Antimicrobial prophylaxis in UTI - an overview of the evidence
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Urinary tract infections are commonly caused by E. coli bacteria entering the urinary tract. Long-term antibiotic prophylaxis can reduce recurrences but increases antibiotic resistance. Studies show it modestly decreases recurrences in children and reduces recurrences and antibiotic use in the elderly by around 50% but resistance is a concern. Alternatives like vaginal estrogen, probiotics, hyaluronic acid and chondroitin sulfate may help reduce recurrences in some groups with fewer resistance issues than long-term antibiotics.
Antimicrobial prophylaxis in UTI - an overview of the evidence
- 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?