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
VHA
UM
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
Cystitis Morbidity
Number of Days
7
6
5
4
3
2
1
0
Symptoms
Restricted
Activity
Unable to Work
In Bed
Foxman B. AJPH 1985
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
Postulated Sequence of Events
in Urinary Tract Infection
Reservoir
Pathogenesis
Input of
virulent
and
resistant
strains
The Three “Families” of E. coli
• Commensal E. coli
• Diarrheagenic E. coli
– EHEC, ETEC, EPEC, EAEC, EIEC, DAEC, Shigella
• Extraintestinal pathogenic E. coli
(ExPEC)
Characteristics of Three
E. coli Groups
E. coli Group
Colonization
Com- Enteric ExPEC
mensal
+++
+
Diarrhea
-
+++
-
Extraintestinal
Infection
+
-
+++
Clinical vs. Fecal E. coli
Clinical
Fecal
(Host Defenses)
ExPEC
4:1
non-ExPEC
1:4
ExPEC
Cell
from Eisenstein B.
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
Host Cell
Receptor
Analogue
Therapy
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)
Interplay Between Host Defenses and
E. coli within the Bladder
FimH vaccine
PNAS. 2000; 97:8834
Postulated Sequence of Events
in Urinary Tract Infection
Reservoir
Pathogenesis
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
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 )
Spermicide
Antibiotics
Estrogen lack
(?)
Vaginal lactobacilli (H2O2)
Vaginal pH
Vaginal E. coli
Risk UTI
Genetic
factors
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
Spermicide
Percent of Women with E. coli
Relationship of Vaginal E.coli and H2O2Producing Lactobacilli
70 (OR 5.0; 95% CI [1.3-20.0])
60
* p<.01
*
(OR 4.0; *95% CI [1.3-11.6])
50
*
40
H2O2 Neg
30
H2O2 Pos
20
10
0
Cases
(RUTI)
Gupta K et al. JID 1998
Controls
All
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
Vaginal Microbial Defense System
Association of Nonsecretor
Phenotype with Recurrent UTI
• Blackwell, et al.
• Shinefeld, et al.
• Hooten, et al.
1982
1989
1989
RR
3.1
3.4
4.0
(95% CI)
(2.0 - 6.8)
(1.5 - 7.9)
(1.5 - 8.5)
• Nonsecretors have increased vaginal E. coli
Vaginal Epithelial Cell Glycosphingolipids
from Secretors and Nonsecretors
Nonsecretors Secretors
SGG =
preferred
receptor
for
P fimbriae
Stapleton A.
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
Postulated Sequence of Events
in Urinary Tract Infection
Reservoir
Pathogenesis
Input of
virulent
and
resistant
strains
Spread of E. coli
Wildlife
Environmental
(Birds, Rodents, Insects)
(Dust, Waste)
Feeds
Farm animal
Humans
Fruits and vegetables
Pets
From Nordmann P. 2005 CNFMI
Person-to-Person Transmission
of Uropathogenic E. coli
• Hospital pyelonephritis outbreaks
• Case reports: “sexually transmitted UTI”
(Tullus JID 1984)
•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)
E. coli Isolates from Women with UTI
and Their Male Sex Partners
Foxman et al. 1996
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
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)
Escherichia coli in 1,648 Retail Food Items
Johnson et al. JID 2005
(390 E. coli-positive retail food items)
ExPEC + O-UTI
(n = 17)
CGA
RAPD
profiles of
food-source
vs.
human clinical
E. coli isolates
Johnson et al. JID 2005
Postulated Sequence of Events
in Urinary Tract Infection
Reservoir
Pathogenesis
Input of
virulent
and
resistant
strains
from Larson G.