CAUTIon – not all UTIs are the same

Abstract

Urinary tract infections are one of the most common infections, accounting for ~400 million diagnoses per year worldwide. Uncomplicated urinary tract infections (uUTIs) occur in healthy individuals with no structural or functional abnormalities of the urinary system and primarily affect women. Catheter-associated urinary tract infections (CAUTIs) are a type of complicated UTI affecting patients who have a urinary catheter in place, often hospitalized patients or patients with conditions that prevent them from urinating naturally. Both infections share common symptoms, diagnostics and treatment options but also differ greatly in pathophysiology, aetiology, risk factors and comorbidities. These differences could explain why antibiotic treatments — which generally lead to positive outcomes in patients with uUTIs — often fail in patients with CAUTIs. Understanding these differences could guide evidence-based insights into why treatments for CAUTIs should be different from those for uUTIs, specifically, by modifying catheters, which initiate the damage-induced segue for UTIs.

Introduction

Urinary tract infections (UTIs) are one of the most common diagnoses in the USA and one of the most common bacterial infections worldwide with ≥30%¹ of diagnoses^2,3. In 2001, UTIs accounted for 150 million hospital visits⁴, which increased to ~405 million in 2019, leading to ~237,000 deaths^5,6. UTIs can be community acquired or hospital acquired, which can also lead to different outcomes (Fig. 1). UTIs are classified as uncomplicated or complicated UTIs⁷. Uncomplicated UTIs (uUTIs) occur in healthy individuals without structural or functional urinary system abnormalities, including absence of kidney dysfunction or impairment, and no concomitant diseases that could promote the UTI⁸. Furthermore, uUTIs affect mainly women (4:1 ratio). This disparity occurs for numerous reasons, including the urethra being much shorter in women than in men, enabling infectious agents to reach the bladder faster; the proximity of the female urethra to the anus and vagina; and hormonal differences — which can change during perinatal periods or menopause in women — that contribute to the microflora of the proximally close vagina^9,10. UTIs can affect either the lower urinary tract (urethra and bladder) or the upper urinary tract (ureter and kidneys), termed cystitis and pyelonephritis, respectively. Antibiotics are successfully used in uUTIs (~80% success rate) to resolve acute symptoms^11,12 but fail to eliminate recurrence risk¹³. Recurring UTIs (rUTIs) occur in ~33% of patients with uUTI, increasing clinical visits and antibiotics use. Importantly, untreated UTIs might disseminate to the kidneys, lead to secondary bloodstream infections and potentially cause urosepsis¹⁴.

Fig. 1 |. Comparison of crucial clinical characteristics between uncomplicated catheter-associated urinary tract infections.

Uncomplicated urinary tract infections (uUTIs) and catheter-associated UTIs (CAUTIs) share many crucial similarities in symptoms, diagnostics from urine culture reports and even treatments. Yet, important differences are also present, including catheterization, population at risk and presentation of some systemic symptoms. Despite the differences, both conditions are treated similarly with antibiotics, with some differences in antibiotics regimes¹⁷⁸. The outcomes of the treatments vary greatly, which could explain why patients with uUTIs have a low risk of bloodstream infections whereas CAUTIs often lead to sepsis. *Relevance for fungal infections. CFU, colony-forming units; E.coli, Escherichia coli.

Complicated UTIs occur when patients are immunocompromised, catheterized, have prostate complications (in men), diabetes, or neurogenic bladder¹⁵. Most health care-associated UTIs are caused by some sort of clinical instrumentation, including the use of urinary catheters, resulting in catheter-associated urinary tract infections (CAUTIs). CAUTIs account for ~80% of all complicated UTIs and ~40% of all hospital-acquired infections (HAIs)¹⁶. CAUTIs cause both cystitis and pyelonephritis, although kidney infections can be more severe than in uUTI¹⁷. CAUTI treatments include removing or replacing catheters and antibiotics regimen. However, success rates of antibiotics are low, barely reaching ~40%¹⁸. Importantly, multidrug resistance is steadily increasing among the urinary pathogens (uropathogens)¹⁹. Urinary catheterization is the primary risk factor for CAUTIs. However, this procedure is very important to help patients safely empty their bladder²⁰, including patients with difficulty urinating naturally, neurogenic bladders, spinal-cord injuries (SCIs), patients undergoing surgeries, or those admitted into nursing homes²⁰.

HAIs drastically surged during the COVID-19 pandemic^21,22; specifically, CAUTI incidences increased by ~19% overall in 2020 compared with pre-pandemic incidences (2019), with a staggering 30% rise in patients in intensive care units (ICUs) alone²². In nursing homes specifically, 13–15% of patients are catheterized on the day of admittance, which predisposes these individuals to developing infections, amongst other complications^23–26. For example, patients catheterized for ≥75% of their time in a nursing home are three times more likely to die within a year than uncatheterized patients, primarily owing to infection²⁷. This phenomenon contributes to the 13,000 annual CAUTI-related sepsis deaths²⁸.

High CAUTI prevalence also causes high financial burden, increasing hospital stay²⁹ and visit cost by an average of US$1,000/patient, resulting in ~US$355 million/year^30–35. This high cost is not covered by Medicare and Medicaid insurance because CAUTIs are considered preventable³⁶. Thus, medical institutions have implemented protocols and guidelines to reduce CAUTI incidence, including improved sterile techniques, reduced catheterization times and regular cleaning^37,38, which have improved patient outcomes. For example, results from a study in which the effects of preventative strategies for reducing CAUTIs were assessed in multiple US hospitals and all Michigan hospitals showed that between 2007 and 2009, reminders todiscontinue catheter use reduced CAUTI incidence from 44% to 23%³⁹. Despite these efforts, CAUTIs remain highly prevalent in the USA, Europe and Asia^1,28,40.

In this Review, we aim to establish that although uUTIs and CAUTIs might be similar in terms of anatomy, prevalent pathogens and sequelae, these infections differ greatly. Emerging evidence suggests that CAUTIs differ from uUTIs in terms of pathophysiology, symptomatology, aetiology and risk factors. Based on these differences and the rise of multidrug-resistant uropathogens, treatments for CAUTI should become CAUTI specific, antibiotic sparring and different from uUTI treatments¹⁴.

Pathophysiology and aetiology

The urothelium and lamina propria are the primary protective components of bladder tissue that act as barriers against infections. The urothelium is composed of umbrella (superficial layer), intermediate and basal layer cells that can secrete protective antimicrobial compounds⁴¹. The lamina propria is the immune defence layer, harbouring resident and recruited immune cells — with resident cells acting as sentinels for infection and other insults — and initiating an early immune response to microbes⁴¹. Yet, these protective barriers are disrupted during both uUTIs and CAUTIs (Fig. 2).

Fig. 2 |. Pathophysiology of uncomplicated and catheter-associated urinary tract infections.

Bacteria in urinary tract infections (UTIs) are currently thought to ascend into the bladder through the urethra. Uncomplicated UTIs (uUTIs) are primarily caused by uropathogenic Escherichia coli (UPEC), whereas catheter-associated UTIs (CAUTIs) have a broad range of causative agents including Gram-negative bacteria, Gram-positive bacteria, and fungal species. Aa, In uUTI, UPEC bacteria use type I pili (FimH) to bind to the innermost epithelial layer of the urinary bladder, the urothelium. Ab, Once bound to the urothelium, bacteria first invade umbrella cells of the urinary bladder and then undergo clonal expansion, in turn forming intracellular bacterial colonies (IBCs), which enable UPEC to evade any surface bacterial-clearance mechanisms by the infected host and, therefore, have a crucial role in UPEC infection. Ac, d, UPEC forms filaments that protrude from IBCs, through the umbrella cells, into the lumen of the bladder, and reinfect the host. Ba, Insertion of the urinary catheter causes damage to the urothelium and leads to a wound-healing response during which fibrin and fibrinogen (Fg) is recruited to the urinary bladder. Bb, Fg coats both the catheter and the bladder, where pathogens bind Fg to form biofilms. Plasmin is crucial to clear Fg, but many disease states and even pathogens are able to inhibit its fibrin-clearing function, leading to fibrin accumulation (Bc). Bd, As fibrin accumulates, infection severity increases and enables pathogens to disseminate to other organs, potentially leading to sepsis.

Uncomplicated urinary tract infections

Years of uUTI research have established uropathogenic Escherichia coli (UPEC) as the primary cause of uUTI (75–95% of instances)⁴, depending on patient populations. Klebsiella spp. and Staphylococcus spp. are also uUTI uropathogens, with lower and variable prevalence compared with UPEC (6–13%⁴² and 6–15%⁴³, respectively) (Supplementary Fig. 1). Proteus mirabilis, Enterococcus spp., and Pseudomonas spp.⁴⁴ can also cause uUTIs, although at a much lower rate than UPEC. High prevalence of UPEC is partly explained by its residence in gut microbiota as a commensal bacterium⁴⁵ but also by UPEC’s specialization and divergence from gut commensals, with an arsenal of pathogenic colonization and immune evasion factors⁴⁶ (Table 1). Contamination of the perineal region can lead to UPEC ascending the urethra into the bladder by using its flagellum⁴⁵ (Fig. 2A). In the bladder, type 1 pilus D-mannose specific adhesin (FimH) on UPEC binds mannosylated uroplakins receptor on umbrella cells^46,47 (Supplementary Fig. 2), leading to bacterial internalization and invasion of umbrella cells (Fig. 2Aa). This internal colonization can lead to intracellular bacterial communities (IBCs; 10³ bacterial cells), quiescent intracellular reservoirs (QIRs; 4–19 non-replicating bacterial cells), or UPEC expulsion^7,46. Infection outcomes depend on host–pathogen interactions. For example, IBC formation could result in active UTI; however, development of QIRs results in pathogen reservoirs, which could lead to recurrent UTIs^14,46,48. However, UPEC has mechanisms to avoid expulsion and immune evasion, which can lead to chronic UTI and subsequent kidney dissemination^41,46,48.

Table 1 |. Comparison of adhesion and virulence factors in uUTI and CAUTI.

Uropathogen	Type	Adherence (uUTI)	Adherence (CAUTI)	Virulence factors (uUTI)	Virulence factors (CAUTI)
UPEC	Gram-negative	Type 1 pili (FimH)7 Type P pili7 Type S pili7 Dr adhesins7 Curli194	Type 1 pili (FimH)195 Type P pili196	Hly197 Capsular antigens7 Cnf17 Yersiniabactin7 Cyclic di-AMP198 Flagellum7 Ecp199 FocG199 TraT199 Vat200 ChuA200 FyuA200 IutA200 PAI200 ShiA200 Eco274 (ref. 200) SisA200 SisB	Fec201 PapC71 SfaS71 Afa1 (ref. 202)
K. pneumoniae		FimH203 Type 1 and 3 pili7	FimH203	Capsule7 Urease204 RmpA204 Enterochelin204 Aerobactin204	Urease204
P. mirabilis		Mannose-resistant proteus-like and P pili205 AipA adhesin7 TaaP adhesin7	NAF fimbriae (also known as UCA fimbriae)205 Mannose-resistant Proteus-like and P pili205	Capsule7 ZapA7 Flagellum206	Swarming207 Urease207 Pst206 RsbA206
P. aeruginosa		T4Pa205	T4Pa205	ExoS7,208 Phospholipase7 Pyoverdine208	Cyclic di-AMP209 Exopolysaccharides210 Extracellular DNA210 Capsule7 LasB7 Rhamnolipids7,208 Pyoverdine208 Pyocyanin208
A. baumannii		NA	Abp1 and Abp2 (refs. 112,113) InvL211	NA	T2SS211
E. faecalis	Gram-positive	Ebp pili7 Ace adhesin7 Esp adhesin7	Ebp pili7,103 Esp205	NA	SprE68
					GelE111
					Cyclic di-AMP212
					MntH2 (manganese acquisition)213
					AcdACB/AdcII system (zinc homeostasis)214
S. aureus		NA	ClfB108	Urease215	LpdA216 MtlD216 SucD216 FumC216
C. albicans	Fungi	NA	NA	NA	EFG1, hyphal morphology77 Phospholipase217 Proteinase217 Haemolysis217

A. baumannii, Acinetobacter baumannii; C. albicans, Candida albicans; CAUTI, catheter-associated urinary tract infection; Clf, clumping factor; E. faecalis, Enterococcus faecalis; K. pneumoniae, Klebsiella pneumoniae; NA, not available; NAF, nonagglutinating fimbriae; P. aeruginosa, Pseudomonas aeruginosa; P. mirabilis, Proteus mirabilis; S. aureus, Staphylococcus aureus; T2SS, type II secretion system; UCA, uroepithelial cell adhesin; UPEC, uropathogenic Escherichia coli; uUTI, uncomplicated urinary tract infection.

Uropathogenic Escherichia coli evasion of TLR-mediated immunity.

Toll-like receptor 4 (TLR4) is able to recognize pathogens and damage-associated molecular patterns. TLR4 recognition of lipopolysaccharide (LPS) on UPEC initiates a signalling cascade, leading to immunological responses directed to the infection site^7,41,46,48. TLR signalling can lead to UPEC expulsion from the infected cell through adenylyl cyclase 3-dependent cyclic adenosine monophosphate (cAMP) production, which stimulates engaging motor protein-mediated transport of bacteria-containing vesicles to the surface of bladder cells⁴⁹, leading to the expulsion of internalized bacteria^7,46. UPEC evades initial TLR responses by escaping phagosomes and promoting multiplication. In the cytoplasm, UPEC forms IBCs that provide a haven for UPEC against the infiltrating immune cells and antibiotic treatments⁴⁶. Propagation of the infection begins with UPEC morphological changes (fluxing and filamenting), which enable bacteria to protrude and breakout from the infected cell and colonize the neighbouring umbrella cells⁴⁶ (Fig. 2A). Furthermore, UPEC filamentous morphology confers immune evasion by inhibiting phagocytosis^7,46. Additionally, UPEC can form QIRs that remain cryptic and dormant within the bladder cell, avoiding immune cells and re-emerging subsequently to lead to rUTIs^7,46.

Uropathogenic Escherichia coli suppression of IL-6.

In addition to immune-evasion, UPEC can also suppress immunity to increase virulence. LPS–TLR activation in response to UPEC infection initiates both nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cAMP–protein kinase A (cAMP/PKA) signalling cascades, leading to the expression of cytokines such as IL-6 and IL-8 by bladder cells⁴⁹. IL-6 signalling is essential for controlling IBC formation and kidney infections. Results from a study in a uUTI mouse model showed an increase in IBC formation and pyelonephritis in Il6-deficient-mice compared with wild type mice⁵⁰. Specifically, STAT3, an IL-6-downstream signalling factor, was shown to be important for controlling IBC formation, as Stat3-deficient mice showed increased IBC formation, similar to Il6-deficient mice⁵⁰. In another study, IL-6 was shown to promote the recruitment of bacteria-clearing immune cells. In this study, monocyte populations were assessed in wild type mice treated with a vehicle or IL-6-neutralizing antibodies, and IL-6-neutralized mice showed decreased Ly6C⁺ monocyte recruitment and inhibition of inflammatory monocyte expansion in situ, which is a crucial step, aiding clearance of UPEC during infection⁵¹. Furthermore, UPEC also modulates host immunity, differently from other E. coli laboratory strains. Results from an in vitro study showed that LPS-induced elevation of IL-6 in 5637 and T24 bladder cells infected with non-pathogenic E. coli (MG1655), differently from 5637 and T24 bladder cells infected with uropathogenic strains such as UTI89 or NU14, where IL-6 levels were suppressed⁵² The immunosuppressive potential of UPEC was further corroborated by another study in which the immunosuppressive effect of UPEC strains (700414, 700415, CFT073, F11, 536, and J96) was compared with that of non-pathogenic E. coli (MG1655)⁵³. Results from these studies suggest that UPEC strains have evolved to reduce bladder immune response, which might lead to chronic colonization and QIR formation to cause subsequent rUTIs. Thus, IL-6 has a crucial role in controlling the IBC formation, increasing infiltrating immune cells and limiting pyelonephritis.

Uropathogenic Escherichia coli infection sensitizes the bladder by inducing epigenetic changes.

rUTIs are a health burden affecting ~33% of all patients with uUTI and can worsen patient quality of life^{4,13,43,54,55}. Mouse models of uUTI have been crucial to identify specific acute host–pathogen checkpoints, including high initial bacterial burden, severe bladder inflammation (oedema), pyuria, and elevated blood pro-inflammatory cytokine levels⁵⁶. These acute checkpoints can determine the disease and rUTI outcomes, both in mice and in humans. In a longitudinal uUTI study in which mice were infected with UPEC, by 4 weeks, ~50% of UPEC-infected mice were not able to clear acute infections, resulting in chronic cystitis⁵⁷. Specifically, mice unable to resolve infections (defined as ‘sensitized’) had increased cystitis and urosepsis after a 6-month convalescence time, and were more prone to infections by other uropathogens, including multidrug-resistant (MDR) pathogens, than mice that resolved the initial infection (defined as ‘resolved’). These results indicate that outcomes of an initial UPEC infection determine chronic inflammation, leading to a molecular imprint that affects mucosal remodelling, inhibits cell maturation and alters mucosal responses during subsequent infections⁵⁸. In another study, the molecular imprint left by UPEC in urothelial stem cells was shown to cause epigenetic changes⁵⁹. In this study, urothelial stem cells derived from mice with chronic infections showed epigenetic modifications (chromatin accessibility, DNA methylation and histone modification) that enhanced caspase-1-mediated cell death compared with cells derived from resolved mice, which cleared the initial infection. Thus, chronic UPEC infection acts as an epi-mutagen by reprogramming the urothelial epigenome, leading to urothelial remodelling and altering the innate response to subsequent infections⁵⁹. Tissue remodelling through increased urothelial cell death after an initial UPEC infection could alter protective features (such as cell shedding to remove IBC-containing infected cells, antimicrobial peptide production and immune signalling) adopted by a mature urothelium in response to subsequent infections, in turn increasing UTI severity and urosepsis, as observed in gut infections, where abnormal gut microflora can alter epithelial barrier integrity, and increasing the risk of sepsis⁶⁰.

Uropathogenic Escherichia coli infections benefit from host COX2 signalling.

During early UPEC UTI, inflammatory and immune responses are triggered as defence mechanisms. However, some inflammatory responses, including activation of cyclooxygenase 2 (COX2) expression, have a role in acute host–pathogen checkpoint. Results from a study in a mouse model of chronic UTIs showed that COX2 expressed by urothelial cells in response to UPEC infection triggered an excessive early neutrophil response (Fig. 2A), which induced bladder tissue damage owing to neutrophil urothelial transmigration, contributing to host susceptibility to rUTI⁶¹. This evidence was further validated in a clinical study in which COX2 was shown to be significantly overexpressed in the inflamed bladder regions of postmenopausal individuals with UTI (P = 0.0007) and in the urine of women with recurrent UTI (P = 0.00001). Notably, COX2 expression predicted UTI recurrence with greater accuracy than any other clinical variable (alone or in combination)⁶². Furthermore, in acute and chronic cystitis mouse models, COX2 inhibition by using the NSAID indomethacin or a COX2-specific inhibitor (SC-236) led to reduced pyuria and mucosal damage⁶¹. Furthermore, COX2 expression levels correlated positively with UTI outcome, as mice with unchanged COX2 expression compared with mock-infected mice had less bacterial colonization (~2 log CFUs) than mice with a ~3 log-fold COX2 increased expression⁵⁴. Upon reinfection, sensitized mice had a ~50-fold COX2 induction, whereas no COX2 expression was found in resolved mice, suggesting that UPEC takes advantage of COX2 induction to circumvent urothelial immunity during UTI⁵⁷. Importantly, results from this study align with the findings from a small clinical trial in which 80 patients with uUTI received either ibuprofen (a COX2 inhibitor) or ciprofloxacin (antibiotic) in a 3-day course treatment for uUTI. In this study, both treatment groups showed similar reduction (~50%) in mean symptomatic score, including dysuria, urine frequency and low abdominal pain. Notably, the ibuprofen-receiving cohort also showed no additional adverse effects or need for secondary antibiotic treatment compared with the ciprofloxacin group⁶³. Results from these studies showed that COX2 inhibition might provide an antibiotic-sparing alternative therapy for uUTI. The fact that COX2 can also be targeted by several over-the-counter NSAIDs and anti-inflammatory steroids supports COX inhibition as a potential therapeutic option to avoid exacerbating antibiotics resistance in patients with UPEC uUTIs. Considering that catheter-induced inflammation drives the CAUTI pathophysiology, understanding whether COX2 or other inflammatory pathways are also activated during CAUTI will be crucial to assess whether targeting catheter-induced inflammation with NSAIDs or anti-inflammatory steroids might also be useful in developing CAUTI treatment options.

Catheter-associated urinary tract infections

Different to uUTIs, CAUTIs develop in the presence of a urinary catheter⁶⁴. Urinary catheterization, despite its benefits, predisposes patients to developing a CAUTI^7,14. Notably, the risk of an infection increases with catheter dwell time^7,14. In humans and mice, urinary catheterization can mechanically injure the urothelium, disrupting host mechanical defences and promoting inflammation^65,66. Urinary pathogens can use different recruited proteins (such as serum albumin, soluble fibrinogen or clotted fibrin) to adhere to catheters and develop biofilm communities^67,68. Biofilms are microorganism communities adhered to a surface and enclosed in an extracellular matrix consisting of proteins, polysaccharides and extracellular DNA⁶⁹. Biofilms are a survival/virulence strategy, which protects microbes against environmental stress and antimicrobial agents, and helps to evade host immunity⁶⁹. Biofilms enable pathogens to evade immune surveillance, persist in the bladder and disseminate to other organs and, therefore, are crucial for the pathogenesis of CAUTIs^7,70–77. Catheter-induced inflammation recruits serum proteins to promote healing, including fibrin and fibrinogen (referred to as fibrin(ogen) in this Review), blood coagulation proteins^{7,14,67,76,78}. Once in the bladder, soluble fibrinogen polymerizes into fibrin to stop bleeding at wound sites⁷⁹. Fibrin(ogen) becomes highly abundant in the catheterized bladder, adhering to the urothelium and to the catheter^{7,14,67,76,78,80}. Paradoxically, fibrin(ogen) provides a scaffold for microbes to develop biofilms and cause an infection from pathogens that would not otherwise be present in the bladder environment^{7,14,67,68,76,78,81–83}. Thus, fibrin(ogen) presence in the bladder is a risk factor for CAUTI.

Fibrin(ogen) is a risk factor for catheter-associated urinary tract infection.

Many of the CAUTI pathogens have low-to-no uUTI prevalence⁸⁴ (Supplementary Fig. 1b). The diversity of CAUTI pathogens could be ascribed to the comorbidities associated with catheterization, such as bladder incontinence, immobility, and other comorbidities, which could influence CAUTI onset alone^30,31,85,86. Notably, fibrin(ogen) presence in the catheterized bladder is exploited by these uropathogens and leads to fibrin(ogen)-dependent biofilms, which are crucial for CAUTI pathogenesis (Fig. 2B) in human and mouse CAUTI^{7,14,67,68,76,78}. Biofilms and infections correlate positively with fibrin(ogen) abundance in vitro and in vivo^67,87. The fact that uropathogens can bind fibrin(ogen) and reside in biofilms during CAUTI might mislead urinalysis for CAUTI diagnosis, which is based on detecting planktonic bacteria from urine samples^84,88,89. Results from numerous studies support that patients with CAUTI had a high catheter colonization by multiple uropathogens, regardless of negative urine cultures and of receiving antimicrobial treatment^73,90–96 (Supplementary Fig. 1b). This unprecedented colonization might contribute to a persistent CAUTI, often leading to in-hospital bacteraemia, with a ~30% 7-day mortality rate and ~40% 30-day mortality rate in patients ≥50 years old^30,32,97; in addition, ~25% of sepsis instances come from complicated UTI, including CAUTIs⁹⁸. Lower percentages of urosepsis death in catheterized patients have been reported in other studies (as low as 5%)⁹⁷; however, the high incidences of catheterization still make this statistic alarming, as over 100 million catheters are being sold in the USA annually⁹⁹. Thus, to date, diagnoses based on urine culture have not provided a full picture of present uropathogens, potentially leading to inadequate antibiotic treatments^100–102.

A question to be addressed is how diverse uropathogens are able to bind to fibrin(ogen). Fibrin(ogen) is a complex glycoprotein composed of two α-chains, two β-chains and two γ-chains and is highly glycosylated, containing a wide variety of sugar residues including mannose, N-acetyl glucosamine, fucose, galactose and N‐acetyl-neuraminic acid^67,103. Therefore, the ability of uropathogens to form protein–protein or sugar–protein interactions with fibrinogen is not surprising (Supplementary Fig. 2) and could explain the diverse range of uropathogens that cause CAUTIs, including Gram-positive, Gram-negative and fungal pathogens⁸⁴ (Supplementary Fig. 1b). Interestingly, the similarity in pathogen diversity between urosepsis and CAUTI suggests that pathogens capable of causing bloodstream infections might also thrive in catheterization-induced inflammation, leading to CAUTIs (Supplementary Fig. 1b–d).

Gram-positive bacteria and enterococci.

Many Gram-positive CAUTI pathogens can bind fibrin(ogen) through ‘lock and key’ protein interactions (in which protein has a binding site that perfectly matches the shape of another protein) (Supplementary Fig. 2d). Staphylococcus aureus and Staphylococcus epidermidis have microbial surface components recognizing adhesive matrix molecules, specifically, the Ser-Asp repeat region (SdrG family) of proteins, to mediate fibrin(ogen) binding¹⁰⁴ (Supplementary Fig. 2). S. aureus has many fibrin(ogen)-binding proteins¹⁰⁵, and this arsenal is differentially used based on the infection site^105–108. In a mouse model of intraperitoneal bacterial sepsis, S. aureus was shown to bind fibrinogen by using clumping factor A (ClfA) to bind the fibrinogen γ-chain. This binding enhanced S. aureus virulence and led to infection^106,107. Interestingly, in a mouse model of CAUTI, S. aureus was shown to use clumping factor B (ClfB), rather than ClfA, to bind fibrin(ogen) (Table 1). ClfB deletion resulted in a defective colonization on urinary catheters and bladders¹⁰⁸, highlighting how the microenvironment of the catheterized bladder can influence adhesin expression, potentially activating a different expression profile compared with that activated in the bloodstream.

Enterococci are the third most prevalent CAUTI pathogen and are a menace in hospital settings owing to their intrinsic and acquired antibiotic resistance, including last-resort antibiotics such as vancomycin¹⁰⁹. Enterococcus faecalis uses the Ebp pilus, specifically the tip adhesin EbpA, to bind to fibrin(ogen) through the MIDAS motif⁷⁶ (Table 1 and Supplementary Fig. 2e). A homologous gene on Enterococcus faecium is probably also capable of binding fibrin(ogen) owing to its 100% similarity to EbpA (Supplementary Fig. 2) and was capable of causing infections in a CAUTI mouse model^76,110. In this study, a vaccine targeting the EbpA N-terminus domain reduced enterococcal CAUTI derived from E. faecalis and E. faecium (uropathogenic laboratory and clinical strains). Importantly, EbpA antibody retrieved from EbpA-vaccinated mice was used as a passive immunization treatment in mice with an enterococcal infection. EbpA antibody treatment substantially reduced enterococcal titres of mice with an existing CAUTI caused by diverse clinical isolates, including E. faecium, E. faecalis and vancomycin-resistant enterococci⁷⁶. Thus, the fibrin(ogen)–EbpA interaction is crucial for enterococcal CAUTIs, suggesting that blocking this interaction could be an efficient antibiotics-sparing treatment.

E. faecalis produces additional virulence factors during CAUTI, including two main secreted proteases, a serine protease (SprE) and gelatinase (GelE) (Table 1). These secreted proteases target the two main circuits of the coagulation cascade, creating an ideal environment for enterococcal colonization. Specifically, GelE degrades fibrin(ogen) and factor XII^68,111, with fibrin(ogen) degradation providing essential nutrients for E. faecalis to thrive in the urinary bladder¹¹¹ environment, which is typically nutrient-deprived in healthy individuals. SprE targets the host fibrinolytic system, which normally degrades fibrin clots, by inactivating plasminogen and plasmin⁶⁸. This action results in fibrin accumulation, enhancing biofilm formation and promoting the persistence of E. faecalis CAUTI (Fig. 2B). The dual ability of E. faecalis to use fibrin(ogen) as a nutrient and inhibit normal host physiological systems that remove fibrin(ogen) from inflamed sites further explains how E. faecalis thrives and exploits the catheterized bladder.

Uropathogenic Escherichia coli and Gram-negative pathogens.

Gram-negative bacteria including E. coli, Klebsiella pneumoniae and Acinetobacter baumannii are known to cause CAUTI and form fibrin(ogen)-dependent biofilms^{14,67,103,112}. The A. baumannii UPAB1 strain was shown to cause CAUTIs through a pAB5 plasmid that promotes the expression of chaperone-usher pili (CUP), increasing this bacterium virulence and fibrin(ogen)-dependent biofilms in CAUTIs¹¹² (Supplementary Fig. 2). In a crystallization study, A. baumannii was shown to use two CUP pili, Abp1 and Abp2 (previously known as CUP1 and CUP2), to bind glycoproteins, including fibrin(ogen); the binding to the sugar components of these glycoproteins occurs through large binding pockets on the pili¹¹³ (Supplementary Fig. 2c). Interestingly, in another study, mice that resolved a priori A. baumannii uUTI experienced an rUTI when catheterized¹¹⁴, indicating that catheterization alone might induce the emergence of QIRs.

Similar to uUTI, E. coli is also the most prevalent CAUTI uropathogen (~33.5%), according to the National Healthcare Safety Network⁸⁴. In uUTI, UPEC uses FimH to attach to the urothelium, facilitating IBC formation by binding to mannosylated uroplakins (Supplementary Fig. 2c). In addition to uUTI, FimH is also crucial for UPEC CAUTI, as FimH deletion or mutations affecting the mannose binding site result in an attenuated CAUTI^47,115. Similar to UPEC, K. pneumoniae also has a FimH adhesin that could be crucial in causing CAUTIs (Supplementary Fig. 2c); however, this hypothesis must be further investigated^42,67,94,96. Unlike what happens in uUTI, IBCs are highly reduced during CAUTI without affecting overall bladder and catheter colonization^47,115. This reduction could happen because CAUTI might not need IBCs, owing to the presence of persistent communities on the catheter. Another explanation could be related to high fibrin(ogen) accumulation and deposition on the urothelium, as shown by immunostaining analyses of mouse catheterized bladder^{67,76,77,92,108,112}, which prevents UPEC interaction with the urothelium, in turn inhibiting IBC formation⁶⁷. Similar to uroplakin, fibrin(ogen) is highly glycosylated and contains a wide variety of sugar residues, including mannose¹¹⁶, which could compete for binding against uroplakin. In fact, fibrin(ogen)-deficient mice and mice with reduced fibrinogen deposition on the catheter undergo UPEC defective colonization on bladders and catheters, respectively, suggesting that UPEC binding to fibrin(ogen) is crucial during CAUTI^67,68. These findings suggest that the catheterized environment affects IBC formation and possibly QIR reservoirs by shifting UPEC intracellular colonization behaviour during uUTI towards an extracellular colonization during CAUTI^67,68.

Candida.

Candida albicans has emerged as a major CAUTI pathogen (Fig. 2B); however, candiduria (Candida in urine) is one of the most problematic issues in patient management, owing to a lack of evidence-based information on the pathogenicity of Candida spp. in the urinary tract. In fact, whether candiduria results from a contamination or an invasive infection is unclear, which is a conundrum for physicians^117–119. This situation is further complicated by the undefined laboratory criteria for diagnosis of fungal UTIs, which are different from bacterial UTI, where standardized criteria are available¹¹⁷. Most fungal UTIs occur in hospitalized patients with indwelling catheters¹²⁰, and candiduria is steadily increasing in catheterized patients in the ICU^121–124. In a study in mouse models of uUTI and CAUTI, only urinary catheterization was shown to significantly (P < 0.005) promote C. albicans colonization of the bladder and systemic dissemination⁷⁷. Additionally, the catheterized bladder environment causes Candida to develop an Efg-1-dependent hyphal morphology (which is associated with virulence) and the expression of Als-1 adhesin (mediated by Efg1). Both Efg1 and Als1 are important for persistent CAUTI⁷⁷: hyphal morphology contributes to immune evasion and invasive colonization, whereas Als1 is crucial for fibrin(ogen)-dependent colonization. Importantly, in the same study, experiments in a mouse model of CAUTI showed that Als1 was overexpressed and contributed to significantly (P < 0.0001) increasing colonization in the bladder, catheter and kidney⁷⁷. Furthermore, Als1 shares great structural similarity to ClfB and SdrG, which are fibrin(ogen)-binding proteins on staphylococci^77,108 (Supplementary Fig. 2d). These mechanisms combined with being a WHO-classified health-threatening fungal pathogen¹²⁵ makes Candida spp. dangerous pathogens.

Current reporting of Candida spp. in CAUTIs is limited. In 2022, a WHO report classified C. albicans as a major fungal threat¹²⁶. Additionally, Candidozyma auris is also a great threat, and has increasingly been isolated from urine from patients, indicating the potential of C. auris as a urinary pathogen¹²⁷. However, to our knowledge, no studies investigating C. auris pathophysiology in the urinary tract are currently available. Additionally, in 2015, the Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network guidelines removed Candida spp. as a causative agent of UTIs, probably because typical symptoms of UTIs such as fever, leucocytosis and decreased renal function are not useful in distinguishing fungal infections, and symptoms are crucial for diagnosing a CAUTI¹²⁸. Results from a 2015 study in which urinalysis was carried out in 1,408 catheterized patients showed that Candida was the second most common pathogen. Among 146 catheterized patients with candiduria, 36% had fever and 33% had leukocyturia (these symptoms are not mutually exclusive). Overall, 64% (n = 93) of patients remained asymptomatic for both fever and leukocyturia, and therefore, did not receive treatment for Candida infections¹²⁸. Lack of treatment in these patients is unfortunate because in another study, patients with candiduria were shown to have higher in-hospital mortality rates than patients without (49% versus 37%)¹²⁹. In addition, a high incidence of fungal CAUTIs are reported in patients in the ICU who are under medication, including opioids, that could mask symptoms¹³⁰, indicating that if the patient did have candiduria, the infection would go undetected.

Classical urinalysis based on CFUs could also provide another reason why Candida infections might be difficult to assess, considering that Candida has virulent morphological changes. Candida switch from yeast to virulent hyphal morphology, where filamentous growth is crucial to penetrate host epithelia and cause disease, as opposed to the yeast form, which could be planktonic and is associated with commensalism⁷⁷. Hyphal morphology was shown to be triggered during urinary catheterization^77,131, and in several clinical studies including patients with candiduria, C. albicans biofilms with hyphal morphology were detected on catheters^90,132–135. Thus, the fungal burden might be underestimated, as hyphal cells are sticky multinucleated cells, leading to one colony per hyphae and less planktonic yeast in urine than that caused by biofilm-bound hyphal fungi. In skin infections, PCR has been used to improve detection of Candida and virulence factors as opposed to CFU counts^90,136. This shift also highlights the importance of proper diagnostic tools and protocols for CAUTI diagnosis to prevent downstream systemic dissemination.

Before 2015 CDC guideline changes, fungal UTI accounted for 15% of CAUTIs, making it the second most common CAUTI, just after UPEC. Removing fungal pathogens as UTI causative agents has not decreased the prevalence of these pathogens in the USA or other countries. Results from a longitudinal study showed that candiduria remained highly prevalent over a 10-year period, with no decrease observed in the ratio of urine samples positive for Candida¹³⁷, indicating no significant decline (P > 0.050) in the prevalence of candiduria (Fig. 1). Additionally, in this study, analysis of urine samples collected from catheterized inpatient wards showed that among Candida species, C. albicans was the primary isolated pathogen (60–65%)¹³⁷. In a 2021 clinical study, the prevalence of candiduria reported in patients in the ICU was significantly (P < 0.004, OR 3.025, 95% CI 1.437–6.369) linked to indwelling catheters alone¹³⁸, different from hospitalized patients who have candiduria associated with other factors including age, other malignancies, parenteral nutrition, Acute Physiology and Chronic Health Evaluation II score, or even antibiotics use¹³⁸. These factors also contribute to Candida-related bloodstream infections and mortality¹³⁹. Interestingly, antibiotics use has been linked to an increased prevalence of Candida infections, probably owing to shifts in the microbiota¹³⁹ that normally control Candida overgrowth. Candiduria caused by catheterization could lead to severe outcomes if untreated; thus, a comprehensive multi-site study in which advanced diagnostic methodologies for candiduria are used is crucial.

Overall, many reasons potentially explain why Candida infections are a menace to hospital settings and CAUTIs, including the fact that 33–55% of all candidaemia instances occur in the ICU; the evidence that many patients in the ICU are under opioid pain medication¹⁴⁰; the lack of reliable fungal UTI diagnoses; and inadequate or no treatment at all for fungal CAUTI infections. These conditions unfortunately lead to a persistent fungal colonization with virulent morphologies and an increased likelihood of septic shock, and to high 30-day mortality¹⁴¹. Thus, future research and improved reporting are required to understand the infection landscape of fungal CAUTIs.

Polymicrobial infections.

Infections are considered polymicrobial when two or more pathogens are cultured from the same sample or from two different samples within 4 days. During UTI diagnostics, when mixed microbes are recovered, the most abundant pathogen (≥10⁵ CFUs/ml)^84,88,89 is considered the causative agent, whereas the other microbes are classified as contaminants¹⁴². A big problem with this approach is that several uropathogens, including E. faecalis, S. aureus and C. albicans, are not motile and predominantly reside in a biofilm community, whereas uropathogens that are motile, including E. coli, K. pneumoniae, Pseudomonas aeruginosa and P. mirabilis, could be represented in urine samples in higher titres. Patients with negative or inconclusive urine cultures, and even under antimicrobial treatment, were shown to have high catheter colonization by multiple uropathogens^73,90–96. Therefore, to date, diagnoses based on urine culture have not provided a full picture of the uropathogens present, leading to inadequate antibiotics treatment^100–102, and potentially contributing to antimicrobial resistance or even urosepsis. Unfortunately, infections with polymicrobial bacteraemia lead to elevated mortality rates (25%) compared with mono-microbial bacteraemia (15–18%)^93,143. In a clinical study including patients with prolonged catheterization, up to 97% of urine samples were shown to have polymicrobial infections⁹³. Different from uUTIs, which are primarily (~95%) monomicrobial¹⁴⁴, CAUTIs are often polymicrobial (~75%)^91,93. Results from both in vitro studies and analysis of clinical samples suggested that many biofilms on urinary catheters are composed of polymicrobial communities^145,146. Results from another study including 19 participants with urinary catheterization over the course of 30 weeks showed that E. faecalis and P. mirabilis were present together 47% of the time, whereas E. faecalis was present 95% of the time and P. mirabilis 58% of the time. These two bacteria were shown to be early colonizers in patients, with persistent colonization throughout 30 weeks⁹². Results from another study in which 366 catheter and urine samples from patients with prolonged catheterization were analysed showed that ~80% of samples were polymicrobial⁹¹. Interestingly, in this study, co-localization of E. faecalis and E. coli was also shown to be potentially beneficial, as these two bacteria consistently co-occurred on catheters throughout the study. Notably, E. faecalis co-occurrence might also be beneficial to various pathogens and lead to persistent infections, as observed in other polymicrobial settings. For instance, E. faecalis is an early colonizer of the neonatal gut, where microbial diversity is crucial, and contributes to the development of healthy immune and metabolic systems¹⁴⁷. Similarly, E. faecalis is an early colonizer in urinary catheters, and has the ability to modulate the bladder environment to benefit itself and possibly other pathogens. This ability might explain why E. faecalis is frequently found in both monomicrobial and polymicrobial infections during acute and prolonged catheterization⁹².

Differences between uncomplicated and catheter-associated urinary tract infection pathophysiology and aetiology

uUTIs and CAUTIs share many common aspects in both pathophysiology and aetiology. For example, pathogens in both conditions must travel through the urethra to infect the bladder. A major difference between these two conditions is that CAUTI pathogens might access the bladder owing to catheter microbial contamination, whereas UPEC migrate through the urethra by using the flagella to ascend to the bladder during uUTIs^4,14 (Table 1, Fig. 2). In fact, UPEC is the major causative agent in both uUTI and CAUTI; however, UPEC prevalence in uUTI is 75–95% whereas UPEC prevalence is reduced to ~33.5% in CAUTI¹⁴⁸. uUTI affects otherwise healthy bladders; thus, the infection onset is dependent on the virulence of UPEC, whereas CAUTIs seem to be driven by catheterization alone. Specifically, considering that IBCs are lower in CAUTIs than in uUTIs, UPEC might have a different binding mechanism in CAUTIs compared with known uUTI mechanisms but still use same binding adhesins. Regarding pathogen diversity, catheter-induced damage to the bladder — or the clinical diagnosis leading to catheterization — might predispose patients to a more diverse range of organisms than uncatheterized patients. Patients with CAUTI have high pathogen prevalence and complex clinical presentation; thus, symptoms of infection in these patients might be similar to or different from symptoms reported in patients with uUTI, or might be masked in patients with CAUTI.

Similarities of symptoms in uncomplicated and catheter-associated urinary tract infections

A positive UTI diagnosis includes a positive urine culture (≥10⁵ CFU) and the presentation of at least one symptom (Fig. 1). Both uUTIs and CAUTIs can present with similar symptoms such as dysuria (painful urination), increased frequency and urgency of urination, suprapubic pain and haematuria^{64,86,149–155}. A major problem in diagnosing CAUTI is that the majority of patients with a urinary catheter are undergoing surgery or have an underlying chronic condition, and require medications that could mask the symptoms. Opioids are common pain medications alongside NSAIDs and acetaminophen during surgery and post-procedure¹⁵⁶. Furthermore, chronic conditions prevalent in catheterized patients, such as comatose state, neurogenic bladders, SCIs, incontinence and urine flow obstruction, can present with symptoms that might overlap with or mask those of a UTI. For instance, UTI symptoms are not pronounced in patients with neurogenic bladders or SCIs owing to dysfunctional brain–bladder communication and underlying nerve damage affecting bladder sensation¹⁵⁷. Consequently, current UTI diagnosis criteria have important caveats, particularly for CAUTIs. Catheterized patients might experience reduced UTI symptoms owing to medication or chronic diseases. Additionally, CAUTI pathophysiology is dependent on biofilms, which reduce planktonic microbial CFUs, potentially leading to false-negative diagnosis, as supported by clinical observations⁹⁰. Furthermore, the duration of catheter-induced bladder damage, which provides an ideal environment for CAUTI pathogens, remains unclear after catheter removal.

Risk factors and comorbidities associated with urinary tract infections

UTIs area common concernin healthcare that can affect just about anyone. Understanding risk factors is important for effective prevention, detection and early treatment to prevent any associated sequelae. Risk factors can range from daily lifestyle choices such as hygiene, sexual intercourse or hydration to gender and health comorbidities associated with age and health¹⁵⁸ (Box 1). Some risk factors are similar in uUTI and CAUTI; for example, the incidence of both types of infection is increased in patients with diabetes mellitus or a weakened immune system, and in older adults (≥65 years old)¹⁵⁹. Yet, how these risk factors are associated with the infection type might be different. For example, older patients might have hormonal changes that can contribute to increased uUTIs but also have age-related issues that contribute to increased rates of catheterization that lead to infections.

Box 1 |. Risk factors for urinary tract infections.

Uncomplicated urinary tract infections  • Abnormal urination (for example, incomplete emptying, or neurogenic bladder)162  • Abnormal anatomical structures that promote recurrent infections162  • Previous antibiotics usage161,162  • Age (young and postmenopausal women)55,161,162  • Birth control  • Cystocele162  • Dehydration162  • Diabetes mellitus55,162  • Diarrhoea162  • Female urethra, which is shorter than the male one55,162  • First urinary tract infection before 15 years of age162  • Frequent pelvic examinations162  • Immunocompromise55,162  • Irritable bowel syndrome162  • Menopause162  • Mother with a history of multiple urinary tract infections162  • New or multiple sexual partners162  • Obesity161  • Poor personal hygiene162  • Pregnancy162  • Sexual intercourse162  • Urinary tract calculi162  • Use of spermicides and diaphragms162 Catheter-associated urinary tract infections  • Urinary catheterization73,159  • Duration of catheterization  • Improper handling  • Cerebrovascular disease218  • Chronic kidney disease219  • Cognitive impairment85  • Diabetes mellitus73,170  • Fibrinolytic deficienciesa  • Congenital malignanciesa  • Acquired through anti-fibrinolyticsa  • Hypertension170  • Neurogenic bladder159  • Paraplegia or mobility issues85,218  • Weakened immune system159

^aMouse model only, not verified with clinical data.

Risk factors of uncomplicated urinary tract infections

Being able to understand individual and population risk factors^55,160–162 (Box 1) associated with increased prevalence of uUTIs is important for predicting infection in susceptible populations and tailoring prophylactic therapies that might better suit individual patients¹⁵⁹. Women are more predisposed to developing uUTIs than men, and some known risk factors associated with gender include anatomy, menopause, birth control, pregnancy and host genetics¹⁵⁸ (Box 1). Specifically, hormones might be crucial contributors to infections. In fact, fluctuation levels of circulating oestrogen in women have been shown to contribute to UTI incidence, as oestrogen receptors on bladder cells can modulate inflammatory cytokines in response to infections through the upregulation of tumour necrosis factor (TNF) signalling¹⁶³. Additionally, obesity and diabetes mellitus are associated with both initial UTIs and increased incidence of rUTIs¹⁵⁹ (Box 1).

Importantly, despite the high clinical burden of rUTIs, a limited number of epidemiological studies focusing on rUTIs is available. Results from a 5-year study including ~375,000 women with UTI showed that ~14% of these women had rUTIs, indicating that rUTIs are common, affecting about 1 in 7 women with a UTI, and poses a clinical problem¹⁶⁴. Characteristics associated with rUTIs affecting young adults and elderly include diabetes mellitus, frequent emergency room visits, frequent antibiotics use, oral contraceptives and antibiotic-resistant organisms. Prophylactic antibiotics are the cornerstone of reducing rUTI events¹⁶⁵. However, the adverse effects of continuous antibiotics use on patient health are now starting to being understood, and include lung and liver toxicity, disturbance to the gastrointestinal tract and skin rashes¹⁶⁵. Non-antibiotic prophylaxis could be a valid alternative; one example could be D-mannosides, which prevent UPEC adhesion and subsequent infection^47,165.

Risk factors and comorbidities associated with catheter-associated urinary tract infections

Unlike uUTIs, CAUTIs are not associated with age or gender, as catheterization alone predisposes hosts to developing a CAUTI, which increases with dwell time⁷³. CAUTI prevention and treatment are associated with major challenges owing to the diverse pathogens (bacteria and fungi) that can cause mono-microbial and poly-microbial CAUTIs, and increasing antimicrobial resistance to these pathogens. Currently, consensus on best practice for CAUTI treatment is lacking. A major challenge is to predict when patients will develop CAUTIs and which populations are at risk of urosepsis. This prediction is crucial, as 25% of sepsis instances derive from urinary isolates. Thus, identification of patient populations with increased susceptibility to CAUTI and urosepsis will enable clinicians to improve patient monitoring to mitigate CAUTI incidence, morbidity and mortality (Box 1). For example, fibrinolytic deficiencies in mice have been associated with increased CAUTI severity⁶⁸, and results from retrospective clinical studies showed an association between diabetes mellitus and hypertension, with increased incidences of CAUTIs. Understanding these associations could be used to identify patients at risk of CAUTI and CAUTI-dependent urosepsis to improve prognosis and outcomes of infection.

Unnecessary catheterization

Notably, many catheterizations are unnecessary, and result in an increase in CAUTI incidences, as catheterization alone predisposes patients to developing an infection³⁶. A total of ~25% of all outpatients receive a catheter, and ~20–50% of catheters are unnecessary¹⁶⁶. Instead of placing indwelling urinary catheters for appropriate reasons — such as for perioperative care, urinary bladder obstruction, or prolonged immobilization — patients are often catheterized as a replacement for nursing care, a means of collecting urine when a patient cannot void voluntarily, or for unindicated prolonged postoperative care; in addition, health care providers frequently forget to remove urinary catheters¹⁶⁶. Patients with geriatric problems — including immobility, falls without hip fracture or patients with bed rest orders — and patients with cognitive impairment are at a high risk of being unnecessarily catheterized⁸⁵. To tackle unnecessary prolonged urinary catheterization, the US guidelines recommend replacing a catheter when certain conditions are met — such as when the catheter has been in place for a specific duration or if signs of infection are present — rather than solely based on urine output¹⁶⁷. Yet, results from a subsequent observational study indicate no improvement in infection outcome when replacing urinary catheters in individuals with long-term indwelling catheters¹⁶⁸. One potential reason why replacing a catheter might be ineffective is that the host proteins that enable infection, such as fibrin(ogen), are still present in the bladder between catheter changes; thus, the remaining urothelial fibrin(ogen)-dependent biofilms could seed the subsequent infection³⁷. To reduce the onset of CAUTIs, medical practitioners recommend reducing catheterization time by limiting the use of urinary catheters to essential medical needs, and when pertinent. In addition, urinary catheterization should be carried out under aseptic conditions, followed by regular catheter care and removal¹⁶. Despite these measures, CAUTI incidences remain high.

Fibrinolytic deficiencies

CAUTI prognosis is associated with host comorbidities including compromise urodynamics, host defences, cognitive impairment, as well as other risk factors that are also associated with uUTIs, such as diabetes mellitus and age (Box 1). Urinary catheterization is a primary risk factor for CAUTI, but the exact mechanisms by which these comorbidities exacerbate CAUTI severity and contribute to CAUTI-related urosepsis remain unclear. Several studies in the past decade have shown that catheter-induced bladder damage emerged as a crucial factor for promoting CAUTI. Results from clinical and animal studies have shown that fibrin(ogen) has a crucial role in establishing and maintaining CAUTIs. Importantly, results from a study in a mouse model of CAUTI showed that removal of fibrin during fibrinolysis is essential in decreasing bacterial burden during catheterization. Any deficiencies in fibrinolysis that cause fibrin accumulation resulted in exacerbated pathogen burden in the catheterized bladder environment and led to increased septicaemia⁶⁸. This phenomenon was observed withy both Gram-positive and Gram-negative bacteria, and fungi as well⁶⁸. Moreover, in this study, catheterized mice treated with the antifibrinolytic agent tranexamic acid showed increased fibrin accumulation in the bladder, exacerbated monomicrobial and polymicrobial CAUTI, and systemic dissemination of UPEC, E. faecalis and C. albicans⁶⁸. Antifibrinolytic agents such as tranexamic acid or ε-aminocaproic acid¹⁶⁹ are commonly used in patients with bleeding disorders and in patients with traumatic injuries, or patients undergoing surgical procedures that increase bleeding risk, including liver transplants, cardiac and caesarean surgeries. As 86% of patients undergoing surgery require urinary catheterization⁶⁸, catheterized patients under antifibrinolytic therapy or with genetic fibrinolytic deficiencies might be at an increased risk of severe and persistent CAUTI and serious bacterial infections. An in-depth retrospective analysis of patient medical history, specifically examining patients who developed CAUTIs that led to urosepsis, is required to elucidate the association between CAUTI prognosis, development and comorbidities.

Other possible comorbidities

Many comorbidities that have not yet been identified might also be associated with coagulopathies. For example, hypertension and diabetes mellitus have a strong association with CAUTI incidence¹⁷⁰. These diseases are highly prevalent in low-income countries and primarily affect Hispanic and Black individuals in the USA¹⁷¹, who have an increased incidence of HAI primarily owing to increased rates of CAUTIs¹⁷². Thus, race and ethnicity could have an important role in identifying patients at a high risk of developing CAUTIs and understanding the comorbidities associated with these sub-populations could help to predict which patients are likely to develop CAUTIs.

Diabetes mellitus and other metabolic disorders can impair immune function, slow healing and modulate haemostasis and coagulation, in turn leading to increased fibrin(ogen), increased hypofibrinolysis or decreased removal of fibrin. For example, conditions such as platelet insensitivity, increased platelet counts in patients with hyperglycaemia, as well as coagulation disorders, can lead to blood clots that are resistant to fibrinolysis¹⁷³. Specifically, patients with type 2 diabetes mellitus have decreased plasminogen activation¹⁷⁴. Increased levels of glucose also have direct effects on plasmin, as hyperglycaemic environments might enhance plasminogen glycation and, therefore, also inhibit plasmin activation¹⁷³, which can increase CAUTI severity. Importantly, plasminogen activation factors return to normal levels under euglycaemia treatments¹⁷⁴, highlighting the importance of proper medication and treatment in preventing impaired fibrinolysis and possibly reducing the onset and clearance of CAUTI. Diabetes-derived increased glucose levels might also be used by pathogens as a nutrient source in an otherwise nutrient-depleted environment such as that found in the urinary bladder, and can lead to CAUTIs in an otherwise healthy bladder.

Treatment and prevention strategies

Distinguishing between uUTIs and CAUTIs is crucial for clinicians and researchers to effectively develop and select treatments. These treatments should be tailored to the specific infection, considering pathogen presentation, virulence mechanisms, patient comorbidity and other risk factors. Antibiotics, empirically prescribed based on urine culture reports, are the most common treatment for UTIs, but other approaches are also being developed, and include antibiotics designed for complicated UTIs, catheter modifications to prevent CAUTIs, and other antibiotic-sparing therapeutics. Novel strategies to mitigate infections can substantially improve patient outcomes, decrease overall UTI prevalence and reduce the rate of antibiotic resistance to uropathogens.

Antibiotics

Currently, both uUTIs and CAUTIs are typically treated with antibiotics¹⁷⁵. The antibiotic choice is guided by the specific pathogen involved and its resistance pattern, but a broad-spectrum antibiotic is also often prescribed³⁷. Antibiotic therapy is often initiated based on local antibiograms until culture results are available¹⁷⁶. Additionally, antibiotic treatment varies depending on the severity of the infection (including acute or chronic cystitis, rUTIs, pyelonephritis or urosepsis) or patient conditions (such as pregnancy or allergies)¹⁷⁷ (Fig. 1). For example, a patient with uUTI is usually prescribed trimethoprim–sulfamethoxazole (TMP–SMX) for 3 days at a dose of 160/800 mg orally¹⁷⁸. However, TMP–SMX treatment for patients with CAUTI has been shown to fail in ~60% of instances¹⁸. Instead, treatment with fluoroquinolones such as ciprofloxacin or levofloxacin, which are typically prescribed orally for 5–7 days at 500–1,000-mg doses, has been associated with reduced onset of CAUTI and lower failure rates than TMP–SMX in patients with CAUTI^82,177. Two new antibiotics, gepotidacin and tebipenem pivoxil hydrobromide, which have been assessed in completed phase III clinical trials, have shown efficacy for the treatment of uUTI and complicated UTI respectively¹⁵⁸. Additionally, antibiotics are also starting to be used specifically to address the multidrug resistance in complicated UTIs, which occurs, for example, in CAUTI. For example, a LepB inhibitor developed by Genentech, which showed in vitro activity against broad Gram-negative bacteria, is currently being assessed in a phase I, randomized, double-blind, single ascending dose clinical trial to assess the safety in healthy individuals after determining low frequency of spontaneous resistance in preclinical stages¹⁷⁹. For urosepsis, intravenous broad-spectrum antibiotics, such as beta-lactams (piperacillin), third-generation cephalosporins, fluoroquinolones and aminoglycosides are recommended¹⁸⁰. However, results from a cohort study showed that early transition to oral antibiotics within 4 days of initial blood culture might be an effective alternative to prolonged intravenous antibiotics treatment in individuals with uncomplicated Gram-negative bacteraemia¹⁸¹. The length of antimicrobial treatment for Gram-negative bacteraemia is debated, as most guidelines recommend a duration between 7 and 14 days for uncomplicated instances, but results from a systemic review of randomized controlled trials comparing antibiotics treatment of ≤7 days to treatment durations of >7 days suggested that shorter courses might be equally effective¹⁸². However, in cases of complicated UTIs, the antimicrobial treatment might be extended to 21 days, depending on the pathogen, drug-resistance profile and patients’ allergies¹⁸⁰.

Patients with CAUTIs must receive antibiotics treatment tailored to urine culture results¹⁶, as antibiotics use can alter the microflora that is able to colonize the catheterized bladder. For instance, previous antibiotics use can exacerbate fungal pathogen prevalence in catheterized patients¹³⁴ or even promote the presence of pathogens that are already antibiotic resistant and eliminate beneficial bacteria that normally help to protect patients against infections. As an example, E. faecalis is inherently resistant to many antimicrobials including penicillin and ampicillin, cephalosporins, clindamycin, aminoglycosides and TMP–SMX¹⁸³; thus, treatment with antibiotics will lead to clearance of other pathogens and promote proliferation of multidrug-resistant enterococci. Additionally, acquired vancomycin resistance of enterococci makes this pathogen extremely dangerous, especially in European hospitals, where vancomycin resistance is highly prevalent¹⁸³.

Catheter modifications

Current research has led to novel catheters that reduce infections by preventing biofilm formation, including catheters loaded with antimicrobial agents, and the use of materials with antimicrobial properties, as well as soft materials⁷⁵. Antifouling coatings decrease infections by repelling biofilm formation on the catheter surfaces. Biofilms are crucial for CAUTI pathogenesis; thus, antifouling coatings constitute a promising strategy to prevent infection onset. These antifouling coating modifications include hydrogels, poly(tetrafluoroethylene), polyzwitterions, polyethylene glycol and liquid silicone infusion⁷⁵. For example, a newly developed novel liquid infused (LIS) catheter with anti-fouling properties decreased biofilm formation from fibrin(ogen) and decreased microbial adhesion to catheters compared with unmodified catheters⁶⁷ in a mouse model of CAUTI. These LIS catheters resulted in reduced colonization on catheters and bladders and systemic dissemination by six different uropathogens, including UPEC, E. faecalis, K. pneumoniae, P. aeruginosa, A. baumannii and C. albicans⁶⁷. Furthermore, LIS catheters reduced CAUTI and also catheter-induced inflammation, which is a hallmark of CAUTI⁶⁷. Thus, LIS catheters hold great potential for the development of lasting, effective and antibiotic-sparing intervention for CAUTI.

Other catheter modifications include equipping catheters with antimicrobial coatings to target microorganism growth by inhibiting microbial protein synthesis, targeting the cell wall and regulating metabolic pathways. Examples of these coatings include silver ions, nanoparticles, antibiotics, antimicrobial peptides and bacteriophages⁷⁵. Bacteriophages provide a great alternative tool to traditional antimicrobial therapies owing to high specificity, accuracy and, possibly, efficacy. Lytic phages can target and degrade biofilm extracellular matrix through secreted lytic enzymes that enable these phages to reach the host bacteria and lyse cells¹⁸⁴. Other pathogen-specific treatments include antibody-based therapies for E. faecalis and E. faecium targeting EbpA⁷⁶. In a study in which FimH-binding mannose analogues (mannosides) were used to treat UPEC CAUTIs,⁴⁷ mannosides alone were shown to decrease bladder colonization and improve the effect of antibiotics⁴⁷, highlighting both the mechanism of infections used by uropathogens and how understanding this mechanism can lead to novel approaches to combating infections.

Currently, the only catheter modifications commercially available are hydrogel-coated, silver-coated, hydrophilic-coated, pre-lubricated and poly(tetrafluoroethylene)-coated catheters¹⁸⁵. Yet, the efficacy of these catheters in the clinic has yielded mixed results. For example, in some studies, silver-coated and hydrogel-coated catheters showed no difference in preventing CAUTIs, whereas in other studies, these modified catheters reduced CAUTIs by 35–47% compared with non-coated catheters^186,187. Additionally, in two small clinical studies including patients with long-term catheterization, the effect of probiotic-coated catheters was investigated, also with mixed results. In one study, a reduction in annual UTI rates was observed, with patients experiencing ~1.5 fewer infections per year than at baseline⁷⁵. Conversely, in the second study, no alterations in UTI rates were identified following the transition from unmodified to probiotic-coated catheters¹⁸⁷. Certainly, further research is required to test the efficacy of different catheter modifications as well as to assess associated risks in patients.

Other non-antimicrobial prevention strategies

Patients with uUTIs are encouraged to increase fluid intake to flush out bacteria, and are also prescribed pain relievers to manage symptoms. Notably, this strategy might lead to inhibition of COX2, as over-the- counter pain relievers such as ibuprofen, acetaminophen, naproxen and aspirin can inhibit COX2 (ref. 188), which is a mechanism contributing to rUTIs. Several other strategies that have shown promise for UTI treatment include anti-adhesives such as analogues of sugars including mannosidases and galactosides, which target UPEC pili adhesins FimH and Fiml, respectively; AKB-4924, which promotes host-cell hypoxia-inducible factor 1α (HIF1α) stabilization, decreasing urothelial invasion; lactoferrin, which enhances the innate immune response against UPEC; and probiotics, which were shown to reduce infection frequency in patients with rUTI⁴⁶.

Home remedies and other non-antibiotic strategies have been explored for UTI prevention and treatment. For example, cranberry products such as cranberry (juice or capsules) have been studied for their potential to treat UTIs. A meta-analysis of 24 studies showed no reduction in symptomatic UTIs from cranberry products, although these products have been shown to be a viable option for pregnant women with asymptomatic bacteriuria¹⁷⁸. Cranberry active ingredients (fructose and proanthocyanidin) and D-mannose have been shown to inhibit UPEC binding to urothelial cells by blocking FimH¹⁵⁸. Yet, evidence of cranberry and D-mannose effectiveness in the clinic is inconclusive. For example, in a clinical trial in which cranberry juice or a placebo beverage was given (in equal volumes) to women with a history of recent UTIs (within the 6 months before enrolment), a significantly lower total number of UTI incidents (P = 0.016) were reported in the cranberry group¹⁸⁹. However, in another study, no difference in rUTI incidence was observed in patients with UTI receiving high doses (18.5 mg) of proanthocyanidin compared with individuals receiving a low dose (1 mg)¹⁹⁰. Similarly, clinical trials assessing the efficacy of D-mannose in preventing and treating UTIs have shown contradictory results. Results from a systematic review of seven clinical trials showed some preventative benefit from D-mannose intervention¹⁹¹. However, results from other clinical trials suggest no reduction in the total UTI incidence compared with a matched volume of placebo powder^158,192. Methenamine hippurate, an antiseptic, has shown clinical efficacy as a preventive treatment for uUTIs¹⁵⁸. Results from one study, in which urine samples from women with UTIs were analysed, showed that methenamine treatment decreased urothelial permeability, indicating improved barrier function against infections¹⁵⁸; however, additional studies are needed to validate the effectiveness of this agent.

People using intermittent urinary catheters are also at risk of developing UTI. Patients reuse disposable catheters for financial or accessibility reasons; however, when cleaned inappropriately, catheters can harbour microbes¹⁹³. Catheter flushes and no-touch catheters have been developed to decrease microbial contamination and biofilm formation, to offset the financial cost of intermittent catheters, and to reduce UTIs¹⁹³. For example, the Aurie system (formerly known as CathBuddy created by Aurie) was developed as a purpose-built catheter washer-disinfector system to remove pathogens from a novel no-touch intermittent reusable urinary catheter. In a preclinical study, the Aurie system effectively reduced the bacterial attachment of E. coli and P. aeruginosa, as well as biofilm formation, on catheters with established polymicrobial biofilms for up to 100 repeat cycles¹⁹³. Overall, efficiently removing pathogens from reusable catheters could serve as a great cost-effective tool in reducing UTI, although additional studies are certainly needed to confirm the efficacy of this approach.

Conclusions

uUTIs and CAUTIs have many common characteristics including symptomology and care. However, most CAUTI treatments are based on uUTI treatments, and prove to be ineffective in fully treating CAUTIs. This phenomenon is primarily ascribed to the existing differences between uUTIs and CAUTIs, including differences in pathophysiology and onset of infection, the increased diversity of pathogens that can cause CAUTIs and the mechanisms through which pathogens modulate host immunity to amplify virulence. Thus, therapies tailored to CAUTIs are urgently needed. In order to develop these treatments, additional research on CAUTIs is encouraged to have an improved understanding of both pathogen virulence and host responses.

Supplementary Material

The online version contains supplementary material available at https://doi.org/10.1038/s41585-025-01065-z.

Key points.

• Urinary tract infections (UTIs) are an extremely common diagnosis in the USA and globally.

• Uncomplicated and catheter-associated UTIs differ greatly in pathogen diversity, pathophysiology and propensity towards secondary bloodstream infections.

• New treatments for catheter-associated UTIs should be specifically designed for these infections, rather than simply adapted from therapies for uncomplicated UTIs To reduce antibiotic resistance among urinary pathogens, modern treatments and preventative strategies can be designed to target specific mechanisms used by uropathogens to cause different types of UTI.