Current and emerging strategies to curb antibiotic-resistant urinary tract infections

Abstract

Rising rates of antibiotic resistance in uropathogenic bacteria compromise patient outcomes and prolong hospital stays. Consequently, new strategies are needed to prevent and control the spread of antibiotic resistance in uropathogenic bacteria. Over the past two decades, sizeable clinical efforts and research advances have changed urinary tract infection (UTI) treatment and prevention strategies to conserve antibiotic use. The emergence of antimicrobial stewardship, policies from national societies, and the development of new antimicrobials have shaped modern UTI practices. Future UTI management practices could be driven by the evolution of antimicrobial stewardship, improved and readily available diagnostics, and an improved understanding of how the microbiome affects UTI. Forthcoming UTI treatment and prevention strategies could employ novel bactericidal compounds, combinations of new and classic antimicrobials that enhance bacterial killing, medications that prevent bacterial attachment to uroepithelial cells, repurposing drugs, and vaccines to curtail the rising rates of antibiotic resistance in uropathogenic bacteria and improve outcomes in people with UTI.

Introduction

Urinary tract infection (UTI) is among the most common bacterial infections encountered in clinical medicine¹. Overall, one in three women will develop a UTI by her 24th birthday and almost half of women will have a UTI in their lifetime^1,2. Certain populations have increased UTI susceptibility, including sexually active women, pregnant women, people with anatomical defects causing urinary stasis, people with diabetes, people with impaired bladder drainage requiring catheterization, and older people. UTI localized to the bladder, also known as cystitis, is associated with symptoms of urinary urgency, dysuria, abdominal pain and incontinence³. UTI that involves the kidneys, also known as pyelonephritis, is associated with symptoms connected to systemic inflammation such as nausea, vomiting, chills and fever⁴. Acutely, UTI can lead to discomfort, pain, mental status changes, pregnancy complications, urosepsis and death. Long-term UTI complications, typically stemming from pyelonephritis, include kidney scarring, hypertension, proteinuria and renal insufficiency⁵. Antibiotics are commonly used for UTI therapy and nearly 20% of all antibiotic prescriptions are for UTI^6,7. Antibiotic treatment for UTI is often empirically started before results of diagnostic cultures are available, so antibiotic overuse or misuse promotes the development of antibiotic-resistant bacteria^7,8.

Organizations such as the WHO recognize antimicrobial resistance as one of the most pressing public health threats of the 21st century⁹. Antibiotic-resistant organisms impose considerable challenges as they are difficult to treat, escalate illness severity, extend hospitalization and increase health-care costs¹⁰. Estimates suggest that 6.22 million global deaths were linked to or caused by antibiotic-resistant bacteria in 2019 (ref. 10). The most prevalent infectious syndromes associated with these antibiotic-resistant pathogens included lower respiratory infections, bloodstream infections, intra-abdominal infections and UTI¹¹. Regional data from 35 countries in the WHO region of the Americas, comprising 13% of the global population, suggest that antibiotic-resistant infections caused nearly one million deaths in 2019. UTI were responsible for 80,000 deaths, making it the fourth most fatal bacterial infection behind respiratory, bloodstream and intra-abdominal infections⁹. In 2017, The World Bank estimated that antibiotic resistance will increase poverty and decrease gross domestic product by approximately $90 billion worldwide by 2050 — having a sizeable effect on the world’s economy, especially in low-income and middle-income countries^12–14.

Escherichia coli infections account for half of the estimated global burden of antibiotic resistance and E. coli is the predominant pathogen linked to mortality resulting from antibiotic-resistant infections^11,15. Uropathogenic E. coli (UPEC) is the most common pathogen causing uncomplicated and complicated UTI^6,15. In the past 30 years, UPEC has developed resistance to antibiotics that are routinely prescribed to treat UTI, including β-lactams and carbapenems, fluoroquinolones, polymyxins and aminoglycosides. Antibiotic overuse, misuse and suboptimal infection prevention practices have accelerated antibiotic resistance among UPEC^16–18. China, India and Vietnam have reported UPEC resistance to fluoroquinolones as high as 70%, and nearly 60% of UPEC strains express extended spectrum β-lactamases. In countries such as Australia, Canada and the USA, resistance rates to fluoroquinolones or third-generation cephalosporins are 10–15% and increasing^17,19.

Updated information is needed that quantifies the magnitude of antimicrobial resistance in uropathogenic bacteria, tracks antibiotic resistance trends in different parts of the world, and identifies the most common antibiotics contributing to antibiotic resistance. If left unchecked, the spread of antibiotic resistance could promote the virulence of many uropathogenic bacteria. Although not specific to uropathogens, initiatives such as Antimicrobial Testing Leadership and Surveillance (ATLAS), ResistanceOpen and ResistanceMap track worldwide antibiotic resistance^20–22. ResistanceMap is a comprehensive web-based resource with publicly available data from 76 countries capturing antimicrobial resistance and antibiotic use in 76 countries²². Given the prevalence of antibiotic-resistant UPEC, definition and implementation tactics that reduce antibiotic use and the incidence of antibiotic-resistant uropathogens are needed. Strategies can include rigorous UTI management policies, improved antibiotic stewardship programmes, new diagnostics, vaccines and investment in the development of new therapeutic or preventative methodologies. These approaches are highlighted in this Review and might be of interest to primary and subspecialty clinicians working in community practices and academic medical centres, individuals engaged in antibiotic and diagnostic stewardship programmes, microbiologists, epidemiologists, policy makers and translational researchers.

Systematic approaches to reduce antibiotic use

Owing to the challenges posed by antibiotic resistance, approaches to reduce antibiotic use are needed; some systematic methods include policies and stewardship programmes.

UTI policies

Clinical practice guidelines, issued from national and international organizations in the fields of infectious diseases, primary care, gynaecology and urology, have provided recommendations to assist clinicians in the management of adult and paediatric UTI — with guidelines encompassing entities such as asymptomatic bacteriuria (ASB), acute and recurrent cystitis, pyelonephritis, catheter-associated UTI and antibiotic-resistant infections^23–32. Despite widespread guideline dissemination, discordance exists between clinical practice guidelines and antibiotic prescribing practices — including unnecessary antibiotic administration, excessive duration of therapy and misuse of broad-spectrum antimicrobials^7,8,33–36. Rates of UTI guideline concordance are relatively low in urology and obstetrics and gynaecology practices compared with other specialties. For example, treatment concordant with the Infectious Diseases Society of America guidelines was more likely in internal medicine (adjusted OR (aOR) 2.87, 95% CI 2.73–3.03), family medicine (aOR 1.81, 95% CI 1.76–1.87), surgery (aOR 1.51, 95% CI 1.36–1.67) and urology (aOR 0.40, 95% CI 0.38–0.43), suggesting that clinicians in some specialties might benefit from targeted policies or programmes that promote guideline adherence^34,35.

Several variables influence provider adherence to UTI guidelines, but lack of uniformity among UTI diagnostic and treatment policies could be a key driver. For example, amongst American and European professional societies that provide guidance on UTI diagnostics, recommendations vary regarding when to complete dipstick urinalysis testing or urine culture in patients with acute or recurrent UTI³⁷. By contrast, guidelines from the Infectious Diseases Society of America and the American College of Obstetricians and Gynecologists lack discussion on UTI diagnostics^38,39. Streamlined and unified national and local guidance on when to perform screening dipstick analysis or urine culture could reduce antibiotic overuse or misuse.

Regarding treatment, non-adherence to UTI guidelines is more common in patients with recurrent or complicated UTI than in patients with acute cystitis. When these patients present with concern for UTI, many providers prescribe broad-spectrum antibiotics, increased antibiotic dosing or extend the duration of therapy, despite the absence of evidence to support these practices. Alternatively, patients might urge clinicians to administer non-guideline-based therapies in the anticipation of reducing UTI frequency or extending the intervals between infections. However, these approaches lack demonstrated efficacy and pose potential harm to individuals by causing allergic reactions, adverse effects (such as nausea, vomiting diarrhoea and yeast infections), promoting phycological dependence on antibiotics, and potentially augmenting future UTI risk by promoting the development of antibiotic-resistant pathogens and disrupting the microbiome^24,40,41. Importantly, UTI treatment recommendations might not universally apply to each community, given the regional variability in antimicrobial resistance patterns. Health-care providers should integrate awareness of their local antibiogram when choosing antimicrobial agents, aiming for those with minimal collateral damage and effects on healthy vaginal and faecal flora. Local antibiograms are often updated annually, often in conjunction with antimicrobial stewardship programmes, to offer a profile of the results from antimicrobial testing for specific microorganisms²⁴.

Antimicrobial stewardship

Antimicrobial stewardship developed in the 1990s to slow or prevent the emergence of antibiotic-resistant bacteria by promoting judicious antibiotic use⁸. Stewardship entails using an antibiotic only when necessary and prescribing the antibiotic for the recommended duration and dose as well as de-escalating therapy when possible. Over the past two decades, antimicrobial stewardship programmes have increased in hospital settings, urgent-care facilities, emergency departments, primary-care clinics and nursing homes⁸.

Mounting evidence illustrates the effectiveness of stewardship programmes, and their value is highlighted by changes in antibiotic prescribing practices, shortened antibiotic duration, decreased excessive diagnostic testing, reductions in hospital days and costs, and curtailment of the incidence of antibiotic-resistant pathogens⁴². Results of a systematic review and meta-analysis conducted across low-income, middle-income and high-income countries show that antibiotic stewardship programmes are associated with a 10% reduction in antibiotic prescriptions and a 28% reduction in antibiotics identified by the WHO as having a high risk of bacterial resistance⁴³. Adult and paediatric data show that antibiotic stewardship programmes reduce antibiotic prescriptions for UTI and antibiotic resistance in UPEC isolates^44–51. These successes hinge on transdisciplinary collaboration between physicians, pharmacists and laboratory staff to support clinicians making the correct diagnosis and selecting the appropriate therapy. Successful stewardship practices involve institutional support, efficient communication, timely provider education and feedback, clinical decision aids and computerized decision support guides, select test reporting to guide clinicians with diagnosis and treatment, and performance measures^8,52. An important target for stewardship teams is reducing inappropriate treatment of ASB. Several guidelines, including the US Preventive Services Task Force, the Infectious Diseases Society of America and the European Association of Urology, advise against performing urine culture for the screening and treatment of ASB, but the practice of treating ASB with antimicrobials remains widespread — promoting antibiotic misuse and resistance^45,53–56. Stewardship teams have sizeably reduced the number of urine cultures ordered by 3.24 cultures per 1,000 inpatient hospital days and outpatient antibiotic use in long-term residents of care facilities by 17%^45,49,57.

Diagnostic stewardship.

Diagnostic stewardship is a component of antimicrobial stewardship that optimizes testing to reduce diagnostic error and improve diagnosis (Fig. 1). Diagnostic stewardship encompasses sample testing, ordering, processing and results reporting. Diagnostic stewardship has been shown to improve UTI management^8,58–61. Over the past 50 years, UTI diagnostic testing has remained largely unchanged. UTI screening continues to depend on detecting urinary nitrates or pyuria by dipstick urinalysis despite large studies and meta-analyses showing suboptimal sensitivity and/or specificity of these tests^62,63. The cornerstone of UTI diagnosis is urine culture, which requires up to 48 h to provide a result. Consequently, culture results are not available when clinicians decide to initiate antibiotic therapy. This common clinical scenario can lead to delayed UTI diagnosis or inappropriate or unnecessary antibiotic therapy. As a result, new point-of-care biomarkers and diagnostic tests are needed to facilitate UTI diagnosis. Ideally, new diagnostics will help clinicians with initial UTI screening, differentiate bacterial UTI from ASB or sexually transmitted infections, facilitate antibiotic selection, predict UTI severity, decrease antibiotic overuse, facilitate de-escalation of therapy and reduce costs. In addition to diagnostic testing, clinical tools such as the Acute Cystitis Symptom Score (ACSS) can improve UTI diagnosis^64,65. The ACSS provides a standard method for evaluating symptoms such as urinary frequency, urgency, dysuria and haematuria. This structured tool helps clinicians gather comprehensive information about a patient’s condition. By assigning numerical values to different symptoms, the ACSS enables quantification of symptom severity, and this objective measurement can assist providers with diagnosis, treatment decision support, monitoring symptom progression and evaluating treatment efficacy. The standardized assessment provided by the ACSS also facilitates research and quality improvement efforts related to UTI diagnosis and management. Consistent use of the tool provides increased reliability of data collection and comparison across studies or health-care facilities^64–67.

Fig. 1 |. Relationship between diagnostic and antimicrobial stewardship.

Schematic showing how diagnostic and antimicrobial stewardship practices interface to improve the management of urinary tract infection.

Urinary biomarkers are a natural preference owing to ease and convenience of collection, sample volumes and the applicability to point-of-care testing. Urinary biomarkers that have been studied extensively but not yet employed in clinical practice include neutrophil gelatinase-associated lipocalin (NGAL) as well as some cytokines and chemokines^57–61. Results of systematic reviews and meta-analyses suggest that NGAL, IL-6 and IL-8 have diagnostic potential for acute cystitis or pyelonephritis but larger, prospective studies spanning unique populations are needed to demonstrate value before they can be implemented in clinical settings^68–72. In addition to a biomarker or panel of biomarkers, the development and approval of diagnostic tools to detect uropathogens could improve outcomes and curtail antibiotic resistance. PCR identification of uropathogens, detection of antibiotic resistance genes, expanded molecular and proteomic technologies, improved automated laboratory processing, and advanced microfluidics and nanotechnologies are not readily available in clinical practice owing to challenges with standardization and regulatory approval, cost, necessary training and expertise, and infrastructure requirements. If implemented, these technologies might supplement antimicrobial stewardship and open the way for personalized UTI management by identifying targeted therapies, aiding in the early detection of antibiotic-resistant pathogens and assessment of treatment response⁶². As an example, PCR testing for sexually transmitted infections is highly specific and rapid, is a cost-effective method that helps clinicians with diagnosis and management, and reduces infection complications⁷³. Metagenomic next-generation sequencing also holds potential as a diagnostic tool for both uncomplicated and complicated UTI. In contrast to PCR, metagenomic next-generation sequencing does not depend on prior knowledge of microorganisms, and has the capacity to capture pathogenic and resident microorganisms. This comprehensive approach aids in identifying the bacteria causing the infection, particularly in cases when multiple organisms are detected. However, the widespread adoption of metagenomic sequencing is hindered by associated costs and the need for specialized expertise to extract clinically relevant information from extensive and incomplete sequencing data⁷⁴. Additionally, enhanced quantitative urine culture, which involves plating increased urine volumes and additional growth media with differing oxygen or carbon dioxide concentrations, could improve the detection of clinically relevant microbes while advancing our understanding of commensal and pathogenic microorganisms. Culturing urine in a physiologically relevant environment would enable improved growth and accuracy of susceptibility profiles as physiological conditions and the presence of commensal microorganisms can influence bacterial metabolism and susceptibility to treatment^75,76. Beyond improving patient care, these tools could influence infection control, promote clinical trial enrolment, and stimulate additional diagnostics research and therapy development.

Clinical tactics to reduce antibiotic use

Several options are available for clinicians to decrease the exposure of patients to antibiotics, in addition to implementing diagnostic and antimicrobial stewardship programmes to reduce antibiotic use. These include antibiotic-conserving therapies, using combinations of antibiotics to limit antibiotic dose exposure, and administering antibiotics to reduce systemic adverse effects⁷⁷. Historically, these approaches have been overlooked, but providers are now beginning to appreciate their utility to limit antibiotic use.

Antibiotic-conserving therapies

Antibiotic-conserving therapies such as cranberry extract, d-mannose, methenamine hippurate, anti-inflammatories and dietary supplements might prevent UTI and reduce antibiotic use. These therapies are not considered front-line UTI management options, but they do show value in UTI management^77,78. In a randomized trial involving women with recurrent UTI, prophylactic treatment with methenamine hippurate was non-inferior to low-dose antibiotics in preventing UTI. These findings could support a shift in clinical practice regarding preventive treatments for recurrent UTI, offering patients and clinicians a credible alternative to daily antibiotics⁷⁹ (Box 1).

Box 1. Established antibiotic-conserving therapies for UTI prevention and their mechanisms of action.

Cranberry extract: Prevents urothelial UPEC attachment and biofilm formation, and inhibits UPEC flagella and pilus assembly70.

d-Mannose: Prevents UPEC attachment to mannosylated urothelial proteins69.

Globotriose: Prevents UPEC adhesion187,188.

Methenamine hippurate: Promotes bacteriostatic formaldehyde production in acidic urine189.

Non-steroidal anti-inflammatories: Suppress inflammatory response by COX2 inhibition, reversing multidrug resistance138.

Probiotics: Maintain acidic pH in the genitourinary system, releasing hydrogen peroxide and bacteriocin174–176.

Vitamin D: Increases antimicrobial peptide expression116.

Ibuprofen: Treatment of symptoms only in uncomplicated UTI resulted in fewer antibiotic prescriptions190.

UPEC. uropathogenic Escherichia coli; UTI, urinary tract infection.

Antimicrobial synergy

Employing combinations of antibiotics to inhibit separate steps in bacterial pathogenicity could produce enhanced bactericidal effects while reducing total antibiotic dose exposure⁸⁰. When the combined effect of two or more antibiotics is greater than the sum of their individual actions, synergy occurs. Antibiotic synergy is appealing because it broadens empirical coverage provided by two or more antimicrobial agents, increases effectiveness against antibiotic-resistant pathogens, facilitates treatment of polymicrobial infections, and can reduce therapy duration. Combination therapy requires lower antibiotic doses, so toxicity profiles and production costs are reduced^81,82. Additionally, resistant bacteria might become re-sensitized to previously effective antibiotics when synergistic combinations are introduced⁸³. Combining antibiotics could potentially decrease antibiotic resistance and impede the evolutionary selection of antibiotic-resistant bacteria. This potential is attributed to enhanced efficacy in pathogen eradication and their multiple modes of action, which encompasses pore formation and inhibition of cell wall synthesis, β-lactamases, DNA synthesis, pili assembly, transcription and translation^81,84. The theoretical effectiveness of reversing antimicrobial resistance through antibiotic synergy is in selectively inhibiting the growth of resistant clones⁸⁵. Despite the promising nature of this concept, clinical studies are required to validate the effectiveness of antibiotic combinations in reversing antimicrobial resistance⁸⁶ (Fig. 2).

Fig. 2 |. Antimicrobial synergy shows promise to reduce antibiotic use for urinary tract infection.

a, The benefits of antimicrobial synergy. b, Examples of how combination therapy targets different mechanisms to promote bactericidal activity. (1) Synergy between two different antibiotics. Ceftolozane complexes with penicillin binding proteins, whereas tazobactam is a β-lactamase inhibitor. (2) Synergy between an antibiotic and an antimicrobial peptide (AMP). The AMP forms pores in the bacterial membrane, enabling fluoroquinolones to enter the bacteria and prevent DNA synthesis. (3) Synergy between nanoparticles and AMPs. Nanoparticles are directly antimicrobial and promote targeted entry of an AMP where it can prevent transcription. (4) Synergy between small molecules and an antibiotic. Pilicides and mannosides inhibit pili formation or binding to urothelial cells, leaving the bacteria exposed and accessible to antibiotics.

Traditionally, antibiotic monotherapy is prescribed for UTI, but antibiotic combinations are sometimes used. Amoxicillin–clavulonate initially showed promise, but it is no longer recommended as an initial UTI therapy as it is not as effective as fluoroquinolones for cystitis treatment⁸⁷. Perhaps the best example of successful combination therapy is trimethoprim and sulfamethoxazole, which is a recommended front-line treatment for cystitis⁸⁸. These antibiotics sequentially block unique enzymes involved in tetrahydrofolic acid synthesis — an essential bacterial growth factor⁸⁸. However, the synergistic value of trimethoprim–sulfamethoxazole for UTI treatment has been challenged. Data suggest that trimethoprim alone might be as effective as the combination product⁸⁸. Thus, health-care providers should refer to local antibiograms to assess the viability of trimethoprim monotherapy is a viable and more targeted therapeutic option than combination therapy. Moreover, in developed countries as many as 30% of UPEC isolates exhibit resistance to trimethoprim–sulfamethoxazole and up to 80% of UPEC isolates are resistant in developing countries¹⁸. Consequently, although trimethoprim–sulfamethoxazole remains an effective UTI therapy in developed countries, its utility is diminishing in developing countries. This underscores the urgency for the development of new UTI treatments.

The FDA has approved two new combination antibiotic therapies for complicated UTI. Notably, these combination treatments have primarily been tested in complicated UTI, and they might not be the ideal solution for the treatment of uncomplicated infections. Relebactam–imipenem–cilastatin (Recarbrio) is an intravenously administered combination of imipenem, which inactivates penicillin-binding proteins and inhibits peptidoglycan crosslinking during cell wall synthesis, the renal dehydropeptidase-I inhibitor cilastatin, and a novel β-lactamase inhibitor relebactam that protects the β-lactam against hydrolysis. Preclinical studies have indicated that this combination has the potential to inhibit the emergence of multidrug-resistant Pseudomonas^89,90. Since its approval, evidence indicates that the effectiveness of this combination therapy is equal to or less than that of imipenem^91,92. Thus, Recarbrio might have utility depending on pathogen resistance patterns, but this evidence could diminish the likelihood of it becoming a common UTI therapy. Ceftolozane–tazobactam (Zerbaxa) is a combination of ceftolozane, a semisynthetic cephalosporin that exerts its bactericidal activity by complexing penicillin-binding proteins, and the β-lactamase inhibitor tazobactam. Unfortunately, mutants resistant to ceftolozane–tazobactam have already been identified^93–96. Resistance rates to this combination remain low, but the occurrence of resistance once again highlights the need for additional UTI therapies^94,96.

Together, these results suggest that combination antibiotic therapy has promise, yet further investigation is needed to test their clinical value. Moreover, new combinations of established antibiotics need testing, and combining antibiotics with emerging UTI therapies could have clinical effects.

Intravesical antibiotics

Intravesical therapy is common in urological practice and provides an opportunity to minimize systemic antibiotic exposure, which in turn can reduce the incidence of antibiotic-resistant UTI. Antibiotic bladder instillations were initially described in the 1960s and are mostly used in patients performing bladder catheterization. Intravesical therapy has gained momentum in broad adult and paediatric populations⁹⁷. For infections involving other organ systems, direct antibiotic administration is routinely prescribed to ensure appropriate drug delivery, offset fluctuations in pharmacokinetics and minimize off-target effects. Examples include eye drop formulations, topical antibiotics and metered dose inhalers. Intravesical antibiotic delivery is superior to systemic antibiotic administration in three important aspects: first, achieving high local drug concentrations at the apical urothelial surface can eradicate pathogens while minimizing selective pressures that promote antimicrobial resistance; second, delivering high concentrations of intravesical antibiotics can enhance penetration of the urothelial barrier to eradicate pathogens residing in the basal urothelium that serve as a source of chronic or recurrent infection; and third, because intravesical antibiotics are restricted to the bladder, the gastrointestinal and genitourinary commensal flora remain unaffected to restrict UTI pathogenesis^97,98.

Within the past 5 years, four systematic reviews have been conducted in which the safety and effectiveness of intravesical antibiotics for UTI management were assessed^99–102. The results showed that aminoglycosides are the most frequently used intravesical antibiotic for the treatment of UTI in adults and children and that intravesical gentamicin is effective for the treatment and prevention of UTI. They also showed that systemic uptake of aminoglycosides is rare, diminishing concerns for ototoxicity or nephrotoxicity^99–102. Owing to the small numbers of patients and heterogeneity of the identified study populations, larger studies are required to assess the safety and effectiveness of intravesical antibiotics. Given the need to develop targeted UTI therapies, additional investment in testing the long-term safety and effectiveness of intravesical antibiotics, designing drug formulations that can be delivered to the bladder or kidneys, and developing new delivery devices could be valuable.

Emerging approaches to reducing antibiotic resistance

New strategies to reduce antibiotic resistance are emerging, including new methods of targeted antimicrobial delivery, nanoparticles, antimicrobial peptides (AMPs), small molecules, bacteriophages, immunomodulation, hormone therapy and microbiome manipulation.

Antimicrobial delivery

Targeted antimicrobial delivery is a fertile area of discovery. New delivery methods for UTI therapies are being designed to deliver high antibiotic concentrations to the source of infection, target the urothelium and sustain drug delivery.

Microbubbles.

Ultrasound-activated microbubbles are an attractive modality for delivering antimicrobials to the bladder. Microbubbles are small gas-filled bubbles stabilized by a polymer or surfactant coating that can serve as delivery vehicles for hydrophobic drugs¹⁰³. Originally designed for use as contrast agents in ultrasonography, microbubbles have the potential to be extended to targeted drug delivery for UTI. When exposed to ultrasound, microbubbles oscillate in response to incoming pressure waves. At low pressures and high frequencies, microbubbles can be directed towards target tissues. At high pressures and low frequencies, microbubbles collapse and deliver their cargo. The motion of microbubbles in response to ultrasound not only releases the drug but also helps promote drug adhesion and penetration of the surrounding tissue¹⁰³. As a proof-of-concept study, microbubbles loaded with gentamicin and decorated with liposomes safely eradicated UPEC in human bladder organoid models¹⁰³. Further studies are needed to gauge the in vivo efficacy of this approach by evaluating the ability to direct microbubbles to the site of infection, the effectiveness of antibiotic delivery, the eradication of uropathogens and the incidence of any off-target effects. Successful outcomes could lead to the rapid translation of microbubbles to the clinic as they are already approved for use as contrast agents.

Mucoadhesives.

Mucoadhesives can be synthetic or naturally occurring molecules that contain hydrophilic polymers that covalently bind to urothelial glycosylated proteins, enabling them and the drug they carry to remain in contact with the bladder wall — enhancing drug retention in the bladder¹⁰⁴. Antibiotics can be embedded in mucoadhesives by dissolving them together during formulation¹⁰⁵. A number of biomolecules, including chitosan, carbomers and hydrogels, have shown promise as mucoadhesives in preclinical models. They can enhance drug permeation into the urothelium while also providing protection to damaged surface tissue in the bladder¹⁰⁴. For instance, chitosan mucoadhesive nanoparticles, originating from the natural polysaccharide chitin, can encapsulate trimethoprim, adhere to porcine bladders and maintain the prolonged release of antibiotic at high concentrations under urine flow¹⁰⁵. Similarly, polymeric hydrogels, that are composed of hydrophilic polymer chains, can be delivered to the bladder lumen as liquids and, in response to pH or temperature changes in the microenvironment, form mucoadhesive gels that act as a physical barrier on the bladder wall preventing bacterial adherence and survival^104,106. Hydrogels can also be loaded with antibiotics to facilitate bacterial clearance or with immunomodulatory agents that stimulate local immune responses in the bladder to minimize bacterial colonization and infection^107–109.

Several challenges must be overcome before hydrogels can be used clinically: the gels must be designed to uniformly coat the urothelium to maximize protection against pathogens and the mechanical properties of the gels must be optimized to prevent detachment from the bladder wall with urine flow or stretching of the bladder wall¹⁰⁹.

Nanoparticles.

Nanoparticles have the potential to enhance the stability and solubility of an encapsulated cargo, improve drug delivery to tissues or targeted cells, and offer synergistic combination chemistry as they have inherent antimicrobial action¹¹⁰. Nanoparticles are complex 3D structures, with a diameter up to 1,000 nm, and can be made of natural or synthetic materials, inorganic materials or lipids¹¹⁰. Factors such as size, shape, charge and surface coating influence nanoparticle distribution, clearance and how they interact with cells. Nanoparticles that have antimicrobial activity or increase antibiotic efficiency are referred to as nanobiotics¹¹⁰ (Fig. 2).

Nanoparticle research is still in the preclinical stage, but in the UTI field current evidence suggests that nanobiotics have the capacity to target intracellular UPEC reservoirs and reduce recurrent infections given their improved urothelial penetration compared with conventional antibiotics^111,112. Effective UTI nanoparticles are primarily based on metals such as gold and silver or metal-based oxides¹¹¹. Metal and metal-based oxides eradicate pathogens or prevent biofilm formation by photothermolysis, generating reactive oxygen species, degrading bacterial cell walls and interfering with bacterial DNA synthesis¹¹². Perhaps the most investigated use of metal-based nanoparticles involves their deposition on urinary catheters or surgical stents. Preclinical in vitro data suggest silver nanoparticles reduce biofilm formation from UPEC and Proteus mirabilis compared with non-coated catheters^110,113,114. The utility of metal-based nanoparticles can be limited by manufacturing practices, aggregation, delivery and expense¹¹⁰. Their promise in UTI management is demonstrated by their direct antibacterial activity, their limited toxicity and their capacity to disrupt biofilms.^111,112,115.

To overcome some of the challenges associated with metal-based nanoparticles, including toxicity, stability, scalability, delivery and cost, organic nanoparticles are being developed and engineered with biocompatible ligands to facilitate receptor-targeted delivery. Organic nanoparticles comprise polymers or lipids and are considered good delivery vehicles because they are biocompatible and have simple formulation parameters¹¹⁰. Therapeutics can be encapsulated within their core, entrapped in a polymer matrix, or chemically conjugated to the polymer. Modulating nanoparticle properties such as composition, stability and surface charge facilitates control of their loading efficiencies and release kinetics¹¹⁰. In addition to serving as carriers, organic nanoparticles can have direct antibacterial properties. For example, chitosan nanoparticles bind negatively charged bacterial membranes increasing their permeability, and nitric oxide-releasing nanoparticles damage bacterial membranes in vitro^111,116. Carbon-based nanodiamonds, or diamond nanoparticles, show antimicrobial activity against gram-positive and gram-negative bacteria in vitro. When loaded with antibiotics or mannosides, they prevent UPEC adhesion and disrupt biofilm formation in vitro^117–119. Organic nanoparticles can coat materials such as silicones and plastics used in urinary tract devices, can be locally administered to target vaginal or bladder uroepithelial cells, and can be injected subcutaneously to deliver UPEC vaccines. Organic nanoparticles show promising utility, but preclinical in vitro and in vivo testing is required before we see translation to the clinic. Many bladder cancer drugs are required to enter target cells, so the opportunity exists for redesigning chemotherapy nanoparticles for antimicrobial delivery^117–119.

Inorganic and organic nanoparticles are promising antibiotic-conserving modalities for UTI management. However, before they are employed in clinical settings, several hurdles must be addressed: comprehensive evaluations testing how nanoparticles interface with the immune system have lagged behind advances in fabrication, often taking a backseat to particle characterization; rigorous preclinical and ultimately prospective studies in humans are needed as strategies are refined that achieve increasingly specific and local delivery; finally, pharmacokinetic and pharmacodynamic studies are needed that will help create regulatory policies controlling their manufacturing and use¹²⁰.

Antimicrobial peptides

AMPs show therapeutic promise against antibiotic-resistant bacteria. AMPs are evolutionarily conserved peptides expressed in plants, insects, and lower-order and higher-order vertebrates¹²¹. Individual AMPs vary in structure and function, but they are predominantly cationic, amphipathic and composed of fewer than 100 amino acids. The antimicrobial activity of AMPs correlates with their net charge, amphipathicity, hydrophobicity and secondary structure¹²². Sizeable research efforts have interrogated how manipulating these biochemical features could augment the therapeutic index of a peptide while minimizing potential cytotoxic effects⁸¹. AMPs principally kill bacteria by disrupting the bacterial membranes causing cell lysis and death, or translocating across microbial membranes to inhibit bacterial transcription or translation (Fig. 2). Some AMPs promote bacterial opsonization, bind specific microbial targets to disrupt cell division or sequester nutrients that pathogens require for survival¹²¹. In addition to their direct activity on microorganisms, AMPs modulate host cytokine or chemokine expression and immune responses. AMPs such as defensins, cathelicidin, ribonuclease (RNase) A superfamily members, and metal binding proteins including lactoferrin, hepcidin and lipocalin 2, demonstrate antimicrobial activity against gram-positive and gram-negative uropathogens. The structure, function and expression of many urinary tract AMPs have been elucidated^{5,121,123–125}.

AMPs are attractive antimicrobials given their broad antimicrobial spectrum, rapid bactericidal action, and low risk of pathogen resistance¹²¹. Several AMPs are being evaluated in clinical trials for oral, respiratory, and skin or tissue infections, but their use in UTI is only beginning to be explored^122,126. Preclinical evidence shows that AMPs can be used as monotherapy, combined for synergistic activity with antibiotics or other AMPs, or packaged with antimicrobial carriers such as nanoparticles to kill uropathogenic bacteria and disrupt UPEC biofilms (Fig. 2). Preclinical data show that mice orally treated with lactoferrin, an immunoregulatory and iron-binding AMP, have decreased UPEC bacterial titres in their kidneys and bladder after UTI¹²⁷. Human neutrophil peptide 1–3 demonstrates synergistic or additive antimicrobial activity with other AMPs such as cathelicidin and ribonuclease 7 (ref. 128). Cathelicidin inhibits curli-mediated UPEC biofilm formation and combination treatment with polymyxin B prevents UPEC and Pseudomonas biofilm formation^129,130. Packaging rifampicin with synthetic polyurethanes with AMP-like properties enhances UPEC and multidrug-resistant UPEC killing — providing a rationale for coating urinary catheters with AMP-based antimicrobials¹³¹ (Table 1).

Table 1 |.

Trials on antimicrobial peptides

Trial identifier	Study title	Condition	Trial treatment	Comparator	Status	Ref.
NCT06045832	Oral Helicobacter pylori eradication	Helicobacter pylori infection	MAXPOWER biological antibacterial liquid	Water	Recruiting	216
NCT05603598	LEAP2 on postprandial glucose metabolism and food intake in obese males	Obesity	LEAP2 protein, human	Saline	Recruiting	217
NCT05530252	Effects of AMP application after non-surgical periodontal therapy on treatment of periodontitis	Periodontitis	Biokiller oral biological antimicrobial gel	Minocycline ointment or no treatment	Not yet recruiting	218
NCT05340790	First in human study in healthy volunteers of antimicrobial peptide PL-18 vaginal suppositories	Colpomycosis, bacterial vaginosis, mixed vaginitis	PL-18 antimicrobial peptide vaginal suppository	Placebo vaginal suppository	Recruiting	219
NCT05137314	Study in patients undergoing debridement, antibiotics, and implant retention (DAIR) for treatment of a periprosthetic joint infection (PJI) occurring after total knee arthroplasty (TKA)	Joint infection	PLG0206 engineered antimicrobial peptide for local intraoperative irrigation	3 mg/ml vs 10 mg/ml	Recruiting	220
ChiCTR2300075881	The effect of antimicrobial peptide mouthwash on the oral microbiome: a clinical trial	Gingivitis	Antimicrobial peptide mouthwash	Good health	Not yet recruiting	221
ChiCTR2100047202; ChiCTR2300071255	Phase IIIb clinical study to evaluate the efficacy and safety of antimicrobial peptide PL-5 topical spray for wound infection	Secondary skin wound infection after mild burn	Antibacterial peptide PL-5 topical spray	Placebo topical spray	Recruiting	222
ISRCTN38383374	Efficacy of a spray formulation in acne of the chest and back	Mild to moderate truncal acne	Antimicrobial peptide BIOPEP.15-containing topical spray	Commercially available topical sprays	No longer recruiting	223
ISRCTN12149720	Treatment of chronic suppurative otitis media with the antimicrobial peptide OP-145 (AMP60.4Ac) in adults	Chronic suppurative otitis media	Antimicrobial peptide OP-145 ear drops	Control ear drops	No longer recruiting	224
NCT02225366	Intratumoral injections of LL37 for melanoma	Metastatic melanoma	Intratumoral injection of antimicrobial peptide LL37	Non-injected lesion on same subject	Completed	225
JPRN-UMIN000013255	Assessment of the antimicrobial activity of the antibacterial peptide fibre	Infection control in health-care setting	Antibacterial peptide fibre wearing group	Non-antibacterial fibre wearing group	Pre-initiation	226
CTRI/2012/04/002592	A phase-III clinical trial of Xylentra versus silver sulfadiazine for efficacy and safety in patients with burn wounds	Partial thickness burn	Xylentra antimicrobial peptide topical treatment	Silver sulfadiazine topical treatment	Completed	227

Preclinical evidence demonstrates that AMPs have therapeutic benefit, but certain gaps must be overcome before their value can be appreciated in clinical practice. First, methods are needed to reduce AMP production costs (production of synthetic AMP is beginning to show potential¹³²). Second, because changes in urinary ionic composition and pH can affect an AMP’s antimicrobial activity, stable AMP formulations are needed that resist these physiological changes¹²¹. Third, given the shear stress generated by urine flow and bladder contractility, packaging AMPs with polymers, hydrogels or nanoparticles might be required to facilitate sustained urothelial binding and AMP delivery^81,115. Fourth, because AMPs are susceptible to proteolysis and can be degraded before they reach sources of infection, new delivery methods are needed⁸¹. Finally, and perhaps most importantly, the use of AMPs does require caution as they are biomolecules that trigger cell death if delivered in high concentrations, and they exhibit immunomodulatory activities that could increase host injury¹²¹.

An alternative strategy for developing AMP-based therapy is to augment their natural production. Drug repurposing screens have identified natural compounds and clinically available drugs that boost their production. A natural compound library screen identified three molecules — andrographolide, oridonin and isoliquiritigenin — from medicinal plants that induce human β-defensin expression, leading to enhanced antibacterial activity against gram-negative and gram-positive pathogens¹³³. In another study, histone deacetylase inhibitors were found to induce expression of RNase 4 and RNase 7 to confer protection against UPEC in vitro and in vivo¹³⁴. Results of other studies show that vitamin D induces cathelicidin production, and metformin augments urothelial cathelicidin and RNase 7 expression to enhance antibacterial activity against UPEC^135,136. Oestrogen therapy also augments AMPs, as post-menopausal oestrogen treatment in women increases the urothelial expression of defensins, cathelicidin and RNase 7 (ref. 137).

AMP-based therapies for UTI management are in the early stages of development, but show promise owing to their antibacterial properties and capacity to modulate the immune response during infection. Nevertheless, further evidence is required to evaluate their safety and clinical effectiveness, and to address the challenges related to stable delivery to the site of infection.

Small molecules

Preclinical data have advanced our appreciation of how uropathogenic bacteria use pili to bind to and invade host cells, and this understanding has facilitated the development synthetic compounds — called pilicides and mannosides — that inhibit pilus activity to reduce bacterial attachment or invasion (Fig. 2).

Pilicides were originally developed to inhibit UPEC type 1 pili assembly, and subsequent data show they also inhibit other pili, pili production in other bacteria, and flagella¹³⁸. Preclinical evidence demonstrates that pilicides prevent UPEC attachment to urothelial cells, thereby impeding the establishment of infection^138–140. Pilicides are not yet clinically available and their pharmacokinetic and pharmacodynamic properties in vivo have not been studied. Given their efficacy against UPEC, further studies are warranted to evaluate their performance.

Mannosides are FimH receptor analogues that bind FimH, a type 1 pilus adhesin, with high affinity and block its ability to bind mannosylated receptors on urothelial surfaces¹³⁸. Mannosides are orally bioavailable, are effective against antibiotic-resistant UPEC, prevent bladder and kidney colonization, and are effective in UTI treatment and prevention^141–145. Mannosides have also been shown to be effective in sensitizing multidrug-resistant uropathogens to antibiotics, which could be a result of their ability to prevent bacterial invasion and formation of intracellular bacterial communities¹⁴⁶ (Fig. 3).

Fig. 3 |. The gastrointestinal and genitourinary microbiomes influence urinary tract infection susceptibility.

a, A healthy microbiome is characterized by high bacterial diversity in which commensal organisms (blue) restrict pathogenic bacteria (red) through competitive exclusion and the production of antibacterial compounds. b, Representative characteristics of microbiome dysbiosis caused by diet, diabetes, antibiotics and bladder catheterization. Dysbiosis decreases bacterial diversity, reduces levels of commensal bacteria (blue), and increases the abundance of pathogenic bacteria such as uropathogenic Escherichia coli (UPEC) (red). c, Strategies to restore the gastrointestinal or genitourinary microbiota to reduce UPEC susceptibility.

Mannosides and pilicides are currently in the preclinical stages of development and have only undergone testing in animal models, but they exhibit considerable potential for the treatment of recurrent UTI. Further investigation is necessary to evaluate their safety and potential off-target effects, including their influence on resident microbiota.

Bacteriophages

Bacteriophages are viruses that infect bacterial cells and promote bacterial lysis¹⁴⁷. Intravesical bacteriophage therapy has been evaluated clinically following kidney and prostate surgery and has been shown to prevent bacterial infection with no adverse effects reported^147–149. In a double-blind clinical trial, intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment for UTIs in patients undergoing transurethral resection of the prostate. However, the trial did not demonstrate the superiority of intravesical bacteriophage therapy over placebo bladder irrigation in terms of efficacy or safety. Nonetheless, the safety profile of bacteriophages seems favourable. Bacteriophages are not currently recognized or approved for UTI treatment, but this trial offers valuable insights to refine the design of future large-scale clinical studies aimed at defining their role in UTI management¹⁴⁷. Bacteriophages might also be an effective tool against multidrug-resistant pathogens, as they can disrupt biofilm formation and restore antibiotic sensitivity. Bacteriophage therapies are in the early phases of development, but are promising alternatives or adjuvants to antibiotics for the treatment of cystitis, warranting further exploration^150,151.

Immunity and immunomodulation

Vaccination is another strategy aimed at limiting antibiotic exposure, and four UTI vaccines are available in Europe and Canada: Urovac, Uro-Vaxom, ExPEC4V and Uromune^5,152,153. These vaccines use combinations of whole, heat-killed bacteria, bacterial extracts, or immunogenic antigens⁵.

Additionally, FimH and bacterial ion-scavenging proteins are being assessed as vaccine targets^152–154. Reviews of randomized clinical trials involving these vaccines demonstrate their potential to reduce UTI recurrence, but these studies are small and responses to vaccination are heterogeneous^{5,152,153,155}. Large randomized clinical trials with defined end-point criteria are needed to support their use as a routine clinical tool to treat and prevent UTI.

Another therapeutic strategy involves immunomodulation. The goal of this approach is to identify therapeutic strategies that boost protective antimicrobial defences while dampening destructive immune responses. Preclinical evidence shows that selected transcription factors or effector molecules, such as IL-1β, matrix metalloproteinase 7 and cyclooxygenase 2, are immunomodulatory targets in UTI — inhibition of these targets could improve cystitis outcomes^156–158. Similarly, silencing interferon regulatory factor 7 could transiently reduce inflammation and minimize pyelonephritis-mediated kidney injury^123,155,159. By contrast, boosting endogenous innate immune responses, including AMPs, might improve UTI outcomes^134,160. Leveraging host innate defences against UTI might offer the optimal approach to prevent bacterial infection and minimize antibiotic usage. Highly specific responses to infectious threats can occur in real time, diminishing the dependence on diagnostics and therapeutic interventions.

Hormones

Hormones affect UTI defences, and a sizeable amount of data substantiate the value of oestrogens in the management and prevention of UTI^77,161,162. After menopause, declining oestrogen levels can lead to changes in vaginal and urethral tissues, making them more susceptible to colonization by uropathogenic bacteria. Evidence suggests that oestrogen therapy, whether administered orally, topically or intravaginally, can help restore urogenital tissue health and reduce the risk of recurrent UTIs in women experiencing the menopause¹⁶¹. Oestrogen therapy can improve vaginal epithelial integrity, increase vaginal pH, enhance local immune responses and promote the growth of beneficial vaginal flora, which collectively contribute to a reduced risk of UTIs^163,164. However, further research is needed to fully understand its efficacy, safety and optimal dosing regimens in this context. Additionally, health-care providers must consider individual factors such as a woman’s medical history, preferences and risks associated with oestrogen therapy before recommending it for UTI prevention^77,161.

Additionally, glucocorticoids, insulin, vasopressin and androgens influence host defences⁵. Hyperglucocorticoidism impairs the ability of mouse neutrophils to kill UPEC, and humans consuming a high-salt diet develop increased plasma corticosterone concentrations and decreased neutrophil antimicrobial capacity¹⁶⁵. Preclinical and clinical studies have shown that insulin and insulin receptor signalling upregulate host defences, and that impaired insulin signalling heightens UPEC susceptibility¹⁶⁶. People with diabetes have reduced serum and urinary AMP concentrations, and insulin therapy restores the expression of some AMPs, preventing UPEC replication^{160,166–168}. Preclinical data show that vasopressin regulates kidney immune defences as vasopressin receptor antagonism increases pro-inflammatory responses to UPEC and prevents pyelonephritis. Conversely, inhibition of vasopressin receptor with diamino-8-d-arginine vasopressin augments UPEC susceptibility by dampening Toll-like receptor 4 immune responses, chemokine secretion and neutrophil recruitment¹⁶⁹. Finally, a growing body of evidence shows that androgens potentiate UTI. In mice, UTI leads to the development of pyelonephritis and renal abscesses more frequently in male mice than in female mice¹⁷⁰. Moreover, elevated testosterone levels heighten renal fibrosis by increasing TGFβ production and polarizing macrophages towards a pro-fibrotic phenotype^170–173. These findings suggest that as we develop an improved appreciation of how hormonal signalling shapes UTI defences, new interventions can be designed to modulate antibacterial responses, reduce UTI susceptibility and curtail antibiotic use.

Microbiome

Resident microbiota shape human health and disease by establishing stable communities that resist pathogens and maintain homeostasis with the immune system¹⁷⁴. Considerable efforts have been made to interrogate gastrointestinal microbial communities, and evidence has established the existence of a genitourinary microbiome^174,175.

Microbiome and UTI pathogenesis

Genitourinary microbiota are interconnected with gastrointestinal microbiota, and disruptions to their structure or function can increase colonization of unwanted pathogens (such as UPEC) and promote UTI^{76,161,174–179} (Fig. 3).

The gastrointestinal tract and faecal flora are common reservoirs for UPEC, and how interactions between the gastrointestinal microbiota and UPEC affect UTI susceptibility are beginning to be understood. Data from kidney transplant recipients show that uropathogen abundance in the gastrointestinal tract is associated with a heightened UTI risk and blooms of intestinal E. coli abundance precede UTI^177,180. Depleting gastrointestinal UPEC reservoirs might reduce UTI susceptibility by preventing UPEC shedding in the faeces and colonization of the periurethral area, vagina and urinary tract¹⁸¹. Mice treated with a UPEC-specific mannoside showed a reduction in intestinal UPEC colonization and subsequent UTI with no apparent disruptions in the overall diversity and composition of the gut microbiome¹⁸². Additionally, women with recurrent UTI exhibit gastrointestinal dysbiosis characterized by reduced microbial diversity and depleted gastrointestinal reservoirs of butyrate-producing bacteria that promote intestinal barrier function and modulate systemic antibacterial defences^183,184. Children with febrile UTI have a gastrointestinal microbiota composition different from that in healthy children, with more Enterobacteriaceae, including E. coli, and fewer Peptostreptococcaceae¹⁸⁵. Together, these data suggest that perturbation of the gastrointestinal microbiota affects UTI susceptibility and provides the basis for studies investigating how changes in the gastrointestinal microbiota influence bladder colonization and UTI-directed immune responses. Ultimately, therapies attenuating gastrointestinal dysbiosis or targeting UPEC in the gastrointestinal tract could be promising antibiotic alternatives.

Vaginal microbiota also influence UTI pathogenesis. In women of reproductive age, ranging from 12 to 49 years of age, the vaginal microbiome is dominated by Lactobacillus species — mostly L. crispatus and L. jensenii^186,187. Lactobacilli establish a microenvironment that prohibits pathogen survival by generating lactic acid to maintain a low vaginal pH of 3.8–4.5, producing antimicrobials such as hydrogen peroxide, surfactants and bacteriocins, and preventing pathogen attachment to uroepithelial cells^174,188. A Lactobacillus-dominant microbiome is considered healthy, but up to one-third of women have a microbiome containing low levels of Lactobacillus and an overgrowth of Gardnerella vaginalis, Mycoplasma species, and other anaerobic bacteria¹⁷⁶. This dysbiosis, termed bacterial vaginosis, augments UTI susceptibility by facilitating UPEC colonization of the vaginal introitus and periurethral areas¹⁷⁶. Evidence demonstrates that women with recurrent UTI have increased rates of E. coli colonization and depletion of Lactobacillus species before UTI onset^189,190. Vaginal dysbiosis also encourages cultivation of less common uropathogens than UPEC and primes the bladder for infection by transitorily exposing the urothelium to vaginal bacteria¹⁷⁶. Vaginal microbiota are now known to have a key role in UTI risk^161,174,176.

The discovery of microbial communities in the urinary tract, supported by high-throughput 16S ribosomal RNA gene sequencing and enhanced urine culture protocols, has uncovered a potential role for the urinary microbiome in shaping UTI pathogenesis⁷⁵. The discovery of urinary microbiota challenges the long-held notion that urine is sterile in the absence of infection^174,175. The urinary microbiome is a relatively new area of study, but evidence suggests that the female urinary microbiome is predominantly composed of bacteria from four phyla: Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria¹⁷⁵. Like the vagina, Lactobacillus is the dominant genus in a healthy female urobiome and Lactobacillus richness influences UTI susceptibility^76,191–193.

Research on the healthy male urinary microbiome is limited compared with that in women, with existing studies often constrained by small sample sizes. Among the few studies available, two involving healthy adult men identified Lactobacillus and Streptococcus as dominant genera in urine samples^194,195. Additionally, evidence indicates that circumcision status can influence the male urethral microbiome, resulting in a shift towards more aerobic and skin-like bacteria. However, the effect of these changes on UTI susceptibility in men remains poorly understood¹⁹⁶.

Modulation of the microbiome

Temporal factors, such as age, sex and medications, affect the gastrointestinal and vaginal microbiome, and evidence is beginning to define how these factors alter the urinary microbiome^174,192. In youth, microbiome changes are associated with sex hormone concentrations in the prepubertal period, and the microbiome in adolescents begins to mirror that in adults. A variety of anaerobes, diphtheroids, staphylococci and E. coli dominate the vaginal microbiome in prepubertal girls, whereas protective Lactobacillus species dominate the postmenarcheal vaginal microbiome^192,197,198. With ageing, declining oestrogen concentrations reduce Lactobacillus richness, and oestrogen replacement therapy restores vaginal lactobacilli. As a result, combined oral contraceptive use with oestrogen and progestin in women of reproductive age or oestrogen therapy in postmenopausal women has value for the management of recurrent UTI^199–202. Moreover, probiotics might protect against UTI by restoring Lactobacillus colonization^203–206 (Fig. 3). Owing to our limited understanding of the male urinary microbiome, we are not yet able to gauge the influence of ageing and how it could affect UTI. Antibiotic exposure also influences the microbiota — causing dysbiosis, increasing pathogen abundance and augmenting UTI risk^207–209. The degree to which dysbiosis occurs primarily depends on the prescribed antibiotic, dose and duration of treatment. Using selective antibiotics, reducing antibiotic treatment duration, or avoiding antibiotic treatment, can avoid collateral damage to the microbiota and potentially reduce recurrent UTI. Additionally, evidence suggests that conditions associated with increased UTI susceptibility, such as diabetes, structural or functional urinary tract disorders and the need for bladder catheterization, can affect the microbiome by triggering inflammation or altering metabolic profiles triggering dysbiosis^{177,184,207–212}. The consequences of these changes on UTI risk are not yet defined.

Finally, our enhanced appreciation of how the microbiome influences disease has led to the use of faecal microbiota transplantation (FMT) in which gastrointestinal microbiota from healthy donors is transplanted into individuals with a dysbiotic gastrointestinal microbiome^213,214. Evidence indicates that individuals undergoing FMT for recurrent Clostridium difficile infections experience a reduction in UTI^213,214. Similarly, vaginal microbiota transplantation has emerged as a therapeutic option for bacterial vaginosis in which a dysbiotic vaginal microbiome is suspected as a contributing factor^176,215. These advances are promising, but further research is essential to evaluate the clinical effectiveness of these approaches for managing UTI.

In total, the importance of preserving healthy intestinal and genitourinary microbiomes across the lifespan cannot be understated. To do so, improved understanding is needed of uropathogen dynamics within the microbiota, and definition is required of how temporal factors or disease states associated with UTI affect the interactions between uropathogens and the microbiota. Bridging these knowledge gaps will help the development of treatment options that reinforce a healthy microbiome, reduce UTI pathogenesis and limit antibiotic use. As these relationships are defined, they will help the development of new antibiotic stewardship practices that shape infection control, guide clinicians on antibiotic use, reduce UTI recurrence and curtail antibiotic-resistant pathogens.

Outlook

The information presented throughout this Review highlights three key areas that could reduce the challenges associated with antibiotic-resistant UTI. First, stewardship must continue to be a fundamental aspect in the fight against antimicrobial resistance. Its scope must not only encompass hospital-based programmes but also extend to community initiatives and long-term care facilities. Stewardship programmes can provide clinicians with access to local antibiotic therapy guidelines and reduce unnecessary antibiotic exposure. In this regard, stewardship can provide necessary infrastructure for clinicians to promptly and accurately diagnose UTI, facilitating targeted antimicrobial use and timely cessation when deemed appropriate⁸. Second, antimicrobial stewardship should become a requirement in both national and international plans and practice guidelines for managing antimicrobial resistance, particularly in low-income and middle-income countries where resistance is highest. Considering the worldwide repercussions of antimicrobial resistance, an urgent necessity exists for a thorough evaluation of the policies and practices that have proven effective and their geographical applicability. Barriers to implementing stewardship programmes and practice guidelines in these regions should be identified and addressed proactively. Also, ensuring equitable access to second-line antibiotics is essential⁹. Third, a substantial investment in advancing the development pipeline for diagnostics, new antibiotics, targeted therapies and vaccines is imperative. Preventing UTI through prophylactic measures such as vaccines, small molecules, microbiota and immunomodulation is paramount for reducing our reliance on antibiotics. Over the past few decades, investments in drug discovery for antimicrobial resistance have been disproportionately modest compared with those allocated to other public health issues with similar or even less impact.

Conclusions

The continued evolution of antibiotic-resistant uropathogens highlights the need for improved UTI diagnostics and treatments. More effective diagnostic methods will enable clinicians to obtain increasingly accurate assessment of a patient’s UTI and guide therapy using antibiotic stewardship programmes. These practices will not only improve patient outcomes but also slow the development of antibiotic resistance and extend the usable life of both current and forthcoming UTI treatments.

Key points.

• Uropathogenic Escherichia coli is the most common cause of urinary tract infections (UTIs), but up to 90% of E. coli strains worldwide are resistant to at least one antibiotic.

• Global, regional and community programmes educating clinicians on the current states of antibiotic use and resistance, monitoring or guiding antibiotic use, expanding pathogen testing, and promoting vaccination could reduce the prevalence of antibiotic resistance in uropathogenic bacteria.

• Antibiotic and diagnostic stewardship programmes have benefited UTI management by reducing antibiotic use, improving patient outcomes, minimizing health-care costs and decreasing the incidence of antibiotic-resistant uropathogens.

• Translational research efforts are leading to the development of nanoparticles, antimicrobial peptides and small molecules as promising antibiotic-conserving therapies for UTIs.

• Diverse and healthy gastrointestinal and genitourinary microbiomes might prevent UTI recurrence and identifying avenues to prevent their dysbiosis could reduce antibiotic use.