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Urinary Tract Infections in Women: Link between Basic Research and Clinical Aspects

V H A. UM. 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. UTI in Women. Acute cystitis Per yr, 10% of women have ≥ 1 episode

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Urinary Tract Infections in Women: Link between Basic Research and Clinical Aspects

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  1. VHA UM 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

  2. UTI in Women • 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 • 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) • Receptor analogue therapy (& other treatments) • Vaccines • Fecal-perineal-urethral hypothesis • Vaginal microflora • Lactobacilli vs. E. coli • Spermicide, estrogen, antibiotics • Epithelial cell adherence (nonsecretors) • Exogenous reservoirs • Sex partners, household members, pets, food supply

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

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

  7. Characteristics of ThreeE. coli Groups

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

  9. ExPEC Cell from Eisenstein B.

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

  11. Host Cell

  12. Receptor Analogue Therapy

  13. Cranberry Products and UTI • 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 (Sobota J Urol 1984; Schmidt Microbios 1988) • 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)

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

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

  16. 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 • Usually as predominant strain • Other strains, if present, appear less virulent (by O antigens, virulence factors) • Vaginal colonization with E. coli (ExPEC) is a risk factor for UTI • So vaginal (fecal) flora = crucial reservoir

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

  18. Genetic factors Spermicide Antibiotics Estrogen lack Vaginal lactobacilli (H2O2) Vaginal pH Vaginal E. coli Risk UTI (?)

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

  20. Spermicide

  21. Percent of Women with E. coli (OR 5.0; 95% CI [1.3-20.0]) * p<.01 * (OR 4.0; 95% CI [1.3-11.6]) * * Gupta K et al. JID 1998 Relationship of Vaginal E.coli and H2O2-Producing Lactobacilli (RUTI)

  22. Topical Estrogen Prevents RUTI in Postmenopausal Women • Placebo vs. estriol x 8 mos. (n = 93) • 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 • Raz NEJM 1993

  23. Vaginal Microbial Defense System

  24. Association of Nonsecretor Phenotype with Recurrent UTI RR(95% CI) • Blackwell, et al. 1982 3.1 (2.0 - 6.8) • Shinefeld, et al. 1989 3.4 (1.5 - 7.9) • Hooten, et al. 1989 4.0 (1.5 - 8.5) • Nonsecretors have increased vaginal E. coli

  25. Vaginal Epithelial Cell Glycosphingolipids from Secretors and Nonsecretors Secretors Nonsecretors SGG = preferred receptor for P fimbriae Stapleton A.

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

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

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

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

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

  31. Clone 1 E. coli colonization patterns among 3 household members (woman, man, & cat) Multiple-host clones: 1, 4, 6, 11 Murray et al. Ann Intern Med 2004

  32. Sharing of E. coli within Households • Cross-sectional point prevalence survey • 53 households (HHs) • 181 individuals (adults, children, pets) • Selective fecal cultures for unique clones • 287 E.coli clones (PFGE) • 43 (15%) clones shared within HH • 19: humans only; 10: pets only; 14: humans + pets • 28 (53%) households had ≥ 1 shared E. coli clone • # 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%) (JRJ unpublished)

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

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

  35. RAPD profiles of food-source vs. human clinical E. coli isolates CGA Johnson et al. JID 2005

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

  37. from Larson G.

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