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URO6310.1177/2051415812472433Journal of Clinical UrologyChristofides et al.

Continuing Medical Education: Review

Contemporary Management of recurrent UTI in adult females

Journal of Clinical Urology 6(3) 140­–147 © British Association of Urological Surgeons 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2051415812472433 uro.sagepub.com

Angelos Christofides, Thomas Swallow, Richard Parkinson Abstract The management of recurrent UTI is subject to significant variation and patients may fall under the care of a variety of specialties. We review the pathogenesis, investigation and management of this group of patients. Accurate diagnosis of UTI is the cornerstone of successful management, and careful interpretation of MSU results is needed. Although prophylactic antibiotic regimes are often successful, the emergence of antibiotic resistance mandates the cautious use of antibiotics and consideration of other initial therapies where possible.

Introduction Urinary tract infections (UTIs) are common in women, with an annual incidence of 30 per 1000,1 and 15% will have recurrent episodes.2 A widely accepted definition of recurrent UTI (RUTI) is two or more episodes over six months, or three or more episodes over 12 months.

Pathogenesis Colonisation of the vagina with uropathogenic enteric bacteria (Table 1) and subsequent migration per urethra to the bladder is a key pathogenic mechanism for the development of UTI (Figure 1). The ability of bacteria to then colonise the bladder is influenced by bacterial virulence factors, which promote urothelial adhesion and immunity or evasion.

Vaginal colonisation Women with recurrent UTIs often have an increased susceptibility to vaginal colonisation with uropathogenic enteric flora which may be genetically determined.3 Buccal mucosa and vaginal epithelium from patients with recurrent UTI exhibit increased binding to Escherichia coli in culture compared to controls (which exhibit greater affinity for non-pathogenic commensals), indicating an inherent predisposition to infection.4 Patients with recurrent UTIs are also more likely to be Lewis blood-group antigen non-secretors, which is thought to have an effect on bacterial adherence.5 The platform for answering on-line CME questions will be released later in 2013

Oestrogen promotes vagina colonisation by Lactobacillus, helping to maintain a low vaginal pH through the production of lactic acid from glycogen, thus inhibiting the growth of many uropathogens.6 After the menopause, Lactobacilli are absent, the vaginal pH rises and colonisation by enteric bacteria, especially E. coli, occurs. It is likely that oestrogen also prevents colonisation through the increased secretion of anti-microbial peptides (AMPs) such as beta-defensin-2.7 In young women, UTIs are frequently triggered by sexual intercourse,8 and the use of barrier contraception and/or spermicidal gels may further increase the risk possibly through the alteration of vaginal flora and subsequent periurethral colonisation by uropathogenic bacteria.9 Sexual intercourse may be responsible for the propulsion of bacteria from the vagina per urethra to the bladder, although the mechanism has not been clearly determined.

Bladder colonisation Free-floating or “planktonic” bacteria are usually expelled from the bladder during normal voiding but UTI may develop if ascending bacteria are not adequately cleared. This may be due to bacterial adherence, urinary stasis or a persisting bacterial source. Fimbriae (Pili) are bacterial appendages, which facilitate adherence, and the expression of certain Fimbriae has been implicated in UTI (e.g. type-1 lower urinary infecNottingham University Hospitals NHS Trust, UK. Corresponding author Richard Parkinson, Nottingham University Hospitals NHS Trust, Nottingham, UK Email: [email protected]

141

Christofides et al. Table 1.  Common uropathogens. E. coli Proteus Klebsiella Enterococci Pseudomonas Enterobacter Citrobacter

80% 10% 5% 2% 2% < 1% < 1%

(50% hospital-acquired UTI)   (15–20% hospital-acquired UTI)        

UTI: urinary tract infection.

tions and type-P in pyelonephritis). Other bacteria have evolved mechanisms to achieve adherence: Proteus mirabilis may undergo a phenotypic change on contact with a solid surface, forming rafts with the ability to move rapidly en masse.10 This swarming process is thought to be critical to the virulence of Proteus in catheterised patients and the expression of virulence determinants such as urease.11 The glycosaminoglycan (GAG) layer may influence bacterial-urothelial interaction, and virulence factors produced by E. coli have been shown to cause damage to this layer, possibly facilitating adherence.12 Bacteria may invade urothelial cells, forming intracellular bacterial communities (IBC),13 thus evading host defence mechanisms as well as clearance by micturition and antibiotics. Planktonic bacteria may be killed by antibiotic treatment, but subsequent release of bacteria from IBCs may be an important mechanism for the early recurrence of UTI.14

Biofilm Biofilm is a complex aggregation of microorganisms characterised by the excretion of polymeric substances, mostly polysaccharides, forming a protective and adhesive extracellular matrix. This matrix facilitates surface attachment and complex community interactions, such as the sharing of genetic material (e.g. plasmids), encoding bacterial virulence factors and antibiotic resistance. The matrix is usually the largest component of biofilm, with bacteria forming around 15% of its mass. Bacteria within biofilm may not cause symptoms but may shed planktonic bacteria causing UTI. Bacteria within biofilm may become metabolically and functionally dormant and thus relatively resistant to antibiotic therapy (“persister cells”). The antibiotic concentration required to eradicate biofilm bacteria is several thousand times higher than the dose required to kill planktonic bacteria.15 With the cessation of an antibiotic course, these cells once again become active and repopulate the biofilm, causing the re-emergence of bacteruria and infection.

Structural abnormalities Anatomical or functional abnormalities may result in stasis and facilitate bacterial colonisation. The significance of

Figure 1.  Pathogenesis and risk factors for urinary tract infections. GAG: glycosaminoglycan.

anatomical abnormalities such as urinary tract foreign bodies, urinary stones, enterovesical fistulae and urinary obstruction are well recognised, and management is directed toward eradication of the underlying condition. Pneumaturia should prompt investigation for enterovesical fistula with cystoscopy (cystography is less sensitive). It has been proposed that normal urethral function may prevent the ascent of bacteria from the vagina to the bladder. Turbulent flow through the urethra, urethral stenosis or poor mucosal co-aptation associated with oestrogen deficiency may be important. The significance of vesicoureteric reflux (VUR) in adults with recurrent UTI is unclear. VUR is a potential cause of urinary stasis and incomplete bladder emptying, and may dispose patients to the development of pyelonephritis. However, VUR may also be an incidental finding and the evidence for treating in the context of recurrent UTI is uncertain.16 Endoscopic subureteric injections can be effective in the treatment of adult VUR,17 but it is unclear whether this is clinically effective in reducing UTIs.

Diagnosis Diagnosis of a UTI is often clinical, but may be supplemented with dipstick testing and microbiological examination of urine. In patients with a suspected UTI, the absence of both nitrites and leukocyte esterase suggests the absence of infection, whereas the presence of both indicates a high probability of infection. Either one or the other positive is equivocal, as shown in Table 2.18 Nitrite production suggests gram-negative bacteria and other uropathogens (e.g. enterococcus) do not produce nitrites. However, there is some evidence that potentially significant bacteruria can be detected in some women with lower urinary tract symptoms and negative urine dipstick results.19

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Table 2.  Accuracy of dipstick testing for prediction of positive MSU. a) Nitrites and leukocyte-esterase: one or both positive Study population

Sensitivity (95% CI)

Specificity (95% CI)

General population Urology

0.75 (0.61–0.93) 0.88 (0.76–1.00)

0.70 (0.63–0.78) 0.87 (0.83–0.91)

MSU: mid-stream urine; CI: confidence interval.

Mid-stream urine testing (MSU) MSUs should be interpreted with caution. Specimens are now analysed by automated cell-counters measuring bacterial, erythrocyte and leukocyte concentrations and determining the necessity for culture based on these findings. However, bacterial counts are influenced by hydration status and prior antibiotic therapy, and some patients with UTI may have low bacterial numbers. The traditional threshold for defining “significant growth” on urine culture of 105 colony-forming units (CFU)/ml was derived from a study of women with pyelonephritis,20 and lower counts may be relevant to lower UTIs;21 20–40% of women with cystitis will have bacterial colony counts of 102–104 CFU/ml. Differentiating patients with “proven” UTIs from those with “no significant growth” reported on MSU can be problematic, and many trials have failed to show any difference in the way these two groups respond to intervention. Arguably, those describing appropriate symptoms with high bacterial and leukocyte counts but “no significant growth” who respond clinically to antibiotic treatment could be regarded as having UTI. Patients with consistently sterile urine specimens but persistent symptoms of dysuria and lower urinary tract symptoms (LUTS) should be assessed for other diagnoses, including urethral diverticulum or bladder pathology. In the absence of underlying pathology, a diagnosis of “urethral pain syndrome” is often applied. The provision of urine specimens for culture may not be essential in cases of simple UTI, yet can be useful to establish a firm diagnosis when there is clinical doubt and to elucidate the causative organisms and its sensitivities. MSU specimens sent from the clinic in the absence of any symptoms of current infection are of little use, and positive culture (i.e. asymptomatic bacteruria) is of doubtful significance. Asymptomatic bacteruria affects 1–5% of premenopausal and 2–10% of postmenopausal women. It is more prevalent in diabetics (5–25%) and is almost universal in patients with indwelling catheters. Although antibiotic treatment resolves bacteruria in the short term, the rates of bacteruria in the long term are similar to those who are not treated, and there is no effect on the rates of symptomatic

UTI in non-pregnant women. Similarly, MSU testing after antibiotic courses to check for resolution of infection is not necessary.

Investigation Assessment should include urine analysis (particularly looking for haematuria) and consideration of screening for a sexually transmitted infection or a vaginal infection. A post-micturition bladder scan may help to identify patients with bladder outflow obstruction, neurological disorders and other anomalies. Upper tract imaging, usually with intravenous urography (IVU) or ultrasound, is commonly requested, although there is little evidence to support this as routine practice. In a study of 60 women with recurrent UTIs, 91.7% IVUs were normal, although the nature of the abnormalities in the remaining 8.3% was not disclosed.22 Other series have found an even lower yield: In a study of 100 patients, only 1.4% of IVUs demonstrated a significant abnormality.23 Furthermore, Fair et al. demonstrated 5.5% of IVUs to be abnormal in 164 patients, but none of the findings affected management,24 and Engel et al. found anomalies in 11% of IVUs in 153 women, but none required treatment.25 A higher yield is found in high-risk patients, however. Nickel et al. reported on 186 women with recurrent UTIs undergoing investigation with cystoscopy and upper tract imaging.26 Significant abnormalities were detected only in those fulfilling prospectively defined selection criteria, as outlined in Table 3. In the 147 “high-risk” patients, upper tract anomalies were detected in eight (5%): three renal stones, three pelviureteric junction (PUJ) obstructions, one ureteric stricture and one vesicoureteral junction (VUJ) obstruction. Ultrasound combined with plain X-ray of the renal tract (KUB) allows upper tract evaluation with lower radiation exposure. In 94 women with RUTIs, ultrasound and KUB X-ray were compared with IVU, and no IVU abnormalities (eight of 94) were missed using ultrasound alone.27 Cystoscopy is another popular routine investigation though, again, the diagnostic yield is poor. Even in Nickel’s cohort of 147 high-risk women, the only significant findings were four patients with superficial bladder tumours (all of whom had frank or persistent microscopic haematuria) and two with bladder stones.26 Cystoscopy should be reserved for patients in whom there is haematuria (frank or dipstick) not associated with UTI or suspected structural abnormalities (e.g. incomplete bladder emptying, pneumaturia). In the majority of women, cystoscopy can safely be omitted.

Management Conservative management Initial management is generally conservative; general advice imparted may include increasing oral fluid intake,

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Christofides et al. Table 3.  Proposed indications for investigation of recurrent UTIs (after Nickel, 1991).26 Frank haematuria Persistent microscopic haematuria between infections Pyelonephritis Atypical presentation •  Obstructive symptoms •  Infection with urea-splitting organisms •  Persistent infection •  Clinical suspicion of stones b) Nitrites and leukocyte-esterase: both positive Study population

Sensitivity (95% CI)

Specificity (95% CI)

General population Urology

0.45 (0.27–0.75) 0.47 (0.37–0.57)

0.99 (0.98–1.00) 0.99 (0.97–1.00)

peri- and post-menopausal women.6,31 Even those on systemic hormone replacement therapy (HRT) may benefit from topical oestrogen application. Recent data suggest that vaginal oestrogen therapy is also of clinical benefit in pre-menopausal patients with RUTI.32

Methenamine Methenamine 1 g twice daily may be effective in preventing recurrent UTIs33 by acting through the production of formaldehyde from hexamine, which is bacteriostatic. Bacterial resistance does not occur, making methenamine an attractive first-line oral therapy before antibiotic strategies are employed. However, methenamine is not effective in complex UTIs. It is uncertain whether urinary acidification and the direct bacteriostatic effect of hippuric acid contribute significantly to its action.

UTIs: urinary tract infections; CI: confidence interval.

regular voiding, avoiding barrier contraception or spermicidal gels, avoiding bath additives and passing urine after sexual intercourse.28 However, such advice is not largely evidence based. The placebo effect may well be very important in RUTI patients, a proportion of whom may have general lower urinary tract dysfunction, and the subjective nature of the outcome measures further compromises the rigorous assessment of efficacy. Cranberry juice (Vaccinium macrocarpon) is a popular recommendation and is believed to act by the inhibition of adhesion of E. coli to the urothelium. The active components are proanthrocyanidins, which inhibit P-fimbrial adhesion, while fructose inhibits type-1 fimbria. However, cranberry juice may interfere with warfarin control and may increase oxalate excretion by up to 40%, posing theoretical problems in stone formers. In a Cochrane review,29 a meta-analysis of two randomised-controlled trials (RCT) of cranberry juice as prophylaxis for recurrent UTIs demonstrated a significant benefit for juice over placebo (response rates (RR) = 0.61, 95% confidence interval (CI) 0.40–0.91). Treated patients took 250 ml of pure, unsweetened juice twice daily. As commercially available cranberry juice contains at most 25% pure juice, patients would need to ingest 1 l twice daily to obtain an equivalent dose. Cranberry tablets would seem a more useful option. Another natural remedy with possible benefit is a combination of nasturtium and horseradish. A recent randomised controlled trial showed a reduction in the number of UTIs during a 90-day period.30 However, the numbers of UTIs were generally small (mean 0.43 and 0.77 in the treated and control groups, respectively, over 90 days).

Vaginal oestrogens The use of local oestrogen replacement has been shown to more than halve the frequency of recurrent UTIs in

Urethral dilatation and urethrotomy Urethral dilatation and urethrotomy for recurrent UTIs have fallen out of favour, and their efficacy is difficult to determine. Farrar et al. studied 200 patients with symptoms of recurrent UTIs who underwent Otis urethrotomy to 30–40 F.34 Ninety per cent were subjectively improved at six months, 85% at 12 months and 75% at more than two years’ follow-up. Similar results have been reported by others, with cure or improvement in around 75% of women.35–37 The benefit seems independent of MSU results38 or urethral calibre.36 Therefore, it is likely that any positive effect of urethrotomy on RUTI is mediated through some mechanism other than improving flow or drainage. Other series have failed to show any benefit from urethral dilatation. Choa et al. reported no change in urodynamics and symptomatology after six weeks in 64 adult patients randomised to either urethral dilatation or rigid cystoscopy.39 However, symptoms were improved in 72% after urethrotomy and only 46% after cystoscopy; the study was underpowered to detect any statistically significant difference. The urodynamic findings were unchanged, yet the role of urodynamics is doubtful in this patient group as it is well documented that few of them have incomplete bladder emptying and there is no consensus for the diagnosis of bladder outflow obstruction in females. Urethral dilatation or urethrotomy in these series are most commonly performed using the Otis urethrotome, up to 35–40 F diameter and in two or three planes. No incontinence was reported in the majority of studies. In a contemporary retrospective series at the authors’ institution (Nottingham City Hospital) in 2008, 100 women aged between 27 and 89 (mean 60 years) with RUTIs underwent urethral dilatation. Seventy per cent reported subjective improvement at a mean of six months’ follow-up (unpublished data). Eighty per cent had proven UTIs pre-operatively.

144 Neither age nor the presence or absence of “significant” bacteruria were predictive of outcome. At present there is no good evidence on which to base our assessment of urethral dilatation.

Prophylactic antibiotics Antibiotic strategies for controlling RUTIs include longterm prophylaxis, post-coital prophylaxis or patientinitiated therapy. Long-term prophylaxis, using a variety of agents, has been shown to be effective in reducing the recurrence rate of UTIs.40 In 11 RCTs, the number of microbiologically proven UTIs per year was between 0 and 0.9 per patient on antibiotics, and between 0.8 and 3.6 per patient on placebo. The relative risk was 0.15 of developing a clinical infection and 0.21 of a microbiologically proven infection, significantly favouring prophylaxis. Trials comparing different antibiotics have shown no difference,40 and examples of different prophylactic doses of commonly used antibiotics as recommended by the 2010 European Association of Urology (EAU) guidelines is given in Table 4. There is currently little evidence to support changing antibiotics periodically during prophylaxis unless resistance develops. Unfortunately, when antibiotics are discontinued, the rate of relapse is similar to that seen before prophylaxis.41 Other problems include an increased predisposition to vaginal candidiasis or other side effects.40 Particular caution should be exercised when prescribing long-term prophylaxis with nitrofurantoin because of the rare but severe complication of pulmonary or hepatic fibrosis, and alternative agents should be used where possible.42 For women reporting UTI precipitated by sexual intercourse, antibiotics may be administered post-coitally, thus avoiding continual antibiotic use. In a randomised study comparing daily prophylactic with post-coital ciprofloxacin in sexually active women, there was no detectable difference between the two groups.43 The rates of side effects were also not significantly different. Patient-initiated therapy may be considered as an alternative to regular prophylaxis. A three-day course of antibiotics is supplied so that treatment can be commenced as soon as symptoms occur.44 Bacterial isolates from urine specimens are increasingly exhibiting resistance to traditional antibiotics. Trimethoprim and amoxicillin resistance has become typical in community- and hospital-acquired UTIs,45 and resistance to other antibiotics varies regionally, perhaps reflecting local antibiotic policies. Our willingness to prescribe antibiotics for urinary symptoms should be examined in light of such increases in resistance patterns, with perhaps more emphasis being placed on non-antibiotic approaches. The use of antibiotic prophylaxis is best restricted to those patients in whom an infective cause for their symptoms is most convincing. Ideally, evidence from multiple

Journal of Clinical Urology 6(3) Table 4.  Example of prophylactic antibiotics schedules for RUTI. Agent

Dose, standard regime

Nitrofurantoin Trimethoprimsulphamethoxazole Trimethoprim Cefalexin Fosfomycin trometamil

50 mg / day 40/200 mg / day 100 mg / day 125 mg / day 3 g / 10 days

RUTI: recurrent urinary tract infection.

microbiological specimens should be available, and these will also help to select the most appropriate drug.

Vaccines Vaccines offer the potential to prevent infection without the undesired effects of chronic antibiotic use. A randomised, placebo-controlled trial of an orally active vaccine against E. coli showed a 34% reduction in microbiologically proven UTIs (0.84 versus 1.28 UTI per patient year).46 Patients received the OM-89 (Uro-Vaxom®) oral vaccine once daily for three months, no treatment for three months, then intermittent oral treatment for another three months, with a total follow-up of 12 months. It is unclear whether vaccination confers any lasting benefit after cessation of treatment. Although E. coli accounts for 80% of UTIs, OM-89 would be expected to have no effect on other uropathogens.

Probiotics Probiotics aim to overcome vaginal colonisation by uropathogenic bacteria by promoting colonisation with non-pathogenic commensals. Interference with adhesion, biofilm formation, bacterial invasion, expression of virulence factors and modulation of host defences have been proposed as potential mechanisms of action. Lactobacilli, the dominant normal vaginal commensal, has been the most extensively studied probiotic, yet different strains may have widely differing antiuropathogenic properties, and the majority of marketed probiotics have little evidence of efficacy in the urinary tract.47 Several clinical trials have demonstrated that certain Lactobacillus species, mainly L. Rhamnosus, L. Reuteri and L. Fermentum, can be given orally or vaginally with resulting colonisation of the vagina, reduction in vaginal coliform counts, and even reduction in UTI recurrence. In one study of 52 women with RUTI, recurrence rates were reduced from six per patient-year to 1.6 per patient-year using once weekly vaginal suppositories of GR-1/B-54.48 However, the quality and variability of the published data precludes any definite conclusions on the efficacy of vaginal probiotics for UTI prevention.

145

Christofides et al.

Paent with: 3 or more UTI in 6 months 4 or more UTI in 12 months

Inial assessment

bladder scan dipsck of urine consider STI?

pregnancy neurological disease long-term catheters renal stones pneumaturia residue > 150ml No haematuria without UTI persistent infecon

NB. does not include asymptomatic bacteruria (bacteruria in the absence of UTI symptoms)

Yes

Condion-specific management

Yes Cystoscopy

pyelonephris urea-spli ng organisms (e.g. Proteus) clinical suspicion of stones

Yes

USS and Xray KUB

Advice sheet Lifestyle management Consider vaginal oestrogens

Intercourseassociated UTIs Post-coital anbiocs

GP follow-up at 6/12 Failed inial management

Other treatments?

Follow-up assessment at 6/12 Improve

Discharge

For example: methanamine 1g bd on demand anbiocs anbioc prophylaxis intravesical GAG layer replacement urethral dilataon vaginal probiocs

Figure 2.  Possible algorithm for the management of recurrent UTI.

UTI: urinary tract infection; STI: sexually transmitted infection; USS: ureteroscopic stone surgery; KUB: ultrasound combined with plain X-ray of the renal tract; GP: general practitioner; GAG: glycosaminoglycan.

146 Conflicting results have been published regarding oral probiotics. Although oral probiotics (GR-1/RC-14) led to a significant reduction in uropathogenic colonisation of the vagina, there is little evidence of reductions in UTI recurrence rates in humans.

GAG layer supplements Intravesical instillations of hyaluronic acid aim to restore the GAG layer, which lines the bladder urothelium, thus reducing bacterial adherence. A pilot study of Cystistat (40 mg in 50 ml) used in weekly instillations for four weeks followed by monthly instillations for four months49 reported a reduction in UTIs from 4.3 per patient-year to 0.3 per patient-year. No UTIs were recorded during the five-month treatment period, and 70% of patients remained recurrence free at 12 months’ follow-up.

Conclusion Recurrent UTIs are challenging to manage, especially when the microbiological results are equivocal. Treatments that have been shown to be clinically effective in preventing or reducing recurrences include vaginal oestrogens, antibiotic prophylaxis and vaccination. The roles of probiotics and intravesical instillations require further investigation, and the benefits of urethral dilatation or urethrotomy remain unclear. A possible management pathway is illustrated in Figure 2, based on some of the principles discussed in this article. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest The authors declare that there are no conflicts of interest.

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