Genes associated with iron acquisition were also highly expressed, including siderophores secreted bacterial proteins that chelate extracellular iron and return it to the bacterial cell. In contrast, tryptophan and cysteine synthetic genes were downregulated, reflecting an abundance of these amino acids within the IBC niche [ 37 ]. Of note, the central metabolic pathways in E. Comparatively less is known about the molecular pathogenesis of infection in the kidney. In traditional mouse models, severe kidney infection including renal abscess formation is uncommon, hampering the study of this entity.
Further, genetics appear to play a role in host susceptibility to acute pyelonephritis. Compared to bacterial cystitis, the understanding of pyelonephritis remains limited and, consequently, represents a fertile area of study.
After ascending the urethra, bacterial pathogens are challenged by innate defenses within the bladder. This inflammatory milieu engenders massive neutrophil influx into the bladder tissue and lumen, correlating with a diagnostic hallmark of UTI.
The importance of this neutrophil influx in controlling UPEC infection has been well established e. Further, many other soluble factors e. Antimicrobial peptides likely protecting the urinary tract include defensins , the human cathelicidin LL, and ribonuclease 7 [ 47 — 50 ]. These molecules may exert direct antimicrobial activity, augment innate cellular recruitment, or function to alter the environmental niche to make it less favorable for uropathogens e.
Recently, the humoral pattern recognition molecule pentraxin 3 PTX3 was shown to help control UTI by serving as an opsonin and promoting bacterial uptake by neutrophils; UTI-prone children and adult cystitis patients who had suffered recurrent UTI as children exhibited polymorphisms in PTX3 [ 53 ], suggesting that the cellular and soluble components of innate immunity can influence disease outcomes. The formation of IBCs is a key means by which bacteria subvert neutrophil activity, as arriving neutrophils accurately locate IBC-bearing facet cells but cannot access the bacteria within [ 39 , 54 ].
UPEC can subvert and delay the innate immune response in multiple ways reviewed in [ 39 ]. For example, secretion of proteins such as UPEC YbcL can lead to a measurable dampening of neutrophil infiltration into the bladder [ 55 — 57 ].
Further, UPEC induces host expression of genes such as IDO , which, via generation of kynurenine metabolites, can cause decreased neutrophil migration across infected bladder epithelia, as evidenced from in vitro Transwell systems, as well as in mice [ 58 , 59 ]. While robust innate defenses are able to repel most bacterial challenges, this inflammatory response may represent a double-edged sword. In murine cystitis, excessive inflammation and resulting bladder tissue damage predisposes the host to worse infection outcomes, including chronic cystitis [ 62 , 63 ].
As mucosal barriers such as the bladder epithelium are repeatedly assaulted with bacteria, they are generally tolerant to a transient microbial presence, and innate defenses are key to preventing infection. However, clinical syndromes such as recurrent UTI raise questions about the importance of adaptive immunity in bladder protection.
Pro-inflammatory cytokines that also elicit adaptive immune effects, such as IL, are prominently secreted during the acute phase of murine experimental UTI [ 64 , 65 ]. Regarding humoral immunity, the prevalence of recurrent UTI in the female population suggests that a lasting protective immune response is not established following cystitis, at least in this subpopulation of women [ 67 ].
Upper-tract UTI pyelonephritis may generate a more robust serological response, although it is not clear if elicited antibodies would subsequently reach the bladder to provide protection against future cystitis. In total, the importance of adaptive immunity in controlling UPEC infection is substantially understudied in comparison with the innate immune system. Understanding the basis of functional adaptive immunity against UTI could have major implications for recurrent UTIs and vaccine development, as further discussed below.
Put simply, UTI therapies are in need of innovation. For decades, finite courses of antibiotics have been prescribed for women with UTIs, often in the absence of bacterial culture data; such empiric treatment is effective at resolving acute symptoms, but clearly fails to eliminate a recurrence risk [ 2 ]. In addition, the rise of multidrug-resistant uropathogens e. As the pace of resistance development especially among Gram-negative uropathogens has overtaken the pace of new antibiotic development, fundamentally new approaches are needed [ 69 ].
Further, prophylactic antibiotics are incompletely effective in preventing infection [ 70 ], and in one mouse study, subtherapeutic levels of ciprofloxacin were shown to augment murine UTI [ 71 ]. To move forward in the therapeutic realm, we must extend our molecular understanding of both the pathogen and the host.
Contemporary development of novel UTI therapeutics has focused on interfering with pathogen binding to bladder epithelium or other key pathogen processes, the development of vaccines based on bacterial components, as well as the modulation of host responses -- specifically those promoting exfoliation to eradicate chronically resident bacteria from the bladder. An emerging example in which basic biology of the host-pathogen interaction has informed therapeutics development is that of mannosides and pilicides , compound families which target the crucial step of bacterial adherence to host cells in distinct ways.
Pilicides interfere with the chaperone-usher pathway for assembly of adhesive type 1 pili, preventing their presentation on the bacterial surface and thereby abolishing epithelial binding [ 72 , 73 ]. In contrast, mannosides serve as competitive inhibitors, occupying the binding pocket of the type 1 pilus adhesin FimH, with affinities that are orders of magnitude higher than those of the mannosylated uroplakins decorating the bladder epithelial surface [ 74 ].
The oral bioavailability and efficacy of mannosides in preventing UTI in mice portend substantial potential utility in the clinic [ 75 , 76 ]. Beyond uncomplicated cystitis, mannosides have also shown efficacy in mouse models for prevention of catheter-associated UTI as reflected by diminished bladder and catheter colonization [ 77 ].
Mannosides are being rationally optimized to exhibit more drug-like pharmacokinetic properties, such as improved metabolic stability and bioavailability [ 74 , 78 ]. Further, due to their known mechanism of action, such agents can be used as tools to further probe the biology of host-pathogen interactions [ 80 ].
Direct application to the bladder luminal surface of nanoparticles, perhaps coated with the FimH adhesin [ 85 ], has also been explored in mice as a means to accomplish targeted delivery of novel therapeutics to the host [ 86 ]. The periplasmic chaperone FimC green delivers structural subunits to the outer membrane usher FimD, red for assembly. Subunits shown represent the pilus tip structure and include the adhesin FimH purple and adapters FimG yellow, within the barrel of FimD and FimF gray.
Each subunit has its immunoglobulin-like fold completed by a strand provided by the next subunit, in a process called donor-strand complementation DSC. The energetic favorability provided by this final structure drives assembly on the periplasmic side of the usher, as the periplasm is devoid of ATP. Successful vaccination against UPEC and other uropathogens could have monumental impact on the lives of those at risk for complicated UTIs or who suffer from recurring episodes.
Multiple groups have worked to identify specific UPEC factors for potential use as vaccine antigens. Candidate antigens include the FimH adhesin, siderophores such as yersiniabactin [ 87 ], and other immunodominant proteins identified in mouse models [ 88 , 89 ] reviewed in [ 3 , 90 ].
Two important considerations may hinder the effectiveness of vaccine candidates against UTI. First, as strains of E. Second, as noted above, it is not clear how much antibody IgG in the healthy urinary tract should reach the bladder lumen.
Therefore, elicitation of serum antibodies against UPEC antigens may be more effective in preventing pyelonephritis, where antibodies are more readily delivered. Further studies into the correlates of adaptive immunity in both the upper and lower urinary tract are thus needed to advance these efforts. As noted earlier, an exuberant inflammatory response predisposes women to chronic cystitis [ 62 ].
In fact, in a mouse UTI model, inhibiting this response using an oral anti-inflammatory COX-2 inhibitor yielded better outcomes without actually targeting the bacteria and thereby applying no selective pressure. These findings corroborated small clinical trials in women receiving ibuprofen, in which symptomatic improvement at 4 and 7 days with ibuprofen treatment alone was equivalent to using oral antibiotics [ 91 , 92 ]. Further, as the bladder exfoliation accompanying acute UPEC cystitis is not complete, bacteria within quiescent reservoirs may re-emerge to seed recurrent infection.
Advanced, more efficacious exfoliants are being designed to unearth these quiescent reservoirs [ 93 , 94 ]. Once these bacteria are forced to emerge, they may be more susceptible to the actions of standard antibiotics. Therefore, combined exfoliant-antimicrobial strategies might rid the host of the UPEC reservoirs that underlie some recurrent UTIs [ 94 ].
Enhanced culture techniques, as well as metagenomics on catheter-collected samples, have detected urinary bacteria in healthy and asymptomatic women [ 96 ]. Interactions between these apparent commensals and soluble mediators such as antimicrobial peptides might alter susceptibility to UTI [ 97 ]. As the urinary microbiome is more extensively defined, we will have to account for it when considering the pathogenesis of UTI, as well as when choosing therapies for symptomatic patients.
Although many uncomplicated UTIs can resolve spontaneously or with antibiotic treatment, more complicated forms of UTI have not, until recently, been reflected in animal models.
The majority of preclinical work in the last two decades on cystitis and pyelonephritis has relied on transurethral inoculation of UPEC into the bladder of female mice [ , ]. Emerging mouse models may enable additional clinically relevant questions to be addressed.
Prolonged urinary catheter usage is a risk factor for UTI, due largely to the ability of bacteria to establish a biofilm on the catheter that resists clearance by host defense and antibiotics. CAUTIs represent the most common nosocomial infections and are associated with increased hospital length of stay, morbidity, and mortality [ , ].
Insertion of a urinary catheter elicits an inflammatory environment in the bladder, which is manifested histologically as exfoliation, edema of the lamina propria and submucosa, urothelial thinning, and mucosal lesions [ 7 ].
Damaged mucosa and the catheter itself offer surfaces for bacterial adhesion [ ]. Recent data indicate that enterococcal adherence to urinary catheter material is mediated by fibrinogen, a host protein that is released into the bladder lumen and deposited on the catheter following insertion.
A structural understanding of bacterial pilus association with catheter material and proteinaceous deposits may enable the design of new strategies to counteract catheter-associated UTI. The subsequent UTI might arise from reinoculation of the urethra with flora from the gastrointestinal tract, or from re-emergence of a bladder epithelial reservoir. In a recent study, isolates from four patients with rUTI were analyzed by whole-genome sequencing [ 10 ].
In two patients, the same UPEC clone dominated both gut and urinary tract habitats at the initial and subsequent infection; in the other two, a new clone had established dominance in both habitats at the time of recurrent UTI. Further, isolates causing subsequent UTI in these patients, when introduced into mice and compared with their initial infecting strain, exhibited increased fitness in both the gut and the urinary tract, demonstrating that fitness in these two important niches is not mutually exclusive [ 10 ].
A leading hypothesis for recurrent UTIs is that an exuberant inflammatory response to initial infection causes bladder remodeling that somehow predisposes the host to recurrent infection or more inflammatory outcomes [ 4 , 62 , ].
This model may enable a mechanistic understanding of apparent predisposition to recurrent infection, in turn informing therapies that could interfere with or dampen this process. The higher prevalence of UTI in females is chiefly attributed to anatomic factors in women, such as shorter urethral length, shorter distance from the anus to urethral meatus, and permissiveness of the vaginal and perineal environments to microbial colonization [ 12 , ].
Among individuals with upper-tract UTI pyelonephritis , males exhibit greater morbidity and mortality than females [ ], suggesting that non-anatomical differences may be at work in these more severe infections.
Until recently, essentially all cystitis and pyelonephritis studies have been performed in female mice, as the male mouse bladder is not reliably accessible by catheter. Of note, instillation of uropathogens into the urethra of male mice elicits prostatic infection [ , ]. In a recently developed, new model of UTI, a small abdominal incision is made and bacteria are inoculated via needle into the bladders of male and female mice, permitting direct sex comparisons [ ].
This inoculation method recapitulates the IBC cascade of acute cystitis established in studies with catheter-infected females. Interestingly, once anatomic barriers are bypassed in this way, male mice experience more severe infection than females, mirroring epidemiologic data observed clinically in men; indeed, male C3H mice uniformly develop severe pyelonephritis and renal abscesses that are seen much less frequently in female mice [ ].
This new model opens doors to study sex differences in UTI pathogenesis and host response, as well as sequelae of severe pyelonephritis and abscess formation; these latter phenotypes are relevant to febrile UTI in children, following which renal scarring is a common complication. Urinary tract infections continue to be among the most common bacterial infections in humans, drawing millions of antibiotic prescriptions annually.
Available therapies have not evolved significantly in recent years, do not prevent recurrences, and are challenged by rising antibiotic resistance.
Creative approaches to treatment, including the development of antivirulence therapeutics, should be prioritized see Outstanding Questions and Box 2.
In addition, the field lacks a thorough understanding of protective host immunity related to UTI, if such is generated after natural infection especially pyelonephritis or can be elicited via vaccination. Given the broad range of organisms that can cause UTI and the unavoidable nature of some risk factors e.
However, the common pathogenic themes in Gram-negative community-onset UTI make this subset of infections a particularly important epidemiologic target. For decades, the diagnosis of UTI has relied on culturing urine samples and looking under the microscope for the presence of white blood cells. Providers also utilize point-of-care dipstick tests to search for the presence of leukocyte esterase, nitrites, and other compounds.
These might rely on a combination of host immune and metabolic markers, as well as on the detection of uropathogens and their components DNA, proteins, etc.
For example, if sample preparation challenges could be circumvented, direct mass spectrometry on infected urine might be useful, detecting bacteria promptly in urine without the need to wait for growth on solid media [ ]. Alternatively, rapid molecular identification of E.
Ultimately, improved and accurate diagnostics for UTI should translate into more satisfying care for patients, less frustration and speculation on the part of providers, and an overall reduction in antibiotic use.
How does UPEC, upon internalization into the superficial epithelial cell in the bladder, escape from the endocytic vesicle into the cytoplasm to form the IBC? A molecular understanding of this apparently critical step in acute cystitis might illuminate a novel bacterial strategy for intracellular pathogenesis, as well as informing new targets for intervention.
Do antimicrobial peptides provide primarily an antimicrobial or immunemodulating role during UTI? Many of these peptide species are secreted into the urinary space, especially upon infection; the immunostimulatory effects of these peptides may be more important than their direct antibacterial activity.
What elicits adaptive immunity to uropathogenic bacteria, and can such immunity help to protect the bladder? Highly expressed bacterial targets such as pili and siderophores are enticing vaccine candidates, but a larger question is whether traditional humoral immunity has a significant role in protecting the bladder lumen.
How does biological sex and associated hormonal milieu influence the outcomes of infection? UTIs are considered a disease of women, but significant male populations are susceptible and may exhibit higher morbidity. Male UTI has been largely ignored in preclinical studies but can now be addressed with updated models.
How can we better understand the biological basis of susceptibility to recurrent cystitis? This is perhaps the most frustrating clinical problem, affecting millions of otherwise healthy women, and remains unresolved with current treatments and lifestyle changes. What can be done therapeutically in the face of emerging multidrug-resistant UPEC isolates? Advanced diagnostics with improved performance characteristics, and available at the point of care, will allow for more accurate selection of empiric therapy when indicated.
Molecular detection methods may allow earlier identification of multidrug-resistant isolates that may require parenteral or inpatient treatment. Mouse and human studies have revealed that during acute cystitis, Escherichia coli and other Gram-negative uropathogens can occupy the cytoplasm of bladder epithelial cells, using this niche as a haven for replication while protected from infiltrating neutrophils.
Novel therapeutics for UTI are being explored, based on detailed molecular and structural information of bacterial virulence factor expression, as well as patterns of bacterial binding to urinary epithelium, iron acquisition, and other pathogenic processes.
Highly expressed and immunogenic bacterial factors, including siderophores, have been identified in rodent models, potentially informing the development of vaccines and immunotherapies for UTI. However, the putative role of adaptive immunity in control of lower urinary tract infection remains unclear. Spencer T. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
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Abstract The clinical syndromes comprising urinary tract infection UTI continue to exert significant impact on millions of patients worldwide, most of whom are otherwise healthy women. Keywords: urinary tract infection, Escherichia coli , cystitis, pyelonephritis. A Pervasive and Persistent Problem Urinary tract infections UTIs are among the most common bacterial infections, affecting million people worldwide each year [ 1 — 3 ]. Open in a separate window. Figure 1. Clinical Features and Virulence Mechanisms in Cystitis and Pyelonephritis UTIs can present clinically in a variety of ways, most often reflecting cystitis infection of the bladder or pyelonephritis infection of the kidney.
Molecular Pathogenesis of UTI Infection of the urinary tract begins when UPEC, likely introduced after colonization of the periurethral area by gastrointestinal tract flora [ 10 — 12 ], accesses and ascends the urethra by an undetermined mechanism.
Immune Control and Pathogen Evasion After ascending the urethra, bacterial pathogens are challenged by innate defenses within the bladder. Figure 2. Catheter-associated UTI CAUTI Prolonged urinary catheter usage is a risk factor for UTI, due largely to the ability of bacteria to establish a biofilm on the catheter that resists clearance by host defense and antibiotics.
Male and Complicated UTI The higher prevalence of UTI in females is chiefly attributed to anatomic factors in women, such as shorter urethral length, shorter distance from the anus to urethral meatus, and permissiveness of the vaginal and perineal environments to microbial colonization [ 12 , ]. Concluding Remarks Urinary tract infections continue to be among the most common bacterial infections in humans, drawing millions of antibiotic prescriptions annually.
Outstanding Questions Box. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. The management of urinary infections: what have we learned in the past decade? Int J Antimicrob Agents. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. O'Brien VP, et al.
Drug and vaccine development for the treatment and prevention of urinary tract infections. Microbiol Spectr. By admin. Related Post. Jan 13, admin. Jan 12, admin. You missed. You performed urine dipstick analysis for her and confirmed the diagnosis of simple cystitis. Urinary tract infection UTI is a collective term that describes any infection involving any part of the urinary tract, namely the kidneys, ureters, bladder and urethra.
The urinary tract can be divided into the upper kidneys and ureters and lower tract bladder and urethra. Uncomplicated lower UTI remains one of the most commonly treated infections in primary care. Renal scarring may lead to complications in adulthood including hypertension, proteinuria, renal damage and even chronic renal failure, which requires dialysis treatment. Other susceptible adults include the elderly and patients requiring urethral catheterisation.
A complicated UTI is an infection associated with a condition, such as a structural or functional abnormality of the genitourinary tract, or the presence of an underlying disease; this increases the risk of the outcome of a UTI being more serious than expected, as compared to its occurrence in individuals without any identified risk factors i. Recurrent UTIs are symptomatic UTIs that follow the resolution of an earlier episode, usually after appropriate treatment.
They are common among young, healthy women even though these women generally have anatomically and physiologically normal urinary tracts. Common risk factors are given in Box 1. Recurrent UTIs can be diagnosed clinically without performing a urine culture, although urine cultures are essential in management.
For women with recurrent UTIs, imaging of the upper urinary tract and cystoscopy are not routinely recommended for evaluation. However, they should be performed without delay in patients with atypical symptoms, such as obstructive symptoms or presence of haematuria after resolution of infection. Asymptomatic bacteriuria ABU does not cause renal disease or damage. Several studies involving women and the paediatric population have demonstrated that treatment for ABU increases the risk of subsequent symptomatic UTIs; hence, it is not recommended except in diagnostic and therapeutic procedures involving entry to the urinary tract with a risk of mucosal damage, such as endoscopic urological surgery and transurethral resection of the prostate.
The diagnosis of acute uncomplicated cystitis can be made with high probability based on a focused history of lower urinary tract symptoms dysuria, frequency and urgency in a patient who has no risk factors for complicated UTI. Urine dipstick analysis, as opposed to urinary microscopy, is a reasonable alternative to urine culture to diagnose acute uncomplicated cystitis. Urine cultures are recommended for patients with risk factors for complicated UTIs and in the following situations: 4 a suspected acute pyelonephritis; b symptoms that do not resolve or recur within 2—4 weeks after completion of treatment; c women who present with atypical symptoms; d pregnant women; and e male patients with suspected UTI.
Urine catheterisation and functional status deterioration in elderly institutionalised women. A practical point to note is the possibility of urogenital tuberculosis TB and malignancy presenting with persistent, non-resolving UTI symptoms. Patients with urogenital TB may have received multiple courses of ciprofloxacin, making the isolation of Mycobacterium tuberculosis very difficult, and delaying diagnosis and appropriate therapy.
It is also important to consider prostate infections and sexually transmitted infections in all male patients with UTI. However, a detailed description of such infections is beyond the scope of this article. The choice of management option for UTIs depends on whether it is simple i. Simple uncomplicated cystitis lower UTI responds very well to oral antibiotics; studies show that clinical outcomes for UTIs treated with antibiotics are better when compared to those treated with a placebo.
Early appropriate treatment can prevent urosepsis. Referral to the emergency department should be considered if patients are clinically septic or there are limitations to early imaging access. Patients with a history of previous urological procedures; recent or long-term catherisation; recent or long-term antibiotics; and recent hospitalisation tend to present with complicated UTIs. Regardless of whether the UTI is community- or hospital-acquired, the urine cultures of these patients tend to show a diversity of micro-organisms with a higher prevalence of resistance to antimicrobials.
Escherichia coli E. The treatment strategy for complicated UTIs depends on the severity of the illness and hospitalisation is often necessary. The Ministry of Health, Singapore, published clinical practice guidelines CPG on the use of antibiotics in adults in It is the latest locally published guideline on the treatment of UTI in adults.
The CPG recommended a three-day course of trimethoprim and sulfamethoxazole as first-line therapy for uncomplicated UTI based on the pattern of uropathogen resistance at that time; however, with the increased resistance among uropathogens and changes in the prevalence of UTI-causing organisms, new guidelines have emerged. The following recommendations are adapted from the guidelines on urological infections published by the European Association of Urology in , taking into account drugs that are available locally in the outpatient setting.
Table II shows the recommended antimicrobial agents for the treatment of acute uncomplicated cystitis in otherwise healthy adults.
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