Lecture 8/9: Urinary Tract Infections Flashcards
What is the lining of the urinary tract?
Urothelium
Is the urine/ bladder a sterile environment?
No
2 studies in 2010/11 used metagenomics to reveal the microbiome of healthy adult urine
How does microbial immigration of the urinary tract occur?
From skin, faeces, vagina
Enter urethra and can ascend all the way to the kidneys
How does microbial elimination of the urinary tract occur?
Urine flow
Innate and adaptive immune defences
Having a healthy UT/ vaginal microbiome
What is the common bacterial load present in the urine?
~10^4-10^5 colony forming units per ml
(low bacterial load)
What is the common bacterial load present in the faeces?
10^12 colony forming units per gram
What percentage of urinary microbiota are shared with the gut?
62.5%
What percentage of urinary microbiota are shared with the vagina?
32%
What are risk factors of UTIs?
Female anatomy
Structural problems
Pregnancy
Catheterisation
Previous UTI
Structural problems
Compromised immune system
Sexual activity
Age
Dehydration
Changed vaginal microbiome
Uncontrolled diabetes
Poor hygiene
What are the defining factors of uncomplicated UTI?
Adult patient
Female anatomy
Functionally normal urinary tract
No fever
Not immunocompromised
Not pregnant
Sensitive to antibiotics
What are the defining factors of a complicated UTI?
Child patient
Male anatomy
Structurally abnormal urinary tract
Fever
Immunocompromised
Pregnant
Resistant to antibiotics
What are the symptoms of a UTI?
More frequent urination
Burning sensation when urinating
Urine is cloudy, darks or smells
Pain in lower abdomen
Hugh or low temperature
Children: being sick
What are the complications of UTIs?
Recurrent infections
Chronic infection
Kidney infection
Premature delivery (pregnant)
Bloodstream infection
Sepsis
When is a UTI considered recurrent infection?
> 2 UTIs within 6 months
> 3 within a year
What percentage of women who have had a UTI will have a recurrence?
20-30%
What is the balloon design of a catheter called?
Foley catheter
What are the short-term uses of a urinary catheter?
Before/ during/ after surgery
During childbirth with epidural
To deliver chemotherapy for bladder cancer
What are the long term uses of urinary catheterisation?
If the urethra is blocked
Never damage that affects urinary control
Last-resort treatment for urinary incontinence
Elective use by wheelchair users due to lack of accessible toilets
How can biofilms form on urinary catheters?
Outside or inside can get contaminated by host-associated or environmental bacteria
What does catheterisation trigger and what is the effect?
Release of fibrinogen into the bladder
This sticks to the catheter - priming it for adhesion of bacteria that have fibrinogen-binding adhesins
What substances can encrust the catheter surface?
Crystallisation of calcium and magnesium phosphate from the urine
What percentage of healthcare acquired infection are catheter acquired-UTIs?
50%
In 12 moths spanning 2016/17 catheter associated UTIs in NHS inpatients caused…
Excess bed days, lost QALYs, deaths, direct hospital costs
45,717 excess bed-days
10,471 lost QALYs
1,467 deaths
£54.4M direct hospital costs
What is the most common pathogen associated with a UTI?
Escherichia coli
What does uropathogenic E. Coli posses to aid with its infectivity causing UTI?
Flagella provides motility
Diverse array of pili allow bacteria to stick to host cells and surfaces
Forms biofilms
Alpha-haemolysin bursts host cell membranes releasing nutrients
Siderophores capture essential iron and copper from host metal-chelating proteins
What is the difference in effect between the type I pili and type P pili associated with E. Coli?
Type 1 pili facilitate attachment to bladder lining
Type P pili facilitate attachment in the kidneys, affects ability of host cells to display immunoglobulins
How does alpha-haemolysin assist the pathogenicity of E. Coli in UTIs?
Bursts host cell membranes, releasing nutrients
Action allows E. Coli to penetrate into deeper layers of the UT lining
(deeper tunnelling in urothelium)
How do the siderophores assist the pathogenicity of E. Coli in UTIs?
Capture essential iron and copper from host metal-chelating proteins
How many Type I pili are present on each E. Coli cell?
Up to 500
How is UPEC established in the bladder?
Umbrella cells on bladder surface express glycoprotein
These are bound to FimH allowing E. Coli to attach and invade cells
Invading bacterium divides into biofilm-like aggregate
Filaments are formed which are resistant to neutrophil-mediated killing and can invade other cells
What are the glycoproteins called that are present on the surface of the bladder urothelium?
Uroplakins
What is the microbiology of S. saphrophyticus?
Gram-positive
Coagulase-negative staphylococci
Very common cause of uncomplicated UTI
What are the virulence factors of S. saphrophyticus?
Lipoteichoic acid in cell wall and surface protein haemagglutinin allow attachment to host cells
Forms biofilms using polysaccharide intercellular adhesin and various protein
Enzyme urease hydrolyses urea in urine to CO2 and ammonia
What is the effect of urease in UTIs with S. saprophyticus infection?
Hydrolyses urea to carbon dioxide and ammonia
Increases urine pH and triggers crystallisation of calcium and magnesium phosphates
Leads to encrustation of catheters
Potentially urinary stones
What is the common microbiology of P. mirabilis?
Motility via swimming or swarming by changing flagellar expression
Attach to host cells via fimbriae and P-like Pili
Haemolysins bursts host cell membranes releasing nutrients
Extracellular protease ZapA digests immunoglobulins and antimicrobial peptide beta-definsin
Inherently resistant to some antibiotics
Urease generates much higher urine pH - forms severe encrusting biofilms
What is the effect of Swarmer cells in P. mirabilis?
Swarmer cells are more able to invade UT epithelial cells
Upregulate production of urease
What is the effect of host cell adhesion in P. mirabilis?
Invades umbrella cells and forms IBCs
What is the common microbiology of C. albicans?
Asymptomatic
Shifts between yeast and hyphal forms
Attaches to tissues via agglutinins and ahdesins
Express invasins which bind cadherins triggering endocytosis
Extracellular proteases and phospholipases - helps nutrients and damage host tissues
Makes biofilms
What are the hyphal forms of C. albicans good for in UTIs?
Tissue invasion
What percentage of non-catheter associated UTIs involve >1 pathogen species?
30-40%
How is a UTI diagnosed?
Dipstick urine test
(looks for leukocytes, RBC, nitrates, pH, protein)
What percentage of infection does a dipstick and urine culture test miss?
Dipstick test miss >50%
Urine culture miss ~60%
What is the common treatment of a UTI?
Antibiotics, antifungals
Management of risk factors
Systematic reviews
What can treatment failure result in for UTIs?
Diagnosis with painful bladder syndrome or interstitial cystitis
Bacteria hidden in bladder lining won’t get picked up in urine sample so tests can be consistently negative
How are the protected niches formed in a UTI?
Host secretion of cytokines result in neutrophils and monocytes being recruited to urothelium
Apoptosis and exfoliation of urothelium leaving gaps where bacteria can invade deeper
Bacteria form quiescent IBCs that persist
What is a standard agar plate broth made of?
Luria Broth
What is present in urine?
Water
Urea
Sodium, potassium, chloride
Creatinine
Trace amounts of proteins
Trace amount of macromolecules
What are the advantages of testing with synthetic urine?
Can be chemically designed to mimic human urine
Can change bladder cell layers and catheter material
What are the advantages and disadvantages of mouse models used to study UTI’s?
Can look at dissemination of infection to other organs
Can be catheterised
(there are key differences between chemistry and organ layout)
What are dynamic in vitro bladder models?
Media flows between chambers representing bladder/ waste
Controlled by pumps
Physiologically realistic physical condition (flow rate, shear forces)
Can add a catheter
What was concluded from the Nottingham study surrounding polymicrobial UTIs?
1-5 bacterial species are present per sample reported by culture-based diagnostics
80% had 2 or more species
What two bacterial species were found to occur more frequently together after being tested in a study to identify pairwise interactions between UTI isolates?
Enterococci and E. Coli
What two bacterial species both express factors that promote coadherence in a UTI?
Candida albicans and Streptococcus agalactiae
Helps both species associate with bladder urothelium
What is an example of UTI cross-feeding?
Enterococcus faecalis releases the non-proteogenic amino acid ornithine during biofilm growth in iron-limited conditions
Ornithine induces production of the siderophore enterobacterin by E. Coli, allowing it to overcome iron restriction
What is an example of UTI competition?
Some clinical isolates of E. faecalis produce a bacteriocin that can lyse Gram-positive bacteria
What is an example of UTI cross-protection?
P. mirabilis mostly harmed other isolates in the absence of antibiotics
Mostly protected other isolates in the absence of antibiotics
In the presence of urea […] produces urease
Proteus mirabilis
What is the effect of increased pH of urine?
Viability of pathogens is reduced
What is the effect of P. mirabilis combined with providencia stuartii?
Helps another pathogen associated CAUTI
Intrinsically resistant to several commonly-used antibiotics
Forms biofilms
Produces urease
What is a reservoir for many UTI pathogens?
The gut
Bacteria in faeces can colonise the UT via perineum
What is the mechanistic pathway of how gut dysbiosis can lead to UTI?
Antibiotic use leads to gut inflammation
Causes increased nitrate availability in the gut
Facilitating overgrowth of E. Coli
Bigger reservoir for UTI
Bigger chance of clones with phenotypes necessary for UT invasion being present
What is bacterial vaginosis caused by?
Inflammation caused by bacterial overgrowth
Can result from antibiotic use or hygiene practices
What is the microbiology of Gardnerella vaginalis?
Normal vaginal flora but often species that overgrows during BV
Invades the bladder, induces apoptosis of umbrella cells, which form the top layer of the bladder epithelium, damaging the epithelium
Triggers reactivation of latent E. coli reservoirs in bladder cells
Caused kidney inflammation making kidneys more susceptible to E. Coli
What do Lactobacillus species do in the vagina?
Help stop E. Coli colonising the vagina
Stopping it from becoming a reservoir for UTI pathogens
What has been suggested as part of a treatment plan for preventing UTI recurrence?
Probiotic preparations of Lactobacillus
