1) The document provides an evidence-based approach for managing recurrent urinary tract infections (UTIs) in women. 2) It discusses the pathogenesis of recurrent UTIs involving both microbial and host factors. 3) Non-antibiotic prophylaxis options like cranberry, probiotics, vaginal estrogen, and intravesical instillations are recommended first due to concerns with long-term antibiotic use, though their effectiveness is limited.

1. Evidence Based Approach for
Recurrent UTI
Wafaa B Basta, MRCOG
Consultant Ob/Gyn MTH
ERC member
Dubai, 9th of December 2016

4. Objectives:
• To understand the pathogenesis of recurrent UTI in women.
• To appreciate the value and limitations of urinary tract imaging.
• To develop an appropriate management strategy according to
latest evidence.

5. Recurrent UTI
• ≥2 acute infections within 6 months or
• ≥ 3 in a year
 The strongest predictors of recurrence: haematuria and
urgency during the initial infection
Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990;80:331-3.

6. Incidence of Recurrent UTI in Women
• 50% : one UTI /lifetime
27% : one recurrence within
the 6 months following initial
infection.
Renard, Infect Dis Ther, 2015

7. Recurrent or Incompletely treated infection
 Recurrent infection = re-infection, different organism, after 2
weeks , are often associated with increased host susceptibility .
 Incompletely treated=Relapse : within 2 weeks , same strain,
associated with an underlying pathological, anatomical or
functional abnormality.
Harris N, Teo R, Mayne C, Tincello D. Recurrent urinary tract infection in gynaecological practice. The Obstetrician & Gynaecologist 2008;10:17-
21.

8. Pathogenesis of recurrent UTI
 Bacterial adherence to the uroepithelium
 Colonisation
 Tissue damage
 Invasion
 Dissemination.

9. Pathogenesis of recurrent UTI
Complex interaction between host and micro-organism.

10. Microbial factors
1. Adherence mechanisms
2. Direct virulence against the host
3. Antibiotic resistance

11. Microbial factors
 Adherence mechanisms
1. Fimbriae (pili):
Type I pili (majority of E. coli causing lower urinary tract
infection)
Type P pili (80% of E. coli isolates causing pyelonephritis).
2. Afimbrial adherence mechanisms :the glycocalix forming the
bacterial cell wall (e.g. lipopolysaccharide).

12. Microbial factors
 Direct virulence against the host:
Bacterial production of endotoxin, exotoxin and haemolysin ---
-microbial invasion, generalised toxaemia with systemic
urosepsis.

13. Microbial factors
 Antibiotic resistance by:
Reduced drug accumulation as a result of active efflux
Antibiotic inactivation (e.g. enzymatic deactivation of penicillin
by beta-lactamases)
Alteration of target sites (e.g. alteration of penicillin binding
protein [PBP] in MRSA).

14. Host factors
 Intrinsic mechanisms that inhibit bacterial colonization:
Unobstructed urine flow
 mechanical washout of bacteria
 rapid urothelial cell turnover.

15. Host factors
Factors that augment the barrier function and inhibit bacterial
adherence:
Uro-mucoid (also known as Tamm-Horsfall protein)
 Mucopolysaccharides
Immunoglobulin

16. Host factors
Factors that inhibits colonization by many pathogenic bacteria:
 Vaginal colonisation by lactobacilli -----production of lactic acid--
--maintain a low pH

17. Host factors
Other factors that also known to influence susceptibility to UTI:
Interleukin-8 receptor (CXCR1) expression
certain human leukocyte antigen (HLA) loci
 Toll-like receptors
 Tamm-Horsfall protein expression
Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis 2004; 4:631-5.
doi:10.1016/S1473-3099(04)01147-8
Svanborg C, Bergsten G, Fischer H, Godaly G, Gustafsson M, Karpman D, et al. Uropathogenic Escherichia coli as a model of host-parasite interaction.
Curr Opin Microbiol 2006;9:33-9. doi:10.1016/j.mib.2005.12.012
Sirard JC, Bayardo M, Didierlaurent A. Pathogen-specific TLR signaling in mucosa: mutual contribution of microbial TLR agonists and virulence factors. Eur
J Immunol 2006;36:260-3. doi:10.1002/eji.200535777

18. Pathogens in UTI
The recent ECO·SENS study ( 16 European countries )
 70-80% : E. coli.
 Gram-positive organisms (especially Staphylococcus saprophyticus) 8%
 Other organisms :
 Klebsiella
 Pseudomonas spp
 Proteus spp.
Enterococcus faecalis.
 Genitourinary candidiasis and tuberculosis can cause infection, particularly
in immunocompromised women.
Kahlmeter G. Prevalence and antimicrobial susceptibility of pathogens in uncomplicated cystitis in Europe. The ECO.SENS study. Int J
Antimicrob Agents 2003;22 Suppl 2:49-52. doi:10.1016/S0924-8579(03)00229-2

19. Risk factors
 Recurrent UTIs are common among young, healthy women, even
though they generally have anatomically and physiologically
normal urinary tracts
(LE: 2a).
. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents, 2001. 17(4): p. 259-68.

20. Risk factors
 In young healthy women:
 sexual intercourse (most important)
spermicide use
 having a new sex partner
 having a mother with history of UTI
having UTI during childhood.

21. Risk factors
 The common risk factors in postmenopausal women are:
 History of UTI before menopause
Urinary incontinence
Atrophic vaginitis due to oestrogen deficiency
Cystocoele
Increased post-void urine volume
Blood group antigen secretory status
Urine catheterisation and functional status deterioration in
elderly institutionalised women
Foxman B, et al. Urinary tract infection among women aged 40 to 65: behavioral and sexual risk factors. J Clin Epidemiol, 2001. 54(7): p. 710-8.
http://www.ncbi.nlm.nih.gov/pubmed/11438412

22. Risk factors
 There is growing evidence that UTIs in children and adults are
associated with genetic mutations that affect the innate immune
system .
Hooton TM, Prevention of recurrent urogenital tract infections in adult women, in EAU/International Consultation on Urological Infections. K.G.
Naber, et al., Editors. 2010, European Association of Urology: The Netherlands. p. 236-239.

23. Risk factors
 Factors although associated with UTI in general but studies
have documented the lack of association with recurrent UTI
reduced fluid intake
 habitual and post-coitial delayed urination
wiping from back to front after defection
 douching
wearing occlusive underwear
• Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990;80:331-3.
• Hooton TM, Scholes D, Stapleton AE, Roberts PL, Winter C, Gupta K, et al. A prospective study of asymptomatic bacteriuria in sexually active
young women. N Engl J Med 2000;343:992-7.

24. Diagnosis of Recurrent UTI
 Symptoms
 Dipstick
 C&S
 US
 Imaging
 Cystoscope

25. Urine Dipstick
 meta- analysis:
 A useful screening test ( nitrite + leucocyte esterase)
Nitrites are produced from the reduction of urea by urea-
splitting bacteria.
Leucocyte esterase is produced as a result of leucocyte
degradation in urine .It is a surrogate marker of pyuria.
 limited sensitivity and/or specificity when used in isolation.
St John A, Boyd JC, Lowes AJ, Price CP. The use of urinary dipstick tests to exclude urinary tract infection: a systematic review of the literature.
Am J Clin Pathol 2006;126:428-36.

26. Midstream specimen of urine (MSSU)
 Recurrent UTIs need to be diagnosed by urine culture
(LE: 4, GR: A).

27. Midstream specimen of urine (MSSU)
 The gold standard : quantitative culture and sensitivity testing
of a freshly voided MSSU.
 Colony-forming units (CFUs) of is 100 000 /ml: indicate
infection .
 However, clinically significant UTI can still be present with
lower counts.
Kass EH. Bacteriuria and the diagnosis of infections of the urinary tract; with observations on the use of methionine as a urinary antiseptic. AMA
Arch Intern Med 1957;100:709-14.

28. Midstream specimen of urine (MSSU)
 Pyuria: >10 WBCs /HPF
 Pyuria as low as 2-5 WBCs/HPF important with appropriate
symptoms.
 Sterile pyuria: tuberculosis, although there are other causes
of sterile pyuria.

29. Residual Urine
 Residual urine should be excluded
(LE: 4,GR: B).

30. Further Diagnostic evaluation
 Imaging of the upper urinary tract and cystoscopy are not routinely
recommended for evaluation of women with recurrent UTIs
(LE: 1b, GR: B)
 However, it should be performed without delay in atypical cases.
Fowler JE, Jr., et al. Excretory urography, cystography, and cystoscopy in the evaluation of women with urinary-tract infection: a prospective study.
N Engl J Med, 1981. 304(8): p. 462-5. [No abstract available]
http://www.ncbi.nlm.nih.gov/pubmed/7453771

31. Further Diagnostic evaluation
 If renal stones are suspected, X-ray (KUB) , (IVU) or (CT)
 If voiding dysfunction is likely, uroflowometry .
11 Ulleryd P, Zackrisson B, Aus G, Bergdahl G, Hugosson J, Sandberg T. Selective urological evaluation in men with febrile urinary tract infection.
BJU Int 2001;88:15-20. doi:10.1046/j.1464-410x.2001.02252.x

32. Cystoscopy
 Voiding difficulty, acute retention or haematuria.
 Recent data has shown that up to 8% of women >50 years of age
with recurrent infection will have significant abnormalities detected
during cystoscopy.
Lawrentschuk N, Ooi J, Pang A, Naidu KS, Botlon DM. Cystoscopy in women with recurrent urinary tract infection. Int J Urol 2006;13:350-3.
doi:10.1111/j.1442-2042.2006.01316.x

33. Treatment of Recurrent UTI

35. The optimum Treatment of Recurrent UTI
is the prevention of recurrence
1.Behavioral Modification
2. Non Antibiotic Prophylaxis
3. Antibiotic Prophylaxis

36. Grabe M et al. European Association of Urology Guidelines on Urological Infections 2015
1. Behavioral
Modification
2. Non Antibiotic
Prophylaxis
3. Antibiotic
Prophylaxis
1. General prophylaxis + Behavioral Modification
2. Prefer the non-antimicrobial prevention, in order to
spare antibiotics
3. Consider the antimicrobial prevention, only when the
non-antimicrobials have been unsuccessful
EAU Guidelines Recommend Non-
Antimicrobial Prevention

37. Behavioral Modification
 Drinking an adequate daily fluid intake encourage mechanical washout of
bacteria .

38. Behavioral Modification
 Void after sexual intercourse
 Empty the bladder as
completely as possible
 Shower after sexual intercourse
 Avoid the use of spermicide
 Wipe from front to back

39. Residual urine management
 Significant residual urine should be treated optimally, which also
includes clean intermittent catheterisation (CIC) when valued
necessary.

40. Non Antibiotic Prophylaxis
 1. Cranberry
 2. Lactobacillus probiotics - vaginal flora regeneration
 3. Vaginal oestrogen in postmenopausal women
 4. Immunoactive prophylaxis - OM-89 (Uro-Vaxom)
 5. D - Mannose
 6. Intra-vesical instillations for GAG layer replenishment

41. - Active components:
proanthocyanidins
- Anti-adhesive activity on bacterial
fimbriae (P fimbriae)
Cranberry (Vaccinium macrocarpon)

42. Cranberry did not reduce symptomatic UTI
in:
24 studies
4473 patients
• Symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04)
• Women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31)
• Elderly population (RR 0.75, 95% CI 0.39 to 1.44)
• Pregnant women (RR 1.04, 95% CI 0.97 to 1.17)
• Children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22)
• People with neuropathic bladder/spinal injury (RR 0.95, 95%CI:
0.75- 1.20)
Cranberry (Vaccinium macrocarpon)

43. However:
24 studies
4473 patients
• Many studies reported
• Low compliance
• High withdrawal/dropout rates (cranberry juice)
• Active ingredient content
• Serious differences
• Or not reported at all
Cranberry (Vaccinium macrocarpon)

44. Cranberry (Vaccinium macrocarpon)
European Association of Urology 2015 Guidelines on Urological Infections
M. Grabe (Chair), R. Bartoletti, T.E. Bjerklund Johansen, T. Cai (Guidelines Associate), M. �ek, B. Kaves (Guidelines Associate), K.G.
Naber, R.S. Pickard, P. Tenke, F. Wagenlehner, B. Wullt
©

45. • Restore the vaginal lactobacilli
• Compete with urogenital pathogens
• Prevent bacterial vaginosis
• After long or repeated antibiotic courses
Use vaginal pH
tests/kits for
measure!
Vaginal Lactobacillus probiotics

46. Vaginal Lactobacillus probiotics
 Accessibility of clinically proven probiotics for UTI prophylaxis is
currently not universal.
Probiotics, intra-vaginal (Lactobacillus sp) 1/2 weekly
Lactobacillus crispatus (Gr. B; LE 1b)
L. rhamnosus GR-1 and L. reuteri RC-14 (Gr. C; LE 4)
Daily use of the oral Probiotic with strains GR-1 and RC-14 is worth
testing , no recommendations are still possible.

47. Vaginal oestrogen in postmenopausal women
Vaginal Estrogens
(Gr. C; LE 1b)
• Vaginal but not oral oestrogen, showed a trend towards
preventing UTI recurrences, but vaginal irritation occurred in 6 -
20% of women
• Help shift the vaginal flora from potentially pathogenic
enterobacteria to protective lactobacilli.
Beerepoot MA, et al. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized
controlled trials. J Urol, 2013. 190(6): p. 1981-9. http://www.ncbi.nlm.nih.gov/pubmed/23867306
Raz R, et al. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J
Med, 1993. 329(11): p. 753-6. http://www.ncbi.nlm.nih.gov/pubmed/8350884

48. Immuno-active prophylaxis

49. Immuno-active prophylaxis

50. Prophylaxis with d-mannose

51. Endo-vesical instillation of hyaluronic acid
and chondroitin sulphate

52. Antibiotic prophylaxis
Consider antimicrobial prevention only after counselling and
behavioural modification has been attempted & when the non-
antimicrobials have been unsuccessful!
Continuous daily, weekly for longer periods of time
(3-6 months)
Post-coital
(LE: 4, GR: B)

53. Antibiotics for prevention comment
nitrofurantoin 50 mg /day
nitrofurantoin 100 mg/day macrocrystal
fosfomycin 3 g every 10 days
cefaclor 250 mg /day in pregnancy
cephalexin 125 mg /day in pregnancy
cephalexin 250 mg /day in pregnancy
trimethoprim/sulfamethoxazole 40/200
mg/day
high resistance
Continuous Antibiotic prophylaxis

54. Antibiotic prophylaxis

55. Antibiotic Prophylaxis
 Drawbacks:
 Candidiasis
GIT upset
Antibiotic resistance
60% recurrence when prophylactic treatment is stopped
Albert X, Huertas I, Pereir6 II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women.
Cochrane Database Syst Rev 2004:CD001209.
15 Schooff M, Hill K. Antibiotics for recurrent urinary tract infections. Am Fam Physician 2005;71:1301-2.

56. Antibiotic prophylaxis
 Choice of antibiotics based upon
the identification and susceptibility pattern of the organism
causing the UTI
 the patient's history of drug allergies
the ecological collateral effects including bacterial selection
of resistance by the chosen antimicrobial.

57. Antibiotic prophylaxis
 Ecological collateral effects mean that oral fluoroquinolones and cephalosporins
are no longer recommended routinely, except in specific clinical situations.
 The worldwide increase of E. coli resistance against trimethoprim casts doubts on
trimethoprim with or without a sulphonamide to be an effective prophylactic agent
still.

58. Super-Bugs
No antibiotics currently available for the treatment of multi-
resistant strains.
We use antibiotics when they're not necessary and accelerate the potential that superbugs will
develop. (Piotr Marcinski/Shutterstock)

60. Resistance rates of E.coli

61. Resistance rates of E.coli
E. Coli That Cause Urinary Tract Infections are Now Resistant to Antibiotics By Veronique Greenwood | May 2, 2012 11:46 am

63.  Rare but serious hepatic
and pulmonary side effects
 DDL in 2011 recommended
not to initiate any
prophylaxis with
nitrofurantoin
 !
Nitrofurantoin side eeffects and rrestriction of use in
Prophylaxis

64. Altogether this underlines the need for reconsidering
long-term antibiotic prophylaxis in recurrent UTI and
assess in each individual case effective alternative
preventive measures.

65. Grabe M et al. European Association of Urology Guidelines on Urological Infections 2010-2105; www.uroweb.org
*** Recommended non-antimicrobial prophylaxis ***
Immunoactive prophylaxis
• E. coli bacterial extract “OM-89” (Uro-Vaxom®) (Gr. B; LE 1a)
• Vaginal vaccine
– Urovac® (Gr. C; LE 1a)
– StroVac® and Solco-Urovac® (Gr. C; LE 1a)
Probiotics, intra-vaginal (Lactobacillus sp)
• Lactobacillus crispatus (Gr. B; LE 1b)
• L. rhamnosus GR-1 and L. reuteri RC-14 (Gr. C; LE 4)
Estrogens (Gr. C; LE 1b)
EAU Guidelines 2016

66. Algorithm for use in management of recurrent
UTI
 1. Ensure history is appropriate for recurrent UTI.
 2. Confirm bacteriological evidence of infection.
 3. Exclude underlying anatomical or functional abnormality using
appropriate imaging and endoscopic evaluation.
 4. Advise on prophylactic lifestyle changes.
 5. Consider non antimicrobial strategies.
 6. Consider a prophylactic antibiotic regimen.

67. Summary
 Recurrent UTI is a common problem encountered in many areas of clinical
practice.
 It is a cause of significant morbidity: urinary infection is one of the commonest
indications for antibiotic prescription in community and hospital settings.
 The majority of cases are uncomplicated and respond rapidly to appropriate
treatment.
 In the management of women with any type of UTI, it is important to have an
appreciation of the pathogenesis, host and bacterial interaction, methods of
diagnosis, treatment algorithms and local antibiotic sensitivities.
 It should be remembered that 20-30% of women with UTI develop at least one
recurrent infection

68. Thank you for your attention
Much
better
now