Infections of the Urinary Tract

UTIs are common. Affect men and women of all ages.

DEFINITIONS

UTI is an inflammatory response of the urothelium to bacterial invasion that is usually associated with
bacteriuria and pyuria.

Bacteriuria is the presence of bacteria in the urine, which is normally free of bacteria.
y y y Studies have indicated that bacteria may be in the urothelium in the absence of bacteriuria. Bacteriuria may represent bacterial contamination of an abacteriuric specimen during collection. Bacteriuria can be symptomatic or asymptomatic.

Pyuria, the presence of white blood cells (WBCs) in the urine.

y y y It s generally indicative of infection and an inflammatory response of the urothelium to the bacterium. Bacteriuria without pyuria is generally indicative of bacterial colonization without infection of the urinary tract. Pyuria without bacteriuria warrants evaluation for tuberculosis, stones, or cancer.

Cystitis describes a clinical syndrome of dysuria, frequency, urgency, and occasionally suprapubic pain.
y DD: infection of the urethra or vagina or noninfectious conditions such as interstitial cystitis, bladder carcinoma, or calculi.

Acute pyelonephritis is a clinical syndrome of chills, fever, and flank pain that is accompanied by
bacteriuria and pyuria.

Chronic pyelonephritis describes a shrunken, scarred kidney, diagnosed by morphologic, radiologic, or

functional evidence of renal disease that may be postinfectious but is frequently not associated with UTI.

UTIs may also be described in terms of the anatomic or functional status of the urinary tract and the health of the host: Uncomplicated describes an infection in a healthy patient with a structurally and functionally normal urinary tract. y The majority of these patients are women with isolated or recurrent bacterial cystitis or acute pyelonephritis, and the infecting pathogens are usually susceptible to and eradicated by a short course of inexpensive oral antimicrobial therapy.

A complicated infection is associated with factors that increase the chance of acquiring bacteria and decrease the efficacy of therapy

Factors That Suggest Complicated UTI

Functional or anatomic abnormality of urinary tract 2 Male gender 3 Pregnancy 4 Elderly 5 Diabetes 6 Immunosuppression 7 Childhood UTI 8 Recent antimicrobial agent use 9 Indwelling (residing) urinary catheter 10 Urinary tract instrumentation 11 Hospital-acquired infection 12 Symptoms for more than 7 days at presentation

Chronic is a poor term that should be avoided in the context of UTIs, except for chronic bacterial prostatitis, because the duration of the infection is not defined. UTIs may also be defined by their relationship to other UTIs: First Infection: is the first documented episode of clinically significant or symptomatic bacteriuria. Unresolved Bacteriuria: refers to failure to eradicate the infecting organism. Causes: 1. Bacterial resistance: Noted in 5% of patients on antibiotics. Tetracyclines, Penicillins, Sulphonamides, Cephalosporins, and Trimethoprim are capable of transferring R-factors that make bacteria simultaneously resistant to multiple agents, including: Ampicillin, Cephalosporins and others. The Fluoroquinolones and Nitrofurantoin are not associated with R-factor resistance. 2. Multiple-Organism Bacteriuria. 3. Rapid re-infection: A new resistant species occur during initial treatment for the original sensitive organism. 4. Azotemia: lead to poor excretion of antibiotics into the urine. 5. Papillay necrosis: lead to poor excretion of antibiotics into the urine. 6. Infected calculi, bladder tumor, or foreign body: protect sensitive bacteria from antibiotics. 7. Patient non-compliance. Recurrent infection: repeated infection interrupted by periods of sterile urine.

Causes: 1. Reinfection: Responsible for 80% of recurrent infection. It tends to occur > 2 weeks after completion of therapy with a new organism. Frequent in: a. Cystitis b. Female: ascending infection from rectum to vaginal introitus to bladder. c. Male with anatomical or functional abnormalities. d. Vesicoenteric or vesicovaginal fistulae should be considered. 2. Bacterial persistence: Refer to cases in which urine is sterilized by therapy, but a persistent source of infection remain (same bacteria). E.g. stone, foreign body, urethral or bladder diverticula, renal abscess. INCIDENCE AND EPIDEMIOLOGY UTIs are considered to be the most common bacterial infection They account for 1.2% of all office visits by women and 0.6% of all office visits by men (1997) SEX: Women is 30 times more than in men (with increasing age, the ratio of women to men with bacteriuria progressively decreases). 30% of women will have had a symptomatic UTI requiring antimicrobial therapy by age 24. 50% of all women will experience a UTI during their lifetime. Prevalence of bacteriuria in females as a function of age Schoolgirls (aged 5 to 14 years): 1% Young adulthood: 4% Per decade of age: additional 1% to 2%

HOSPITALIZATION AND CONCURRENT DISEASES: UTIs account for approximately 38% of the 2 million nosocomial infections each year (1999). > 80% of nosocomial UTIs are secondary to an indwelling urethral catheter. UTIs is also increased during pregnancy and in patients with spinal cord injuries, diabetes, multiple sclerosis, and human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS). The financial impact: Community-acquired UTIs is nearly $1.6 billion in the United States alone ( 2002); The annual cost of nosocomial UTIs has been estimated to range from between $515 million and $548 million.

PATHOGENESIS
Ascending Route:
Most bacteria enter the urinary tract from the bowel Adherence of pathogens to the introital and urothelial mucosa plays a significant role in ascending infections. Most episodes of upper urinary tract infection are caused by retrograde ascent of bacteria from the bladder. Reflux of urine is not required for ascending infections, edema associated with cystitis may cause sufficient changes in the ureterovesical junction to permit reflux. Other predisposing factors: pregnancy and ureteral obstruction. Urinary bladder Ureter Renal Pelvis Calyces Collecting ducts Collecting tubules.

Hematogenous Route
Uncommon in normal individuals. E.g. patients with Staphylococcus aureus bacteremia originating from oral sites.

Lymphatic Route E.g. severe bowel infection or retroperitoneal abscesses.

Urinary Pathogens
E. coli is by far the most common cause of UTIs, accounting for 85% of community-acquired and 50% of
hospital-acquired infections. Other gram-negative Enterobacteriaceae, including Proteus and Klebsiella, and grampositive E. faecalis and S. saprophyticus. Nosocomial infections are caused by E. coli, Klebsiella, Enterobacter, Citrobacter, Serratia, Pseudomonas aeruginosa, Providencia, E. faecalis, and S. epidermidis. Less common organisms are Gardnerella vaginalis, Mycoplasma species, and Ureaplasma urealyticum. Anaerobes: Distal urethra, perineum, and vagina are normally colonized by anaerobes. Clinically symptomatic UTIs in which only anaerobic organisms are cultured are rare. Anaerobic organisms are frequently found in suppurative infections of the genitourinary tract, e.g. scrotal, prostatic, and perinephric abscesses The organisms found are usually Bacteroides species, including: B. fragilis, Fusobacterium species, anaerobic cocci, and Clostridium perfringens.

Mycobacterium
may be found during evaluation for sterile pyuria.

Bacterial Virulence Factors

It is generally believed that uropathogenic strains resident in the bowel flora, such as uropathogenic E. coli (UPEC), can infect the urinary tract not by chance but rather by the expression of virulence factors that enable them to adhere to and colonize the perineum and urethra and migrate to the urinary tract where they establish an inflammatory response in the urothelium.

Autotransporter proteins constitute a family of outer membrane/secreted proteins that possess unique structural properties that facilitate their independent transport across the bacterial membrane system and final routing to the cell surface. Autotransporter proteins have been identified in a wide range of Gramnegative bacteria and are often associated with virulence functions such as adhesion, aggregation, invasion, biofilm formation and toxicity. The importance of autotransporter proteins is exemplified by the fact that they constitute an essential component of some human vaccines. Autotransporter proteins contain three structural motifs: a signal sequence, a passenger domain and a translocator domain. Here, the structural properties of the passenger and translocator domains of three type Va autotransporter proteins are compared and contrasted, namely pertactin from Bordetella pertussis, the adhesion and penetration protein (Hap) from Haemophilus influenzae and Antigen 43 (Ag43) from Escherichia coli. The Ag43 protein is described in detail to examine how its structure relates to functional properties such as cell adhesion, aggregation and biofilm formation. The widespread occurrence of autotransporterencoding genes, their apparent uniform role in virulence and their ability to interact with host cells suggest that they may represent rational targets for the design of novel vaccines directed against Gramnegative pathogens
Virulence Factors of uropathogenic E. coli (UPEC): 1.