1. Urinary Tract Infections in Women: Link between Basic Research and Clinical Aspects James R. Johnson, MD Mucosal and Vaccine Research Center VA Medical Center University of Minnesota Minneapolis, MN VHAVHAVHAVHAUM

2. UTI in Women Acute cystitis Acute cystitis – Per yr, 10% of women have ≥ 1 episode – Most episodes occur in women with prior UTI – 33% of women have ≥ 1 episode by age 24 – 11 million episodes per yr. in U.S. – $1.6 billion per yr. direct health care costs Acute pyelonephritis Acute pyelonephritis – 700,000 episodes per yr. in U.S. Foxman Ann Epidemiol 2000

3. Cystitis Morbidity Foxman B. AJPH 1985

4. How Has Basic Research Helped? Extraintestinal pathogenic E. coli (ExPEC) Extraintestinal pathogenic E. coli (ExPEC) – Receptor analogue therapy (& other treatments) – Vaccines Fecal-perineal-urethral hypothesis Fecal-perineal-urethral hypothesis – Vaginal microflora Lactobacilli vs. E. coliLactobacilli vs. E. coli Spermicide, estrogen, antibioticsSpermicide, estrogen, antibiotics Epithelial cell adherence (nonsecretors)Epithelial cell adherence (nonsecretors) – Exogenous reservoirs Sex partners, household members, pets, food supplySex partners, household members, pets, food supply

5. Postulated Sequence of Events in Urinary Tract Infection Input of virulent and resistant strains Pathogenesis Reservoir

6. The Three “Families” of E. coli Commensal E. coli Commensal E. coli Diarrheagenic E. coli Diarrheagenic E. coli – EHEC, ETEC, EPEC, EAEC, EIEC, DAEC, Shigella Extraintestinal pathogenic E. coli (ExPEC) Extraintestinal pathogenic E. coli (ExPEC)

7. Characteristics of Three E. coli Groups

8. Clinical vs. Fecal E. coli Clinical non-ExPEC ExPEC Fecal (Host Defenses) 4:14:14:14:1 1:41:41:41:4

9. ExPECCell from Eisenstein B.

10. Practical Relevance of Virulence Factors Interventions Interventions – drugs, other treatments (microbe or host) – vaccines ?Diagnostic tests? ?Diagnostic tests? – length of Rx – unrecognized host compromise – reservoir (family members?) Research tool Research tool – identify reservoirs – track transmission – understand drug-resistant strains

12. Host Cell

13. ReceptorAnalogueTherapy

14. Cranberry Products and UTI Cranberry & blueberry juice contain inhibitors of type 1 and P fimbriae Cranberry & blueberry juice contain inhibitors of type 1 and P fimbriae (Zafriri AAC 1989; Ofek NEJM 1991; Howell NEJM 1998) Urine exhibits anti-adherence activity after consumption of cranberry juice Urine exhibits anti-adherence activity after consumption of cranberry juice (Sobota J Urol 1984; Schmidt Microbios 1988) Clinical trials (cranberry +/- lingonberry) Clinical trials (cranberry +/- lingonberry) – Positive results (ABU, cystitis); small, design flaws – Additional studies needed (basic and clinical) (Kontiokari BMJ 2001; Walker J Fam Prac 1997; Jepson Cochrane Lib 2002)

16. Interplay Between Host Defenses and E. coli within the Bladder PNAS. 2000; 97:8834 FimH vaccine

17. Postulated Sequence of Events in Urinary Tract Infection Pathogenesis Reservoir

18. Fecal-Perineal-Urethral Hypothesis In most women with acute UTI the causative organism is present in host’s vaginal and fecal flora at time of UTI In most women with acute UTI the causative organism is present in host’s vaginal and fecal flora at time of UTI Usually as predominant strain Usually as predominant strain Other strains, if present, appear less virulent (by O antigens, virulence factors) Other strains, if present, appear less virulent (by O antigens, virulence factors) Vaginal colonization with E. coli (ExPEC) is a risk factor for UTI Vaginal colonization with E. coli (ExPEC) is a risk factor for UTI So vaginal (fecal) flora = crucial reservoir So vaginal (fecal) flora = crucial reservoir

19. Risk Factors for Recurrent UTI in Pre-menopausal Women Sexual intercourse, new sex partner Sexual intercourse, new sex partner Nicolle JID 1982, Scholes JID 2000Nicolle JID 1982, Scholes JID 2000 Spermicide-diaphragm use Spermicide-diaphragm use Hooton JAMA 1991, Scholes JID 2000Hooton JAMA 1991, Scholes JID 2000 Recent antibiotic use (15-28d) Recent antibiotic use (15-28d) Smith CID 1997Smith CID 1997 Recent UTI (Hooton NEJM 1996) Recent UTI (Hooton NEJM 1996) Nonsecretor of blood group substances Nonsecretor of blood group substances Sheinfeld NEJM 1989Sheinfeld NEJM 1989 Maternal UTI history (Scholes JID 2000) Maternal UTI history (Scholes JID 2000) First UTI prior to age 16 (Scholes JID 2000 ) First UTI prior to age 16 (Scholes JID 2000 )

20. SpermicideAntibiotics Estrogen lack Vaginal lactobacilli (H 2 O 2 ) Vaginal pH Vaginal E. coli Risk UTI (?)Geneticfactors

22. Diaphragm-Spermicide Exposure Associated with markedly increased introital colonization with E. coli Associated with markedly increased introital colonization with E. coli Also lactobacillus depletion, increased vaginal pH, colonization with Candida, group B Strep, group D Strep Also lactobacillus depletion, increased vaginal pH, colonization with Candida, group B Strep, group D Strep Likely due to differential microbicidal action of N-9 Likely due to differential microbicidal action of N-9 Hooten et al. CID 1994

23. Spermicide

24. Relationship of Vaginal E.coli and H 2 O 2 - Producing Lactobacilli Gupta K et al. JID 1998 Percent of Women with E. coli * * * p<.01 (OR 4.0; 95% CI [1.3-11.6]) (OR 5.0; 95% CI [1.3-20.0]) * (RUTI)

25. Topical Estrogen Prevents RUTI in Postmenopausal Women Placebo vs. estriol x 8 mos. (n = 93) Placebo vs. estriol x 8 mos. (n = 93) Estriol treatment Estriol treatment – Restored lactobacilli (0 --> 61%) – Reduced vaginal pH (5.5 --> 3.8) – Reduced vaginal E. coli colonization (67% --> 31%) – Reduced UTI risk (6/yr --> 0.5/yr.) Further study of mechanism needed Further study of mechanism needed Raz NEJM 1993

26. Vaginal Microbial Defense System

27. Association of Nonsecretor Phenotype with Recurrent UTI RR(95% CI) Blackwell, et al. 19823.1(2.0 - 6.8) Blackwell, et al. 19823.1(2.0 - 6.8) Shinefeld, et al. 19893.4(1.5 - 7.9) Shinefeld, et al. 19893.4(1.5 - 7.9) Hooten, et al.19894.0(1.5 - 8.5) Hooten, et al.19894.0(1.5 - 8.5) Nonsecretors have increased vaginal E. coli Nonsecretors have increased vaginal E. coli

28. Vaginal Epithelial Cell Glycosphingolipids from Secretors and Nonsecretors from Secretors and NonsecretorsNonsecretors Secretors SGG = preferredreceptorfor P fimbriae Stapleton A.

29. Management Options for Recurrent UTI Behavior change (spermicide use) Behavior change (spermicide use) ?Cranberry, probiotics, vaccine? ?Cranberry, probiotics, vaccine? Topical estrogen (postmenopausal) Topical estrogen (postmenopausal) Antimicrobial therapy Antimicrobial therapy – continuous prophylaxis Nicolle Infection 1992Nicolle Infection 1992 – intermittent patient-initiated therapy Wong Ann Intern Med 1985; Gupta Ann Intern Med 2001Wong Ann Intern Med 1985; Gupta Ann Intern Med 2001 – post-coital prophylaxis Stapleton JAMA 1990; Pfau J Urol 1994Stapleton JAMA 1990; Pfau J Urol 1994

30. Postulated Sequence of Events in Urinary Tract Infection Input of virulent and resistant strains Pathogenesis Reservoir

31. Spread of E. coli Wildlife (Birds, Rodents, Insects) Environmental (Dust, Waste) Farm animal Pets Feeds Humans Fruits and vegetables From Nordmann P. 2005 CNFMI

32. Person-to-Person Transmission of Uropathogenic E. coli Hospital pyelonephritis outbreaks (Tullus JID 1984) Hospital pyelonephritis outbreaks (Tullus JID 1984) Case reports: “sexually transmitted UTI” Case reports: “sexually transmitted UTI” Wong JAMA 1983; Hebelka SJID 1993; Bailey Nephron 1986Wong JAMA 1983; Hebelka SJID 1993; Bailey Nephron 1986 Same-strain colonization (cohort studies) Same-strain colonization (cohort studies) – Sex partners (Foxman JID 1996) associated with specific VFs, sexual practices associated with specific VFs, sexual practices (Foxman Am J Epi 2002) – Other household members (including pets) (Murray Ann Intern Med 2004)

33. E. coli Isolates from Women with UTI and Their Male Sex Partners Foxman et al. 1996

34. Murray et al. Ann Intern Med 2004 E. coli colonizationpatterns among 3 householdmembers(woman, man, & cat) Clone 1 Multiple-hostclones: 1, 4, 6, 11

37. Sharing of E. coli within Households Cross-sectional point prevalence survey Cross-sectional point prevalence survey 53 households (HHs) 53 households (HHs) 181 individuals (adults, children, pets) 181 individuals (adults, children, pets) Selective fecal cultures for unique clones Selective fecal cultures for unique clones 287 E.coli clones (PFGE) 287 E.coli clones (PFGE) 43 (15%) clones shared within HH 43 (15%) clones shared within HH – 19: humans only; 10: pets only; 14: humans + pets 28 (53%) households had ≥ 1 shared E. coli clone 28 (53%) households had ≥ 1 shared E. coli clone # shared clones per HH: 1 (18 HH), 2 (5), 3 (4), 4 (1) # shared clones per HH: 1 (18 HH), 2 (5), 3 (4), 4 (1) by HH size: 2 (23%), 3 (60%), 4-5 (72%), ≥ 6 (100%) by HH size: 2 (23%), 3 (60%), 4-5 (72%), ≥ 6 (100%) (JRJ unpublished)

40. Escherichia coli in 1,648 Retail Food Items Johnson et al. JID 2005

41. ExPEC + O-UTI (n = 17) (390 E. coli-positive retail food items)

42. RAPD profiles of food-sourcevs. human clinical E. coli isolates CGA Johnson et al. JID 2005

44. Postulated Sequence of Events in Urinary Tract Infection Input of virulent and resistant strains Pathogenesis Reservoir

45. from Larson G.