1. Uncomplicated Urinary Tract Infections
Amar Mohee
Milan Thomas
Steve Bromage
18th April 2013

2. Outline MCQs & EMQ Definitions Epidemiology
Case-based Discussions of relevant conditions

3. MCQ
Which mode of bacterial entry is not a recognised mode of transmission for UTIs?
Per urethra
Per nasal
Haematogenous
Lymphatogenous
Direct contact

4. MCQ
Which mode of bacterial entry is not a recognised mode of transmission for UTIs?
Per urethra T
Per nasal F
Haematogenous T
Lymphatogenous T
Direct contact T

5. MCQ Which one of the following is not a bacterial pathogenic factor?
Increase adherence
Resistance of bactericidal properties of serum
Formation of spores
Production of haemolysin
Increased expression of K-antigen

6. MCQ Which one of the following is not a bacterial pathogenic factor?
Increase adherence T
Resistance of bactericidal properties of serum T
Formation of spores F
Production of haemolysin T
Increased expression of K-antigen F

7. MCQ
Which of the following urine findings are typical of pyelonephritis?
Turbid
High pH
Low specific gravity
High protein
Low RBC

8. MCQ
Which of the following urine findings are typical of pyelonephritis?
Turbid T
High pH T
Low specific gravity T
High protein F
Low RBC F

9. MCQ What is the mechanism of action of Ciprofloxacin?
Interferes with bacterial folate metabolism
Interfere with bacterial DNA gyrase
Inhibits bacterial enzymes and DNA activity
Inhibit bacterial DNA and RNA
Inhibit bacterial cell wall synthesis

10. MCQ What is the mechanism of action of Ciprofloxacin?
Interferes with bacterial folate metabolism F
Interfere with bacterial DNA gyrase T
Inhibits bacterial enzymes and DNA activity F
Inhibit bacterial DNA and RNA F
Inhibit bacterial cell wall synthesis F

11. EMQ A. Enterococcus faecalis B. Escherichia coli C. Candida albicans
Dorothy is a diabetic, catheterised patient nearing the end of her course of IV antibiotics for right lower lobe pneumonia. To top it off she’s now developed a UTI. What’s the most likely agent?
Disrupts bladder mucosal integrity and causes urinary tract obstruction and stasis
Cause of 70-95% of both upper and lower UTIs.
Associated with UTIs with instrumentation of the urinary tract due to ‘swarming capability’ (expression of specific genes when these bacteria are exposed to surfaces such as catheters)
Possesses UafA (a unique adhesion protein allowing adherence to human uroepithelial cells and mediating haemagglutination)
A. Enterococcus faecalis
B. Escherichia coli
C. Candida albicans
D. Chlamydia trachomatis 
E. Klebsiella pneumoniae
F. Mycobacterium tuberculosis
G. Proteus mirabilis
H. Salmonella typhimurium
I. Schistosoma haematobium
J. Staphylococcus saprophyticus

12. EMQ A. Enterococcus faecalis B. Escherichia coli C. Candida albicans
Dorothy is a diabetic, catheterised patient nearing the end of her course of IV antibiotics for right lower lobe pneumonia. To top it off she’s now developed a UTI. What’s the most likely agent? C
Disrupts bladder mucosal integrity and causes urinary tract obstruction and stasis. I
Cause of 70-95% of both upper and lower UTIs. B
Associated with UTIs with instrumentation of the urinary tract due to ‘swarming capability’ (expression of specific genes when these bacteria are exposed to surfaces such as catheters). G
Possesses UafA (a unique adhesion protein allowing adherence to human uroepithelial cells and mediating haemagglutination). J
A. Enterococcus faecalis
B. Escherichia coli
C. Candida albicans
D. Chlamydia trachomatis 
E. Klebsiella pneumoniae
F. Mycobacterium tuberculosis
G. Proteus mirabilis
H. Salmonella typhimurium
I. Schistosoma haematobium
J. Staphylococcus saprophyticus

13. Definitions Bacteriuria
The presence of bacteria in the urine (>104 colony-forming units (cfu) per ml of urine)
Urinary tract infection (UTI): inflammatory response secondary to bacteriuria
At least one of the following symptoms or signs, with no other recognised cause:
Fever>380C in a patient aged ≤65 years of age
Lower urinary tract symptoms (urgency, frequency, dysuria, suprapubic tenderness, loin pain)
A positive urine culture of ≥105 cfu/ml with no more than two species
Uncomplicated UTIs: acute cystitis and acute pyelonephritis
Otherwise healthy individuals
mostly in women without structural and functional abnormalities

14. Definition Pathogenicity Virulence
the ability of an organism to cause disease
Virulence
the degree of pathogenicity

15. Epidemiology Age (y) Female (%) Male(%) Risk factors <1 0.7 2.7
Foreskin, Abnormal anatomy
1-5
4.5
0.5
Abnormal anatomy
6-15
Abnormal function
16-35 20
Sex, diaphragm
36-65 35
Surgery, BOO, Catheter
>65 40
Incontinence, Catheter, BOO
Most UTI single organism. E.Coli: 80%
Community
Klesiella, proteus, enterobacter
Hospital
Staph, pseudomonas
Pregnancy
GpB Strep
Children
Klebsiella, enterobacter
50% of UTIs do not come to medical attention
Lifetime prevalence
14 per 100 men
53 per 100 women

16. Case 1 22y female, pyrexial. Dysuria and frequency
How would you assess the patient?
Focused history
Lower urinary tract symptoms
Systemic and associated symptoms
Triggers (sexual intercourse, cyclical)
Past/childhood history  Normal urological tract
Absence of vaginal discharge
Relevant examination
Abdominal
?PV
Investigations
Urine Dipstick may be sufficient
MSU

17. Pathogenesis – Bacterial Factors
4 modes of bacterial entry
Per Urethra (most common)
Ascending
Explains why female>male
Haematogenous
S. Aureus, Candida spp, TB
Lymphatogenous (?)
Rectal, colonic, uterine
Direct spread
Fistulas, abscesses
Bacterial pathogenic factors
Increased adherence
Resistance to bactericidal activity of human serum
Increased expression of K capsular antigen (protects from phagocytosis)
Production of haemolysin
Invasion of host cells – biofilms (uroplakin coated)

18. Pathogenesis – Host Factors
Unobstructed urine flow
Washout of bacteria
Stasis/retention : BOO, neurological, diabetes, pregnancy
Reflux – allows ascent of bacteria
Urine characteristics
Osmolality, pH, urea conc, organic acid conc
Tamm-Horsfall glycoprotein: inhibit adherence
Urothelium
GAG-layer
Toll-like receptors (TLR) – inflammatory mediators (IL-8Neutrophils)
Serum and urinary antibodies (defense vs damage)
Bacterial binding sites (> in females with recurrent UTIs)
Genetics
Blood group antigens – prevent bacterial adherence
Normal flora
Women periurethral area: lactobacillus
Altered by antibiotics, low estrogen, faecal incontinence
Men prostatic secretions: zincantibacterial
Foreign bodies (catheters, stents, stones)
Allows bacteria to hide from host defense

19. Case 2

20. Diagnosis & Investigations
Urine sample
MSU, SP aspiration, In/out catheter
Urinalysis
Leucocyte esterase: breakdown of WBC
Nitrites: Breakdown of nitrates by GNB
Dipstick: negative for blood, nitrite, leucocyte and protein: <2% positive culture
Test
Sensitivity (%)
Specificity (%)
Leucocyte esterase 83 78
Nitrite 53 98
WBC 73 81

21. Interpreting urinalysis
Appearance: clear
Turbid: infection
pH: Normal values
Alkaline: infection
Specific gravity: Normal values to 1.025
Low in pyelonephritis
Protein: Normal 0-trace
Renal disease

22. Flow Cytometry Flow cytometry Fully automated (eg Sysmex UF-100)
Measures impedance of particles in urine
Uses 2 fluorescent dyes
Carbocyanine: stains the cell membrane
Phenanthridine stains nucleic acids
Clinica Chimica Acta, Volume 301, Issues 1–2, November 2000, Pages 1-18

24. Culture Urine plated on agar (specific loop size)
Incubated for hours, 370C in air
Plates read: positive >103-5 cfu/ml
Identification of bacteria
Biochemical (eg API)
Molecular (bacterial DNA and PCR)
Sensitivity
Conditions of growth (agar, conditions)
Antibiotics strips
Bacterial genes detected by PCR

25. Case 3
22y female, pyrexial, shakes & shivers, right loin pain, vomiting. Dysuria prior to this episode.
E. Coli in urine
How would you manage this patient?
How would you assess the patient?
Focused history
Lower urinary tract symptoms
Systemic and associated symptoms
Triggers (sexual intercourse, cyclical)
Past/childhood history  Normal urological tract
Absence of vaginal discharge
Relevant examination
Abdominal
?PV

26. Acute Pyelonephritis Inflammation of kidney and renal pelvis
Sepsis (20-30% of all sepsis urological)
IV Abx if pyrexial or bacteremic
USS
Rule out obstruction
Poor at diagnosing inflammation
CT Findings
Enlarged kidney
Stranding
Perfusion defects & attenuated areas (constriction of peripheral arterioles) – can be seen on a nuclear scan
Compression of collecting system

28. Escherichia Coli Gram-negative rods
Part of the lower gastrointestinal microbiome
Sero-groups O, K and H
Pilli (tips of bacterial fimbriae) - Binds to glycoproteins/lipids on urothelium
Internalisation of bacteria: bacterial persistence
P pili: can bind to urothelial cells, RBC, renal tubular cells
90% of E.Coli pyelonephritis
Type 1 pili: can bind to urothelium
Increases bacterial adherance
More common in cystitis

29. International Journal of Medical Microbiology Volume 297, Issue 6, 15 October 2007, Pages 401–415

30. Case 4 OP department, 18y female, recurrent UTIs Management
Focused history
Lower urinary tract symptoms
Systemic and associated symptoms
Triggers (sexual intercourse, cyclical)
Past/childhood history  Normal urological tract
Absence of vaginal discharge
Relevant examination
Abdominal
?PV
Investigations
Urine (Dipstick + MSU)
?USS + Flexi

31. Recurrent Bladder Infection
Bacterial persistence
Bacterial re-infection
USS: Screening evaluation of urological tract
CT: Detailed anatomy
Localisation studies
Ureteric catheter and fluid sent for culture
Management: removal of cause (eg stone, PUJO, BPH)
Assessment for fistula
Imaging not necessary
Management: Fistula repair, Abx prophylaxis
ABx Prophylaxis: can reduce UTIs episodes by 95%
Regular voiding (increase oral intake)
Cranberry juice
Estrogenisation of introitus
Self-medicated Abx
After sex
When patient feels onset of symptoms

32. Antibiotics Bacterial susceptibility Patient characteristics
Organism, hospital vs community, single vs polymicrobial
Patient characteristics
Allergies, age, previous Abx, pregnancy, PO vs IV
Antibiotics
Mechanism
Action
Septrin
(co-trimoxazole)
Interferes with bacterial folate metabolism
Most UTIs except enterococcus and pseudomonas
Floroquinolones
Interfere with bacterial DNA gyrase, preventing replication
GNB, Staph but not Strep
Nitrofurantoin
Inhibits bacterial enzymes and DNA activity – long term use may lead to pulmonary interstitial changes
GNB (except pseudomonas and proteus), Staph and enterococci
Aminoglycosides
Inhibit bacterial DNA and RNA
GNB, Enterococci (with ampicillin)
Cephalosporins
Inhibit bacterial cell wall synthesis
GNB, GPB (3rd generation better for former)
Penicillins – only amoxicillin/ampicillin
GNB (with clavulanic acid)

33. Antibiotics Antibiotics resistance INCREASING Geographical variability
E. Coli
up to 50% to ampicillin
Up to 27% to trimethroprim
Up to 49% to septrin
Up to 30% to floroquinolone
Only 25% of ABx use for ‘UTIs’ have documented bacteriuria
50% for LUTS
25% prophylaxis

34. Case 5
35 year old female, 18 weeks pregnant, right loin pain, pyrexial, positive urine dipstick
Urine MC&S
Serratia marcescens
Amoxicillin – R
Cefelexin – R
Trimethoprim – R
Tazocin – R
Gentamicin - S

35. UTI in pregnancy Pregnancy changes
Renal length increases & GFR increases by 30-50% (secondary to CO)
Ureteral dilatation with stasis
smooth muscle relaxing (progesterone)
Physical compression at pelvic brim
Increase in bladder capacity + hyperemia
Bacteriuria 4-6% 30% (vs 2%) develop pyelonephritis
Bacteriuria should be treated in pregnancy and eradication confirmed
Pyelonephritis
1-4% of pregnant women
If untreated  Prematurity of fetus and perinatal abnormality
Penicillin, Cephalosporins safe
Gentamicin: FDA pregnancy category D. Safety of gentamicin has not been established; potential benefit should outweigh the potential risk.

36. Aminoglycoside (Gentamicin)
Inhibit bacterial DNA and RNA
Together with ampicillin, has GP cover
Bactericidal synergy
Gentamicin decreases lytic effect of penicillin
Nephrotoxicity
Excessive accumulation in PCT cells : 40 – 50 times than in blood
Direct effect on GFR
Toxicity reversible initially- renewable PCT cells
Ototoxicity
Vestibular and auditory dysfunction
Accumulate in perilymph & endolymph
Irreversible
J Antimicrob Chemother Apr;25(4):

37. Gentamicin dosing Pharmacokinetics Loading vs maintenance dosing
Small volume of distribution (0.25l/kg)
Half life: 2-3 hours
Mainly renal clearance (glomerular filtration)
Loading vs maintenance dosing
Antimicrobial effect is concentration dependent
Once daily (more common) vs multiple dosing
Therapeutic dose monitoring

38. Hartford Regime 7mg/kg, serum concentration at 12 hours
Efficacy: Minimum inhibitory concentration (MIC) reached
2184 patients
1.2% reversible nephrotoxicity
0.14% ototoxicity
Antimicrobial Agents and Chemotherapy March 1995 ; 39 :

39. Summary Very common but can be very serious
Urologists tend to be involved with complex UTIs
Anatomical considerations
Iatrogenic
Urological pathology?
Antibiotics is effective but should not be abused
Follow local guidelines

40. References EAU guidelines Comprehensive Urology
Previous slides from Milan Thomas
Pubmed