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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

Case 2

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

Interpreting urinalysis Appearance: clear Turbid: infection pH: Normal values 4.5-7.2 Alkaline: infection Specific gravity: Normal values 1.005 to 1.025 Low in pyelonephritis Protein: Normal 0-trace Renal disease

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

Culture Urine plated on agar (specific loop size) Incubated for 24-48 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

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

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

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

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

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

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

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)

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

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

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.

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. 1990 Apr;25(4):551-60.

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

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 : 650-655

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

References EAU guidelines Comprehensive Urology Previous slides from Milan Thomas Pubmed