Urinary tract infection caused by staphylococcus aureus filetype pdf

No definition of urinary tract infection was given, and molecular typing to confirm identity of the initial colonizing and subsequent infecting strains was not performed. There is evidence that S. In a subsequent study of hospitalized nursing home patients, Mylotte et al.

The specific urinary tract symptoms supporting a diagnosis of urinary tract infection were not given. In our prospective study of patients with S. We intentionally used a more restrictive definition of infection than that used in reporting nosocomial infection because of the difficulty in differentiating asymptomatic bacteriuria from urinary tract infection in elderly persons and in persons with indwelling catheters in place.

Even with a highly restrictive definition, we found that one-third of patients 33 of with S. PFGE typing of the initial isolates and subsequent isolates associated with infection showed that the initial and subsequent isolates were identical or closely related in 5 of 7 patients whose isolates were typed.

Thus, we document that, in the long-term care population, a urinary tract that is persistently colonized with S. This risk appears to be greater than the risk associated with nares colonization alone. These findings have important implications for patient care. Because urinary catheterization is a major risk factor for S. Efforts to limit the acquisition of MRSA by catheterized patients through appropriate infection-control measures and limitation of unnecessary antibiotic administration are warranted in long-term care facilities.

Given the high risk of subsequent infection in patients whose urine is persistently colonized with S. In a general population of long-term care patients with MRSA colonization of the nares, application of mupirocin to the nares has not been shown to significantly reduce the risk of MRSA infection [ 24 ]. It is unlikely that intranasal mupirocin would have any effect on urinary colonization in any event. Systemic therapy with antimicrobial agents that are excreted in the urine is a possible approach, but the results of the limited clinical trials involving this patient population have been disappointing.

For example, the combination of rifampin and minocycline had a high failure rate with regard to eradicating MRSA in long-term care patients; resistance to both rifampin and minocycline occurred [ 25 ].

Our study has some potential limitations. The first is that the initial identification of staphylococcal bacteriuria required that a urine sample be obtained by a clinician' order.

Thus, the patient population identified may have differed from that identified by systematic surveillance of all patients for S. The second is that concomitant blood cultures were not performed for all patients with staphylococcal bacteriuria; some cases of bacteremia may have been missed. We note that this would cause underestimation of the importance of the urinary tract as the source for S.

In summary, our study demonstrates that S. One-third of patients with MRSA bacteriuria have symptomatic urinary tract infection at presentation, and one-third of these patients have concomitant bacteremia. Persistent urinary colonization carries with it a high risk of subsequent infection and bacteremia.

In patients who present with fever or sepsis, previous identification of S. This study demonstrates that focusing on the urine as a potential reservoir for infection may be an effective strategy for prevention. We thank Larry M. Baddour, Kent Crossley, and Daniel M. Musher, for their valuable reviews of the manuscript. Potential conflicts of interest. All authors: no conflicts. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Materials and Methods. Muder , Robert R.

Oxford Academic. Carole Brennen. John D. Marilyn M. Asia Obman. Janet E. Victor L. Cite Cite Robert R. Select Format Select format. Permissions Icon Permissions. Abstract Background. Open in new tab Download slide. Google Scholar Crossref. Search ADS. Antibiotic sensitivity of bacteria associated with community-acquired urinary tract infection in Britain. The association between Staphylococcus aureus bacteremia and bacteriuria.

Clinical risk factors for methicillin-resistant Staphylococcus aureus bacteriuria in a skilled-care nursing home. Bacterial changes in urinary samples of patients with long-term indwelling catheters. Antibiotics that fight the Staphylococcus aureus urinary tract infection include nafcillin, vancomycin, cefazolin, clindamycin, dicloxacillian or trimethoprim—sulfamethoxazole. For severe cases of urinary tract infection, hospitalization with intravenous antibiotics is required.

Homecare for treatment of a Staphylococcus aureus urinary tract infection should include rest. Use a heating pad on your abdomen for pain. Also drink plenty of water to flush out the bacteria. Urinary tract infections can be very uncomfortable, but there are some measures you can take to prevent them. After urinating or defecating, wipe front to back to prevent bacteria from entering the urethra.

Also drink plenty of fluids including cranberry juice, and avoid products such as douches and feminine sprays. Michele A. Clarke has been a writer for over 30 years. She enjoys writing articles on health care. She has a bachelors degree from the University of Albany in Biology and Sociology.

Adherence is a key event initiating each step in UTI pathogenesis. A UTI typically starts with periurethral contamination by a uropathogen residing in the gut, followed by colonization of the urethra and subsequent migration of the pathogen to the bladder, an event that requires appendages such as flagella and pili FIG.

In the bladder, the consequences of complex host—pathogen interactions ultimately determine whether uropathogens are successful in colonization or eliminated. Subsequent migration to the bladder step 2 and expression of pili and adhesins results in colonization and invasion of the superficial umbrella cells step 3.

Host inflammatory responses, including neutrophil infiltration step 4 , begin to clear extracellular bacteria. Some bacteria evade the immune system, either through host cell invasion or through morphological changes that result in resistance to neutrophils, and these bacteria undergo multiplication step 5 and biofilm formation step 6.

These bacteria produce toxins and proteases that induce host cell damage step 7 , releasing essential nutrients that promote bacterial survival and ascension to the kidneys step 8. Kidney colonization step 9 results in bacterial toxin production and host tissue damage step If left untreated, UTIs can ultimately progress to bacteraemia if the pathogen crosses the tubular epithelial barrier in the kidneys step However, in order for the pathogens to cause infection, the bladder must be compromised.

The most common cause of a compromised bladder is catheterization. Owing to the robust immune response induced by catheterization step 3 , fibrinogen accumulates on the catheter, providing an ideal environment for the attachment of uropathogens that express fibrinogen-binding proteins. Infection induces neutrophil infiltration step 4 , but after their initial attachment to the fibrinogen-coated catheters, the bacteria multiply step 5 , form biofilms step 6 , promote epithelial damage step 7 and can seed infection of the kidneys steps 8 and 9 , where toxin production induces tissue damage step If left untreated, uropathogens that cause complicated UTIs can also progress to bacteraemia by crossing the tubular epithelial cell barrier step Multiple bacterial adhesins recognize receptors on the bladder epithelium also known as the uroepithelium and mediate colonization TABLE 1.

Uropathogens such as UPEC survive by invading the bladder epithelium, producing toxins and proteases to release nutrients from the host cells, and synthesizing siderophores to obtain iron FIG. By multiplying and overcoming host immune surveillance, the uropathogens can subsequently ascend to the kidneys, again attaching via adhesins or pili to colonize the renal epithelium and then producing tissue-damaging toxins FIG.

Consequently, the uropathogens are able to cross the tubular epithelial barrier to access the blood stream, initiating bacteraemia. UPEC and K. By contrast, complicated UTIs are initiated when the bacteria bind to a urinary catheter, a kidney stone or a bladder stone, or when they are retained in the urinary tract by a physical obstruction.

However, others such as P. Subsequently, these uropathogens often form biofilms that are responsible for colonization and persistence 22 , 23 BOX 1.

Uropathogens use different mechanisms for survival in response to stresses in the bladder such as starvation and immune responses. By forming biofilms and undergoing morphological changes, uropathogens can persist and cause recurrent infections 40 , , Extracellular DNA eDNA , exopolysaccharides called extracellular polymeric substances, pili, flagella and other adhesive fibres create a scaffold to form a multicellular bacterial community that is protected from immune responses, antimicrobial agents and other stresses The antimicrobial recalcitrance of uropathogens increases on biofilm maturation, as the biofilm provides a physical barrier to antibiotic entry.

Therefore, understanding species-specific biofilm formation and dispersal mechanisms is crucial for the development of novel therapies that prevent colonization, such as biofilm inhibitors, anti-adhesive molecules and molecules that induce bacterial dispersion. Type 1 pili, antigen 43 and adhesive surface fibres called curli induce biofilm formation by mediating interbacterial interactions and attachment to surfaces.

Transcription of antigen 43 is regulated by oxidative stress regulator OxyR; also known as hydrogen peroxide-inducible genes activator , whereas type 1 pilus and curli fibre genes are regulated by polymyxin-resistant protein B PrmB; also known as BasS on iron sensing 3 , leading to phosphorylation of polymyxin-resistant protein A PmrA; also known as BasR and quorum sensing regulator B QseB UPEC biofilm formation on catheters is dependent on type 1 pili The type 1 pilus adhesin, FimH, binds mannosylated uroplakins and integrins that coat the surface of umbrella cells.

Uroplakin binding by FimH induces actin rearrangement and bacterial internalization via unknown mechanisms. Inside the host cell, UPEC can subvert host defences and resist antibiotic treatment. UPEC subverts this innate defence mechanism by escaping into the cytoplasm, where it then multiplies to form intracellular bacterial communities IBCs.

QIRs consist of 4—10 non-replicating bacteria within membrane-bound compartments encased in F-actin and can remain viable for months. In addition, UPEC survives within the harsh bladder environment by secreting several factors that are important for nutrient acquisition.

The siderophores expressed by UPEC allow the bacterium to scavenge iron and thus promote survival during a urinary tract infection UTI. HlyA also triggers epithelial exfoliation to promote the spread of UPEC to other hosts following urine expulsion or to expose deeper layers of the uroepithelium for QIRs.

Activation of RAC1 also induces the host cell anti-apoptotic and pro-survival pathways, preventing apoptosis of colonized epithelial cells and allowing the UPEC population to expand. The extracellular survival of UPEC also requires evasion of the innate immune system by the adoption of a filamentous morphology, which renders the bacterium more resistant to neutrophil killing than their bacillary form.

This results in impaired immunoglobulin A IgA transport across the epithelium, thereby modulating the local secretory antibody immune response and preventing UPEC opsonization and clearance. Proteus mirabilis produces urease, which hydrolyses urea to carbon dioxide and ammonia. This increases the urine pH and generates calcium crystals and magnesium ammonium phosphate precipitates, which are incorporated into polysaccharide capsules, forming crystalline biofilms on the catheter FIG.

The phosphotransferase regulator of swarming behaviour RsbA upregulates polysaccharide expression, represses swarming 23 and enhances biofilm formation. Similarly, expression of the fimbrial operon regulator MrpJ leads to decreased motility, promoting biofilm formation 53 , Subsequent urease production induces the formation of calcium crystals and magnesium ammonium phosphate precipitates in the urine through the hydrolysis of urea to carbon dioxide and ammonia, resulting in a high pH. The production of extracellular polymeric substances by bacteria attached to the catheter traps these crystals, allowing the formation of a crystalline biofilm, which protects the community from the host immune system and from antibiotics.

In addition, these structures prevent proper urine drainage, resulting in reflux and promoting the progression to pyelonephritis, septicaemia and shock. Finally, production of the bacterial toxins haemolysin HpmA and Proteus toxic agglutinin Pta is important for tissue destruction and bacterial dissemination to the kidneys. HpmA induces pore formation by inserting itself into the cell membrane and destabilizing the host cell, causing tissue damage, exfoliation and nutrient release.

Pta punctures the host cell membrane, causing cytosol leakage and resulting in osmotic stress and depolymerization of actin filaments, thus compromising the structural integrity of the cell. The release of nutrients via these toxins also allows the bacteria to scavenge iron using siderophores. Pseudomonas aeruginosa has the ability to form biofilms on catheters and damaged bladder tissue 82 through several mechanisms, including quorum sensing autoinducers that bind to the transcriptional regulators LasR which regulates elastase LasB expression and RhlR which regulates the synthesis of rhamnolipids.

Quorum sensing induces the production of eDNA, rhamnolipids, lectins, elastases and toxins. The amphiphilic rhamnolipids allow microcolony formation by changing the hydrophobicity of the P. Biofilm maturation is promoted by lectin adhesins, which are important for bacterial cell—cell interactions The production of alginates and extracellular polymeric substances is activated when cyclic di-GMP binds to the transcriptional regulators alginate biosynthesis 44 Alg44 and pellicle formation regulator D PelD Small RNAs from the regulator of secondary metabolites rsm family, such as rsmZ and rsmY , regulate exopolysaccharide production by reducing the availability of RsmA, which is the transcriptional repressor for exopolysaccharide-encoding genes 81 , , Uropathogens also adopt morphological changes, such as filamentation, to circumvent the host immune system , When the resulting filamentous bacterial cells emerge from epithelial cells, they are resistant to killing by neutrophils and can colonize other naive uroepithelial cells and re-enter the IBC cycle , FIG.

Alternatively, during colonization by P. Contact creates a torsional change in the outer membrane, and this is sensed by upregulator of the flagellar master operon Umo proteins, which induce the expression of flagella to produce the highly flagellated cells that are required for swarming during a UTI 6 , 23 , 53 , FIG.

Many uropathogens initiate a UTI using pili that mediate adhesion to host and environmental surfaces, facilitate invasion into the host tissues and promote interbacterial interactions to form biofilms 24 — For example, numerous Gram-negative pathogenic bacteria — including E. The chaperone—subunit complex is then targeted to the usher assembly protein in the outer membrane, where the usher selectively differentiates chaperone—subunit complexes and catalyses the ordered assembly of pili on the cell surface via a mechanism termed donor-strand exchange.

Importantly, understanding the most basic principles of molecular biology — such as how a protein folds into domains that serve as assembly modules for building large supramolecular structures, and how an outer-membrane macromolecular machine the usher assembles these structures from individual subunits, which are delivered as chaperone—subunit complexes and then transported in a regulated manner across a biological membrane — has led to the development of anti-virulence compounds that block CUP pilus assembly or function and that result in the dysregulation of virulence factors.

These compounds have the potential for broad-spectrum activity against numerous Gram-negative bacteria see below. Thirty-eight distinct CUP pilus operons have been identified in E. The multitude of CUP pili encoded by UPEC are tipped with different adhesins, some of which are known to mediate distinct tropisms in the lower and upper urinary tract by recognizing receptors with stereochemical specificity, notably in the bladder or kidney epithelium Type 1 pili and pyelonephritis-associated P pili are the better characterized CUP pili.

Type 1 pili binding to these cells triggers a signal transduction cascade that activates Rho GTPases, such as those from the Rac family, to cause actin rearrangement and internalization of UPEC by a zippering mechanism consisting of a plasma membrane sheathe that engulfs the bacterium 36 FIG.

Invasion allows UPEC to subvert certain host defences and become recalcitrant to antibiotic treatments. However, an innate defence expulsion mechanism defends the uroepithelium from UPEC invasion; this expulsion mechanism depends on Toll-like receptor 4 TLR4 expression by uroepithelial cells. After their maturation, bacteria disperse from the IBC to invade other cells, where the IBC cycle is repeated 38 — IBC formation is a common mechanism for clinical UPEC isolates and has been observed in multiple mouse backgrounds and also in exfoliated uroepithelial cells in the urine of patients with acute UTIs but not in the cells in urine from healthy controls 41 , The process of invasion and IBC formation provides UPEC with the ability to survive stringent bottlenecks in the urinary tract, including TLR4-mediated expulsion, umbrella cell exfoliation, ascension to the kidneys, urination and inflammation 7 , In contrast to the metabolically active IBCs, QIRs typically contain 4—10 non-replicating bacteria that can remain viable for months and can be re-activated to serve as seeds that initiate a recurrent UTI 7.

It has been proposed that during uroepithelial turnover, in which the underlying immature cells terminally differentiate into umbrella cells, the redistribution of actin and perhaps other associated signals might trigger UPEC revival from QIRs, releasing the bacteria back into the bladder lumen Unlike the mannose-binding adhesin FimH of type 1 pili, the adhesin of P pili, PapG, binds globosides containing glycolipids that are present in the human kidneys 33 FIG. In addition, PapG modulates the local secretory-antibody immune response by interacting with TLR4 to reduce polymeric immunoglobulin receptor PlGR expression, thus impairing immunoglobulin A transport through the lamina propria and epithelial cells to the kidney lumen 45 FIG.

By inhibiting immunoglobulin A transport into the urinary space, UPEC evades a key host protective mechanism, allowing the establishment of ascending infection 45 , Importantly, the initial innate host response to UPEC colonization and invasion not only dictates the outcome of the original infection but is also crucial for determining host susceptibility to subsequent infections An increased susceptibility to recurrent UTIs can occur not because of a deficient host response to UPEC infection, as is commonly accepted, but rather as a result of an unrestrained lymphocyte-dependent innate inflammatory response to acute infection, leading to severe acute injury to the mucosal uroepithelium and potentiating subsequent infections Interestingly, although the K.

Moreover, K. Despite the relatively poor adhesive properties of K. In addition , K. Following initial attachment, P. Other CUP pili encoded by P.

In addition to CUP pili, P. AipA can adhere to human bladder and kidney cell lines in vitro but is only required for kidney infection and not for bladder infection in mice. Conversely, TaaP is required for bladder infection by P. Importantly, both autotransporters bind to extracellular-matrix proteins in vitro: AipA preferentially binds to collagen I, and TaaP to laminin, which might provide an explanation for their different tissue tropisms.

Enterococci encode several adhesion factors, including the collagen adhesin Ace, enterococcal surface protein Esp , enterococcal polysaccharide antigen Epa , and endocarditis- and biofilm-associated Ebp pili 54 TABLE 1. Clinical studies have shown that mechanical stress induced by urinary catheterization produces histological and immunological changes in the bladder, resulting in a robust inflammatory response, exfoliation, oedema, and mucosal lesions of the uroepithelium and kidneys 57 , Importantly, a mouse model of CAUTI seems to recapitulate these immunological changes that are induced by urinary catheterization, exhibiting catheter-induced inflammation, severe uroepithelial damage, exfoliation and the onset of bladder wall oedema, which is exacerbated by increased catheterization time Urinary catheters provide a surface for E.

However, E. Following fibrinogen deposition, the Ebp pilus adhesin — EbpA, which contains an N-terminal fibrinogen-binding domain — mediates catheter colonization and biofilm formation during CAUTIs caused by E.

Furthermore, E. This resolution of the paradox has been recapitulated in vitro by the demonstration that E. The bladder environment is limited in nutrients; thus, in order to survive and grow within the urinary tract, uropathogens produce proteases and toxins that damage the host tissue to release nutrients, while also providing a niche for bacterial invasion and dissemination TABLE 1.

This results in pore formation in the umbrella cells and promotes their lysis, which facilitates iron and nutrient acquisition by the bacteria FIG. HlyA also triggers exfoliation, exposing deeper layers of the uroepithelium for colonization and promoting bacterial spread to other hosts following cell expulsion in the urine 62 — 65 FIG.

Furthermore, HlyA is highly expressed in IBCs, suggesting that it is important during this stage of infection 39 , 63 , CNF1 enters the host cell in endocytic vesicles, by binding to the receptor basal cell adhesion molecule BCAM; also known as LU 69 , and then constitutively activates RHO GTPases via deamination of a glutamine residue; this causes actin cytoskeletal rearrangements and membrane ruffling, leading to increased levels of bacterial internalization 67 , By contrast, the surface-associated cytotoxic protease Pta is functional only in an alkaline pH, such as that induced by the activity of P.

In the proposed mode of action, Pta punctures the host cell membrane, causing leakage of the cytosol, osmotic stress and depolymerization of actin filaments; the structural integrity of the cell is therefore compromised, resulting in bladder and kidney damage 53 , 73 FIG. Pta also induces bacterial cell—cell interaction via autoaggregation 53 , Elastase induces tissue destruction through its protease activity, releasing nutrients including iron for continued bacterial growth The expression of all of these virulence factors is regulated by the quorum sensing system Quorum sensing is activated at high cell density by the accumulation of small molecules called autoinducers.

When a threshold level of autoinducers is reached, they bind to transcriptional activator proteins and activate the expression of virulence factors 81 , 82 BOX 1. Urease is encoded by several uropathogens, including P. This enzyme catalyses the hydrolysis of urea to carbon dioxide and ammonia 87 , resulting in elevated urine pH and the production of calcium crystals apatite and magnesium ammonium phosphate ammoprecipitates struvite in urine and on catheters 53 FIG.

Importantly, the accumulation of ammonia becomes toxic for the uroepithelial cells, inducing direct tissue damage The P.

This urease is highly active, hydrolysing urea several times faster than those produced by other species, such as Providencia stuartii , Providencia rettgeri , Proteus vulgaris and Morganella morganii The high activity level of the P. The crystalline biofilms provide P. These structures also block urine drainage from the ureters, potentially resulting in reflux and promoting progression to pyelonephritis, septicaemia and shock The bladder environment is limited in iron.

UPEC produces several siderophores 93 , of which two — aerobactin and yersiniabactin — are essential in the urinary tract 93 FIG. Aerobactin is highly expressed, stable at low pH and displays higher levels of iron binding than enterobactin 94 , Yersiniabactin is important in bio-film formation in urine and has a protective role against intracellular killing by copper stress, as it sequesters host-derived copper Numerous iron-scavenging siderophore systems are utilized by other uropathogens: K.

Siderophore systems are important potential targets for vaccine development 98 and for designing small molecules that interfere with their function. UTIs result in considerable economic and public health burdens and substantially affect the life quality of afflicted individuals Currently, antibiotics — such as trimethoprim sulfamethoxazole, ciprofloxacin and ampicillin — are the most commonly recommended therapeutics for UTIs 4. However, increasing rates of antibiotic resistance and high recurrence rates threaten to greatly enhance the burden that these common infections place on society.

Ideally, alternative therapies will be established that will be recalcitrant to the development of resistance. Many promising approaches are being developed, from leveraging what we have learned about the basic biology of UTI pathogenesis to specifically target virulence pathways. Below, we discuss the current challenges that have arisen from the emergence of multidrug-resistant bacterial strains and highlight the progress that is being made towards the development of antivirulence therapeutics for UTIs.

We also discuss how an understanding of the evolution of bacterial resistance mechanisms and their spread is providing new approaches for the modification and improvement of current therapeutic options. UTIs are becoming increasingly difficult to treat owing to the widespread emergence of an array of antibiotic resistance mechanisms 3 , 4 , 15 , 99 — see Supplementary information S1 table.

Of particular concern are members of the family Enterobacteriaceae, including E. These plasmids rapidly spread resistance to third-generation cephalosporins as well as other antibiotics 15 , 99 — BOX 2.

The expression of AmpC enzymes is also associated with carbapenem resistance in K. Originating in Klebsiella pneumoniae and Escherichia coli , ESBLs are now prevalent throughout the Enterobacteriaceae family, as frequent use of cephalosporins in the nosocomial setting and the carriage of ESBL-encoding genes on transferrable elements together create an ideal environment for the selection of antibiotic resistance 99 , Troublingly, ESBLs are encoded on plasmids that typically carry other resistance genes which provide activity against aminoglycosides, sulfonamides and quinolones, making the bacteria that acquire these plasmids multidrug resistant , CTX-Ms are active against narrow-, broad- and extended-spectrum penicillins, classical and extended-spectrum cephalosporins, and monobactams 99 , , Notably, they also confer high-level cefotaxime resistance 99 , To date, OXAs have been shown to be expressed only in Pseudomonas aeruginosa 99 , Carbapenemases are ESBLs that confer the ability to inactive carbapenems in addition to penicillins and extended-spectrum cephalosporins 99 , , The two most clinically relevant carbapenemases, K.

Multidrug resistance is also common among enterococci, as they are naturally resistant to trimethoprim, clindamycin, cephalosporins and penicillins 15 , , Recently, Enterococcus spp. The mechanism of resistance for VanA, the most common PBP expressed by enterococci, is to replace the cell wall precursor D-alanine—D-alanine with D-alanine—D-lactose, effectively reducing the binding affinity of vancomycin The troubling trend towards a high prevalence of multi-drug-resistant uropathogens has spurred the development of alternative control measures and treatment options.

These combination therapies have been shown to be effective in vitro against carbapenem-resistant members of the family Enterobacteriaceae. Future studies are needed to test the efficacy of ceftazidime—avibactam against ESBL-, KPC- and AmpC-producing Gram-negative pathogens during infection, as the drug combination has the potential to be effective against a broad range of cephalosporin-resistant Enterobacteriaceae family members. Moreover, the effectiveness of specific antibiotic—inhibitor therapies is dependent on the antimicrobial-resistance patterns encoded by each pathogen, as the expression of certain combinations of ESBLs and carbapenemases can provide resistance to an antibiotic—inhibitor therapy — Therefore, it is crucial to know which antibiotic mechanisms are available to a specific uropathogen in order to determine an effective treatment.

As adherence has a key role at nearly every step of UTI pathogenesis, one attractive strategy for the development of antivirulence therapies, including vaccines, has been to target CUP pili.

As a general rule, vaccination with whole pili has been ineffective at generating an antibody response that can protect against UTIs.

However, adhesin-based vaccines have been shown to be effective at blocking host—pathogen interactions, thus preventing the establishment of disease — The effectiveness of the FimC—FimH vaccine was shown to be due, in large part, to antibodies that block the function of FimH in bladder colonization Furthermore, the anti-FimH antibodies did not seem to alter the E.

Modifications of this vaccine are currently under development, with the aim of inducing greater immune stimulation , For example, one approach has been to fuse FimH to the flagellin FliC in order to induce a more substantial acute inflammatory response, which functions through TLR4 signalling via the MYD88 pathway A Phase I clinical trial began in January to evaluate the efficacy of a FimC—FimH vaccine using a synthetic analogue of monophosphoryl lipid A as the adjuvant.

In a mouse model of UTI, vaccination with the P. Moreover, a vaccine strategy that is efficacious against E. This strategy induced high antibody titers and reduced bacterial burdens in a mouse model of CAUTI In conclusion, adhesin-based vaccines represent a promising area for the development of therapeutics against uropathogens. Thus, understanding the molecular basis of host—pathogen interactions is crucial for vaccine development strategies. The UPEC pore-forming toxin HlyA has also received attention as a potential vaccine target and was evaluated in a mouse model of pyelonephritis to assess protection against renal damage , Vaccination with HlyA reduced the incidence of renal scaring compared with controls; however, it did not protect against UPEC colonization of the kidneys In addition, in a mouse model of UTI, vaccination with the P.

However, vaccination with Pta, an alkaline protease with toxic effects towards epithelial cells, displayed promising results in a mouse model of UTI, protecting against upper UTI, although bacterial burdens in the bladder remained unaffected Thus, although haemolysins and proteases might provide effective vaccine targets for preventing upper UTIs, additional studies are needed to determine the effectiveness of these enzymes as targets for vaccines.

Iron acquisition systems have shown great promise as targets for vaccine development because uropathogens require a source of iron during colonization and persistence. Furthermore, siderophore and haem acquisition systems have been shown to be upregulated during experimental infection, as well as in the urine of women with a UTI 86 , 94 , 97 , These parameters sparked vaccine development based on ferric yersiniabactin uptake receptor FyuA , haem acquisition protein Hma , iron uptake transport aerobactin receptor IutA and the siderophore receptor iron-responsive element A IreA Vaccination with FyuA and Hma protected mice against pyelonephritis 98 , , whereas vaccination with IutA and IreA reduced bladder colonization in mice, confirming the importance of these proteins during infection 98 , Interestingly, the differential tissue-specific protection seen with these four proteins suggests that these systems have different roles or expression profiles in different niches, including the bladder or kidneys.

Vaccinations with other siderophore systems in mouse models of UTI, including the iron receptors FitA and ChuA 98 , were not protective against infection and were correlated, to a large extent, with lower antigen-specific humoral responses during experimental UTI.

These studies suggest that effective siderophore-based vaccines function in part by preventing cognate siderophore uptake, as is the case with FyuA, Hma, IutA and IreA 98 , , making this an exciting area of therapeutic development against UTIs. Several urease inhibitors have been developed as potential drugs for UTI treatment, with varying results Many of the early inhibitors were active against ureases from several different bacterial species, including Helicobacter pylori, P.

The best characterized urease inhibitor, acetohydroxamic acid AHA , even had some success in treating UTIs caused by urease-producing organisms; this inhibitor works by preventing urine alkalization and was approved by the FDA in REF. However, many of these inhibitors had severe side effects related to toxicity. For example, AHA resulted in teratogenicity, as well as psychoneurological and musculo-integumentary effects. Subsequent studies showed that derivatives of AHA also had considerable inhibitory properties, but again, these compounds had mutagenic properties that made them undesirable therapeutics Another group of urease inhibitors, the phosphoramidites, exhibited potent activity against P.

However, this class of compounds displayed low stability in the low pH of gastric juice, making them impractical Finally, the heterocyclic compounds termed benzimidazoles have garnered much attention because they function as proton pump inhibitors that irreversibly inactivate ATPase systems These compounds are currently the standard treatment for peptic ulcers and gastroesophageal reflux disease Benzimidazoles interact with the gastric hydrogen potassium ATPase, thereby inactivating them and effectively limiting the disease Interestingly, benzimidazoles also bind to the urease metallocentre, effectively blocking the active site of the enzyme through steric hindrance Benzimidazoles also have a bactericidal activity against H.

Great strides have been made to identify and characterize urease inhibitors, but more work is needed to bring these potential treatments to the market. Our detailed understanding of pilus assembly and pilus—receptor binding has opened the door to the development of two classes of small, rationally designed synthetic compounds to inhibit pili: mannosides, which inhibit pilus function; and pilicides, which inhibit pilus assembly.

Targeting CUP pilus function or assembly has therapeutic potential, as it should block UPEC colonization, invasion and biofilm formation, thus preventing disease 30 , 31 , , Pilicides were originally developed to specifically inhibit the assembly of UPEC type 1 pili.

They have a 2-pyridone scaffold 28 , 30 , 31 , and function by selectively targeting and interfering with crucial chaperone—usher interactions. Further studies have been carried out to investigate their broad spectrum of activity against other CUP pili A recent analysis of 35 Escherichia spp.

A single Escherichia sp. For example, pilicide ec was found to disrupt several virulence-associated pili, including type 1 pili, P pili and S pili, as well as flagellar motility The effect of ec on the transcriptome and proteome of the cystitis isolate E. Type 1 pilus expression is controlled by inversion of the type 1 fimbriae promoter element fimS , which can oscillate between phase ON and phase OFF orientations.

Thus, the potency of pilicide ec is largely due to its ability to induce a phase OFF orientation of the type 1 pilus promoter, rather than any interference with chaperone—usher interactions.