1. Urinary Tract Infections Myths and Reality
Dr Steve Holden
Consultant Microbiologist and NUH Lead for Antimicrobial Stewardship
Declaration of interest: Consultancy with Profile Pharma
Dr Annie Joseph
Microbiology Registrar and Co-author of Nottinghamshire Primary Care Antibiotic Guidelines

2. Session overview What are the key issues? UTI diagnosis in the elderly
Laboratory processing of samples
Management of UTIs
Asymptomatic bacteriuria
Local susceptibility data and guidelines
Special circumstances
Future local work

4. Recent publications
Health & Social Care Act 2008 Code of Practice on the prevention and control of infections
New Criterion 3: antimicrobial stewardship
NICE Antimicrobial Stewardship Guideline (NG15)
Recommendations for prescribers, providers & commissioners
Patient Safety Alert (NHSE, HEEM and PHE)
TARGET (Treat Antibiotics Responsibly, Guidance, Education, Tools)

5. The Key Issues Increasing bacterial resistance (locally and globally)
Emergence of pan-resistant coliform bacteria.
Diagnosing UTI in the elderly
Unnecessary treatment of asymptomatic bacteriuria.
Joined up approach for sending samples, processing and interpretation of results needed.
New guideline on management of UTI.
80% Abx use in primary care – biggest driver for resistance. Biggest potential to improve practice.

6. UTI diagnosis in elderly
Considerations:
Catheterised vs Non-catheterised
Lower vs Upper UTI
Complicated vs Uncomplicated UTI
Structural e.g. obstruction, calculi.
Neurogenic bladder
Diabetes, immunosuppression
Alterative diagnoses
Catheter vs non-catheterised – affects the diagnostic tests and management eg. Duration of treatment
Lower vs Upper – basis of the appropriate empirical agent ie. Want good systemic cons for upper UTI, high risk of progression with sepsis. Guidance reflects this: eg. Would ever use nitrofurantoin if signs of systemic infection.
Complicated vs Uncomplicated – treatment duration recommended is longer in complicated – typically 7 days.
Alternative diagnoses – atrophic vaginitis, other causes of increased confusional state, viral infections

7. National Guidance: PHE
SIGN:
Symptoms – presence of two or more symptoms increases diagnostic certainty. Difficult when patients have only one symptom – is it early UTI or due to another cause?
In catheterised patients, no role for lower UTI symptoms – presence of systemic features should prompt suspicion.
SIGN guidance reflects this too.

8. National Guidance: SIGN
Emphasis on signs of systemic infection in catheterised patients, and presence of two or more symptoms in non-catheterised.

9. Catheter-associated UTI (CAUTI)
Urinalysis and culture positivity not helpful unless symptoms or signs of CAUTI
The following do not predict infection:
Odorous or cloudy urine
Positive dipstick for LE/nitrites; presence of pyuria.
Therefore urine dipstick is of no clinical value in catheterised patients, can lead to confusion / pt harm.

10. Sample processing overview
Dipstick?
Dipstick screen useful as a negative (but not positive) predictor in those with equivocal symptoms.
Poor evidence to support use of dipsticks in the elderly.
Sample sent to lab for MC&S
All samples have automated microscopy performed by flow cytometry.
Samples flagged by flow cytometer that require culture & sensitivities.
Despite poor PPV (50%) in elderly, we know that positive dipstick is often the trigger for culture +/- treatment. Evidence supports its high NPV in the elderly, but is it used in this way? PPV low as dipsticks positive in asymp bacteriuria which is common I elderly, and probably poorer sample acquisition.
SIGN guidance advises against uses dipsticks in the elderly all together.
In those with classical or strongly suggestive symptoms, no additional benefit added by dipstick.
Has become routine – anyone can do it.

11. Microscopy and culture
Flow cytometers set up for sensitivity, not specificity
Very high negative predictive value (99% in women)
Positive microscopy indicates need to culture sample.
Negative = immediate result.
Presence of excess epithelial cells indicates poorly obtained sample.
Evaluation for microscopic haematuria should be done by dipstick.
Culture and direct sensitivities now performed giving 24hr result.
Amoxicillin removed from testing
Current agents: co-amoxiclav, cefalexin, ciprofloxacin, pivmecillinam, nitrofurantoin, trimethoprim and piptazobactam.
Dipstick is more sensitive for microscopic haematuria.
C&S results available for >80% samples within 24hrs – could enable early decision-making eg. Watch&wait approach, rv empirical treatment with sensitivities.

12. Asymptomatic bacteriuria (ASB)
Presence of bacteria in the urine without clinical evidence of urinary tract infection
Different from perineal or other contamination i.e. when the bugs cultured were not in the patient’s urine at all.
Presence of pyuria does not indicate infection
Odorous or cloudy urine does not indicate infection
Common in the elderly and catheterised

13. Source: Infectious Diseases Society of America, CID 2005;40:643-54

14. ASB: What’s the problem?
Treatment is not indicated.
Does not reduce frequency of symptomatic infection or prevent further episodes of ASB
Contributes to increasing antimicrobial resistance; risk of side effects including C.diff.
Number Needed to Harm = 3
Probably the most significant contributor to inappropriate antimicrobial use.
Therefore looking for it should be avoided.
Exceptions are pregnancy (UK guidance to confirm with second sample) and prior to invasive urologic procedures e.g. TURP
No supportive evidence to do prior to orthopaedic surgery even if prosthetic material being inserted – not linked to the organisms causing later prosthetic joint infection.
Not a local problem – evidence to support widespread / international issue.

15. Experience at NUH and elsewhere
Audit on admissions wards at QMC showed >40% of patients treated for UTI actually had ASB.
ED audit showed 15% of patients treated for LE +/- nitrite positive dips with no evidence of infection.
Sample sent “routinely”  clinician reviewing result does not know why sample sent and treats out of caution.
Toronto: 48% of patients with ASB treated unnecessarily vs. 12% after lab withheld antibiotic susceptibility results (CID 2014:58)
Evidence to support lack of understanding amongst all levels of clinicians regarding ASB and indications for treatment.
“Labelling” patients as UTI or recurrent UTI – patient harm, mis-diagnoses (eg viral encephalitis, endocarditis), resistance, C.diff.
How can we prevent this happening?

16. Requests and sample labelling
Type of urine e.g. MSU, CSU
Affects processing and reporting
Clinical details:
Difficult or multi-resistant isolates are reviewed by medical microbiologist
We can release certain sensitivities or provide extra interpretative comments.
Many studies estimate over 60% of urine samples are unnecessarily sent for MC&S.
Education of nursing staff and anyone who can send urine samples
“Let’s send it, just in case…..”
Reducing number of inappropriate samples sent, reducing inappropriate dipsticks, restrictive reporting, education.
Cost pressure of inappropriate use of laboratory resources.

17. Genuine UTI… what to treat with?

18. Resistance in urinary pathogens
Multiple mechanisms
No longer test or report “ESBLs” as one of many types of betalactam resistance and does not help to know clinically.
Resistance to betalactam agents e.g. co-amoxiclav often accompanied by resistance to certain others e.g. trimethoprim.
Drivers of resistance
Individual patients: Antibiotic exposure over time, broad-spectrum agents with effects on flora, cross-infection in hospital/care facilities.
Global: Injudicious (and valid) use of antimicrobials; international spread.
Concerning emergence of carbapenem-resistant coliforms (CRE). Becoming endemic in certain countries and UK centres. Few or even no therapeutic options.
BMJ systematic review showed for UTIs – odds ratio for resistant organisms was 2.5 at 2months post-treatment, and 1.33 at 12months post-treatment. Risk of resistance is highest immediately post-treatment but still persists at 12 months after a single antibiotic course. Increases population carriage of organisms resistant to first-line antibiotics, as primary care responsible for 80% of all antibiotic usage.

19. 20% cut-off for empirical use recommended
by IDSA guidelines
Local Data:
IDSA cut-off for recommendation of empirical treatment with trimethoprim in acute uncomplicated UTI
Are these resistance rates likely to be representative of all patient groups? No.
New PHE guidance recognises this for the first time and recommends stratifying treatment choice based on risk of resistant organisms.
Rising rates of community-onset E.coli bacteraemia, importance of appropriate empirical Abx in the community to prevent sepsis and admission.
Note the amox and co-amox resistant rates

20. Welsh data from 2005-2011. Significant difference in trimethoprim resistance across age ranges.
In 2006 Wales also collected data on acute uncomplicated UTIs in women aged <65yrs – trimethoprim resistance rate was 13% - about half that of the overall resistance rate. No Uk data on trends in resistance in uncomplicated UTIs since then (lack of sentinel surveillance).
PHE guidance recommends all >65yrs and paediatrics have pre-treatment sample sent, therefore more accurate of all UTIs in this age group.
How does this compare to local more recent data?

21. Consistent. All groups fall above the 20% - but some data less representative.
Clearly age is a significant risk factor for trimethoprim resistant organisms. Why important – also those at risk of rapid progression with bacteraemia and admission with sepsis – need to avoid by using a better first-line agent for lower UTIs.
Paeds and elderly should be more representative.
Interesting that paediatric urine cultures also consistently >20% trimethoprim resistance – again, all children should have a pre-treatment sample sent so this should represent all UTIs in this group. Risk of serious and long-term complication if under-treated in children.

22. Updated UTI guidance June 2015
Empirical therapy ie when no culture result available to guide narrow spectrum therapy.
In >65yrs – samples should be sent and therefore culture result will be available, most within <24hrs of receipt in the lab – option to select the narrowest spectrum choice the organism is sensitive to.
Most important change is that need to consider risk factors for resistance before making choice of antibiotic:
Risk factors taken from PHE guidance.
Some are standard already – recurrent UTI and treatment failures
Rest - >65 years, care home, and recent hospitalisation. Elderly frail / care home patient fall into these categories on multiple fronts.

23. CAUTI management & prevention
Treatment of CA-UTI and removal of catheter if inserted for >2 weeks.
Treatment duration poorly defined
IDSA suggest 7 days
What doesn’t work:
Antibiotic prophylaxis or treatment of CA-ASB
Adding antimicrobials to catheter drainage bags
Routine use of antibiotic prophylaxis for catheter change
PHE suggests 7 days, IDSA guidelines suggest 2 weeks. Will remove ongoing source – antibiotics will not eradicate organisms from biofilm on the catheter.
IDSA and local guidance advises 7d of therapy.
Review of ongoing need for catheters and catheter insertion and care bundles.
Specific circumstances covered in local guidance – history of recurrent sepsis following catheter change, persistant MRSA colonisation of the urine – community IPCT can advise.

24. What are the ideal agents?
What do we need?
Low rate of resistance
Unique mode of action
Highly concentrated in the urine
Minimal impact of normal flora
Low rate of allergy, intolerance and contra-indications
Cheap and easily available
Easy to test in the laboratory for sensitivity

25. Nitrofurantoin
Remains very active against coliforms except Proteus spp.
Concerns about use in elderly / renal impairment
Possible pulmonary and hepatotoxicity
Failure to concentrate in renal tract
MHRA has recently updated guidance:
Avoid if eGFR <45 unless no alternatives (CI if <30)
Not suitable for pyelonephritis or systemic symptoms eg. fever
Mention re: toxicity and monitoring in long-term use in elderly.

26. Pivmecillinam Betalactam drug
Low rate of resistance – Europe 4.2% resistance
Now testing first line for all urine isolates at NUH
Minimal effect on GI flora
CI in penicillin allergy
Unique mode of action
Highly concentrated in the urine
Cost comparable with nitrofurantoin
Safe in pregnancy and children
No liquid formulation.
Not for repeated or prolonged courses in pregnancy (no data, theoretical risk of carnitine deficiency)

27. Others
Trimethoprim resistance now unacceptably high for empirical use in the elderly
Amoxicillin and co-amoxiclav similar
Major drivers of resistance and C.diff
Cephalosporins
Acceptable resistance rates but again major drivers of resistance
Ciprofloxacin
Surely not…??
Currently the third line option for empirical therapy and first-line for pyelonephritis

28. Ciprofloxacin Highly effective drug for treating most types of UTI
Concerns about selecting MRSA and C.diff
Prevalence of MRSA now very low
Main problem with quinolones is selection of 027 strain (of Stoke Mandeville fame). This is now rarely seen.
Prior to this has been relatively C.diff sparing.
Should not be used empirically for other conditions outside of the guideline indication
However, can also select more resistant coliforms and should be avoided if we can find a more suitable alternative.
Nitro and piv more suitable for lower UTI. Fosfo also more suitable – as yet unlicensed.
Not a ‘green light’ to start using cipro again. Never use for resp tract infections unless advised to.

29. Fosfomycin >90% of multi-resistant coliforms susceptible
Currently unlicensed in UK but widely used in some other European countries
UK licensed product likely by end of 2015 (Profile Pharma)
Single 3g sachet for uncomplicated UTI
Well tolerated
Minimal impact on GI flora
Safe in penicillin allergy
Can be used currently unlicensed to avoid admission
Under microbiology/ID advice (Amber 2 indication)
Available via wholesalers
If likely delay >24hrs then community script to QMC or KMH pharmacy
Also mention IM gent

30. Unusual problems
Pseudomonas: Genuine uncomplicated infection very rare
Only susceptible to ciprofloxacin. Resistance develops after exposure. Urology referral may be indicated if genuine recurrent infection.
Staphylococcus aureus: Very rare cause of uncomplicated UTI
In a woman could reflect perineal flora
Repeated isolation from male MSU could indicate extra-renal systemic infection with excretion in urine. This is well described and requires investigation.
Common catheter coloniser that may cause ascending infection. MRSA can be troublesome although often trimethoprim susceptible.
Candida spp.: Most likely commensal or thrush but genuine urinary tract infection requires investigation with imaging. Only likely if predisposing factors e.g. severe immunosuppression or renal tract abnormality

31. Pre-surgical screening
No evidence that this is useful or that treating ASB prior to most surgery including prosthetic joint insertion reduces post-op infection.
Exception is for urological procedures where mucosa will be breached
Risk of ascending infection and sepsis
Use sensitivities to guide peri-op prophylaxis
This should be organised or advised by urologists.
Continue to liaise with the surgeons at NUH about this. No national guidance on this – local practice varies from centre to centre.

32. Recurrent UTIs ≥ 3 symptomatic UTIs in one year
Microbiological confirmation should be obtained prior to considering antibiotic prophylaxis
Indications for referral to Urology (NICE CKS)
Review prophylaxis after 6 months
Evidence for long-term prophylaxis:
In women <65 years
Combined data for all agents studied (including quinolones and beta-lactams)
Long-term efficacy not studied
Side-effects in about 20% of patients

33. Recurrent UTIs Choice based on prior sensitivity results
Breakthrough resistant UTIs – indication to stop
No evidence for drug holidays or rotational antibiotics
Pivmecillinam not advised as prophylaxis
Failure of trial of prophylaxis Urology referral
Cases of nitrofurantoin toxicity – regular monitoring, esp as renal func may decline over time increasing the risk of toxicity.
Not uncommon to see patients who have had consistently resistant organisms but continuing prophylaxis – risks of drug toxicity without any benefit.

34. Take home messages Antibiotic resistance rising dramatically.
Treatment of asymptomatic bacteriuria is a global medical error that needs work.
New guidelines now in place.
We are here to help. QMC extension between 9am to 5.30pm– there is a medical microbiologist available or one who will shortly get back to you.

35. Future work
Newly formed Antimicrobial Stewardship Committee at NUH with Primary Care representation
Integrated Fellowship in Clinical Microbiology and Antimicrobial Stewardship starting in May 2016
Interested in getting involved?
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36. Questions?