages cytochrome bd respiration, iron/zinc acquisition, and toxin-induced nutrient release. Host defenses include TLR4-mediated inflammation (IL-1β, IL-6, IL-8), urothelial exfoliation/apoptosis, antimicrobial peptides, and nutrient sequestration (lipocalin-2, calprotectin). - Urinary microbiome: Healthy female urobiome dominated by Lactobacillus; dysbiosis (↓Lactobacillus, ↑Gardnerella) associates with rUTIs and can reactivate latent UPEC reservoirs. - Non-antibiotic preventive/treatment options: • Behavioral and hormonal: Hydration, timely voiding, hygiene. Topical vaginal estrogen restores Lactobacillus, lowers pH, induces antimicrobial peptides, and strengthens junctions; meta-analyses support efficacy for rUTI prophylaxis (weekly doses ≥850 μg associated with higher efficacy), though 22–67% still experience rUTIs. • Probiotics: Evidence mixed across meta-analyses; strain-specific benefits noted. Highest efficacy reported with L. rhamnosus GR-1, L. reuteri B-54/RC-14, L. casei Shirota, L. crispatus CTV-05; 2022 EAU guidelines recommend formulations containing these strains. • Antiadhesive agents: - Cranberry (proanthocyanidins, PACs): Inhibits P-fimbriae adhesion (effective concentrations reported; recommended PAC dose ≥36 mg/day in studies), reduces motility and biofilms, may synergize with antibiotics. Evidence heterogeneous; some meta-analyses show benefit in women, children, and middle-aged adults, but 2022 EAU guidelines do not recommend cranberry due to inconsistent data. - D-mannose: Blocks FimH-mediated attachment; in vivo shows prevention of colonization/invasion, activity against MDR UPEC, and synergy with antibiotics. Meta-analyses/systematic reviews suggest reduced rUTI and prolonged UTI-free duration; dosing regimens vary. 2022 EAU guidelines recommend D-mannose with counseling about limited high-quality data. - GAG layer replenishment (intravesical hyaluronic acid + chondroitin sulfate): Two RCTs show reduced rUTI frequency and prolonged time to recurrence; 2022 EAU weakly recommends for patients failing less invasive prevention. • Alternative antibacterial: Methenamine hippurate generates urinary formaldehyde in acidic urine; older Cochrane review suggested benefit; more recent RCTs show non-inferiority to daily low-dose antibiotics over 6–12 months; guideline recommendations remain cautious (2022 EAU does not recommend due to mixed evidence). • Immunomodulation: IL-1 receptor antagonist (IL-1RA) reduces hyperinflammation and accelerated bacterial clearance in UPEC-infected mice, comparable to cefotaxime; clinical trials needed. • Vaccines: - Adhesion-targeting (FimC-FimH): Phase 1 showed safety and strong immunogenicity; phase 2 ongoing. - Bacterial extracts (OM-89/Uro-Vaxom): Meta-analyses show ~39% reduction in UTIs at 6 months vs placebo with minimal adverse effects; 2022 EAU strongly recommends in women with rUTIs. - Toxins/proteases and siderophore receptor targets (e.g., FyuA, Hma, IutA, IreA) show protection in animal models, particularly against kidney/bladder colonization. - Combined strategies targeting multiple mechanisms are likely to improve prophylaxis while curbing antibiotic use and resistance.

The review argues that focusing on UPEC antivirulence mechanisms and augmenting host defenses provides viable non-antibiotic strategies to prevent rUTIs, addressing the core problem of antibiotic resistance and microbiome disruption. By interrupting adhesion (cranberry PACs, D-mannose, FimH antagonists), restoring urothelial barriers and antimicrobial capacity (topical estrogen, GAG replenishment), modulating immune responses (IL-1RA), and leveraging adaptive immunity (OM-89 and adhesin-based vaccines), these approaches directly counter key steps in UPEC pathogenesis—colonization, invasion, intracellular persistence, and nutrient acquisition. Evidence strength varies: OM-89 has consistent clinical efficacy; topical vaginal estrogen shows benefit in postmenopausal women; D-mannose shows promise with supportive meta-analyses; intravesical GAG therapy benefits selected patients; methenamine hippurate may be non-inferior to antibiotics in RCTs; probiotics are strain-dependent with mixed outcomes; cranberry evidence is heterogeneous. Integrating multiple modalities tailored to patient phenotype (e.g., menopausal status, microbiome profile, recurrence pattern) may enhance durability of prevention while reducing antibiotic exposure and resistance selection.

Non-antibiotic options that target UPEC virulence and host factors represent promising strategies to prevent recurrent uncomplicated UTIs. Mechanism-based interventions—antiadhesive agents (D-mannose, selected cranberry PAC formulations, GAG replenishment), hormonal restoration (topical estrogen), immunomodulators, and vaccines (notably OM-89)—can disrupt colonization and persistence while preserving the microbiome and mitigating resistance. Future UTI management will likely employ combination therapies aimed at multiple pathogenic steps. Robust, long-term randomized trials are needed to confirm efficacy, define optimal dosing/regimens, assess durability and safety, and identify biomarkers to personalize prevention.

As a narrative review, no formal systematic search protocol or bias assessment is presented. Evidence across modalities is heterogeneous in study design, populations, definitions of rUTI, dosing, strain selection (for probiotics), and duration, limiting comparability and long-term conclusions. Several promising approaches (e.g., IL-1RA, adhesin-based vaccines, vaginal laser therapy) rely on preclinical or early-phase data without definitive clinical outcomes. Cranberry and probiotic findings are inconsistent, and optimal D-mannose regimens remain unclear.