Inflammatory Bladder Disease Flashcards
(29 cards)
Normal defences against LUTI
Micturition - complete voiding flushes out bladder
Continence
High pressure in urethra during voiding
Anatomy:
Length of urethra preventing ascending infections
Mucosal defences: IgA, antimicrobial defensins, commensal microbiome, innate immune cells and regular exfoliation of mucosa
Antimicrobial properties of urine: high osmolality, high urea, organic acids, Tamm-Horsfall mucoproteins
Systemic immunocompetance
Virulence factors possessed that can increase pathogenicity of bacteria for UTI
Production of haemolysins
Urothelial adherance pili proteins - fimbriae present in up to 75-100% of pyelonephritis
Iron acquisition abilities
Host risk factors for LUTI
Obesity –> skin folds around genitalia, altered immunity
Abnormal micturition –> reduced frequency, incontinence, incomplete voiding
Endocrinopathy - altered immune function, altered urine osmolality?
Urogenital malformation or neoplasia
Presence of implants from interventional procedures.
CKD
Evidence for prevalence of SBU in vet med, and ISCAID recommendations
2-12% of dogs, up to 28% of cats. May provide protection from clinical UTI, as with GI biome. 45-90% prevalence reported in dogs with CKD or endocrine disease.
Possible that lack of clinical signs may be lack of recognition or other comorbidity masking symptoms (such as anti-inflam effects of GC), or truly an avirulent bact strain
→ Patient inability to display CS (ie spinal injury) complicate decision making but a short course could be considered in these cases or base decision to treat on presence of other systemic signs (ie fever)
Studies on clinical implications of SBU in dogs and cats are currently minimal but have so far not shown a significant detriment to outcome in not treating
→ study of older cats with subclinical bacteriuria found no effect on survival if not treated
→ copious human evidence that ABx not needed if asymptomatic, even in high risk patients (endocrinopathy, CKD)
JAVMA 2018 - CKD dogs most positive UC were subclinical 45%, 40% had pyelonephritis and 15% had cystitis
JVIM 2019 - 32% of 65 dogs with CKD had positive culture. Only 1 dog had symptoms of LUTI
JFMS 2020 - prevalence of SBU in 180 older cats was 6% with various comorbidities - only presence of hepatic disease assoc with increased risk
ISCAID says
No CS, Tx not indicated UNLESS undergoing urological procedure.
IF unclear whether or not CS are present/attributable to LUTI then a 3-5 day course could be considered
Culture of MDR organism is not indication to Tx - resistance genes are NOT assoc with increased virulence, and may be replaced with susceptible organisms given time w/o Tx.
Definition for persistent, relapsing and reinfection in LUTI
Persistent = not responsive to appropriate ABX
–> positive culture while on ABx
–> consider absorption, metabolism or compliance issues
–> bact protected by biofilm or other mechanism (innate resistances in enterococcus)
Relapsing = urine is cleared of infection during Tx then relapses with same organism after discontinuation
–> look for infection reservoir (prostate, vagina, kidneys, uroliths)
Reinfection = new infection develops after previous treatment stops. Often different organism (may not be able to tell without genotyping)
–> usually means host defences are inadequate for one reason or other.
NZVJ Approach to MDR LUTI recommendations
- Ensure urinary origin of bacteria (cysto)
- Don’t treat if subclinical
- Address/control concurrent comorbidities contributing to infection as much as possible (increases chance of resolution and prevents reinfection)
- Use breakpoints for tissue/urine depending on suspected location
→ assess for other physiological factors that could be preventing ABx absorption or metabolism. - Ensure dosing frequency keeps time-dependent ABX above MIC for most of interval.
For concentration dependent aim for 8-10x MIC. - Dosing interval dose not need to be prolonged, 14 days for tissue based infection should be sufficient.
No evidence of ancillary Tx methods being beneficial despite lots of research
Available Tx options for MDR UTI: - Tetracyclines (not doxy) concentrate in urine and may reach sufficient concentrations to be effective in vivo.
- Aminoglycosides (amikacin) for non-tissue based infections of Enterococcus or Pseudomonas. Combination with azithromycin may help Tx biofilm
- Nitrofurantoin sensitivity is often present in MDR E coli and Staph
→ Aim for CLINICAL not microbiological cure.
What is follicular cystitis and what causes it
inflammatory change in the urinary bladder wall characterized by the formation of tertiary lymphoid structures (TLSs) in the submucosa.
JVIM 2023 study demonstrated E.coli RNA in 8 cases to varying degrees.
–> indicating this invasive E.coli may be a triggering cause for development of follicular cystitis
Significance of Corynebacterium urealyticum (recent pub)
JSAP 2019 - 11 cats and 10 dogs
all cats had hx of ucath placement
Dogs had hx preexisting urological conditions.
–> tissue culture used for diagnosis, 7 had had previous negative culture results.
–> AMR was common, 13 isolates sensitive to tretracyclines
9 had encrusting cystitis diagnosed on u/s
Preventatives for recurrent LUTI and what is the ISCAID recommendation
none recommended by ISCAID
Cranberry extract - inhibits adherence to uroepithelium in humans of UPEC. In vitro efficacy present but clinical evidence lacking
Probiotics - only 1 prospective controlled study with multistrain formula found no benefit
JVIM 2018 - live biotherapeutic E.coli ASBU strain administered to 6 healthy dogs caused no CS. Given to 9 dogs with persistent UTI → microbiological cure in 4
Intra-vesicular Tx: ABX, antiseptics, DMSO trialled and no success
Prevention - where underlying cause cannot be removed:
- SID nitrofurantoin reported JSAP 2023
→ 13 cases, 4 developed bacteriuria with spp resistance to Tx
→ Proteus and Corynebacterium innate resistance.
- Studies of other therapeutics (probiotics, cranberry extract) have not demonstrated efficacy.
JSAP 2021 14 cases: TID for 2 weeks, 12 had bacteriological cure.
Recommended mgmt (tx and monitoring) of recurrent bacterial cystitis
Recurrent Bact Cystitis
- >3 sporadic events in 12 months, >2 in 6 months.
- DDX: persistent (vs relapse) vs reinfection vs superinfection (new infection during Tx)
→ evaluate for nidus (persistent or relapsing), risk factors for reinfection, repeated ABx unlikely to provide long term cure and may increase MDR risk
→ u/s, radiographs, contrast imaging, cystoscopy/biopsy for tissue culture
→ if bladder wall infection identified on tissue culture ensure ABx selection has adequate penetration (fluoroquinolone, TMS, cephalosporins)
→ need to ensure ABx chosen is achieving therapeutic levels at the intended site of action
Duration: due to broad range of underlying conditions a blanket duration is no longer applicable.
→ primary goal is CLINICAL CURE and no adverse effects (including MDR)
→ long term therapy is not automatically warranted
3-5 day courses are suitable for reinfection
→ culture during Tx not necessary
7-14 days may be necessary for persistent/relapsing infection
→ benefit in mid-Tx culture not known, may help differentiate relapse/reinfection/persistent infection BUT may not indicate need for longer Tx.
* If positive → evaluate compliance and investigate for cause of lack of cure if appropriate ABx (poor penetration, innate resistance)
No evidence for use of intravesicular ABX
- Culture 5-7 days after stopping ABx is part of diagnostic process (differentiate persistent from relapse from reinfection) BUT positive culture in absence of CS does not indicate need to Tx
Aust UTI resistance prevalence
Urinary E. coli from dogs 95% resistant to cephalothin, 45% resistance to potentiated amoxicillin; and 11% resistance to cefovecin.
In cats: 6.5% cefovecin resistance up to 100% amoxi-clav resistance.
Ecoli most common isolate of LUTI in multiple countries though specific Australian study of prevalence is lacking.
UCaths - incidence of LUTI assoc, ISCAID recommendations for prevention, investigation and Tx
Incidence of true bact cystitis (and not subclinical) after ucath placement is not well characterised (may be 10-55%). And is likely dependent on multiple factors
Prevention: asepsis, closed collection, regular checks for leaks, routine replacement, keep duration short as possible, consider intermittent catheterisation in amenable patients;
Prophylactic ABX are NOT recommended, nor are intra-vesicular infusions of ABx.
JAVMA 2018 silver coated ucaths did not reduce risk
Culture only indicated if CLINICAL SIGNS (may not be LUT but could get PUO, or bacteraemia without another focus)
→ if suspected remove ucath, take cysto sample then replace new ucath.
Tx more likely to be successful if remove ucath, in rare case this cannot be done Tx as per sporadic cystitis
Recommendations for pre-surgical/urological procedure screening
Implications of infection may be high in some situations because of the potential for persistent colonisation of devices such as stents
In humans:
- Screened prior to surgery for asymptomatic bacteriuria, if positive with significant growth then treat as per sporadic bacterial cystitis
- Perioperative antimicrobial prophylaxis should be considered for procedures that involve stone manipulation or open surgical procedures that involve the urinary tract if pre-procedure culture of a cystocentesis-collected urine specimen yields significant bacterial growth
-Perioperative prophylaxis should not be continued for more than 24h post-procedure (in the absence of other complicating factors). If bacteriuria was identified prior to the procedure, treatment may need to be considered for a longer time period postoperatively than 24 h (e.g. 3–5 days), depending on the procedure
CYSTOSCOPY - Anecdotally, development of bacterial cystitis does not appear to be a common problem in companion animals when urological procedures are performed without peri-procedural antimicrobial prophylaxis
Moreover, if cultures of bladder wall are required, it would be ideal to obtain these specimens when the animal has not received antimicrobials
–> If pre-existing bacteriuria is present, in addition to treatment for 3–5 days in advance of the procedure, a 1st or 2nd generation cephalosporin should be administered IV no more than 60 min before the start of the procedure, repeated every two drug half-lives (as needed) during the procedure
UROLITH REMOVAL
In animals without lower urinary tract signs, it is ideal to obtain a culture 1 week prior to the procedure and treat patients with positive cultures, based on susceptibility results, for 3–5 days before the procedure, followed by administration of a 1st generation cephalosporin (i.e. cefazolin) IV no more than 60 min before the start of the procedure
OPEN SX
- Approximately 30% of cats treated with SUBs were reported to develop post-operative bacteriuria (Culp et al., 2016; Kopecny et al., 2017) and based on univariate analysis, post-operative antimicrobial administration appeared to reduce the risk of infection.
- Peri-operative antimicrobial prophylaxis is indicated and should consist of a 1st or 2nd generation cephalosporin administered IV no more than 60 min before the start of the procedure, repeated every two drug half-lives (as needed), and not continued more than 24 h following the procedure
- Prospective, randomized studies that evaluate the effect of post-operative antimicrobial use in cats following stent or SUB placement are required
Proposed pathogenesis/physiology of FIC
A syndrome of acute onset symptoms of lower urinary tract disease accompanied by haematuria and often pyuria. In most cases the symptoms are self limiting but are often recurrent.
Current perception of pathogenesis is that it is related to an imbalance of sympathetic NS and HPA axis brought about by stressful situations, to which the bladder is merely a victim of a systemic stress process.
- Increased bladder substance P receptors in bladder with increased afferent excitability compared to healthy controls.
→ may trigger neurogenic inflammation, altered blood flow or inflammatory cell infiltration - Altered bladder mucosa with evidence of neutrophilic inflammation and reduced in GAG
- Altered central stress response system a result of in utero development in presence of maternal stress
→ increased activity of Stress Response System (SRS). → activation of sympathetic outflow → increased catecholamines
→ impaired local blood flow, increased inflammatory mediators → pain which alters sphincter tone and perpetuates pain cycle.
→ chronic psychological stress causes low grade systemic inflammation and sickness behaviours (V, D, anorexia, lethargy, hyperalgesia, reduced activity and body care) - Affected cats often have increased display of sickness behaviours in response to stressors
Risk factors for FIC
- Low hunting behaviour, low activity
- Obesity
- Use of litter trays
- Multicat households
- Often reported lower water intake
- Frequent diet changes
What is Pandora syndrome
proposed in JFMS 2015 review to describe cats with recurrent LUTS (and others) in the presence of comorbid disorders (CVS, GI derm, endocrine, behavioural) until a more biologically appropriate nosological term is identified.
→ does not identify a specific cause or organ affected
→ captures the dismay and dispute associated with so many problems.
→ often associated with early abandonment, waxing and waning signs.
→ improves with MEMO
Findings of JFMS 2020 long term FIC follow up (did not include UO cats)
- 61.5% had recurrence of FIC symptoms, most within 1y of first presentation some were much longer. Earlier prospective study reported 65% recurrence.
- 14/50 with recurrence suffered from different causes of LUTD at different times.
- Looked at relapse in FIC (not UO)
- Mortality due to FLUTD was 5%
What is MEMO - what are the components of Tx
Modal Environmental MOdification enriched conditions focussed on resource management and reduction of perceived threats. Increase their perception of control
→ implement in a way that permits cat to express its preferences, do so gradually
→ unrestricted access to food, water, play and litter. If multicat then needs to be multiple sources in different rooms.
→ opportunities for play/predatory behaviour
→ clean litter, don’t change brand
→ safe hiding places
In laboratory studies sickness behaviours were reported to resolve in response to implementation of MEMO
Current lack of controlled trials makes recommendation of one/any of these factors over the other impossible.
** Increase water intake: likely to have the most effect on risk of recurrence particularly in those with urolithiasis.
→ freshness, taste, flowing, multiple sources
→ bowl shape (some don’t like their whiskers to touch it)
** Conflict:
Usually associated with resources: food, water, hiding spots, perches. May develop once cats mature at around 2-4y
FIC more often develops in the threatened cat (hiding, avoids eye contact, yields resources, crouches/cowers) rather than the assertive/aggressor.
Dietary recommendations in FIC
many cats can be managed effectively without diet change, unless there is concurrent urolithiasis
→ not enough evidence currently to recommend diet change in cats with struvite crystals in absence of UO.
→ Though wet foods where MEMO cannot be implemented may be beneficial.
If UO has occurred with struvite crystalluria then diets high in moisture and reducing pH and supersaturation of components are justified but have limited evidence
Role of central threat/stress response system in FIC
Region of brain that is overactive/hyperresponsive in FIC
(a result of in utero maternal stress most likely)
–> can be activated by central and peripheral signals of real or perceived threat
–> SNS activation and increased catecholamine production from adrenals
–> with chronicity see sickness behaviours
How is HPA axis different in FIC cats
See decreases in cortisol in cats with high catecholamine levels during acute and chronic stress
–> suggests uncoupling of normal stress response.
Different ISCAID categories for UTI
Subclinical
Sporadic
Recurrent
UCath
Urological Sx
Pyelonephritis
Prostatitis
What is bacterial breakpoint
A breakpoint is a chosen concentration (mg/L) of an antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic. If the MIC is less than or equal to the susceptibility breakpoint the bacteria is considered susceptible to the antibiotic
Depends on Distribution of susceptibility, drug pharmacodynamics (ie serum not always equivocal to target tissue); drug pharmacological properities, clinical outcome data.
In veterinary medicine most of the breakpoints used are based on human clinical trials.
Urotheelial cell carcinoma behaviour and stage
Prognostic facotrs
Locally aggressive/invasive neoplasm, considered high grade in most cases with almost all affected animals dying due to local disease.
In dogs metastasis at diagnosis is generally <10%, but by death is 60%.
Stages:
T1 = superficial papillary tumour
T2 = tumour invading bladder wall (78% at Dx)
T3 = tumour invading neighbouring organs
N0-2 - with 2 being juxtaregional LN involvement
M0/1
Most consistent variables assoc with survival are staging related
