Overview
This lecture covers urinary tract infection (UTI): the anatomical division into upper and lower tract, the causative pathogens and the ascending route by which they establish infection, the clinical syndromes (cystitis, pyelonephritis, urethritis) and the body’s defence mechanisms against them, epidemiology and predisposing conditions, UTI in pregnancy, the special relationship between Proteus mirabilis and infection stones, antimicrobial treatment and resistance, distant (non-renal) effects of infection, prevention advice, and two worked clinical case studies.
Anatomy and major pathogens
- The urinary tract is divided into an upper tract (kidneys - renal cortex, calyx, renal pyramid, renal pelvis, renal papilla, ureteropelvic junction - and the ureters) and a lower tract (bladder, vesicoureteral orifice, urethra), with the division point at where the ureters enter the bladder.
- Most UTI arises via the ascending route: bacteria from skin, the genital tract or the large bowel travel from the urethra to the bladder, and potentially on to the kidneys.
- Causative pathogens (female urogenital tract): Escherichia coli (75-95%), Proteus, Klebsiella, Enterobacter, Staphylococcus (less common).
- Community- vs hospital-acquired data (Greenwood, Antimicrobial Chemotherapy): E. coli is the dominant organism in both settings (highest in community-acquired, ~75-80%, somewhat lower but still dominant in hospital-acquired, ~50%). Klebsiella and Proteus mirabilis are grouped with E. coli as “Gram negative enteric” organisms. Staphylococci and others (e.g. Enterococci, Candida) are minor contributors, roughly similar or slightly higher in hospital-acquired infection.
Pathogenesis of ascending UTI
Stepwise pathway (numbered 1-11 on the source diagram):
- Contamination of the periurethral area with a uropathogen from the gut.
- Colonisation of the urethra and migration to the bladder.
- Colonisation and invasion of the bladder, mediated by pili and adhesins. (A parallel, catheter-associated branch shows inflammatory response in the bladder and fibrinogen accumulation on the catheter.)
- Neutrophil infiltration.
- Bacterial multiplication and immune system subversion.
- Biofilm formation.
- Epithelial damage by bacterial toxins and proteases.
- Ascension to the kidneys.
- Colonisation of the kidneys.
- Host tissue damage by bacterial toxins.
- Bacteraemia.
The slide shows a catheter-associated variant pathway (fibrinogen accumulation, catheter, bacteria) running in parallel to the main numbered pathway at step 3, but the exact branching relationship between the two is not stated verbally on the slide.
Clinical syndromes
- Cystitis (bladder infection, lower urinary tract): increased urinary frequency, urgency, dysuria (painful urination), suprapubic pain, WBCs and bacteria in urine, possible haematuria; more common in women.
- Pyelonephritis (kidney infection, upper urinary tract): flank pain (costovertebral angle), high fever, malaise, WBCs and bacteria in urine, urinary symptoms similar to cystitis.
- Urethritis (lower urinary tract): raises the question of genital tract infection; associated organisms Neisseria gonorrhoeae, Chlamydia, Ureaplasma.
Host defence mechanisms
- Hydrodynamic: peristaltic action of the ureters; ureteral valves prevent reflux; flushing action of bladder and urethra emptying.
- Mucosal immunity: secretory IgA, IgG.
- Urine constituents: antibacterial at night, osmotic effects.
- Prostatic fluids: antibacterial.
Epidemiology and predisposing conditions
- Incidence in children is similar between males and females.
- In adults, incidence increases in females from puberty onward (rises steeply and stays higher, with a further gradual rise into old age).
- In males, incidence stays low and flat until around age 50, then rises steeply, converging close to the female rate by old age.
- Benign prostatic hyperplasia (BPH): an enlarged prostate compresses the urethra and obstructs/restricts urine flow, compared with normal, unobstructed flow through a normal prostate.
- Predisposing conditions (community- and hospital-acquired): onset of sexual activity, congenital abnormalities, hormonal changes, significant bladder residue, urinary catheter, inadequate immune function, surgery, underlying disease (e.g. prostatitis/cancer, diabetes).
Which of these predisposing factors are specifically "community acquired" vs "hospital acquired" is implied by label position/box colour on the source mind-map rather than shown with explicit connecting lines, so the exact grouping is not certain from the slide.
UTI in pregnancy
- Maternal: occurs in 2-10% of pregnancies; increased risk of pyelonephritis, sepsis, pulmonary oedema.
- Fetal: risk of infection; possible association with low birth weight/preterm delivery.
- Antibiotic safety in pregnancy: beta-lactams are safe; avoid tetracyclines, fluoroquinolones and trimethoprim; nitrofurantoin is safe for cystitis in the 1st/2nd trimester.
Proteus mirabilis and infection stones
- P. mirabilis is a Gram-negative bacterium, clinically often seen in patients with long-term catheterisation.
- Causes cystitis and pyelonephritis; can cause asymptomatic bacteraemia in elderly patients and those with type 2 diabetes.
- Causes 1-10% of UTIs; recognisable on blood agar culture by a concentric-ring “swarming” growth pattern.
- Mechanism of stone formation: P. mirabilis produces urease, which converts urea to NH4+ (note: E. coli is urease-negative). This raises urine pH, causing phosphate salt deposition. Deposition of magnesium and calcium salts, if untreated, results in infection stones: struvite (NH4MgPO4.6H2O) and carbonate apatite (Ca10(PO4)6CO3).
- Bacteria embedded within stones can cause re-infection after antibiotic treatment.
- Stones can block urinary flow once larger than 1 cm2.
- Catheter obstruction with P. mirabilis occurs via crystalline biofilm.
- Red blood cells in the urine may colour the deposits.
- Large, branching stones filling the renal pelvis and calyces are called staghorn calculi (visible on plain X-ray and as excised specimens).
Treatment
- Uncomplicated cystitis in non-pregnant women:
- First line: single high dose, or 3-day course, of trimethoprim or nitrofurantoin.
- Second line: cephalexin, norfloxacin, co-amoxiclav.
- Upper tract infection/complicated UTI:
- Mild/moderate: e.g. ciprofloxacin (3-5 days).
- Severe (e.g. acute pyelonephritis): IV gentamicin.
- Men: treat for more than 7 days.
- Renal stones: investigate with ultrasound.
- Catheter-associated UTI (2-10%): treat and remove the catheter.
- Asymptomatic bacteriuria: treatment is considered only in children and pregnant women.
- Antimicrobial resistance: extended-spectrum beta-lactamases (ESBLs) are common among Enterobacteriaceae, particularly E. coli and Klebsiella species. They confer resistance to penicillins, most cephalosporins and aztreonam. Treat ESBL-producing infections with a carbapenem (meropenem or imipenem).
Distant effects of infection
- Impetigo due to Streptococcus pyogenes can lead to glomerulonephritis.
- Shiga toxin-producing E. coli (STEC) gastroenteritis (e.g. E. coli O157) can lead to haemolytic uraemic syndrome (HUS) in children up to 12 years old; the shiga toxin localises to cell endosomes.
Prevention
Steps to reduce UTI risk:
- Drink plenty of liquids, especially water, to dilute urine and increase urination frequency, flushing bacteria from the tract before infection begins.
- Wipe from front to back after urinating and after a bowel movement, to prevent bacteria from the anal region spreading to the vagina and urethra.
- Empty the bladder soon after intercourse, and drink a full glass of water to help flush bacteria.
- Avoid potentially irritating feminine products (deodorant sprays, douches, powders in the genital area), which can irritate the urethra.
- Consider changing birth control method, since diaphragms and unlubricated or spermicide-treated condoms can contribute to bacterial growth.
Case study 1: recurrent cystitis
- 23-year-old woman, married one year, five attacks of acute cystitis in that time; symptoms dysuria, increased frequency and urgency.
- Attacks 1, 2 and 5 caused by E. coli; attack 3 by Enterococcus; attack 4 by Proteus mirabilis. Each infection responded to short-term antibiotics, with recurrences 3 weeks to 3 months after completing therapy.
- Presents again with 2 days of dysuria, increased frequency and urgency.
- Examination: no vaginal discharge, normal cervix, no evidence of an STD, no evidence of upper UTI (no fever or flank pain) - suggesting another attack of acute cystitis.
- Lab (mid-stream urine): WBC count 1.09 x 10^7/mL; culture 1 x 10^6 bacterial cells/mL; Gram stain shows Gram-positive cocci; catalase-positive and coagulase-negative.
- Reasoning: catalase-positive rules out Enterococci and Group B streptococci; coagulase-negative rules out Staphylococcus aureus.
- Diagnosis: Staphylococcus saprophyticus, currently the most likely coagulase-negative Staphylococcus to cause cystitis in young women.
- Recurrent UTIs are either a relapse of the original infection (usually within 2 weeks of completing antibiotic therapy) or, more commonly, a new infection with a different organism (as in this case). About 10% of all women experience this problem at some point in their lives.
Case study 2: catheter-associated pyelonephritis
- 67-year-old man with urinary obstruction and retention, diagnosed with benign prostatic hyperplasia. Undergoes transurethral resection of the prostate; a urinary catheter is attached to a closed drainage system.
- Two days later develops fever (38C); the next day becomes confused and disoriented with a shaking chill (temp 39C and low blood pressure). Mild tenderness over the left kidney.
- Urine sample collected from the catheter port with needle and syringe; blood cultures also taken.
- WBC count 1.8 x 10^7/mL; urine sediment shows many WBCs, white blood cell casts, a few RBCs and numerous bacteria.
- Culture: Gram-negative, non-fermentative bacteria from both urine and blood cultures - Pseudomonas aeruginosa.
- Diagnosis: pyelonephritis, supported by elevated temperature and the organism being present in the bloodstream. This is a nosocomial infection, common with catheterisation.
Self-test
- Define cystitis, pyelonephritis and urethritis, including their key distinguishing symptoms.
- List the main defence mechanisms of the urinary tract and briefly state how each works.
- Describe the steps of the ascending route pathogenesis pathway, from periurethral contamination to bacteraemia.
- Which organism is the leading cause of both community- and hospital-acquired UTI, and how do the two settings differ in the overall organism profile?
- Distinguish the incidence pattern of UTI by age and sex between males and females.
- Explain why Proteus mirabilis, but not E. coli, is associated with infection stone formation, describing the mechanism.
- What are struvite and carbonate apatite stones composed of, and what is the clinical significance of bacteria embedded within stones?
- List the predisposing conditions for UTI mentioned in the lecture.
- Describe how benign prostatic hyperplasia predisposes to UTI.
- What are the risks of UTI in pregnancy for mother and fetus, and which antibiotics should be avoided?
- Describe the first-line and second-line treatment for uncomplicated cystitis in a non-pregnant woman.
- How does treatment differ for severe upper tract infection/acute pyelonephritis compared with uncomplicated cystitis?
- What are extended-spectrum beta-lactamases, which organisms commonly carry them, and how are ESBL-producing infections treated?
- Describe two distant effects of infection mentioned in the lecture and their triggering organisms.
- In case study 1, explain the laboratory reasoning that identifies Staphylococcus saprophyticus as the causative organism.
- In case study 2, what features support a diagnosis of pyelonephritis rather than uncomplicated cystitis, and why is this classed as a nosocomial infection?
- A postmenopausal woman with a long-term indwelling catheter develops recurrent UTIs and is found to have a large branching kidney stone. Which organism is most likely responsible, and by what mechanism did the stone form?
Answers
Reveal answers
- Cystitis is bladder infection: increased frequency, urgency, dysuria, suprapubic pain, WBCs/bacteria in urine, possible haematuria, more common in women. Pyelonephritis is kidney infection: flank/costovertebral angle pain, high fever, malaise, WBCs/bacteria in urine, cystitis-like urinary symptoms. Urethritis is infection of the urethra, often linked to genital tract infection (Neisseria gonorrhoeae, Chlamydia, Ureaplasma).
- Hydrodynamic: peristaltic action of ureters, ureteral valves preventing reflux, flushing of bladder and urethra. Mucosal immunity: secretory IgA and IgG. Urine constituents: antibacterial at night, osmotic effects. Prostatic fluids: antibacterial.
- Contamination of the periurethral area with a gut uropathogen -> colonisation of the urethra and migration to the bladder -> colonisation/invasion of the bladder via pili and adhesins -> neutrophil infiltration -> bacterial multiplication and immune subversion -> biofilm formation -> epithelial damage by toxins and proteases -> ascension to the kidneys -> colonisation of the kidneys -> host tissue damage by toxins -> bacteraemia.
- E. coli, at roughly 75-80% in community-acquired and ~50% in hospital-acquired infection. Hospital-acquired infection has a broader profile, with staphylococci and other organisms (e.g. Enterococci, Candida) making up relatively more of the total compared with community-acquired.
- In children incidence is similar in males and females. In females it rises steeply from puberty and stays high, rising further gradually into old age. In males it stays low and flat until about 50 years, then rises steeply, converging close to the female rate in old age.
- Proteus mirabilis produces urease, which converts urea to NH4+ (E. coli does not, being urease-negative). This raises urine pH, causing phosphate salts to deposit; deposition of magnesium and calcium salts, if untreated, forms infection stones.
- Struvite is NH4MgPO4.6H2O and carbonate apatite is Ca10(PO4)6CO3. Bacteria embedded within stones can cause re-infection even after antibiotic treatment has cleared the urine, since the organisms are protected within the stone matrix.
- Onset of sexual activity, congenital abnormalities, hormonal changes, significant bladder residue, urinary catheter, inadequate immune function, surgery, underlying disease (e.g. prostatitis/cancer, diabetes).
- An enlarged prostate compresses the urethra, obstructing/restricting urine flow; this differs from the unobstructed flow seen with a normal prostate, and the resulting incomplete bladder emptying/urinary retention predisposes to infection.
- Maternal risk: occurs in 2-10% of pregnancies, with increased risk of pyelonephritis, sepsis and pulmonary oedema. Fetal risk: infection, and possibly low birth weight/preterm delivery. Avoid tetracyclines, fluoroquinolones and trimethoprim; beta-lactams are safe, and nitrofurantoin is safe for cystitis in the 1st/2nd trimester.
- First line: a single high dose, or a 3-day course, of trimethoprim or nitrofurantoin. Second line: cephalexin, norfloxacin or co-amoxiclav.
- Mild/moderate upper tract/complicated UTI is treated with e.g. ciprofloxacin for 3-5 days; severe disease (e.g. acute pyelonephritis) is treated with IV gentamicin. Men are treated for more than 7 days, renal stones are investigated with ultrasound, and catheter-associated infection requires catheter removal in addition to treatment.
- Extended-spectrum beta-lactamases (ESBLs) are enzymes common among Enterobacteriaceae, particularly E. coli and Klebsiella, that confer resistance to penicillins, most cephalosporins and aztreonam. ESBL-producing infections are treated with a carbapenem (meropenem or imipenem).
- Impetigo due to Streptococcus pyogenes can lead to glomerulonephritis. Shiga toxin-producing E. coli (STEC) gastroenteritis (e.g. E. coli O157) can lead to haemolytic uraemic syndrome in children up to 12 years old, with the toxin localising to cell endosomes.
- Gram stain showed Gram-positive cocci that were catalase-positive (ruling out Enterococci and Group B streptococci, which are catalase-negative) and coagulase-negative (ruling out Staphylococcus aureus, which is coagulase-positive). This leaves Staphylococcus saprophyticus, the most likely coagulase-negative Staphylococcus to cause cystitis in young women.
- Fever, confusion/disorientation, shaking chills, low blood pressure and flank tenderness, together with elevated WBC count, white cell casts in the urine, and the same organism (Pseudomonas aeruginosa) cultured from both urine and blood, support pyelonephritis rather than uncomplicated cystitis. It is nosocomial because it arose after catheterisation performed during a hospital procedure (transurethral resection of the prostate).
- Proteus mirabilis is most likely, via its urease enzyme converting urea to NH4+, raising urine pH and causing magnesium/calcium phosphate salts (struvite and carbonate apatite) to deposit and form a staghorn calculus; long-term catheterisation is a recognised clinical association with P. mirabilis infection.