UTI Pathogenesis and Diagnosis,

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UTIPathogenesis and diagnosis

Tom Walton January 2011 1

Urinary tract infectionCommensal Non-pathogenic colonising organism in healthy hostPathogen Organism with an ability to cause diseaseVirulence Degree of pathogenicityBacteriuria Presence of bacteria in urine

UTI Bacterial invasion of the urothelium resulting ininflammatory response

Opportunistic inf. UTI caused by non-pathogens due to weakened hostdefences

Isolated inf. First infection or separated from last infection by 6months

Unresolved inf. Denoted by failed resolution of UTI on culturedespite ABx. Due to:

Initial bacterial resistanceAcquired bacterial resistanceMultiple organismsselective overgrowth of

resistant strainRenal impairmentreduced urinary concentrationStaghorn calculusPoor compliance

Recurrent inf. UTI after confirmed resolution on cultureDefined as 2 infections in 6 months or 3 in a yearDivided into re-infection and persistenceReinfection - from outside UT (usually ascending)accounts for 95% all recurrent UTIs in femalestypicallydifferent organisms, but not always.Persistence - from within UT more common in males andhighlighted by rapid infection with same organism

Complicated inf. UTI a/w higher likelihood of sepsis, tissue necrosis, organdysfunction and death. Factors a/w complicated UTI:

Functional/structural UT abnormality*Male sexElderlyPregnantHistory of childhood UTIFebrile UTILikely obstruction

History of stone diseaseDM, immunosuppression, renal impairmentRenal tract instrumentationRecent antibiotic therapyDuration of therapy longer than 7 days

* Catheter in situPVR > 100mlNeurogenic bladderObstuctive uropathyVUR

Urinary diversion


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PathogenesisClinical significance of UTI dependent on type of organism, bacterial virulenceand host defence factors

A. Types of organism

Community E. Coli (85%)Other enterobacteria (5-10%)

KlebsiellaProteus*Enterococcus faecalisPseudomonasProvidentia*CitrobacterSerratia

Staph. Saprophyticus (10-30% of young women)* more common in men

Hospital E. Coli (50%)PseudomonasEnterococcusCitrobacter

B. Bacterial virulence factorsFimbrial adhesins

Type 1 piliCommonest typeMannose-sensitive haemagglutinin (addition of mannosecan prevent/reverse haemagglutination)Bind to uroplakins 1a and 1b

Type p piliLess commonType II found in ~80% pyelonephritisType III found in cystitis(Type 1 in animals only)mannose-insensitive haemagglutininbinds to p blood group antigens

Non-fimbrial adhesins

Glycocalyx(e.g. Dr adhesins on E Coli)Toxin productionEndotoxin produced from GNB [lipopolysaccharide secretedfrom outer membrane of bacterial cell wall: lipid componenttoxic; polysaccharide component immunogenic. Heat stable toboiling point]

HaemolysinsEnzyme secretion (protease, urease etc.)Swarming factor (P.mirabilis)Avoidance of phagocytosis

Intracellular growth

Biofilm formation


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C. Host defenceUrinary flowUrinary acidityUrinary osmolality (high or very low)Tamm-Horsfall protein (uromodulin)

From AloH and DCTBinds type 1/type S fimbriated bacteriaActivates phagocytosis

Mucosal defenseIgALysozymeLactoferrinBladder mucin

Commensal bacteriaLactobacillus acidophilusOestrogensglycogenmetabolised by l.a. to lactic acidpH

drop inhibitory to pathogensGeneral integrity of immune system

InnateAcquired (Humoral and cell-mediated)

Genetic susceptibilityHLA-A3 antigen a/w 4x risk of recurrent UTI (?why)Non-secretor phenotype for Lewis blood group antigens

Diagnosis

Urine dipstick testingUrinary nitrite and leukocyte esterase surrogates for bacteria and WBCrespectively. Reference bacteruria > 10

5orgs/ml

Early morning urine has increased sensitivityUrinary Nitrite

Dietary nitrates - urinary nitrates - nitrate reducing bacteria(enterobacteria) -urinary nitrites - react with amine-impregnated dipstixreagent - pink diazonium compoundSensitivity = 35-85%, Specificity = 92-100%False positives:

Contamination

False negatives:Nonenteric bacteriaDilute urine/ frequent voidingVitamin CHigh osmolality/ urinary H+Urobilinogen

Urinary Leukocyte EsteraseLE from neutrophil/ basophil granules reacts with reagent strip -indoxyl moeity produces colour changes by oxidation of diazonium saltSensitivity = 72-97%, Specificity = 64-82%False positives

Specimen contaminationFalse negatives


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Old specimen (leucocyte lysis)High osmolality/specific gravityVitamin CUrobilinogen

When Nitrite and LE combined; Sensitivity = 70-100%, Specificity = 60-98%

Urine microscopy and cultureClean catch MSU specimenFirst voided morning specimenexamine within one hourCentrifuged samples 5 mins at 3000rpmresuspendExamine at low power (100x) and high power (400x) 1 hpf = 1/20,000 mlRoutine examination for:

RBCsRBC casts GlomerulonephritisWBCs > 10wbc/hpf = significant inflammationWBC casts Pyelonephritis

Bacteria 5/hpf = 100,000/ml*

* Significance controversial. Original studies by Kass (1950s). Found that only15% women with 50% with counts over 100,000/ml had Hx UTI and organisms typicallypathogenic. However well known that a subpopulation of women (up to 30%)can have symptomatic UTI with counts 10

3-10

5orgs/ml (Finding of pyuria can

be very helpful)

EAU significance criteria 10

3cfu/ml in women with acute uncomplicated cystitis

104cfu/ml in women with acute uncomplicated pyelonephritis 10

5cfu/ml in women with complicated UTI

105cfu/ml in asymptomatic bacteriuria in pregnancy

104cfu/ml in men with complicated UTI

Asymptomatic bacteruriaSeldom associated with adverse outcomes except in following groups:

ChildrenPregnant females

Before urological proceduresScreening or treatment not of proven benefit in following groups:Pre-menopausal womenDiabetic womenElderly patientsSpinal cord injuryCatheterised patients


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Urosepsis

SIRSremember acronym THReW

Severe sepsis and organ dysfunction:

Severe sepsis and septic shock a/w mortality 20-40% (recently ~18%)Urogenital tract a source in ~5%Increased incidence and mortality in elderly, diabetics and immuno-compromised. TNF-a, IL-1, IL-6 and IL-8 commonly implicated cytokinesC-reactive peptide and particularly procalcitonin believed to be specific forbacterial vs. viral/other infections

ManagementSimultaneous investigation, resuscitation and treatment

See Surviving SepsisCampaignrecommendations belowEstablish IV access2 large bore cannulae antecubital fossae


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Send blood for FBC, U+E, LFTs, CRP, serum lactate and clottingArterial blood gasesBlood cultures

2 peripheral cultures + and line > 48 hours oldUrine culture and catheterisation

Fluid resuscitation20ml/kg crystalloid or equivalent1000ml or 330ml colloid over 30minsSlow fluids and refer for inotropes/CVP monitoring if refractoryhypotension after 20ml/kg fluid challenge (~1500ml in 75kgman)

High-flow oxygen therapyBroad spectrum antibioticsConsider further adjunctive measures

Relief of urinary obstructionDebridement of necrotic tissue

Early ITU opinionCentral venous and arterial pressure and cardiac indexmeasurementInotrope administration (if MAP


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AppendixHuman infective organisms (in descending size order):

ArthropodsHelminths

Nematodes, cestodes & trematodes (including schistosomiasis)

EukaryotesProtazoaFungi

ProkaryotesBacteriaRickettsiaeChlamydiaMycoplasmaSpirochaetes

VirusesRNA (HIV, HAV, HCV)

DNA (Herpes, HPV, HBV)


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Parasites Arthropods, helminths and protozoaEukaryotes > 1 chromosome, double membrane intracellular structuresProkaryotes 1 chromosome, no nuclear membrane, no mitochondria

Gram +ve Gram ve

Cocci

StaphylococciCoagulase +ve S. aureusCoagulaseve S. epidermidis

Streptococci-haemolytic

Gp A S. pyogenesGp B,C,D Neonatal

infections-haemolytic S. viridans,

S. pneumoniae

non-haemolytic S. bovisE. faecalis

Neisseria meningitidisNeisseria gonorrhoea

Rods

BacilliAerobic

Bacillus anthracisCoynebacterium diphtheriaeListeria monocytogenesNocardia

AnaerobicClostridia botulinum

perfringenstetanidifficile

Actinomyces israelii

EnterobacteriaceaeE. ColiProteus mirabilisKlebsiellaSalmonellaShigellaeneterobacterSerratiaYersinia

Haemophilus InfluenzaeBrucellaPseudomonasLegionellaHelicobacter PyloriBacteroides (anaerobic)

Beta haemolysis = clear zone of haemolysis on blood agar due tohaemolysins O and SAlpha haemolysis = partial clearing with green discoloration not due tohaemolysins

Gram stainingGram-positive bacteria have a thick mesh-like cell wall made ofpeptidoglycan(50-90% of cell wall), which stains purple while gram-negative bacteria have athinner layer (10% of cell wall), which stains pink.4 steps:

Crystal violet both types stain purple

Iodine CV trapped in cells
http://en.wikipedia.org/wiki/Peptidoglycanhttp://en.wikipedia.org/wiki/Peptidoglycan


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Ethanol wash Degrades GN cell membrane and leaches CV fromGNB. No effect on GPB

Safranin Counterstain allows identification of translucentGNB

Multi-resistant organismsESBL

Extended spectrum beta lactamaseTend to be carried in bowelimpossible to eradicate with antibioticsand promotes overgrowth and further resistanceResistant to third-generation cephalosporins and monobactamsRetained sensitivity to cefomycins (e.g. cefotetan) carbapenems (e.g.imipenem)Also sensitive to beta-lactamase inhibitors like clavulanic acid but co-

amoxyclav does not work clinicallytoo much beta lactamaseproduced to allow amoxycillin to be efficacious

Plasmid mediatedexplains cross-resistance among organisms andtherefore reason for isolation

MRSAMethicillin-resistant staphylococcus aureusResistant to all penicillins, including those with beta lactamase (due tothe production of penicillin-binding protein PBP-2Vancomycin and teicoplanin always sensitive; fusidic acid, rifampicinusually, trimethoprim and doxycycline occasionally; cipro neverMRSA prostatitis may be troublesome

IV vancomycin/teicoplaninPO doxycycline, trimethoprim, rifampicin or if desperate linezolid

Oral vancomycin does not get absorbedonly for CDTVRE

Low grade infectionsgenerally not septicSpectrum narrowIV or PO linezolid

Surviving sepsis resuscitation and management bundles


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UTI Pathogenesis and Diagnosis,