1

To list and describe the common microbes

involved in urinary tract infection (UTI)

To discuss the epidemiology, pathogenesis, clinical manifestation, lab diagnosis, and management of UTIs (particularly cystitis

and pyelonephritis)

To discuss the host defense of the urinary tract

2

The urinary bladder and upper urinary tract are sterile under normal conditions

The male urethra is normally sterile, except near the external opening.

UTI may involve only the lower urinary tract (LUT) or both lower and upper urinary tract (UUT)

There are microorganisms that infect the urethra, bladder, kidney, and even the prostate

So, infections of the urinary tract include: - Urethritis = infection of the urethra - Cystitis = infection of the urinary bladder - Pyelonephritis = infection of the kidney - Prostatitis = infection of the prostate gland

Microbial diseases of the urinary system can result from infection from an outside source or from opportunistic infection by members of the normal microbiota.

Most UTIs result from contamination of the urethra with organisms found in the colon

Bacteria are the most common cause of UTIs UTIs occur as a result of the interaction of bacterial virulence and host biologic & behavioral factors, as opposed to highly efficient host defense mechanisms

There are 3 possible routes whereby bacteria can invade and spread with in the urinary tract. These are:
5

- the ascending, hematogenous, and lymphatic pathways

Bacterial infection is usually acquired by the ascending route from the urethra to the bladder - N.B. In F the urethra is usually colonized with bacteria

Ascending infections may then proceed to the kidney Occasionally, bacteria infecting the urinary tract invade the bloodstream to cause septicemia

From epidemiological viewpoint UTIs occur in 2 general setting: - Community acquired UTIs:- more common type - Hospital (nosocomial) acquired is less common
6

and most often being associated with catheterization

Bacterial etiology of UTIs

Opportunistic gm ve bacteria from the intestines often cause urinary tract infections.

Nosocomial UTIs are usually occur following catheterization in the urinary system.

E. coli causes more than half of these infections Among the gram ve rods:

UPEC is the most common cause of ascending UTIs Proteus mirabilis is often associated with urinary stones (calculi).
7

- b/c the organism produces a potent urease, which acts on urea to produce ammonia, rendering the urine alkaline.

Klebsiella, Enterobacter, Serratia spp. and Pseudomonas are more frequently found in hospital-acquired UTI
-b/c

their resistance to antibiotics favors their

-selection

in hospital patients

Among the Gram +ve species:

- S. saprophyticus has a particular propensity for causing

UTIs, especially in young sexually active women. - S. epidermidis and Enterococcus species are more often associated with UTI in hospitalized patients where multiple antibiotic resistance can cause treatment difficulties. - More recently, capnophilic species (organisms that grow better in air enriched with carbon dioxide) such as corynebacteria

has been implicated as possible causes of UTI.

Anaerobic & fastidious organisms are rarely cause UTI When there has been hematogenous spread to the urinary tract, other species may be found e.g. - S. typhi, S. aureus and M. tuberculosis (renal tuberculosis)

Viral etiology of UTIs

Viral causes of UTI appear to be rare A number of viruses particularly mumps virus, CMV, and coxsackieviruses, can be present in the kidneys and urine, but rarely cause symptoms or any consequences

Adenoviruses (particularly type 11) have been strongly implicated as causative agents in hemorrhagic cystitis
10

in pediatric patients

A number of sexually transmitted pathogens example: - Neisseria gonorrhoeae may invade the urethra - C. trachomatis and HSV can present with symptoms that mimic acute cystitis in both men and women

Other causes of UTI include: - The fungi Candida spp. and Histoplasma capsulatum. - The protozoan Trichomonas vaginalis , which can cause urethritis in both males and females, but is most often considered as a cause of vaginitis. - Infections with Schistosoma haematobium , which result in inflammation of the bladder and commonly hematuria.
11

Most cases of UTI occur in women (female to male ratio is 30:1). - b/c the female urethra is short & is in proximity to vulvar and perianal areas, making contamination likely

About 40% of all females have at least one UTI at some time in their lives.

Males experience a rapid increase in the incidence of UTI some time in the fifth decade of life - This is due to obstruction of the urethra following development of benign prostatic hypertrophy

The incidence of UTIs increases with age and with

sexual activity.

12

Postmenopausal women have higher rates of UTI. This is b/c of: - bladder or uterine prolapse - estrogen deficiency= causes vaginal flora changes with loss of protective lactobacilli, which are replaced by coliforms (e.g., E coli) and other uropathogens - higher likelihood of concomitant medical illness (e.g., diabetes mellitus).

Spermicide use increase: - colonization of the vagina with uropathogens - adherence of E.coli to vaginal epithelial cells
13

Table-1: Risk factors for urinary tract infections

FEMALE
Sexual intercourse, Menopause, Pregnancy Few lactobacilli in vaginal mucosa, Douching Immunosuppression, Diabetes mellitus Use of diaphragm and spermicides Use of foley catheters, Kidney stones Bladder or uterine prolapse Neurogenic bladder or bladder diverticulum Congenital abnormalities that obstruct or Slow urine flow
14

MALE
Enlarged prostate gland Kidney stone Diabetes mellitus Immunosuppression Congenital abnormalities that obstruct or slow urine flow Use of foley catheters

Bacteria invade the urinary tract by ascending or

hematogenous routes .

The ascending route is the most common one Infection of the kidney with gm ve bacilli rarely occurs by the hematogenous route.

Urovirulence in bacteria

Although most UTIs are caused by E. coli, only a few serogroups such as E. coli 01, 02, 04, 06, 07, 08, 075, 0150, 018ab cause a high proportion of infections.

The most important virulence factor for these bacteria is the enhanced ability to adhere to uroepithelial cells.
15

This attachment is mediated by specific pilus adhesins on the surface of E coli.

Two major fimbrial adherence systems have been identified in E. coli strains associated with UTI: pap and sfa/fac - The PAP adhesion, for example, is present on the tip of P fimbriae - The term P fimbriae stems from the fact that the PAP adhesin recognizes the human digalactoside P blood group determinants on human erythrocytes and urothelial cells, - leading to increased adhesion - So, the binding of P fimbriae to blood group determinants has important implications for host susceptibility to infection
16

Another adhesin is the type 1 pilus (fimbria), which all E. coli strains possess but not all E. coli strains express it.

Type 1 pili are thought to play a key role in initiating E. coli bladder infection. - they mediate binding to uroplakins on the luminal surface of bladder uroepithelial cells. - The binding of type 1 fimbriae of E. coli to receptors on uroepithelial cells initiates a complex series of signaling events that leads to apoptosis and exfoliation of uroepithelial cells, with the attached E. coli organisms carried away in the urine.

N.B. Here, E. coli strains from cystitis patients are more likely to

bind than those from pyelonephritis.

17

Adhesin
Type-1 fimbriae (MS) (Bind to THP and SIGA)
P-fimbriae (MR) S/FIC fimbriae (MR) (adherence inhibited by THP)

Receptor
Uroplakin Ia (mannosylated proteins on epithelial cells) and PMNs
Gal alpha 1-4 (P-blood group antigen) Sialyl (alpha2-3) galactoside

G fimbriae (MR)
M fimbriae (MR) Type 3 fimbriae (contribute to biofilm formation ) Dr family

Terminal N-acetyl-D-glucosamine
Galactose N-acetyl-galactosamine Blood group M (glycophorin A)

Dr blood group antigen component of DAF and type IV collagen

18

Several additional factors also affect the virulence of E. coli.

These include:
- The presence of flagellae, which are necessary for motility. N.B. Motility has been shown to facilitate ascending infection - Production of a hemolysin, which induces formation of pores in the cell membrane. - Bacterial endotoxin: which can decrease urethral peristalsis - Bacterial capsules: resistance to plasma bactericidal properties.

Proteus mirabilis is armed with various virulence factors, including the production of hemolysin and IgA protease, iron acquisition, flagella, fimbriae and, most importantly, the secretion of urease
19

Urease hydrolyzes urea to ammonia and carbon dioxide.

Ammonia combines with hydrogen to form ammonium; the

ensuing reduction in free hydrogen ion concentration leads to alkalinization with the urine pH being well >7.0 and sometimes as high as 9.0.

The alkaline urine promotes the precipitation of phosphate, carbonate and magnesium, leading to the formation of struvite stones that often form large staghorn calculi.

These infection stones contain a mixture of a proteinaceous matrix, leukocytes, struvite and bacteria.
20

The clinical manifestations of UTI are variable.

Approximately 50% of infections do not produce

recognizable illness and are discovered incidentally during a general medical examination.

Infections in infants produce symptoms of a nonspecific nature, including fever, vomiting, and failure to thrive.

Manifestations in older children and adults, when present, often suggest the diagnosis and sometimes the localization

of the infection within the urinary tract.

21

Cystitis

The typical symptoms of cystitis are: - dysuria (painful urination), - frequency (frequent voiding of urine), - and urgency (an imperative call to toilet).

It is clinically distinguished from pure urethritis by a more acute onset, more severe symptoms, the presence of bacteriuria, and in approximately 50% of cases, hematuria.

The urine is often cloudy and malodorous and occasionally flankly bloody.
22

Cystitis patients also experience pain & tenderness

in the suprapubic area.

Fever and systemic manifestations of illness are usually absent

Pyelonephritis

The typical presentation of upper urinary infection consists of flank or loin pain and fever that exceeds 38.3C.

Rigors, vomiting, diarrhea, and tachycardia are present in more severely ill patients.
23

Specimen collection for microbiology lab.

The diagnosis of UTI is based on examination of normally sterile urine

To achieve this appropriate specimen collection is needed Urine is most easily obtained by spontaneous micturition Unfortunately, voided urine is invariably contaminated with urethral flora and, in female patients, perineal and vaginal flora, thus the results of laboratory test is affected.

So, to overcome this: - clean-voided midstream urine should be used for microbiology lab. - catheterization or suprapubic aspiration from the distended bladder
24

may be necessary if it is difficult to obtain clean catch sample

Note: Urine collected in a normal individual by suprapubic aspiration of the bladder is sterile and does not contain leukocytes. - This method represents the gold standard in the diagnosis of UTI. - It is, however, not performed routinely in clinical practice : MSU sample should be collected into a sterile wide-mouthed container after careful cleansing of the genitalia. : MSU sample is collected by allowing the first part of the urine stream to be voided as this helps to wash out contaminants in the lower urethra. : For collecting urine from babies & young children usually suprapubic aspiration of urine is applied
25

Microscopic examination

Microscopic examination of urine gives a rapid preliminary report

Bacteria may be seen on microscopy when present in the specimen in large numbers. However, they are not necessarily indicative of UTI. Why?

The presence of RBCs & WBCs , although abnormal, is not necessarily indicative of UTI. Why?

Approximately 90% of patients with acute symptomatic UTI have pyuria (that is > 10 (4) white cells/ml of urine). - More specific is the presence of white cell casts, which

occur primarily in patients with acute pyelonephritis.

26

Note the following:

-

Pyuria is defined as the presence of at least 10,000 leukocytes per mL of uncentrifuged urine, which corresponds to 2 to 5 leukocytes per high power field in a centrifuged sediment

Dipsticks test

Dipsticks may be used as a screening tool for diagnosis of UTI They detect the presence of leukocyte esterase, nitrite and other parameters in urine.

The dipstick nitrite test depends on the conversion of nitrate (from dietary metabolites) to nitrite by bacteria in the urine.

Normally no detectable nitrite is present.

27

Leukocyte esterase corresponds to pyuria and nitrite reflects the presence of Enterobacteriaceae, which convert urinary nitrate to nitrite.

Reasons for a negative nitrite test in the presence of bacteriuria: - insufficient bladder incubation time for conversion of nitrate to nitrite. - low urinary excretion of nitrate Q. To overcome these problems what should be done? - inability of some organisms to convert nitrate to nitrite (such as E. faecalis, S.saprophiticuis) and - decreased urine pH (due to cranberry juice or other

dietary supplements)

28

29

Urine culture

Quantitative bacteriology has been the gold diagnostic

standard for UTI

The standard definition of a positive urine culture is usually 10(5) CFU/mL together with pyuria (eg, leukocyte count 10(4) WBC/mL).

Normal values in a noninfected midstream clean-catch sample are usually <10(5) colony-forming units and <10,000 leukocytes per mL of urine.
30

Culture results depends up on a variety of factors. These factors relate to: - Collection = specimen should be collected properly

- Storage = urine must be cultured with in 1hr of collection

or held at 4oC for not more than 18 hrs before culture - Antibiotic treatment - Fluid intake = less or more fluid intake influence the quantitative result
31

Uncomplicated UTI (cystitis) is treated with an oral antibacterial as a single dose or for 3 days

Sulfonamides and trimethoprim alone or in combination with sulfamethoxazole, a fluoroquinolone, and nitrofurantoin are the agents most commonly used

Complicated UTI (pyelonephritis) should be treated with a systemic antibacterial agent - The organism should be known to be susceptible to the antibacterial, and systemic treatment should continue until the signs and symptoms subside. - It can then be replaced by oral therapy.
32

The usual length of treatment is at least 10 days, but longer treatment may be necessary to sterilize the kidney

Recurrent infections in healthy women can be prevented by regularly emptying the bladder. - This washes bacteria out of the urinary tract and is particularly important following intercourse.

The prophylactic use of antibiotics may also prevent recurrent infections, but in the presence of underlying abnormalities there is a tendency to select antibiotic-resistant strains.
33

UTIs are among the most common bacterial infections, especially in women.

Most UTIs are acute episodes without sequelae. UTIs are usually endogenously acquired, with colonizing bacteria ascending the urinary tract from the periurethral area.

E. coli is the predominant pathogen; other gram-negative rods are also

responsible, especially in hospitalized patients.

Viruses are not important causes of UTI. Structural or mechanical factors in the host, or catheterization, predispose to UTI.

Bacterial attributes such as adhesions and capsular polysaccharides may be important in the development of UTI.

Specific toxins are not implicated, but hemolysins (cytotoxins) may be.

34

Lower UTI (cystitis) usually presents with acute frequency and dysuria. - Asymptomatic infection is common in pregnancy and in children. - Infection is recurrent in a significant proportion of people

Pyelonephritis (upper UTI) has a more severe presentation than lower UTI, with fever and loin pain; recurrent infection results in renal damage.

Bacteriologic confirmation of the diagnosis requires quantitative methods.

Short-course treatment with oral antibacterials is effective for lower UTI; But pyelonephritis needs longer treatment, often commencing with systemically administered drugs.

Hospital-acquired UTI is often caused by multiple-resistant Gram -ve bacteria, and treatment should be based on the results of antibiotic susceptibility tests.
35

Fauci Longo et al; Harrisons Principles of Internal Medicine, 18th edition (2012)

Ronald et al; principles of infectious disease, 7th edition (2010).

James J.Champoux et al; Sherris Medical microbiology, 4th edition (2004)

Barons Medical Microbiology, 4th edition (2000)

36