An exploration of current evidence existing around the use of antimicrobial prophylaxis for UTI.

1. Urinary Tract Infection
What is the current evidence basis for the use of long-term
antibiotic prophylaxis?
!

2. Definition
• A urinary tract infection occurs when a pathogen enters the urinary
tract, and concentrates in the urine (> 105 cfu/mL). (N.B. Urine is not sterile!)
• Classification
• Level of anatomy
• Lower (cystitis)
• Upper (pyelonephritis)
• Level of complexity
• Uncomplicated
• Occurs in a normal host who has no structural or functional abnormalities, or has no history
of recent instrumentation/catheterisation
• Complicated
• Counterpart to above, and all pregnant women, men and children
• Some authors suggest this classification should be expanded to involve UTIs caused by
multidrug-resistant uropathogens

3. Diagnosis
• Urinary symptoms + positive urine culture
• Normal threshold > 105 cfu/mL of urine (variable threshold)
• These can occur independently of one another
• Asymptomatic bacteriuria increases the risk of UTI, but should not be treated
unless the patient is pregnant or undergoing invasive genitourinary
procedures – unnecessary treatment can increase rates of resistance
• Clinical features and positive WTU for leucocytes + nitrites:
• Sensitivity 80.3%
• Specificity 53.7%(low specificity à higher no. of false-positives)
• Generally, UTIs are overdiagnosed and overtreated

4. Recurrence
• Recurrence (in adult patients) is defined as:
• > 2 UTIs in past 6 months;
• or > 3 UTIs in past 12 months.

5. Catheter-associated infection
• Most common hospital-acquired infection
• Screening and treatment of asymptomatic bacteriuria in these
patients is not recommended (NICE CG 2019)
• Those with and without bacteriuria have fever, dysuria, urgency and
flank pain
• Presence of symptoms (new onset/worsening fever, rigors,
confusion, malaise or lethargy of unexplained source; flank pain, loin
tenderness, acute haematuria, pelvic discomfort) AND > 1,000
cFu/mL bacteria à treat!

6. Clinical history
• Clinical features
• Dysuria, polyuria and nocturia
• Present or increased incontinence
• Macroscopic haematuria
• Suprapubic pain
• Offensive-smelling urine, or turbid
in appearance
• History of previous UTIs
• Changed or new PV discharge
• Risk factors
• Sexual intercourse in previous 2
weeks
• Contraception with vaginal
diaphragm or spermicide
• Contraception with depot
• Antibiotic use in past 2 to 4 weeks
• Anatomical anomalies e.g.
neuropathic bladder, vesico-
ureteric reflux
• Diabetes mellitus

7. Bacteriology
• Majority of infections are caused by E. coli (gram-negative, facultative
anerobic, uropathogenic)
• UPEC are different from E. coli that colonise the GI tract
• Other common organisms:
• Enterobacteriaciae
• Streptococci sp.
• Staphylococci sp.
• Candida sp.

9. Mechanism of transmission
• It is believed that UTIs are caused by the translocation of gut bacteria
into urinary tract
• Healthy individuals are normally able to clear bacteria not adapted to
survive in this environment
• Transmission of uropathogens is likely to occur via contact
(transmission via hands either directly via sexual activity OR indirectly
via contamination of food/water)

10. Antibiotic resistance
• ‘The ability of a microbe to resist the effects of medication that once
could successfully treat the microbe’
• (1) Natural resistance (e.g. enterococci & penicillins)
• (2) Genetic mutation
• (3) Horizontal transfer (acquisition from other species)
• Extended use of antibiotics promotes selection for resistance in
antimicrobial populations

11. Patterns of resistance
• Historically, extended-spectrum beta lactamase (ESBL) resistances
• “SMART” surveillance programme – global prevalence of 17.9% of ESBL based
on 2009-10 susceptibility analysis (18.8% in Europe) in E. coli isolates from
hospital UTI specimens
• Key emerging resistances:
• Carbapenemase-producing Enterobacteriaciae (CPE)
• K. pneumoniae is the most prevalent pathogen (KPC)
• Multidrug-resistant Enterococci (incl. glycopeptide resistance, i.e. VRE)
• Fluoroquinolone resistance (incl. ciprofloxacin resistance)
• Resistance assessed in 10% of pathogen isolates

12. Source: Perletti et
al. (2018)

13. Source: Perletti et
al. (2018)

14. • Experimental studies suggest that long-term exposure of UPEC strains
to subtherapeutic concentrations of antibiotics induces drug
resistance
• In-vitro, ciprofloxacin induces resistance the fastest – not only to
itself, but to other antibiotics (‘cross resistance’)

15. Source: Adamus et Bialek., 2018

16. NICE Guidance on antibiotic prophylaxis
• Not recommended to prevent catheter-associated UTIs in individuals
with short or long-term (indwelling/intermittent) catheters
• For men and pregnant women, only if behavioural and personal
hygiene measures, and vaginal oestrogen in postmenopausal women,
are not effective
• Review every 6 months to assess success of prophylaxis
• 1st choice: trimethoprim, nitrofurantoin (if eGFR > 45 mL/min)
• 2nd choice: amoxicillin, cephalexin

18. Meta-analysis in children
• Meta-analysis of RCTs involving 1,299 children with vesicoureteric
reflux and recurrent UTI show patients treated with prophylaxis are
more likely to have multidrug resistant infection (33% vs 5%, p <
0.001) (Selekman et al., 2018)
• Meta-analysis of RCTs involving 1,427 children showed no benefit to
use of antibiotic prophylaxis in terms of reduction of renal scarring
following pyelonephritis

19. Cochrane review – children
• A Cochrane review published in April 2019 analysing 16 studies with a
total of 1,977 analysed subjects found:
• Compared to placebo/no treatment, antibiotics did modestly decrease the
no. of recurrent symptomatic UTIs in children (RR 0.75, 95% CI 0.28-1.98)
• 3 studies reported data for antibiotic resistance, with analysis estimating the
risk of UTI being caused by an antibiotic resistant to prophylaxis being 2.5
times greater (RR 2.40, 95% CI 0.62 - 9.26)
• ‘Long-term antibiotics may reduce the risk of repeat symptomatic UTI… but
the benefit may be small and considered together with the increased risk of
antimicrobial resistance’

20. Elderly population
• A retrospective cohort study (Ahmed et al., 2018) involving 19,696
adults >65 years with a history of recurrent UTIs started on > 3
months prophylaxis with trimethroprim, cefalexin or nitrofurantoin
showed:
• Reduced risk of clinical recurrence in both men and women by approx.
50% (HR 0.49, 95% CI 0.45-0.54 and HR 0.57, 95% CI 0.55-59 respectively)
• Reduced rate of acute antibiotic prescriptions by 50-60% (HR 0.54, 95% 0.51-
0.57 and HR 0.61, 95% CI 0.59-0.62 )
• Reduced rate of UTI-related hospitalisations, but to a lesser extent in women
(HR 0.78, 95% CI 0.64-0.94, and HR 0.82, CI 0.72-0.94)

21. Older women
• A meta-analysis of RCTs (Ahmed et al., 2017) comparing antibiotic
prophylaxis with non-antibiotic therapy:
• Found 3 RCTs comparing long-term antibiotics with vaginal oestrogens, oral
lactobacilli and D-mannose powder in postmenopausal women;
• Long-term antibiotics reduced risk of UTI recurrence by 24% (RR 0.76%,
CI 0.61-0.95; NNT = 8.5) with no statistically significant risk of adverse events
• One trial showed 90% of urinary and faecal E. coli isolates were resistant to
trimethoprim-sulfamethoxazole after 1 month of prophylaxis
• Follow-up periods were relatively short

22. Intermittent self-catheterisers
• One AnTIC RCT (Fisher et al., 2018) assessed the benefits of
continuous low-dose prophylaxis for prevention of recurrent UTIs in
adult users of CISC
• 404 adult users were enrolled and randomised to receive prophylaxis or
treatment
• Incidence of symptomatic antibiotic-treated UTIs was 1.3 cases/person/year
in the prophylaxis arm, compared to 2.6 cases/person/year in the untreated
group (total of 48% risk reduction)
• Resistance was more frequent in the prophylaxis group:
• 24% prophylaxis vs 9% control for nitrofurantoin
• 67% prophylaxis vs 33% control for trimethoprim
• 53% prophylaxis vs 24% control for co-trimoxazole

23. Radical cystectomy
• An observational study involving 84 patients (42 in prophylaxis group,
42 in control group) in a centre in Oregon (Werntz et al., 2018)
demonstrated:
• 12% rate of postoperative UTI in prophylactic group vs. 36% control (p <
0.004);
• 2% (1 patient) readmitted for urosepsis in prophylactic group vs. 17% in
control (p = 0.02);
• Median time to UTI was 19 days, and most common organism implicated was
Enterococcus.

24. Women in general
• A ‘rapid literature’ review based on 49 RCTs, 23 systematic reviews
and 2 practice guidelines attempted to synthesise approaches:
• Use of vaginal oestrogens +/- lactobacillus containing probiotics in
postmenopausal women;
• Low-dose post-coital antibiotics for young women experiencing recurrent UTI
associated with sexual activity;
• Low-dose daily prophylaxis for premenopausal women with infections
unrelated to sexual activity.

25. What alternatives to antibiotics exist?

26. Fecal microbiota transplantation
• One case study (Biehl et al., 2018) used faecal microbiota
transplantation in a kidney transplant recipient with recurrent UTIs.
This was administered using frozen capsulised microbiota and led to
resolution of symptoms.
• One trial examined whether a change in intestinal microbiota
composition could predict the development of UTIs in
postmenopausal women with previous recurrent UTIs.
• It found that, although microbiota composition was altered following use of
prophylaxis compared to women receiving lactobacillus, this did not predict
new onset of UTIs.

27. Hyaluronic acid and chondroitin sulfate
• A systematic review, analysing 2 RCTs and 6 non-randomised trials,
looked at the efficacy of intravesical hyaluronic acid +/- chondroitin
sulfate in prevention of UTIs in adult women.
• Combination therapy appears to decrease the rate of
UTI/patient/year by 2.56 (95% CI -3.86, -1.26; p< 0.00001) and
increase time to first recurrence.
• The proposed mechanism is based on the re-establishment of the
GAG layer of the bladder uroepithelium.

28. Vaccines
• Vaccines have been trialled and developed, with limited success.
• One such example is Uromune, a sublingual vaccine containing four
common uropathogens (inactivated), which had good results in a
Spanish cohort (90.28% absolute risk reduction).
• Of 75 patients in the UK, 78% of patients had no UTI in a 12-month
follow-up period (but there was no control group).

29. Cranberry juice
• Cranberry juice has historically been thought to be preventive, the
mechanism by which is prevention of binding of P-fimbriated E. coli to
uroepithelial cells by anthocyanins.
• Evidence shows that it decreases recurrences by 30-40% in
premenopausal women, but an optimum dose has not been
established and it is an inferior remedy to antibiotic prophylaxis.

30. A parting question…
So although the evidence is mixed, antimicrobial prophylaxis does
appear to work in several patient groups. However, is its benefit worth
the risk of increasing antibiotic resistance in patient populations?