Urinary Tract Infection

1. Urinary Tract Infection WaseemTayeb, KKNGH R3

2. Contents • Definitions • Incidence and epidemiology • Pathogenesis • Clinical manifestations • Diagnosis • Antimicrobial therapy • Bladder infection • Kidney infection • Bactreremia, sepsis and septic shock • Catheter associated UTI • UTI in spinal injury Pt

3. Definitions • UTI : An inflammatory response of the urothelium to bacterial invasion that is usually associated with bacteriuria and pyuria. • Bacteriuria : The presence of bacteria in the urine, which is normally free of bacteria. • Pyuria: The presence of white blood cells (WBCs) in the urine, is generally indicative of infection and an inflammatory response of the urothelium to the bacterium.

4. Bacteriuria without pyuria →bacterial colonization • Pyuria without bacteriuria → tuberculosis stones cancer

5. Infections defined by their site of origin • Cystitis A clinical syndrome of dysuria, frequency, urgency, and occasionally suprapubic pain. • Acute pyelonephritis An acute bacterial infection of the kidney. • Chronic pyelonephritis Describes a shrunken, scarred kidney, diagnosed by morphologic, radiologic, or functional evidence of renal disease that may be postinfectious

6. UTIs definition in terms of functional status of the urinary tract and the health of the host. • Uncomplicated UTI : An infection in a healthy patient with a structurally and functionally normal urinary tract. • A complicated infection Associated with factors that increase the chance of acquiring bacteria and decrease the efficacy of therapy

8. UTIs defined by their relationship to other UTIs. : First or isolated infection An individual who has never had a UTI or has one remote from a previous UTI. :Unresolved infection One that has not responded to antimicrobial therapy. :Recurrent infection One that occurs after successful resolution of an antecedent infection. Reinfection : Describes a new event associated with reintroduction of bacteria into the urinary tract from outside.

9. INCIDENCE AND EPIDEMIOLOGY

10. Account for: >7 million visits to physicians' offices >1 million complicate office visits 1 million emergency department visit 100,000 hospitalizations annually 1.2% of all office visits by women 0.6% of all office visits by men • Surveys screening for bacteriuria in female : 1% of schoolgirls have bacteriuria 4% by young adulthood 1% to 2% per decade of age

11. The prevalence of bacteriuria in women has been estimated at 3.5%, and increasing with age in a linear trend • 30% of 24 y women with symptomatic UTI requiring antimicrobial therapy • Half of all women will experience a UTI during their lifetime. • Bacteriuria in young women is 30 times >men. • with increasing age, the ratio of women to men progressively decreases. • 20% of women and 10% of men older than 65 years have bacteriuria

12. Pathogenesis

13. UTIs are a result of interactions between the uropathogen and the host. • Successful infection of the urinary tract is determined by The virulence factors of the bacteria, The inoculum size The host defense mechanisms.

14. Routes of Infection : • Ascending Route: Bowel reservoir Adherence to the introital and urothelial mucosa • Hematogenous Route: Uncommon Secondarily infected in patients • Lymphatic Route: Occur in unusual circumstances, such as: Severe bowel infection Retroperitoneal abscesses..

15. Urinary Pathogens • community-acquired infections : E. coli accounting for 85% gram-negative Enterobacteriaceae,(Proteus and Klebsiella,) gram-positive (E. faecalis and S. saprophyticus) • Nosocomial infections   E. coli, accounting for 50% Klebsiella, Enterobacter, Citrobacter, Serratia, Pseudomonas aeruginosa, Providencia, E. faecalis, and S. epidermidis Gardnerellavaginalis, Mycoplasma species, and Ureaplasma urealyticum may infect patients with intermittent or indwelling catheters

16. Anaerobes in the Urinary Tract The distal urethra, perineum, and vagina are normally colonized by anaerobes. Anaerobic organisms are frequently found in suppurative infections of the genitourinary tract. Bacteroides species, including B. fragilis, Fusobacterium species, anaerobic cocci, and Clostridium perfringens • Mycobacterium tuberculosis and Other Non-TuberculousMycobacteria • Chlamydia

17. Bacterial Virulence Factors • play a role in determining the ability of an organism to invade the urinary tract and level of infection within the urinary tract. • uropathogenicE. coli (UPEC), can infect the urinary tract 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. • A recent genomic analysis of a UPEC strain revealed the presence of genes for putative chaperone-usher that may function as adhesins, toxins, proteases, invasins, serum resistance factors, or motility mediators

18. Early Events in UPEC Pathogenesis • Bacterial Adherence Bacterial adherence is a specific interaction that plays a role in determining the organism, the host, and the site of infection. • This interaction is influenced by: The adhesive characteristics of the bacteria, The receptive characteristics of the epithelial surface The fluid bathing both surfaces.

19. UPEC expresses a number of adhesins that allow it to attach to urinary tract tissues • classified as either fimbrial or afimbrial, • A typical piliated cell may contain 100 to 400 pili. The pilus is usually 5 to 10 nm in diameter, is up to 2 μm long, • Pili are defined functionally by their ability to mediate hemagglutination of specific types of erythrocytes. • The most well-described pili are types 1, P and S.

20. Type 1 (Mannose Sensitive) Pili: • Expressed on both nonpathogenic and pathogenic E. coli • Facilitate bacterial colonization of the vaginal mucosa and bladder. • These pili mediate hemagglutination of guinea pig erythrocytes • The reaction is inhibited by the addition of (mannoseMSHA) • Consist of a helical rod composed of repeating FimA subunits joined to a 3-nm wide distal tip structure containing the adhesinFimH

21. Binding of the FimH adhesin to mannosylated host receptors on the uroepithelium → colonization of E. coli in the vaginal introitus, urethra, and bladder and cause cystitis • The luminal surface of the bladder is lined by umbrella cells. appear as a quasi-crystalline array of hexagonal complexes composed of four integral membrane proteins known as uroplakins • Two of the uroplakins, UPIa and UPIb, can specifically bind UPEC expressing type 1 pili.

22. P (Mannose Resistant) Pili: • Found in most pyelonephritogenic strains of UPEC • Mediate hemagglutination of human erythrocytes that is not altered by mannose (MRHA) • The adhesinPapG, at the tip of the pilus, recognizes the α-d-galactopyranosyl-(1-4)-β-d-galactopyranoside moiety present in the globoseries of glycolipids which are found on P-blood group antigens and on uroepithelium . • Other Adhesins: • S pili: which bind to sialic acid residues via the SfaSadhesin, It is associated with both bladder and kidney infection • F1C pili: bind to glycosphingolipids in renal epithelial cells and induce an interleukin-8 inflammatory response

23. Epithelial Cell Receptivity • Vaginal Cells: • E. coli strains that cause cystitis adhere more to epithelial cells from susceptible women • The increased bacterial adherence was also characteristic of buccal epithelial cells. • A small variation in both vaginal cell and buccal cell receptivity from day to day • premenopausal women susceptible at certain times during the menstrual cycle and early pregnancy • Uropathogens attached in larger numbers to uroepithelial cells from women > 65 years

24. Blood group antigens are important part of the uroepithelial cell membrane. • women with Lewis blood group Le(a−b−) and Le(a+b−) (nonsecretor) phenotypes have higher incidence of recurrent UTIs than women with Le(a−b+) phenotype • The protective effect in women with the Le(a-b+) phenotype may be due to fucosylated structures at the vaginal cell surface or in the overlying mucus which decreases availability of putative receptors for E. coli

25. Bladder Cells • the initial step in the intricate cascade of events leading to UTIs is fimH-mediated binding to the bladder epithelium • FimH binds mannosylated residues on the uroplakin molecules covering bladder superficial epithelial cells.

26. UPEC Persistence in the Bladder: • After attachment to the epithelium, UPEC is quickly internalized into the bladder superficial cells → establish a new niche to protect itself from the host innate immune response • Once intracellular, the UPEC organisms rapidly grow and divide within the cell cytosol→ small clusters of bacteria(early intracellular bacterial communities IBCs ) • As they grow, the bacteria maintain their typical rod shape of 3 μm and form a loosely organized cluster, with microorganisms randomly oriented in the cell cytoplasm. • Between 6 to 8 hours after inoculation, early IBCs show a drop in bacterial growth rate → doubling times greater than 60 minutes, a significant shortening of the bacterial morphology to of 0.7 μm, → a biofilm-like community

27. Biofilms shield bacteria from antimicrobial agents and the host immune response by: Slower growth rate of the bacteria Expression of factors that inhibit antimicrobial activity, Inability of the antimicrobial agent to penetrate the biofilm Protects the bacteria from neutrophils because they are unable to effectively penetrate the IBC and engulf the bacteria. • Bacteria on the edge of IBCs eventually detach then escape the host cell into the bladder lumen (fluxing) to readhere and reinvade superficial cells →second IBC formation.

28. Natural Defenses of the Urinary Tract • Periurethral and Urethral Region: • The normal flora usually contain microorganisms such as lactobacilli, coagulase-negative staphylococci, corynebacteria, and streptococci that form a barrier against uropathogenic colonization. • Changes in the vaginal environment related to estrogen, cervical IgA, and low vaginal pH may alter the ability of bacteria to colonize.

29. Urine • The most inhibitory factors : - Flow of urine and voiding  #1 defense - High osmolality with a low pH inhibitory to bacterial growth - High urea and organic acid content can reduce survival of bacteria within the urinary tract - Uromodulin (Tamm-Horsfall protein), saturating all the mannose-binding sites of the type 1 pili, →blocking bacterial binding to the uroplakin receptors of the urothelium   - Lactoferrin within urine: can scavenge essential iron away from bacteria • Bladder • Factors responsible for defense : - The ability of the bladder to empty - Innate and adaptive immunity • - Exfoliation of epithelial cells.

30. Immune Response: • mediated by a series of pathogen-associated molecular pattern receptors (PAMPs), • Toll-like receptors (TLRs) : • provide the link between recognition of invading organisms and development of the innate immune response. •  TLRs are conserved among many species of pathogens, such as (LPS) and peptidoglycan (PG), • activate signaling pathways that initiate immune and inflammatory responses to kill pathogens. •  TLR4 expressed on Superficial bladder epithelial cells with CD14 → recognize LPS from the bacteria and → the innate immune response • TLR11 expressed on uroepithelial cells → recognizes UPEC and protects the kidneys from ascending infection cells

32. CLINICAL MANIFESTATIONS

33. Symptoms and Signs

34. Diagnosis • Urine Collection: • Voided and Catheterized Specimens • Men: Circumcised men→no preparation. Not circumcised,→ the foreskin should be retracted and the glans penis washed with soap and then rinsed with water before specimen collection. • Women: contamination with introital bacteria and WBCs is common, • The first 10 mL of urine: urethra • Midstream specimen bladder • Prostatic fluid • First 10 mL after massage • catheteraization • Suprapubic Aspiration

35. Urinalysis • Sediment from an approximately 5- to 10-mL specimen obtained by centrifugation for 5 minutes at 2000 rpm is analyzed. • Bacteriuria, Pyuria, and Hematuria

36. Bacteriuria: • Microscopic bacteriuria→105 colony-forming units (cfu) per milliliter of urine • The bacterial count must be approximately 30,000/mL before bacteria can be found in the sediment, stained or unstained, spun or unspun False-negative : Early infection due to low no of bacteria and WBCs Diluted samples False-positive: Contamination of the urine specimen collection.

37. Pyuria : • Examining the centrifuged sediment or using a hemocytometer to count the number of WBCs in the unspun urine. • 1 to 2 WBCs per high-power field (HPF) in sediment from a centrifuged specimen = 10 WBCs/mm3 in an unspun specimen. • > 2 WBCs per HPF in a centrifuged specimen or 10 WBCs/mm3 of urine correlates well with the presence of bacteriuria and is rarely seen in nonbacteriuric patients • Hematuria : • Microscopic hematuria is found in 40% to 60% of cases of cystitis and is uncommon in other dysuric syndromes • Nitrites: formed when bacteria reduce the nitrate present in urine • Leukocyte esterase : sensitivity of 75% to 96% in detecting pyuria associated with infection

38. Urine Culture: Two techniques: A: Direct surface plating of urine on split-agar disposable plates. - Blood agar G+tive – G-tive bacteria - Desoxycholate or eosin–methylene blue (EMB) G-tive • 0.1 mL of urine onto each half of the plate. • Overnight incubation, • The number of colonies multiplied by 10 to report the number of cfu per milliliter of urine.   Urine must be refrigerated immediately on collection and should be cultured within 24 hours of refrigeration.

39. B: The dip slides • Soy agar (a general nutrient agar to grow all bacteria) on one side and EMB or MacConkey’s agar on other. •  A slide is dipped into urine, the excess is allowed to drain off, and the slide is replaced in its plastic bottle and incubated. • The volume of urine that attaches to the slide is between 1/100 mL and 1/200 mL. • the colony count is 100 to 200 times the number of colonies that become visible with incubation.

40. IMAGING TECHNIQUES • Plain Film of the Abdomen • Radiopaque calculi • Gas patterns • Absent psoas or abnormal renal contour, perirenal or renal abscess • Plain Film Renal Tomograms • Small or poorly calcified stones despite overlying gas • Struvite and uric acid stones that contain small amounts of calcium may be seen

41. Excretory Urogram • Useful to determine the exact site and extent of urinary tract obstruction • Not the best screening test for hydronephrosis, pyonephrosis, or renal abscess • Unnecessary for routine evaluation • Voiding Cystourethrogram • Neuropathic bladders • Female patient who has a urethral diverticulum causing her persistent infections • VUR

42. Ultrasonography • Useful in r/o hydronephrosis associated with UTI, pyonephrosis, and perirenal abscesses • No radiation or contrast agent risk • CT and MRI • Best antomic detail • More sensitive than IVP or U/S for acute focal bacterial nephritis and renal and perirenal abscesses • MR: advantages in delineating extrarenal extension of inflammation

43. Radionuclide Studies • Indium-111 • Indium 111–labeled WBC accumulate only in sites of inflammation and not in normal kidneys or tumors • - highly specific for inflammation Gallium-67 • used to distinguish some upper tract from lower tract infections • possible mechanisms: • concentration within labeled PMNs • leakage of protein-bound gallium through capillaries • increased vascularity of the lesion • can see focal bacterial nephritis and infected renal cysts

44. PRINCIPLES OF ANTIMICROBIAL THERAPY

45. Efficacy of the antimicrobial therapy is critically dependent on: - The antimicrobial levels in the urine - The duration that this level remains above the minimal inhibitory concentration of the infecting organism • Resolution of infection is closely associated with the susceptibility of the bacteria to the concentration of the antimicrobial agent achieved in the urine • The concentration of the antimicrobial agent achieved in blood is not important in treatment of uncomplicated UTIs.

46. In renal insufficiency, dosage modifications are necessary for agents that are cleared primarily by the kidneys • In renal failure, the kidneys may not be able to concentrate an antimicrobial agent in the urine; →difficulty in eradicating bacteria may occur. • A decision regarding the antimicrobial selection and the duration of therapy must consider: - The spectrum of activity of the drug against the pathogen - Uncomplicated or complicated, - Potential adverse effect - Cost.

47. Bacterial Resistance • Inherited chromosomal resistance • Exists in a bacterial species because of the absence of the proper mechanism on which the antimicrobial agent can act. • Proteus and Pseudomonas species are always resistant to nitrofurantoin .

48. Acquired chromosomal resistance • Selection of resistant mutants within the urinary tract during therapy • Resistant organism (clone) was present before, but only in one per 105 to 1010 organisms • The remainder of the bacteria, which are susceptible to the administered antimicrobial agent, will be eradicated by therapy, but within 24 to 48 hours a repeat urine culture will show high bacterial counts of the resistant mutant. • This phenomenon is most likely to occur when the antimicrobial level in the urine is close to or below the minimal inhibitory concentration of the drug

49. Extrachromosomal-mediated resistance • Acquired and transferable via plasmids, which contain the genetic material for the resistance, called R-factor resistance • Much more common • Produces multiply resistant strains, making therapy more difficult • Occurs only in the fecal flora, never within the urinary tract • Patients previously exposed to β-lactams, aminoglycosides, sulfonamides, TMP, and tetracycline will often have R-factor resistance to both the antimicrobial agent to which the bacteria were exposed and also to other antimicrobial agents.