Editing Urinary Tract Infections (section)

== Pathogenesis ==

* UTIs are a result of interactions between the uropathogen and the host. Successful infection of the urinary tract is determined in part by the:
** Virulence factors of the bacteria
** Inoculum size
** Inadequacy of host defense mechanisms
* '''Routes of infection (3)'''
*# '''Ascending (most common)'''
*#* '''Most bacteria enter the urinary tract from the bowel''' '''via ascent through the urethra into the bladder.'''
*#** Adherence of pathogens to the introital and urothelial mucosa plays a significant role in ascending infections.
*#** This route is further enhanced in individuals with significant soilage of the perineum with feces, women who use spermicidal agents, and patients with intermittent or indwelling catheters.
*#* '''Most episodes of pyelonephritis are caused by retrograde ascent of bacteria from the bladder through the ureter to the renal pelvis and parenchyma'''.
*#** Although reflux of urine is probably not required for ascending infections, edema associated with cystitis may cause sufficient changes in the ureterovesical junction to permit reflux.
*#** Once the bacteria are introduced into the ureter, they may ascend to the kidney unaided. However, ascent is increased by any process (endotoxins from Gram-negative bacteria, pregnancy, ureteral obstruction) that interferes with the normal ureteral peristaltic function
*#** Bacteria that reach the renal pelvis can enter the renal parenchyma through the collecting ducts at the papillary tips and then ascend upward within the collecting tubules.
*# '''Hematogenous'''
*#* '''Uncommon in normal individuals; occasionally, the kidney is secondarily infected in patients with Staphylococcus aureus bacteremia''' originating from oral sites '''or with Candida fungemia'''
*# '''Lymphatic route'''
*** '''Direct extension of bacteria from the adjacent organs via lymphatics may occur in unusual circumstances, such as a severe bowel infection or retroperitoneal abscesses'''
* '''Urinary pathogens'''
** '''Most UTIs are caused by facultative anaerobes''' (organisms that are able to grow in both aerobic and anaerobic environments)''', usually originating from the bowel flora.'''
*** '''Uropathogens such as Staphylococcus epidermidis and Candida albicans originate from the flora of the vagina or perineal skin.'''
**** '''Note that staphylococci are gram-positive cocci in clusters, streptococci are gram-positive cocci in chains'''
** '''Common pathogens: KEEPPS (Klebsiella, E. Coli, Enterococcus, Proteus, Pseudomonas, Staph. Saprophyticus)'''
*** '''Gram-negative:'''
**** '''Enterobacteriaceae family'''
****# '''E. coli (gram-negative bacilli)'''
****#* '''Most common cause of UTIs'''
****#** Accounts for 85% of community-acquired and 50% of hospital-acquired UTIs
****#* E. coli sequence type ST131 (serotype O25b:H4) is a rapidly emerging cause of multidrug-resistant infections, including UTI; β-lactamases and fluoroquinolone resistance are common with this isolate
****# '''Proteus (gram-negative bacilli)'''
****# '''Klebsiella (gram-negative bacilli)'''
**** '''Pseudomonadaceae family'''
***** '''Pseudomonas'''
*** '''Gram-positive (responsible for the remainder of most community-acquired infections)'''
**** '''Enteroccocus faecalis'''
**** '''Staphylococcus saprophyticus'''
*** '''Nosocomial infections are caused by E. coli, Klebsiella, Enterobacter (enterobacteriacea family), Citrobacter (enterobacteriacea family), Serratia, Pseudomonas, Providencia, E. faecalis, and S. epidermidis'''
*** The prevalence of infecting organisms is influenced by the patient’s age.
**** '''S. saprophyticus causes ≈10% of symptomatic lower UTIs in young, sexually active females whereas it rarely causes infection in males and elderly individuals'''
**** '''Neonates and young infants should be covered for Enterococcus species when choosing empiric antibiotics since the incidence of infections with this uropathogen is higher in early infancy than at a later age.'''
** '''Fastidious organisms'''
*** '''Obligatory anaerobes (organisms that die in the presence of oxygen)'''
**** Clinically symptomatic UTIs in which only [obligatory] anaerobic organisms are cultured are rare
**** '''Frequently found in suppurative infections of the genitourinary tract'''.
**** '''The organisms found are usually:'''
***** '''Bacteroides species, including B. fragilis'''
***** '''Fusobacterium species'''
***** '''Anaerobic cocci'''
***** '''Clostridium perfringens'''
**** '''Must be suspected when a patient with bladder irritative symptoms has cocci or gram-negative rods''' seen on microscopic examination of the centrifuged urine '''and routine quantitative aerobic cultures fail to grow organisms'''
*** '''Mycobacterium TB and other non-TB mycobacteria'''
**** Mycobacterium tuberculosis and other nontuberculous mycobacteria '''do not grow under routine aerobic conditions and may be found during evaluation for sterile pyuria.'''
* '''Early events in uropathogenic E.Coli (UPEC) pathogenesis'''
** '''UPEC expresses a number of adhesins that allow it to attach to urinary tract tissues. These adhesins are classified as either fimbrial or afimbrial'''
** Type 1 (mannose-sensitive) pili are commonly expressed on both nonpathogenic and pathogenic E. coli.
** '''“P” (“P” for pyelonephritis) pili, are found in most pyelonephritogenic strains of UPEC'''
* '''Epithelial cell receptivity'''
** '''Vaginal cells'''
*** '''Women susceptible to UTI may have vaginal epithelial cells with increased adherence potential for pathogenic bacteria'''; this increased adherence in susceptible women is also shown in their buccal cells, suggesting a '''genetic trait''' for epithelial cell receptivity
*** The presence or absence of '''blood group determinants''' on the surface of uroepithelial cells may influence an individual’s susceptibility to a UTI, further emphasizing the role of genetics in susceptibility to UTI
*** '''Uropathogens attach more to epithelial cells in menopausal compared to pre-menopausal women'''; estrogen decreases the susceptibility to recurrent UTI
** Bladder cells
*** FimH-mediated binding to the bladder epithelium is the initial step in the intricate cascade of events leading to UTIs
**** FimH is essential for UPEC invasion
* '''Natural defenses of the urinary tract'''
** '''Peri-urethral and urethral region'''
*** '''The normal flora of the vaginal introitus, the peri-urethral area, and the urethra usually contain microorganisms that form a barrier against uropathogenic colonization, including (4):'''
***# '''Lactobacilli'''
***# '''Corynebacteria'''
***# '''Coagulase-negative staphylococci'''
***# '''Streptococci'''
** '''Urine'''
*** '''The most inhibitory factors are (4):'''
***# '''Osmolality'''
***# '''Urea concentration'''
***# '''Organic acid concentration'''
***# '''pH'''
**** '''Bacterial growth is inhibited by either very dilute urine or a high osmolality when associated with a low pH'''
*** '''Uromodulin (Tamm-Horsfall protein),''' a kidney-derived protein '''may play a defensive role''' by saturating all the mannose-binding sites of the type 1 pili thus potentially blocking bacterial binding to the uroplakin receptors of the urothelium
** '''Bladder'''
*** '''Immune response'''
**** The host recognition of the pathogen is mediated by a series of pathogen-associated molecular pattern receptors (PAMPs), such as Toll-like receptors (TLRs), which provide the link between recognition of invading organisms and development of the innate immune response.
**** The innate system response to an infection in the bladder or kidneys is primarily local inflammation.
**** The innate immune response occurs more rapidly than the adaptive response and involves a variety of cell types, including polymorphonuclear leukocytes, neutrophils, macrophages, eosinophils, natural killer cells, mast cells, and dendritic cells.
**** The innate response aids in establishing adaptive immunity because of interactions of macrophages, dendritic cells, and natural killer cells with T and B lymphocytes.
**** Adaptive immunity involves the specific recognition of pathogens by T and B lymphocytes and production of high-affinity antibodies, a process that occurs 7-10 days after infection.
**** UPEC enhances virulence by modulating inflammatory responses at the level of TLRs recognition, thereby extending a “window of opportunity” to establish infection by evading innate surveillance mechanisms.
** '''Alterations in host defense mechanisms'''
*** '''Obstruction''' to urine flow is a key factor in increasing host susceptibility to UTI. Stasis also contributes to the growth of bacteria in the urine and their ability to adhere to the urothelial cells.
*** '''Vesicoureteral reflux'''
**** '''Children with gross reflux and UTIs usually develop progressive renal damage manifested by renal scarring, proteinuria, and renal failure.'''
***** Those with a lesser degree of reflux usually improve or completely recover spontaneously or after treatment of the UTI.
**** '''In adults, the presence of reflux does not appear to decrease renal function unless there are stasis and concurrent UTIs'''.
*** '''Renal papillary necrosis (RPN)'''
**** Defined as necrosis of papillae and inner portions of renal medulla (which receives 10% of renal blood flow).
**** '''Conditions associated with the development of renal papillary necrosis (POSTCARDS)§:'''
****# '''Pyelonephritis'''
****# '''Obstruction''' of the urinary tract
****# '''Sickle cell disease'''
****# '''Tuberculosis'''
****# '''Cirrhosis'''
****# '''Analgesic abuse'''
****# '''Renal vein thrombosis'''
****# '''Diabetes mellitus (most common'''§''')'''
****# '''Systemic vasculitis'''
***** '''Miscellaneous: cryoglobulinemia, renal candidiasis, contrast media injection, amyloidosis, calyceal arteritis, necrotizing angiitis, rapidly progressive glomerulonephritis, hypotensive shock, acute pancreatitis, renal transplant rejection, dehydration, hypoxia, and jaundice of infants'''
***** The role of infection in the development and progression of renal papillary necrosis is controversial.
**** Early diagnosis is important to improve prognosis and reduce morbidity.
**** '''Acute ureteral obstruction caused by a sloughed papilla with concomitant UTI is a urologic emergency'''