EVERYBODY HURTS SOME TIME: URINARY TRACT INFECTIONS

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1 EVERYBODY HURTS SOME TIME: URINARY TRACT INFECTIONS Je Bartges, DVM, PhD, DACVIM, DACVN Prfessr f Medicine and Nutritin The University f Gergia jbartges@uga.edu INTRODUCTION Urinary tract infectin refers t clnizatin f ne r mre parts f the urinary tract with an infectius agent Urinary tract infectin (UTI) can induce urethritis, prstatitis (in intact male dgs), cystitis, and pyelnephritis and all f the urinary tract is at risk f clnizatin nce UTI is established. Mst UTI is caused by bacteria emanating frm the gastrintestinal tract crssing the perineum and clnizing the external genitalia prir t retrgrade invasin f the urethra and bladder against the flw f urine. A lesser number f lwer UTI s g n t further ascend with clnizatin f the ureters and kidneys. Hematgenus renal infectin, e.g., frm bacterial endcarditis, can induce septic infarcts and pyelnephritis althugh this is relatively uncmmn. In additin t bacteria, UTI may ccur due t infectins with fungal, viral, r parasites ETIOPATHOGENESIS Urinary tract is in cntact with external envirnment and bacteria nrmally reside in the distal urgenital tract Develpment f UTI depends upn the balance between infectius agents and hst resistance. Althugh UTI can ccur when a very virulent rganism invades a nrmal urinary tract, many times UTI develps when there is a disturbance f anatmical r functinal hst resistance factrs that nrmally prevent micrbial invasin. Urinary tract has many defense mechanisms t prevent bacterial urinary tract infectin Anatmically Length f urethra Presence f high pressure znes in urethra Urethral and ureteral peristalsis Vesicureteral flaps Extensive renal bld supply and flw Mucsal defense barriers Glycsaminglycan layer Antibdy prductin Intrinsic mucsal antimicrbial prperties Exfliatin f cells Cmmensal nn-pathgenic micrbes in distal urgenital tract Cmpsitin f urine Cncentratin/smlality High urea nitrgen cncentratin Organic salts Lw mlecular weight carbhydrates Tamm-Hrsfall mucprtein Cell-mediated and humral-mediated immunity Frequent and cmplete viding A UTI als requires a pathgenic bacterial rganism Nt all bacteria are pathgenic Fr UTI, bacteria must pssess 1 r mre urvirulence factrs fr mtility, adherence, invasin, prductin f enzymes, and prductin f txins Urpathgenic bacteria invade primarily frm ascensin frm the lwer urgenital tract

2 PHYSICAL EXAMINATION FINDINGS AND CLINICAL SIGNS May be symptmatic r asymptmatic Bacterial infectin f the lwer urinary tract is ften assciated with signs similar t ther lwer urinary tract diseases including hematuria, pllakiuria, dysuria, stranguria, and inapprpriate urinatin Bacterial f the upper urinary tract may be assciated with hematuria If septicemia develps, systemic illness may ccur May be assciated with recurrent lwer urinary tract infectin and clinical signs Bacterial urinary tract infectins ccur in 2-3% f dgs and in female dgs mre ften than male dgs It is mre cmmn in lder dgs Bacterial urinary tract infectins ccur in <1% f cats It is uncmmn in cats <10 years f age It ccurs in >40% f cats >10 years f age DIAGNOSIS Urinalysis and urine culture IT S GOLD FOR A REASON! Urine shuld be cllected by cystcentesis Urine in the bladder is nrmally sterile r cntains very lw numbers f bacteria The mre distal in the urgenital tract, the larger the numbers f bacteria Even if a single rganism is cultured frm a vided sample, it des nt mean that a UTI is present r that is the ffending rganism Always examine urine sediment Pyuria (>5 WBC/hpf) is ften present, unless animals are immunsuppressed Identificatin f bacteria is helpful, but nt accurate Staining urine sediment imprves predictive value Unstained Stained Sensitivity 82 % 93 % Specificity 76 % 99 % Psitive Predictive Value 40 % 95 % Negative Predictive Value 96 % 99 % Urine specific gravity shuld be nrmal; hwever, dilute urine may be a risk factr fr develpment f bacterial urinary tract infectin r may indicate infectin f the upper urinary tract Urine sediment examinatin may reveal struvite crystalluria assciated with UTI Struvite crystalluria, hwever, can be nrmal We will discuss further with urlithiasis Cylindruria may be present with upper urinary tract UTI Cellular casts are always abnrmal Urine culture is mst definitive means f diagnsing a bacterial urinary tract infectin Urine shuld be cllected by cystcentesis and transprted in a sealed cntainer and prcessed as sn as pssible If prcessing is delayed, refrigerate the sample Pint-f-care bacterilgical testing. Several in-huse f pint-f-care bacterilgical testing is available. In-huse culture plates. Bld agar and MacCnkey s agar plates may be inculated and incubated fr hurs. A calibrated bacterilgic lp r a micrliter mechanical pipette that delivers exactly 0.01 r ml f urine t the culture plates shuld be used t estimate cfu/ml, and urine shuld be streaked ver the plates by cnventinal methds. Bld agar supprts the grwth f mst aerbic bacterial urpathgens, and MacCnkey s agar prvides mrphlgic infrmatin that aids in the identificatin f

3 bacteria and prevents swarming f Prteus spp. Plates are incubated r placed under an incandescent light. If bacterial grwth is nted within 48 hurs, the plates may be submitted fr identificatin and determinatin f antimicrbial sensitivities Flexicult. An agar plate with ne cmpartment fr quantitative analysis using a chrmgenic substrate allwing fr bacterial identificatin and 5 antibitic impregnated cmpartments: ampicillin, amxicillin plus clavulanate, cephalthin, enrflxacin, and trimethprim-sulfamethxazle. Accurately excludes urinary tract infectin but less reliable fr diagnsing infectin, especially with Gram-psitive ccci. Mst f the antimicrbial susceptibilities had nly fair cncrdance with standard micrbilgical culture technique EZ-PZ. A rapid catalase based urine-screening test. Screens fr bacteriuria, hematuria, pyuria and the presence f ther smatic cells. A psitive result indicates that urine requires further diagnstic evaluatin Indicatr RX. This is a 24 hur test that detects the presence f bacteria in canine r feline urine samples. Identifies bacteria as ne f the primary gram-negative urpathgens (i.e., Escherichia cli, Klebsiella, Enterbacter spp., and Prteus spp.) that are respnsible fr feline and canine urinary tract infectins (UTI). Predicts the antibitic resistance pattern fr the UTI-related gram-negative bacteria fund in canine and feline urine samples. Device is cmpsed f 5 test wells, labeled BAC (bacteria), GM(-) (Gram negative), FQ (flurquinlne), AMO (amxicillin), CEP (cephalsprins first generatin) and 2 cntrl wells labeled POS (psitive) and NEG (negative Uricult Vet. A UTI screening by prviding a semi-quantitative clny cunt alng with a presumptive identificatin f many cmmn urpathgens. Prduct cnsists f a tw sided paddle cntaining selective and nn-selective media that fits securely int a screw cap plastic vial t maintain sterility. One side cntains C.L.E.D. agar that changes clr in the presence f varius rganisms including E. cli, Prteus, Pseudmnas, Enterbacter, and thers. The ppsite side cntains EMB (Esin Methylene Blue) agar, a selective medium that will supprt the grwth f mst Gram negative rganisms while prviding additinal infrmatin regarding the suspected pathgen Antimicrbial susceptibility testing Kirby-Bauer agar diffusin test After an rganism is islated and identified, it is transferred t an agar plate Antimicrbial discs are placed n the plate Zne f inhibitin arund the antimicrbial discs are measured t determine susceptibility f the bacterium This is an inexpensive and readily available technique Hwever, cncentratin f antimicrbial n mst discs are nt similar t cncentratin f antimicrbial achieved in urine Minimum inhibitry cncentratin Mre sensitive and specific than Kirby-Bauer methd Mre expensive and mre time cnsuming technique and nt widely available Lwest cncentratin required t inhibit bacterial grwth Perfrmed using a series f dilutins f each antimicrbial in a multi-well plate t which a standard number f bacteria are added When using MIC, chse an antimicrbial agent that achieves a urine cncentratin at least 4 times the MIC There are published tables f urinary cncentratin f antimicrbials in dgs and cats; hwever, data are unavailable fr many antimicrbials that we use Kirby-Bauer technique is acceptable fr mst bacterial urinary tract infectins

4 Dsage and mean urinary cncentratin f the drugs cmmnly used t treat UTI Mean Urine Agent Dse Rute Cncentratin (±S.D.) MIC µg/ml µg/ml Ampicillin 25 mg/kg tid P.O. 309 (±55) 77 Amxicillin 11 mg/kg tid P.O. 202 (±93) 50 Enrflxacin 2.5 mg/kg bid P.O Tetracycline 15 mg/kg tid P.O. 138 (±65) 35 Chlramphenicl 33 mg/kg tid P.O. 124 (±40) 31 Cephalexin 18 mg/kg tid P.O. 500 (?) 125 Sulfisxazle 22 mg/kg tid P.O (±832) 366 Nitrfurantin 5 mg/kg tid P.O. 100 (?) 25 Trimethprim-Sulfa 12 mg/kg bid P.O. 246 (±150) mg/kg bid 55 (±19) 14 Kanamycin 6 mg/kg bid S.Q. 530 (±151) 132 Gentamicin 1.5 mg/kg tid S.Q. 107 (±33) 27 Amikacin 5 mg/kg tid S.Q. 342 (±143) 85 Tbramycin 1 mg/kg tid S.Q. 145 (±86) 36 Cmmn bacterial islates Escherichia cli is mst cmmn in dgs and cats accunting fr 1 / 3 t ½ f infectins Gram psitive rganisms are secnd mst cmmn cause Staphylccci and streptccci accunt fr ¼ t 1/ 3 f infectins Bacteria accunting fr remaining ¼ t 1 / 3 f infectins Prteus spp., Klebsiella spp., Pasteurella spp., Enterbacter spp., Pseudmnas spp., Crynebacterium spp., and Mycplasma spp. Labratry evaluatin Shuld be nrmal unless assciated with septicemia, aztemia due t renal failure r dehydratin, r predispsing metablic disease (e.g. hyperadrencrticism, diabetes mellitus, hyperthyridism, etc) Radigraphy, ultrasngraphy, endscpy Usually nrmal unless bacterial infectin is assciated with a predispsing cause Struvite stnes may frm secndary t a urease-prducing bacterial urinary tract infectin Renal pelvic and prximal ureteral dilatin may be present with pyelnephritis TREATMENT Treatment f bacterial urinary tract infectin is dependent n whether the breech in hst defenses is temprary r persistent Antimicrbial agents Supprtive care, if necessary Crrect r cntrl identifiable predispsing cause(s) Bacterial urinary tract infectins can be classified as simple/uncmplicated, r cmplicated

5 UTI Antibitic Therapy Intact male r female dg? Predispsing systemic and/r lcal factr(s)? Recent previus UTI s? YES Cat? NO Treat fr 4-6 weeks based n C & S Red C & S days after start - Befre stp days after start Empiric antimicrbial therapy Treat fr days based n: C & S Best guess Simple/uncmplicated bacterial urinary tract infectin Bacterial urinary tract infectin with n underlying structural, neurlgic, r functinal abnrmality Occurs in mst dgs Usually successfully treated with a day curse f the prper antimicrbial administered at apprpriate dse and frequency Recent study demnstrated effectiveness f a 3-day curse f nce-a-day, high dse, enrflxacin Clinical signs shuld reslve and urinalysis results shuld imprve within 2 days Cmplicated bacterial urinary tract infectin Bacterial urinary tract infectin assciated with a structural, neurlgic, r functinal abnrmality Reprductively intact dgs, all cats, and animals with predispsing causes fr bacterial urinary tract infectins (e.g. renal failure, hyperadrencrticism, diabetes mellitus, etc) In additin, animals that have bacterial urinary tract infectins that are relapses, reinfectins, r superinfectins

6 Pyelnephritis and prstatitis are examples f cmplicated bacterial urinary tract infectins Cmplicated infectins shuld be treated fr 3-6 weeks Urine shuld be evaluated in the first week f treatment Twards the end f therapy 5-7 days after discntinuing antimicrbial treatment Relapse Recurrence f a bacterial urinary tract infectin with the same rganism Usually ccur within days t weeks f discntinuing antimicrbial treatment Pssible causes include Chice f inapprpriate antimicrbial agent Antimicrbial agent given at inapprpriate dsage, frequency, r duratin Cmplicating factrs A urine culture shuld be evaluated prir t instituting antimicrbial treatment and further diagnstic testing is indicated Reinfectin Recurrence f a bacterial urinary tract infectin with a different rganism than what was initially present Usually ccur weeks t mnths after cessatin f antimicrbial treatment Althugh predispsing factrs may be present, many animals that becme reinfected d nt have identifiable risk factrs If reinfectins are infrequent (<3 per year), then each episde may be treated as an uncmplicated bacterial urinary tract infectin unless a predispsing cause is identified If reinfectins ccur with greater frequency (>3 per year), then the animal shuld be cnsidered as having a cmplicated bacterial urinary tract infectin and treated accrdingly Diagnstic testing fr predispsing cause(s) shuld be dne if nt perfrmed previusly Prphylactic antimicrbial treatment may be warranted in these animals Cmplicating factrs fr recurrent UTIs Breaks in hst defenses Lcal defenses Recessed vulva Deep-seated infectin: In ur experience, 1-2% f bladder wall cultures are psitive in dgs with negative urine culture wh d nt have urliths Anatmic defects (e.g. ectpic ureter) Indwelling urinary catheter Cncmitant antimicrbial administratin decreases incidence f UTI Hwever, when UTI develps, it is highly resistant We d nt administer antimicrbial agents with an indwelling urinary catheter unless there is anther reasn Systemic hst defenses Assciated cmplicating disease (e.g. diabetes mellitus, hyperadrencrticism, hyperthyridism, renal failure) Bacterial factrs Multi-drug resistance Unusual rganism (e.g. Crynebacterium, methicillin-resistant Staphylcccus) Failure f an antimicrbial agent t sterilize the urine shuld alert the clinician t ne r mre f the fllwing pssibilities: Inapprpriate drug, dse r duratin f therapy. Owner cmpliance is imprtant in this respect.

7 Failure f the antimicrbial agent t reach sufficient cncentratins in urine despite apprpriate drug administratin. Intestinal malabsrptin, impaired renal cncentrating capacity, and develpment f antimicrbial resistance shuld be cnsidered. The presence f a nidus f infectin that is capable f reclnizing the urinary tract nce antimicrbial therapy is withdrawn. Pyelnephritis, prstatitis, neplasia, persistent urachal remnant and urlithiasis shuld be cnsidered. The presence f anatmical r functinal abnrmalities f the urinary tract that lwer resistance t bacterial clnizatin. Many defects may be undetectable by available clinical diagnstic methds. PREVENTION Minimize bacterial cntaminatin f the urinary tract and avid r minimize cnditins that impair hst defenses Catheterizatin and endscpy f the urinary tract always carries a risk f inducing a bacterial urinary tract infectin Magnitude f risk increases with degree f pre-existing urinary tract disease, amunt f any additinal injury caused by the prcedure, and duratin f the prcedure Risks can be decreased by being careful t perfrm invasive prcedures nly when necessary, by perfrming the prcedure as atraumatically as pssible, and by remving the catheter r endscpe as sn as pssible Catheter-induced bacterial urinary tract infectin Bacteria migrate alng utside f catheter Risk f bacterial urinary tract infectin increases with pre-existing urinary tract disease Risk is greater in animals with indwelling urinary catheters than in thse that are intermittently catheterized Despite the lw risk, ne study dcumented bacterial urinary tract infectins in 7 r 35 dgs that were catheterized ne time Bacterial urinary tract infectin ccurs in>50% f animals after 4 days with an indwelling urinary catheter Antibitic treatment while an indwelling catheter is in place decreases the frequency f bacterial urinary tract infectin; hwever, when infectin ccurs, the rganisms exhibit a greater degree f antimicrbial resistance. Therefre, d nt give antimicrbials t animals with indwelling urinary catheters unless indicated fr sme ther reasn Catheter-induced bacterial urinary tract infectin may be minimized by Using intermittent catheterizatin when pssible Remving indwelling urinary catheters as sn as pssible Using a clsed cllectin system Aviding antimicrbial agent administratin while catheters are inserted Cats with perineal urethrstmies are at high risk fr develping bacterial urinary tract infectins RESISTANT URINARY TRACT INFECTIONS Resistant E cli UTI Several ptins may exist depending n results f culture and sensitivity: Flurquinlnes: May be effective when used at high Aminglycsides: Are ften an effective antimicrbial agent. Amikacin appears t be less assciated with nephrtxicity than gentamycin, but shuld nt be given t animals with aztemia. It can be administered by wners at hme Ptentiated beta-lactams: may be tried if intermediate susceptibility is present. I usually use amxicillinclavulanic acid at a higher dsage. Ampicillin-sulbactam may als be used Penems: Merpenem may be useful fr highly resistant 3 rd generatin cephalsprins: May be useful. Cefpdxime (Simplicef) des nt have as much activity as parenteral frms and may nt be effective even with a favrable sensitivity pattern Cefvecin: A newer parternal lng-acting cephalsprin has been shwn t be effective against E cli in dgs and cats; hwever, effectiveness with resistant rganisms is unknwn

8 Staphylcccus UTI (methicillin resistant) These appear t be mre difficult t treat. With resistance t methicillin, beta lactam antibitics even ptentiated nes will nt be effective. Staphylccci are inherently resistant t flurquinlnes (as are mst Gram psitive ccci) even with a favrable sensitivity pattern. Chlramphenicl: mnitr liver enzymes as can be hepattxic, GI side effects ccur cmmnly Linezlid: An xazlidinne antibitic with activity against Gram + rganisms. It is ften effective against methicillin-resistant Staphylccci, but is Vancmycin: Standard fr treating methicillin-resistant Staphylccci, it is discuraged frm being use because f ptential fr inducing resistance that may spread t human medicine Entercccus - Oftentimes Entercccus UTI is nt assciated with clinical signs and there is suggestin that nt treating may be better than treating. In sme animals withut clinical signs r urinalysis changes (pyuria, hematuria), n treatment with re-culture in 2 weeks may reveal eradicatin f the rganism. Treatment shuld be cnsidered fr animals with active clinical infectin r that are immuncmprmised. Penicillins: may be sensitive t amxicillin/ampicillin especially ptentiated nes at higher dsages Inherently resistant t cephalsprins, flurquinlnes, trimethprim-sulfa, erythrmycin even if favrable sensitivity results Can cmbine amikacin with a penicillin Penems may be effective fr E faecalis, but nt E faecium infectins Linezlid and vancmyin may be effective ASYMPTOMATIC BACTERURIA (ABUTI) There is evidence that if a UTI is nt assciated with clinical signs, that it may be better t nt treat. In studies, mre than 80% f asymptmatic bacteruria will reslve withut treatment. The incidence f ABUTI is 10-15% in lder cats and up t 25% in mrbidly bese dgs. PROPHYLACTIC ANTIMICROBIAL TREATMENT May be indicated in animals with relapses r frequent reinfectins Antimicrbial agent shuld be chsen based n urine culture and susceptibility pattern The agent is administered at ½ t 1 / 3 f daily therapeutic dse and is usually given at night Urine shuld be re-cultured every 4-6 weeks If a break thrugh infectin des nt ccur during a 6 mnth perid, then antimicrbial treatment can usually be discntinued Disadvantages f this apprach include develpment f resistant bacteria and side effects f the antimicrbial agent Methenamine is an effective preventative in select cases It is a cyclic hydrcarbn that is hydrlyzed t frmaldehyde at ph < 6.5 It is ften given with acidifiers It is effective against many rganisms, but may cause systemic acidsis because it has acidifying prperties It shuld nt be used with renal failure Nitrfurantin Has activity against many rganisms Is nt used much in veterinary medicine; therefre, susceptibility is high Cmplicatins include GI upset, hepatpathy, peripheral neurpathy Estrgens May be helpful in female dgs with recurrent vagincystitis May increase epithelial turnver keeping bacterial cunts dwn N data Dse as with incntinence Cmplicatins are uncmmn

9 Urinary acidifiers d NOT wrk fr preventin f bacterial UTI in dgs and cats Bacteria can live in ph values f 4.0 t 9.0 Dgs and cats cannt achieve urine ph values f < 5.5 r > 9.0 Therefre, it is nt physically pssible t acidify urine enugh t prevent UTI s Ectherapeutics Ectherapeutics include prbitics (live bacteria) and prbitics (fiber surces that select fr certain strains f bacteria) The idea is t ppulate the GI tract with nn-pathgenic healthy bacteria such as Bifidbacteria spp r nnpathgenic enteric bacteria Since bacterial UTI riginate frm distal urgenital tract bacteria and since these bacteria are primarily enteric bacteria, the premise is that changing the intestinal flra will result in changing f the distal urgenital tract bacteria These bacteria are nt as hearty as the pre-existing nrmal bacteria; therefre, it is necessary t cntinue prbitics nce yu start There is minimal evidence that this aids in preventing UTI s; hwever, it des seem t help sme dgs There are several veterinary prbitics (Frti-Flra, Prstra Maxx, PrViable); hwever, there are many mre human prbitics. There is really n such thing as a dg r cat specific prbitic Usually want large numbers and multiple rganisms Visbime cntains mst rganisms and multiple rganisms (450 billin per packet) Cranberries and cranberry extract The active ingredient in cranberries are pranthcyanidins Pranthcyanidins are fund in cranberries, blueberries, and chclate; hwever, nly the pranthcyanidins fund in cranberries are useful with bacterial UTI Pranthcyanidins bind t adhesins, primarily PapG pilli, that are virulent factrs invlved with binding f the bacteria t urepithelial cells PapG pilli are fund n 25-50% f canine E cli, but nt with ther bacteria Therefre, pranthcyanidins might be helpful in preventing certain strains f E cli frm binding t urepithelia, but nt all E cli and nt all bacteria There is evidence in human medicine (nearly 2 dzen psitive randmized, cntrlled clinical trials), but ne study in dgs failed t shw benefit; nnetheless, sme dgs may benefit frm pranthcyanidins fund in cranberry extract D-mannse is a sugar that may prevent bacterial adherence. It is als incrprated int the GAG layer and may prevent bacterial invasin int urepithelial cells. It has been shwn t be beneficial in rdent mdels and human beings. Clarithrmycin is a macrlide antimicrbial agent that has been shwn t degrade bifilm thereby expsing the bacterial cmmunity t the envirnment that may include an antimicrbial agent. UTI: FUNGAL, VIRAL, PARASITIC FUNGAL UTI Fungal urinary tract infectins are a rare cause f lwer urinary tract disease in dgs and cats. Funguria may be due t primary (cnfined t the urinary tract and presumptively due t ascending infectin) r secndary (systemic infectins resulting in shedding f rganisms int the urine) infectins. Organisms f the genus Candida are mst cmmnly identified. Regardless f the infecting species, fungal urinary tract infectins ften are challenging t treat because f the strng apparent assciatin with cncurrent immunsuppressive diseases r breaches in lcal immunity that ftentimes cannt be cmpletely reslved.

10 Candida spp. UTI Candida spp. are nrmal inhabitants f the genital mucsa, upper respiratry tract, and gastrintestinal tract in peple, dgs, and cats Candida spp. are yeast, as they reprduce by budding and are capable f fermenting carbhydrates; hwever this is a mrphlgic rather than a true taxnmic classificatin. Yeasts mst cmmnly have a budding, vate appearance, but they will als ccasinally appear filamentus, particularly in bifilms which frm n mucsal and catheter surfaces r when tissue invasin has ccurred As with bacterial urinary tract infectin, candiduria presumptively ccurs in dgs and cats fllwing ascending infectin t the lwer urinary tract. The majrity f infectins in dgs, cats and peple are due t C. albicans, but several ther species have been reprted Althugh bacterial urinary tract infectins may ccur in the absence f predispsing factrs, in human and veterinary patients candidal infectins appear t be highly assciated with breaches in lcal lwer urinary tract defenses r systemic immuncmprmise. Apprximately 17% f reprted cases f candidal urinary tract infectins have been in dgs r cats previusly r simultaneusly diagnsed with diabetes mellitus. In additin, many reprted cases in dgs r cats have had cncurrent lwer urinary tract disease, with permanent stma frmatin (urethrstmy r cysttmy tube placement) reprted in apprximately 40% f cases when the tw largest veterinary retrspective studies are cmbined As expected, a variety f antibitics, sterids, and chemtherapeutic agents have been cmmnly administered t affected animals within ne mnth f diagnsis f Candida spp. infectins. There are n histrical r physical examinatin findings which allw differentiatin f candiduria frm ther causes f lwer urinary tract disease. The mst cmmn reasn Candida spp. urinary tract infectins are first suspected is due t visualizatin f fungal elements n urine sediment examinatin. Althugh cutaneus Candida spp. are usually budding, rganisms shed in urine may be budding r filamentus in appearance, reflecting shedding frm the bifilm that ften adheres t the bladder mucsa Finding fungal elements n rutine urinalysis usually suggests that grwth f Candida spp. is heavy. Identificatin f fungal elements shuld always be fllwed by urine culture t determine the infecting species. Treatment (see algrithm at end f sectin) Treatment f candiduria in peple is recmmended in all symptmatic patients, patients with systemic immunsuppressive diseases (and wh are thus at risk f develping systemic candidiasis), and patients with nn-crrectable risk factrs. Patients with asymptmatic infectins and n identifiable risk factrs are initially recultured prir t treatment in rder t cnfirm that candiduria is nt transient; likewise, treatment is delayed in

11 asymptmatic patients with crrectable risk factrs (such as indwelling urinary catheters) until these factrs are remved and infectin is fund t persist. Unfrtunately, because the mst cmmn risk factrs in dgs and cats are nt easily crrected (e.g. diabetes mellitus, permanent urinary tract stmata, and urinary tract neplasia), withhlding treatment in small animal veterinary patients is nt recmmended at this time. Ineffective treatment may lead t candidal pyelnephritis and/r fungemia. Treatment f primary candiduria requires adequate excretin f active drug r metablites int the urine. Of the antifungal agents widely used in veterinary medicine, nly flucnazle and amphtericin B are excreted in significant amunts in active frm by this rute; in peple. Flucnazle is currently recmmended as first line therapy in peple, dgs, and cats because it can be administered rally and has a high therapeutic margin The majrity f C. albicans islates are sensitive t flucnazle, and thus rutine antifungal sensitivity testing f this species des nt appear necessary at the time f first diagnsis. Hwever ther Candida spp., particularly C. glabrata and C. krusei, are mre likely t be resistant t flucnazle, and sensitivity testing at first diagnsis is recmmended t guide dse f flucnazle (as the MIC and break pint may suggest that higher dses culd be effective), r t determine if an alternative drug shuld be used Infectins shuld always be cnsidered cmplicated because f the assciatin between candiduria and lcal r systemic immune system cmprmise. Treatment shuld be cntinued fr a minimum f 4 t 6 weeks, with urine sediment examinatins and/r cultures perfrmed at 2-3 week intervals t cnfirm treatment efficacy. Frequency f reslutin f infectin in dgs and cats with flucnazle is unknwn, but is felt t be apprximately 50%, likely because predispsing factrs in veterinary patients are mre difficult t cntrl r reslve. Fr thse patients wh have persistent candidal urinary tract infectins despite apprpriate flucnazle therapy r wh have recurrent infectins, sensitivity testing f islates shuld be perfrmed. Several alternative treatment ptins have been reprted by thers and/r attempted by this authr with varying degrees f success; nne have been directly cmpared t flucnazle r each ther t determine relative efficacy. Intravenus amphtericin B is primarily used fr treatment f systemic candidiasis Of ther available antifungal drugs, ral itracnazle r ketcnazle d nt result in high cncentratins f active drug within urine. Newer parenteral triazle drugs (e.g. psacnazle, vricnazle) are nt excreted int urine in active frm and have nt been used t treat candiduria; the same is true f terbinafine, which may be synergistic with sme azle drugs but is nt excreted int urine in active frm Persistent r invasive candidal urinary tract infectins in peple have been treated with echincandins (i.e. caspfungin, micafungin) despite pr urinary excretin f active drug It has been suggested that urine alkalinizatin may be a useful adjunctive therapy fr candiduria in dgs and cats, as Candida spp. grwth is inhibited at higher ph in vitr. Adequate alkalinizatin f urine withut cncurrent dietary therapy ften requires high dses f sdium bicarbnate, and urine alkalinizatin is n lnger favred in peple with candiduria; as a result I d nt manipulate urine ph as part f my standard treatment prtcl. Intravesicular infusin f antifungal drugs has als been described Advantages f this mdality include direct instillatin f large vlumes f high cncentratin drugs, the ability t use drugs whse safety (i.e. amphtericin B) wuld be limited by pre-existing renal disease, and n need fr wner administratin f ral medicatins.

12 Disadvantages include the need fr repeat evaluatins by veterinarians t perfrm drug instillatin, difficulties assciated with urinary catheterizatin (particularly in cats and female dgs), and risk f iatrgenic infectin r bladder rupture. Intravesicular infusin f 1% cltrimazle either transurethrally r via needle and syringe using ultrasund-guidance Mdified 1% cltrimazle prtcl With a minimum f three infusins, success rate fr reslutin f infectin in patients wh have failed flucnazle is apprximately 50%. Unfrtunately, because 1% cltrimazle is supplied in plyethylene glycl, it is highly viscus and very difficult t infuse thrugh small diameter urinary catheters. Intravesicular 1% cltrimazle prtcl fr treatment f flucnazle-resistant fungal urinary tract infectins in dgs and cats 1. Catheterize and empty the bladder. Balln catheters are preferred in dgs as they prevent premature viding f drug in nn-anesthetized patients; mst cats will retain the infused drug if nt allwed access t a litter bx. 2. Infuse ml/kg f 1% cltrimazle slutin; vlume shuld be determined by bladder palpatin during infusin. 3. Infused fluid shuld be retained fr a minimum f minutes. 4. Repeat infusin q7 days fr 3 treatments. 5. Repeat fungal urine culture 7 days after third treatment t determine whether additinal infusins r alternative therapy shuld be cnsidered. 6. Oral flucnazle therapy shuld be cntinued thrughut the infusin prtcl. Despite these varius treatment ptins, apprximately 25% f dgs and cats with candiduria will have persistent, asymptmatic infectins despite at least tw different treatment mdalities. In these patients mnitr infectins, and nly reattempt treatment when clinical signs recur, Nn-candidal primary UTI Althugh much rarer than Candida spp., ther fungal rganisms may als cause primary urinary tract infectins in dgs r cats Of the cmmn systemic mycses, Aspergillus spp. and Cryptcccus nefrmans rarely may cause primary infectin f the lwer and upper urinary tract in bth dgs and cats. Despite these reprts, if either agent is islated frm urine, clinicians shuld initially assume infectin is systemic and determine ther rgan invlvement befre pting fr ral flucnazle r lcalized intravesicular therapy. If rganisms are resistant t flucnazle then ral therapy with an alternate agent in cnjunctin with intravesicular infusin f cltrimazle r amphtericin B shuld likely be cnsidered. Secndary funguria Althugh rarer than primary urinary tract infectins, Candida spp. and ther typically nn-pathgenic fungi may ccasinally cause systemic infectins in bth dgs and cats. In mst cases the primary surce f entry is unknwn. The kidneys are a cmmn site f invlvement in dgs with systemic aspergillsis, and thus fungal hyphae are cmmnly identified in urine by rutine sediment examinatin r culture Systemic infectins are usually treated with itracnazle and/r amphtericin B. Dgs with systemic blastmycsis will n rare ccasins als have rganisms visible n rutine urinalysis r cncentrated urine sediment examinatin The blastmycsis serum r urine antigen test detects a surface antigen cmmn t several fungal rganisms rather than intact rganisms.

13 Althugh lcalized nasal infectin in cats is the mst cmmnly encuntered frm f Cryptcccus nefrmans infectin, systemic infectins are uncmmnly encuntered in cats and rarely in dgs. Prpsed treatment algrithm fr fungal urinary tract infectins 1. Identify and aggressively crrect any cncurrent breaks in lcal immunity r causes f systemic immunsuppressin. 2. Identify genus and species f infecting rganism via urine fungal culture a. If C. albicans: i. Flucnazle, 5-10 mg/kg PO q12 hrs fr 4-6 weeks ii. Repeat urine sediment examinatin and urine culture at 2-3 week intervals t cnfirm reslutin f infectin iii. Repeat urine sediment examinatin and urine culture ne and tw mnths after stpping therapy b. If nn-c. albicans: i. Perfrm sensitivity testing f islate against antifungal drugs t guide initial therapy ii. Cnsider penetratin f drugs int urine when selecting therapy 3. If initial treatment with flucnazle fails t reslve infectin, repeat antifungal drug sensitivity testing and cnsider: a. Intravesicular infusin f 1% cltrimazle (dgs; cats with permanent urinary tract stmata) b. Intravesicular infusin f amphtericin B (cats r dgs) c. Intravenus r subcutaneus amphtericin B (cats r dgs which have failed intravesicular therapy) d. Flucnazle at maximally recmmended dse with additin f terbinafine (cats r dgs whse wners decline ther treatment ptins) e. Benign neglect and regular mnitring fr disease prgressin VIRAL UTI As with all infectius diseases, clinical manifestatins f viral UTIs are the cumulative result f the ability f a micrrganism t establish infectin and cmprmise hst functin and, cnversely, the hst's ability t resist r curtail infectin Viral UTIs may be asymptmatic r may be assciated with substantial mrbidity and mrtality. In general, viral pathgens may cause disease by (1) inducing cell injury r death; (2) altering cellular functins; (3) suppressing immune respnses; r (4) stimulating systemic r rganspecific pathlgic immune respnses. It is ntewrthy that virus-assciated autimmune diseases may ccur in the absence f detectable viruses as a result f persistent nn-replicating viral cmpnents, virus-induced alteratins in antigenic prfiles f infected cells, r inductin f antiviral antibdies capable f crss-reacting with self-prteins Upper urinary tract disrders Renal injury may be the direct result f virus-induced cytpathic effects n renal vascular, glmerular, tubular, and/r interstitial tissues, the secndary cnsequence f systemic infectin and immunemediated injury, r the result f bth prcesses. Clinical manifestatins f viral upper UTIs will be similar t ther infectius and nninfectius causes f renal injury and may include varying cmbinatins and degrees f prteinuria, hematuria, issthenuria, and aztemia.

14 Several viruses have been assciated with canine and feline kidney disrders including: Canine adenvirus Canine adenvirus type 1 (CAV-1) is the cause f infectius canine hepatitis and is serlgically and genetically distinct frm canine adenvirus type 2 (CAV-2) CAV-1 is assciated with systemic viremia, hepatitis, glmerulnephrpathy, interstitial nephritis, and viruria; whereas CAV-2 is largely cnfined t the respiratry tract Canine herpesvirus Canine herpesvirus (CHV) is a member f the alpha herpesvirus subfamily that causes severe, usually fatal, generalized systemic infectins in sernegative nenatal puppies r immuncmprmised animals; immuncmpetent dgs expsed after 2 weeks f age develp nly mild r inapparent upper respiratry tract r genital infectins Nenatal puppies less than 2 weeks f age are uniquely predispsed t CHV systemic infectins because f their lwer bdy temperature, inability t munt a febrile respnse, and prly develped immune systems The hallmarks f generalized systemic infectins in affected puppies are disseminated fcal necrsis and hemrrhage in multiple rgans, especially in the kidney, liver, lung, and spleen Grssly, kidneys are mttled in appearance due t multiple subcapsular crtical hemrrhages assciated with wedge shaped hemrrhagic lesins radiating utward frm the medulla In dgs surviving acute infectin, CHV is shed in nasal, rpharyngeal, and geniturinary secretins, and in feces fr up t 2 weeks; the extent and duratin f virus shedding in urine has nt been determined After an apprpriate hst immune respnse, virus shedding ceases and CHV establishes lifelng latent infectins f lcal ganglinic neurns and lymphid tissues including lumbsacral ganglia, the celiac plexus, and hypgastric lymph ndes Reactivatin f latent CHV infectins and subsequent geniturinary shedding f virus may be induced by stressful situatins r by administratin f crticsterids r ther immunsuppressive agents; hwever, the rle f latent r recrudescent CHV infectins in the develpment r prgressin f renal disease has nt been determined. Feline crnavirus Feline infectius peritnitis (FIP) is a systemic, prgressive, and ultimately fatal immunpathlgic disease caused by a highly pathgenic feline crnavirus strain derived frm a mutatin f the mre cmmn and less pathgenic enteric strain f feline crnavirus The disease principally affects yung cats less than 2 years f age Renal injury is cmmn and is the direct result necrtizing pygranulmatus vasculititis/nephritis assciated with perivascular lcalizatin f activated crnavirus-infected mncyte/macrphages and crnavirus-specific immune cmplexes In additin, glmerulnephritis with r withut cncurrent vasculitis has been bserved in cats with FIP. In ne study f 85 naturally ccurring cases f FIP, 71% f affected cats had light micrscpic lesins f membranus, mesangiprliferative, r membranprliferative glmerulnephritis Feline immundeficiency virus Feline immundeficiency virus (FIV) is a member f the lentivirus subfamily f retrviruses that is similar t human immundeficiency virus (HIV) in structure, bilgical prperties, and clinical manifestatins f infectin Renal abnrmalities have been reprted in 8% t 24% f naturally infected FIV-psitive cats frm Japan, The United Kingdm, Australia, and New Zealand Abnrmalities bserved in naturally r experimentally infected FIV-psitive cats include varying cmbinatins and degrees f clinical signs cnsistent with renal failure, uremia, and the nephrtic syndrme, and labratry findings f aztemia, hypalbuminemia, and prteinuria Renal lesins cmmnly bserved in FIV-infected cats include mesangial thickening, segmental t diffuse glmerulsclersis, tubular degeneratin and/r necrsis, and interstitial mnnuclear cell infiltrates; less cmmn lesins include mesangial cell prliferatin, glmerular r interstitial amylid depsitin, interstitial fibrsis, and micrcystic tubular dilatin

15 Feline leukemia virus Feline leukemias virus (FeLV) is a member f the ncrnavirus subfamily f retrviruses that has been assciated with membranus glmerulnephrpathy, interstitial nephritis, prteinuria, nephrtic syndrme, and renal failure in chrnically infected cats with r withut cncurrent lymphsarcma r ther myelprliferative diseases Glmerulnephrpathy was bserved in 25% t 37% f necrpsy specimens btained frm cats living in husehlds with large ppulatins f FeLV infected cats; hwever, a substantially lwer prevalence f glmerulnephrpathy was bserved in large necrpsy-based surveys f FeLV psitive cats frm the general ppulatin Lwer urinary tract disrders Viruses have lng been implicated as causative agents in the etipathgenesis f sme frms f naturally ccurring feline idipathic cystitis This hypthesis was supprted by the islatin f a gamma herpesvirus (aka bvine herpesvirus type 4), retrviruses (aka feline famy virus), and a calicivirus (aka feline calicivirus; FCV) frm urine and tissues btained frm cats affected with lwer urinary tract disease Clinical manifestatins f viral lwer UTIs are ften indistinguishable frm ther infectius and nninfectius urinary tract diseases Althugh the light micrscpic features f acute viral UTIs have nt been well characterized, urinary bladder lesins in cats with calicivirus-induced urinary tract infectins cnsisted f urinary bladder mucsal petechial hemrrhages, urthelial ulceratin, and submucsal edema and mnnuclear inflammatin These mrphlgic features are nt unlike thse bserved in the urinary bladders f a limited number f cats with nnbstructive idipathic cystitis Feline calicivirus FCV may have a causative rle in the pathgenesis in at least sme cases f feline idipathic cystitis Transmissin electrn micrscpic examinatin f urethral matrix-crystalline plugs btained frm male cats with urethral bstructin revealed virus-like particles, Gamma herpesvirus (bvine herpesvirus type 4) There is cnsiderable evidence that BHV-4 can induce lng-term viral UTIs in cats in a labratry setting and that BHV-4 infectin is endemic in the feline ppulatin; hwever, reprducible evidence that gamma herpesviruses cause naturally ccurring symptmatic feline lwer urinary tract disease is lacking. Diagnsis f viral UTI Exclusin f ther knwn causes f upper r lwer urinary tract disease shuld precede attempts t establish a diagnsis f viral UTI. Generally, diagnstic criteria fr viral infectins include (1) islatin and identificatin f viral agents; (2) direct demnstratin f virus particles, viral antigens, r viral nucleic acids in tissues r bdy fluids; and/r (3) detectin and quantitatin f specific viral antibdies.(murphy et al 1999b) Mlecular diagnstic methds, such as PCR r RT-PCR, circumvent many f the difficulties assciated with cnventinal virus islatin methds and are increasingly being used fr rapid detectin f many viral agents Treatment f viral UTI The mst effective treatment f viral UTIs lies in their preventin thrugh use f apprpriate immunizatin strategies and husbandry practices Althugh interest in antiviral chemtherapeutics and bilgic agents has grwn cnsiderably in recent years, antiviral agents available fr clinical use are relatively few in number and are accmpanied by nly limited infrmatin regarding their safety and efficacy One exceptin is feline calicivirus Parenteral administratin f FCV-specific antiviral phsphrdiamidate mrphlin ligmers effectively inhibited calicivirus replicatin, increased survival, decreased virus shedding, and hastened clinical recvery in kittens expsed t a severe virulent strain f FCV

16 In the absence f safe and effective antiviral agents, management f suspected virus-induced urinary tract disease in dgs and cats is limited t supprtive and symptmatic care t alleviate clinical signs and minimize sequelae f infectin. PARASITIC UTI Dictphyma renale Of the nematdes knwn t affect dmestic animals and humans, few can rival the size and appearance f the giant kidney wrm Adult male and female D. renale are typically bld (r vermillin) red in clr when they are alive, but becme brwnish black after they die and degenerate The eggs are lemn-shaped and cnstant in size Althugh the lifespan f D. renale apparently has nt been determined experimentally, there are estimates that sme naturally ccurring infectins have lasted fr 3 t 5 years Free-living annelids (Lumbriculus variegatus), als called blackwrms and mudwrms, are related t earthwrms and are essential intermediate hsts Cases f D. renale have been encuntered in virtually every part f the wrld with a temperate climate including Mississippi, Luisiana, Minnesta, Wiscnsin, Michigan, and the central and eastern prvinces f Canada Clinical signs The feeding f L. variegatus infected with D. renale t dgs typically induces vmiting due t effects f the parasite n the gastric mucsa If nly ne kidney has been invaded with D. renale and the ppsite kidney is nrmal, signs attributable t D. renale infestatin are ften absent Hematuria bserved by wners may be the first indicatin f an abnrmality Palpatin f the abdmen may reveal an enlarged and/r misshaped hydrnephrtic kidney If bth kidneys are parasitized, clinical signs attributable t renal failure r uremia may ccur; hwever, the hst will die befre extensive hydrnephrsis f bth kidneys has time t develp. The degree f renal dysfunctin is influenced by 1) the number f parasites in the kidney, 2) the duratin f infectin, 3) the number f kidneys parasitized, and 4), and the presence f c-mrbid renal diseases. Diagnsis If the gravid female parasite is lcated in the pelvis f a kidney that has a patent ureter, characteristic va may be fund by micrscpic examinatin f urine sediment When the wrms are free in the peritneal cavity, the diagnsis is usually made by ultrasngraphy, laparscpy, cmputed tmgraphy and/r explratry celitmy Treatment Nephrectmy is usually the treatment f chice when nly ne kidney is affected and the ppsite kidney is capable f sustaining hmestasis In patients with parasites in bth kidneys, nephrtmy and remval f the parasites may be indicated if sufficient functinal tissue remains in bth kidneys t maintain a reasnable quality f life Pharmaclgic treatment f adults and/r infective larvae discvered in any species has been virtually nnexistent Capillaria Plica, Capillaria Felis-Cati C. plica and C. felis-cati are lumen dwellers (i.e. they are celzic) C. plica and C. felis-cati are small, fragile, thread-like yellwish parasites

17 The eggs have biplar plugs, are clrless, and have a slightly pitted shell Capillaria plica is widely distributed thrughut the wrld It has been fund in the urinary bladder, and less frequently in the ureters and renal pelves, f dgs, fxes, cytes, raccns, martens, mink badgers, tters, bbcats, skunks, weasels, and wlves Capillaria felis-cati is fund less cmmnly in the urinary bladder f cats Clinical signs Mst dgs and cats with urinary capillariasis are asymptmatic; sme becme pllakiuric, plydipsic, and periuric. Labratry findings Urinalysis may reveal results (hematuria, prteinuria, and pyuria) typical f inflammatin Numerus clumps f transitinal epithelial cells have als been bserved in urine sediment C. plica eggs are usually easy t identify, althugh at times they are difficult t find Diagnsis A diagnsis is made by finding typical eggs via micrscpic examinatin f urine sediment Treatment Urinary capillariasis is mst ften asymptmatic and, may be self- limiting. Suggested treatments include: 1. Several dgs appear t have been cured by single dses f ivermectin, 0.2 mg/kg, administered by subcutaneus injectin. 2. Prlnged treatment with albendazle was effective in 85% f dgs infected with C. plica. The urine was negative fr eggs 30 days after initiatin f treatment. Oral dses f 50 mg/kg f albendazle were given twice daily fr up t 30 days 3. Mebendazle r albendazle (200 mg given rally twice per day) has been reprted as the treatment f chice fr human intestinal capillariasis Because evidence indicates that in the absence f reinfectin, urinary capillariasis may be selflimiting, islatin f dg and cats frm earthwrms shuld sufficient t eliminate a Capillaria bladder infectin in less than 90 days