The pathophysiology of urinary tract infections

The pathophysiology of urinary tract infections

BASIC SCIENCE The pathophysiology of urinary tract infections anomalies, renal calculi or prostate enlargement; or the presence of a foreign body e ...

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BASIC SCIENCE

The pathophysiology of urinary tract infections

anomalies, renal calculi or prostate enlargement; or the presence of a foreign body e such as a urethral or suprapubic catheter.2

Practical interpretations of commonly used terms2e4

Chloe Walsh

Cystitis: bladder inflammation. Clinical syndrome of dysuria, urinary frequency and urgency, which may be accompanied by supra-pubic tenderness. The commonest cause of the inflammation is infection, but not exclusively. These symptoms and signs can be termed those of the ‘lower urinary tract’, and the infection has not ascended beyond the bladder.

Tim Collyns

Abstract Urinary tract infections are amongst the most bacterial infections. They can occur in either an uncomplicated host setting, where there is no underlying structural or functional abnormality of the patient’s genitourinary tract, or complicated, where there is. For the latter, common predisposing factors are the presence of a foreign body, including urinary catheter, or disruption of normal urinary flow by obstruction or retention. Bacteria vary widely in their ability to successfully invade the urinary tract; the vast majority of such infections being due to a small number of species. The route is usually ascension from the urethra. Certain uropathogenic strains of Escherichia coli are the most proficient as measured by their frequency of being the identified cause. Such strains display a number of virulence factors which enable them to occupy this niche e which with increasing understanding, may promote different methods of treating. Other species are often implicated only in the presence of an underlying urological abnormality. The presence of a urinary catheter, or other urine drainage device, provides a ready scaffold for organisms to develop a biofilm, which in turn shields them from being eradicated successfully. Renal calculi similarly can be linked to biofilm production.

Urethritis: inflammation of urethra, usually due to infection. Associated symptoms may mimic those of cystitis. Infective causes, such as Neisseria gonorrhoeae or Chlamydia trachomatis, are usually acquired during sexual contact and do not ascend to the bladder, so although the urethra is normally the final passageway for urine from the body (and the primary route for organisms to gain access to the bladder and beyond), specific urethral infections are not usually included in the term UTI. Acute urethral syndrome: the typical symptoms of cystitis in the absence of a ‘significant’ bacteriuria. Some of these patients still have bladder involvement but with relatively low pathogen counts, whilst in a proportion, the inflammation and associated uropathogen (usually Escherichia coli) is genuinely limited to the urethra. (NB: these symptoms can also be caused by sexually transmitted pathogens.) Acute pyelonephritis: this describes the symptoms and signs which are generated when a kidney (the ‘upper urinary tract’) is infected e such as flank pain and tenderness, and pyrexia. Noninfectious causes, such as renal stone or infarction, can mimic this presentation. Upper urinary tract involvement is also usually accompanied by lower urinary tract symptoms and signs.

Keywords Biofilm; catheter; cystitis; Escherichia coli; pyelonephritis; urease

Introduction Urinary tract infection (UTI) is one of the most common bacterial infections, particularly affecting women. Up to half of women will suffer at least one episode of UTI in their lifetime and one in four of these women will develop a recurrence.1,2 Signs and symptoms differ according to the site of infection; upper UTI (pyelonephritis) classically presents with fever and flank pain whilst lower UTI (cystitis) typically presents with some or all of the following: dysuria, frequency, haematuria and suprapubic tenderness. Here we examine the mechanism of UTIs and the host and microbiological factors associated with these infections. Key predisposing host factors involved in complicated UTIs are either obstruction of normal urinary flow, such as by congenital

Uncomplicated UTI: infection in a normal urinary tract, both structurally and neurologically. Complicated UTI: symptomatic infection of the bladder or kidneys, in the presence of a structural or functional abnormality of the genitourinary tract. Common factors include presence of a foreign body (e.g. in-dwelling urinary catheter or other drainage device or renal calculus); disruption of normal urinary flow (e.g. by obstruction or urinary retention) or immunosuppression. Infection in children or men should be assumed to be complicated unless confirmed to the contrary. Recurrent urinary tract infection: a further symptomatic episode following previous resolution of a UTI. It can reflect either re-infection or bacterial persistence. Significant recurrent UTI is defined as three or more episodes of UTI within a 12month period.5

Chloe Walsh MA MB BChir MRCP is a Specialist Joint Medical Microbiology and Infectious Diseases Registrar at the Leeds Teaching Hospitals Trust, Leeds, UK. Conflicts of interest: none declared.

Significant bacteriuria: bacteriuria is the presence of bacteria in urine. Urine in the bladder is normally sterile e however, low numbers of organisms in a urine sample may be due to contamination by normal anterior urethral flora. A significant bacteriuria is one where the bacterial count is sufficiently great to

Tim Collyns MA MB BChir FRCPath is a Consultant Medical Microbiologist and the Lead Infection Control Doctor at the Leeds Teaching Hospitals Trust, Leeds, UK. Conflicts of interest: none declared.

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peri-urethral area.7 Once within the bladder, bacteria may then multiply and ascend the ureters to cause upper UTI.

indicate a genuine bladder bacteriuria. Historically, this has been defined as a count 105 colony forming units (cfu) of the ‘same’ organism per mL of urine in two consecutive clean-catch, voided urine samples in women. In men, a single sample of clean-catch voided urine with a count of 105 of one species is sufficient. It is important to recognize that symptomatic infections can still be associated with lower counts e notably if a pure growth of a well-recognized uropathogen. Conversely, significant bacteriuria in the absence of symptoms often does not require treatment (see below). For samples derived via a urinary catheter, a lower threshold may be applicable due to the reduced risk of contamination. For practical laboratory testing purposes, 103 cfu/mL of 1 bacterial species in a single catheter-derived sample is a useful cut-off.

Haematogenous infection Less commonly, upper UTI can be a result of haematogenous spread of bacteria, for example in prolonged bacteraemia, often associated with a deep source of infection such as endocarditis. Direct animal studies support this, showing that intravenous injection of Staphylococcus aureus can result in pyelonephritis.8 However, it is more difficult to produce pyelonephritis in similar models with Gram-negative bacteria, suggesting that this is not the common route of infection for most pathogens.

Host factors in urinary tract infections Women UTIs are more common in women because of their anatomy; the shorter urethra and the relative proximity of the urethra to the anus. Several other factors have also been shown to increase the risk of UTI in women: particularly sexual intercourse and the use of spermicide,9 which is thought to affect the vaginal microbial flora resulting in a reduction in lactobacilli allowing for an increased proportion of potentially pathogenic Gram negative bacteria, such as E. coli to colonize the genital tract.10 Postmenopausal women are particularly prone to recurrent UTI. Reduced oestrogen levels increase the risk of vaginal atrophy, which results in vaginal dryness and increased pH, which in turn alters the vaginal microbial flora, reducing the proportion of (‘protective’) lactobacilli.11 In addition, low oestrogen levels are associated with post-voiding residual urine in the bladder, which is a further risk factor for UTI.

Asymptomatic bacteriuria: bacteria may be isolated from urine at significant counts, in the absence of any accompanying symptoms. This is more common with increasing age e being reported to be present in a tenth of men and a fifth of women over the age of 65.2 Unlike in younger adults, where significant bacteriuria is 30 times more common in women than men, there is a progressive decrease in the ratio of women to men with this phenomenon with increasing age. Factors which make older men more prone to bacteriuria include reduced bactericidal activity of prostatic secretions, and prostatic enlargement leading to urinary retention. In both genders, there is a high rate of spontaneous clearance of bacteriuria e followed by subsequent reinfection. Antimicrobial treatment of asymptomatic bacteriuria in adults is rarely warranted; and is more likely to be associated with patient ‘harm’ than benefit and so should be avoided. This includes people of either gender over the age of 65; catheterized individuals; and younger women who are not pregnant. The two groups of adult patients with asymptomatic bacteriuria in whom treatment is recommended are pregnant women and those prior to a urological procedure where mucosal bleeding is anticipated.

Genetic factors Recurrent UTIs in women are more common in those with a family history, suggesting a genetic pre-disposition. Host factors to protect against UTI include physical barriers (such as unidirectional urine flow), proteins that hinder bacterial adhesion and the cells of the innate immune system, including neutrophils. Polymorphisms of various genes have been found to be associated with recurrent UTI.12 CXCR1 and 2 are IL-8 receptors that play a role in neutrophil recruitment and reduction in CXCR1 expression has been associated with recurrent UTI in children.12 CXCR2 levels have been shown to be lower in women with recurrent UTI compared to controls.13

Pyuria: presence of a raised count of polymorphonuclear leukocytes (PMLs) in urine (e.g. 10 PMLs per mm3 of urine), but unit of measurement and definition vary with counting method used. This is indicative of an inflammatory response in the urinary tract e however, it is neither specific for infection, nor for symptoms in the presence of a bacteriuria. Ninety per cent of asymptomatic elderly institutionalized patients with a bacteriuria will also have a pyuria. Pyuria in the absence of bacteriuria can be associated with other pathologies, such as renal stone disease, malignancy and tuberculosis of the renal tract, which should be considered depending on the clinical scenario.

Structural abnormalities Certain renal tract pathologies increase the risk of recurrent UTI. Conditions resulting in a residual volume of urine post voiding, for example neurogenic bladder, reduce the protection of the unidirectional flow of urine and so increase the risk of UTI. The same applies to the increased risk of UTI associated with vesicoureteric reflux. Renal stone disease is also associated with UTI. The foreign material provides a surface for bacteria to form a biofilm. This prevents bacteria from being easily removed from the urinary tract by the flow of urine and renders the bacteria more difficult to eradicate by the host immune response.

Mechanism of infection Ascending infection The most common route of infection is ascension of bacteria from the urethra to the bladder. Early animal studies supported this, showing that if bacteria were directly instilled into the bladder, and one ureter was ligated, the unligated kidney was more likely to develop pyelonephritis.6 The most common bacterial causes of UTI are the same bacteria that colonize the gut and they enter the urinary tract following colonization of the

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Catheterization Indwelling catheters are well known to increase the risk of recurrent UTI, by enabling bacteria to form biofilms, providing a

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reservoir of potential pathogens that are in contact with bladder. Almost all catheters in situ for four or more weeks colonized by bacteria.14 In addition, if the biofilms formed crystalline, they can block the flow of urine, exacerbating problem.

containing receptors, such as uroplakin, on the latter.2,15 This binding can lead to host cell shedding and bacterial invasion of deeper cell layers of the bladder wall. The expression of the fimbriae can be modulated by the organism e such that they may be present at the start of a UTI but be down-regulated later on when their ongoing presence is no longer to the bacteria’s advantage.2 Co-trimoxazole has been shown to reduce the synthesis and function of type I fimbriae at concentrations well below the concentration required to inhibit bacterial growth, which may partly explain its efficacy as prophylactic agent. Another adhesin is found on P fimbriae. These fimbriae have the ability to bind to globoseries glycosphingolipid receptors that are contained in the P blood group antigen complex (hence name) present on red blood cells, but also on renal uroepithelial cells of approximately 99% of the population. Its pathogenic importance is highlighted by the finding that uncomplicated upper UTI due to E coli is virtually never seen in the other 1%. Various other adhesins have been identified on UPEC; such as on M, G and S fimbriae.2,15 E coli strains that carry Dr adhesins can be associated with persistence e either in the kidney or within bladder epithelial cells. Infections by such organisms may then give rise to symptomatic relapses following a course of seemingly effective antibiotic therapy. Iron is an essential element for virtually all organisms, acting as a co-factor for some vital enzymes. The bladder is an iron-poor environment and so successful UPEC strains have various siderophores e proteins which scavenge this element, such as aerobactin. UPEC can also produce toxins, such as haemolysin and cytotoxic necrotizing factor 1.2,15 UPEC can also downregulate the host’s acute immune response, by suppressing the transepithelial movement of neutrophils and reducing their production of antibacterial reactive oxygen species. Some E coli strains associated with asymptomatic bacteriuria have been shown to have a loss of expression of various functional virulence genes. Klebsiella pneumoniae: K. pneumoniae is second only to E. coli in causing bloodstream infections (bacteraemias), associated with a UTI.2 This species can also produce various types of fimbriae, including type 1.2,15 However, K. pneumoniae also produces a polysaccharide capsule surrounding its outer cell membrane, of which there are over 70 antigenic types. The capsule inhibits phagocytosis, and its’ presence has been shown to have role in UTIs in animal models. Klebsiella species also produce a urease, the pathogenic role of which is described below. Proteus mirabilis: there are various species of Proteus, but the most common ones causing human infections are Proteus mirabilis and Proteus vulgaris. P. mirabilis may be the cause of an uncomplicated UTI, but more commonly causes infection in the setting of an abnormal urinary tract, including if an indwelling catheter is present. P. mirabilis may also possess a variety of fimbriae, the most important of which in the setting of UTIs, are the MR/P fimbriae, which have been shown to be associated with bladder colonization/infection in the murine model and whose production can be regulated similar to type 1 fimbriae in E. coli.2,15 P. mirabilis also produces a potent urease enzyme, which hydrolyses urea into carbon dioxide and ammonia. This, in turn, raises the urine pH, causing the precipitation of struvite, magnesium ammonium phosphate, which in turn agglomerates

the are are the

Microbiological factors in urinary tract infections The urinary tract can potentially be infected by a very wide range of organisms e including viruses, bacteria, fungi and parasites. However, in reality, a limited number of bacterial species are the cause of the vast majority of UTIs, with usually only a single species involved in any one infection.2 The relative percentages vary with underlying host factors e i.e. whether uncomplicated or complicated. The archetypal species is E. coli (E. coli), which tops both lists (Table 1). The virulence factors enabling an organism to establish an infection vary between, and within, species. Organisms capable of causing uncomplicated UTIs (i.e. effectively where there are not predisposing host features to ‘assist’ the bacteria) are the ones that usually display the greater specific uro-virulence factors. Some of these species, and characteristics of associated infections, are considered below. Gram-negative bacteria Escherichia coli: the most common cause of all UTIs is E. coli e but not all strains of this bacterium are equal in their ability to infect successfully the urinary tract. The natural reservoir for the species is the human gastrointestinal tract, where it is the most common facultative anaerobe present. Uropathogenic E. coli (UPEC) strains have several virulence factors, which increase their ability to invade the urinary tract. Some of the features which enable strains to cause urinary tract infections also promote their ability to cause other infections outside the gut, and so a broader term is extra-intestinal pathogenic E coli (ExPEC).2 Fimbriae (from the Latin for thread), also known as pili (from the Latin for hair), are surface nanofilaments which may extend for several micrometres in length from the bacterial cell. They serve a variety of functions, including allowing bacterial adherence to host cells, aggregation of bacteria and exchange of genetic material. The presence of ‘type I’ fimbriae has been shown to be a key factor in enabling bacterial binding to superficial bladder uroepithelial cells, due to the presence of mannose

Common causes of UTI (uncomplicated and complicated) in descending order of prevalence2,15 Uncomplicated UTI

Complicated UTI

Escherichia coli Klebsiella pneumonia Staphylococcus saprophyticus Enterococcus faecalis Streptococcus agalactiae (Group B Streptococcus) Proteus mirabilis Pseudomonas aeruginosa Staphylococcus aureus

Escherichia coli Enterococcus species Klebsiella pneumonia Candida species Staphylococcus aureus Proteus mirabilis Pseudomonas aeruginosa Streptococcus agalactiae (Group B Streptococcus)

Table 1

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to form a renal calculus.16 Viable bacteria may be embedded within the crystal, which can then act as a nidus for recurrent infections. Therefore, recurrent isolation of P. mirabilis should raise the suspicion of renal stones. Of note, there is likely to be a loss of white cells in urine, with the increased alkalinity, leading to a lack of an accompanying pyuria. Other organisms can also produce ureases, such as Klebsiella, Pseudomonas, Staphylococcus and Corynebacterium urealyticum.2,15 In addition to the potency and amount of urease produced, the host’s inflammatory response to the presence of the infecting organism may also have a role in stone generation; with the more exuberant response having been shown to be more likely to be associated with stone formation in a rat model.17

the face of osmotic and pH changes.2,15 UTIs due to this organism have been found to be more common in late summer and autumn; and may be concomitant with vaginal candidiasis.2 Other coagulase-negative Staphylococci: genuine infections due to these organisms are almost entirely restricted to hospitalized patients with underlying urological issue(s) e usually with an indwelling catheter in place.2 90% of these infections are due to Staphylococcus epidermidis. This organism, although being of very low virulence in an otherwise healthy host, is welladapted to adhering to, and forming biofilm on, foreign material e such as a urinary catheter. It can produce autolysins which bind directly to plastic and other compounds; and bacterial products such as accumulation associated protein, Bap homologue protein, polysaccharide intercellular adhesion and extracellular DNA contribute to biofilm formation.2

Other Enterobacteriaceae: species such as Enterobacter, Serratia, or Citrobacter rarely cause UTIs in normal hosts e but not uncommonly cause healthcare associated UTIs e notably in the presence of an indwelling catheter.2 The commonly isolated species in these genera are intrinsically resistant to ampicillin and the first-generation cephalosporins, such as cephalexin or cephradine, due to a chromosomally encoded AmpC betalactamase. Pseudomonas aeruginosa, along with other pseudomonads, are ubiquitous in diverse environments, such as water, soil and plants. However, P. aeruginosa does not usually form a significant portion of the normal resident microbial flora, the microbiome, in healthy hosts; such as in the gastro-intestinal or vaginal tracts. P. aeruginosa usually causes urinary infections in a healthcare setting, often associated with a urinary catheter. It rarely causes community ‘acquired’ infections, unless there is an underlying urological issue, such as obstruction, recent instrumentation or neurogenic bladder. P. aeruginosa is intrinsically resistant to many commonly used antibiotics, such as trimethoprim, nitrofurantoin, co-amoxiclav, and most cephalosporins e which gives it a survival advantage over other potential pathogens in hospital. This organism has various virulence factors; including a well-developed quorum sensing (QS) pathway, which enables communication between bacterial cells. QS is involved in the establishment and control of biofilms.2,15

Enterococci: Enterococci cause fewer than 5% of uncomplicated UTIs. However, they are well-established as a cause of healthcare-associated infections, in the presence of a urinary catheter and/or other urological abnormality or procedure. They have intrinsic resistance to a number of commonly used antibiotics. The main two species involved in infections are Enterococcus faecalis and Enterococcus faecium, the latter being intrinsically resistant to penicillins such as ampicillin or piperacillin. Enterococci are well-adapted to colonizing the human gastrointestinal tract and receipt of antibiotics by the host, such as a cephalosporin, can alter the balance in favour of enterococcal proliferation as they are naturally tolerant to various antimicrobial classes. Enterococci can produce various adhesins and aggregation substances which establish and maintain biofilms.2,15 Enterococci are of relatively low pathogenicity and may colonize catheters rather than causing symptomatic infection. Similarly, their presence may prevent a more pathogenic species from successfully invading the urinary tract e i.e. treatment of an asymptomatic enterococcal bacteriuria can be followed by a symptomatic infection, due to a different organism. Group B Streptococci (Streptococcus agalactiae): similar to enterococci, Streptococcus agalactiae is very capable of colonizing the lower gastro-intestinal tract (10e25%) and in women, also the genital area, (10e40%).2 Various factors have been identified, which can increase female genital carriage, such as increased sexual activity, diabetes and black ethnic origin. Group B streptococci can be associated with the full gamut of clinical presentation from asymptomatic bacteriuria to urosepsis. If a bacteriuria with Group B streptococci is identified during a pregnancy, then this is a marker of heavy genital colonization e and intra-partum prophylaxis is warranted to prevent invasive infection in the neonate. Corynebacterium urealyticum: Corynebacteria, ‘diphtheroids’, are common skin commensal flora. This organism is no exception, having been found to colonize the skin of over a third of hospitalized patients.2 However, unlike most other corynebacterial species, it is able to adhere to uroepithelial cells and is a potent urease producer. It can cause chronic or recurrent UTIs, usually in patients with underlying predisposing factor(s) for a UTI. Due to the urease produced, it can cause ‘encrusted cystitis’, where there is chronic bladder mucosal inflammation with crystal deposits and surrounding erythema; or ‘encrusted pyelitis’ if there is upper urinary tract abnormality.2

Gram-positive pathogens Staphylococci: the staphylococcal species that cause UTIs can be divided into three e S. aureus, Staphylococcus saprophyticus and other coagulase-negative staphylococci. S. aureus: this organism has been described as the ‘prince of pathogens’ due to its array of virulence factors and success in colonizing, and causing infections, in humans. However, it rarely causes uncomplicated UTIs. In the absence of a catheter, the detection of S. aureus in urine may represent contamination by perineal flora; or be due to haematogenous spread, involving the kidneys, from a focus elsewhere resulting in ‘descending’ urinary tract involvement.2 Occasionally, the source may be the prostate. S. saprophyticus: this organism has a specific niche as a cause of UTIs e it is second only to E. coli in causing uncomplicated infections in sexually active, young women; however, it rarely causes infections in men or older women. It has a unique adhesion protein, UafA, which facilitates its adhesion to uroepithelial cells. It produces urease, as well as having various transport proteins, which enable it to survive, and multiply, in

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and proliferate. As the lesions expand, the organisms are shed into the renal tubules, involving the medulla. Here, the hypertonicity impedes macrophage function, allowing further destructive organism proliferation. Sloughing of renal papillae may lead to caliceal, even ureteric, obstruction. The tubercle bacilluria may also lead to ureteral and bladder involvement. Patients with renal TB are often asymptomatic for some time, but then may present with urological complaints, such as dysuria, frequency, haematuria and back pain.2

Other pathogens Candida: Candida species are normal human commensal flora, and can be found harmlessly in the gastro-intestinal and female genital tracts. Candida spp. are also able to form biofilms on prosthetic surfaces and are commonly found in urine of patients with indwelling catheters without causing symptomatic infection.2 Disturbance of the natural balance of constituents, notably by antibiotics, enables Candida species to proliferate, which may then yield mucous membrane infections, such as vaginitis. In women, urinary tract infection may then develop by extension; whilst men may acquire urethral candidiasis after sexual contact with Candida vaginitis.

Biofilms and catheters Biofilms are multicellular microorganism communities, enmeshed within a protective scaffold of extracellular material, including polysaccharides and DNA. Biofilm formation protects the individual organisms within from the host’s immune response; as well as from other existential threats such as antibiotics. UPEC can form such bacterial communities within the uroepithelium, and quiescent intracellular reservoirs can then act as niduses for recurrent infections. P. aeruginosa is able to establish a biofilm on damaged bladder tissue, by various mechanisms, including quorum sensing to induce the production of rhamnolipids, which change the hydrophobicity of the bacterial cell surface, and lectin adhesins, both of which promote microcolony formation; coupled with elastases and extracellular DNA.15 Urinary catheters and other prosthetic devices are particularly ‘tempting’ targets for biofilm formation by microorganisms. The urease of P. mirabilis leads to the formation of crystals as described above e which in turn are trapped by extracellular material produced by the bacteria on the surface of the catheter, forming crystalline biofilms. These structures in turn disrupt urine drainage, which can lead to infection extension. In contrast, E. faecalis utilizes fibrinogen, released due to bladder inflammation and deposited on the catheter; both as a nutrient source and as an extracellular scaffold by endocarditis and biofilm-associated (Ebp) pili binding.15

Viruses: a number of viruses have been linked to haemorrhagic cystitis or other urinary tract pathologies. Haemorrhagic cystitis may be a benign self-limiting illness in children, presenting with gross haematuria which resolves in a few days; or following renal or haemopoietic stem cell transplants (HSCT). Viruses implicated include the BK virus and the adenovirus. BK virus (BKV), a polyoma virus, is ubiquitous globally, and up to 90% of adults possess antibodies against it, having acquired the organism asymptomatically as children.2 BKV exhibits tropism for cells of the genito-urinary tract, including those of the renal tubular epithelium, where it may remain latent. It does not cause disease in immunocompetent hosts e although up to 20% of such individuals may shed the virus in urine. However, in immunocompromised patients, it may reactivate. The virus is actually named after the initials of a renal transplant patient who developed BKV-associated ureteral stenosis. It can also be associated with interstitial nephritis or other nephropathies post kidney transplant. In HSCT recipients, it has been implicated in 10e25% cases of haemorrhagic cystitis.2 Although viruria can be detected in equal rates in allogeneic and autologous HSCT recipients, it usually only causes disease in allogeneic recipients with concurrent graft-versus-host disease. It presents with haematuria, dysuria and other lower urinary tract symptoms. The bleeding and associated clot formation can be sufficient to cause obstruction and renal failure. In haemorrhagic cystitis in children, boys are affected two to three times more commonly than girls; and the proportion due to Adenovirus can vary geographically e being reported to be associated with up to 70% in Japan whereas only a fifth of cases are linked to acute adenoviral infection in the United States. In the post HSC transplant setting, the urinary tract may be involved alone or as part of a more widely disseminated infection.2 Other viruses that have been less commonly associated with haemorrhagic cystitis post HSCT include the other main human polyomavirus pathogen, JC virus, and members of the Herpesviridae family, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6).2 Mycobacterium tuberculosis: the kidneys may be involved in haematogenous spread of M. tuberculosis organisms from a site elsewhere, usually located in the lung.2 This may occur at the time of initial organism acquisition prior to cellular immunity developing. The renal cortices are a favoured site for this organism due to the high oxygen tension present. As the host’s immune system responds, the organisms become entombed in calcified foci, though still remaining viable for decades. If the immune response then weakens, the organisms may reactivate

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The prostate and prostatitis The prostate is a genital organ. However, due to its position entwining the neck of the bladder and its function, prostatic infections can be intimately connected to those of the male (genito)urinary tract.2 Prostatic antibacterial factor, which contains zinc, is the most important antimicrobial prostatic secretion. Patients with chronic bacterial prostatitis have lower levels of zinc in their prostatic secretions. Bacterial infections of the prostate, both those of ‘acute’ and ‘chronic’ presentations, can give rise to an associated bacteriuria. Such infections are usually caused by Gram-negative uropathogens, including E coli and P. aeruginosa.2 Chronic bacterial prostatitis is an important source of bacterial persistence in the male urinary tract, and can present with recurrent bacterial UTIs due to the ‘same’ organism. Most antibiotics do not penetrate well into the prostate parenchyma, and their efficacy may be hindered by prostatic fluid pH changes associated with the infection. The organism strains involved, notably E coli, often share similar urovirulence profiles to those associated with pyelonephritis in women.2 Successful eradication of such foci requires a prolonged course (4e6weeks) of an antibiotic that penetrates the prostate reasonably well, such as a fluoroquinolone, infecting organism susceptibility permitting.

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Conclusion

6 Vivaldi E, et al. Ascending infection as a mechanism in pathogenesis of experimental non-obstructive pyelonephritis. Exp Biol Med 1959; 102: 242e4. 7 Brumfitt W, Gargan RA, Hamilton-Miller. Periurethral enterobacterial carriage preceding urinary infection. Lancet 1987; 1: 824e6. 8 De Navasquez. Experimental pyelonephritis in the rabbit produced by staphylococcal infection. J Pathol Bacteriol 1950; 62: 429e36. 9 Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000; 182: 1177e82. 10 Hooten TM, Roberts PL, Stamm WE. Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin Infect Dis 1994; 19: 274e8. €thje P, Hirschberg AL, Brauner A. Estrogenic action on 11 Lu innate defense mechanisms in the urinary tract. Mauritas 2014; 77: 32e6. 12 Zaffanello M, Malerba G, Cataldi L, et al. Genetic risk for recurrent urinary tract infections in humans: a systematic review. J Biomed Biotechnol 2010; 32: 1082. 13 Godaly G, Ambite I, Svanborg C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis 2015; 28: 88e96. 14 Stickler DJ. Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. J Intern Med 2014; 276: 120e9. 15 Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015; 13: 269e84. 16 Thomas B, Tolley D. Concurrent urinary tract infection and stone disease: pathogenesis, diagnosis and management. Nat Clin Pract Urol 2008; 5: 668e75. 17 Reyes L, Reinhard M, O’donell LJ, Stevens J, Brown MB. Rat strains differ in susceptibility to Ureaplasma parvum e induced urinary tract infection and struvite stone formation. Infect Immun 2006; 74: 6656e64.

UTI is a term used to cover a broad range of clinical presentations. It is important to further classify the patient’s diagnosis in terms of upper versus lower and complicated versus uncomplicated UTI as this will alter management. Bacteriuria in itself does not always warrant treatment unless the patient is pregnant or is to undergo certain urological procedures, which carry a risk of mucosal bleeding. The development of UTI is dependent on both host and microbiological factors. Women, people with structural or neurological bladder abnormalities, people who are catheterized and those undergoing instrumentation of the urinary tract are at highest risk. Most urinary tract infections are caused by Gram-negative bacteria (particularly E. coli) but a wide range of pathogens have been implicated. Biofilm formation is a particular problem in UTI and successful source control (e.g. change/removal of catheter or eradication of stones) is key in trying to manage such infections. A REFERENCES 1 Franco AVM. Recurrent urinary tract infections. Best Pract Res Clin Obstet Gynaecol 2005; 19: 861e73. 2 Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 8th edn. Philadelphia: Elsevier Saunders, 2015. 3 Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America Guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005; 40: 643e54. 4 Hooton TM, Bradley S, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2009; 50: 625e63. 5 Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women. Can Urol Assoc J 2011; 5: 316e22.

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