URINARY TRACT INFECTIONS
From the University of Miami Miller School of Medicine’s 45th Annual Postgraduate Course, Advances in Medicine
2008
Educational Objectives
| The goal of this program is to improve management of urinary tract infections (UTIs). After hearing and assimilating this
program, the clinician will be better able to:
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 | 1. Explain the proposed sequence of events that leads to UTI and recurrent UTI (RUTI).
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| 2. Recognize and describe the major risk factors for acute uncomplicated cystitis (AUC) and pyelonephritis in women.
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| 3. List the underlying pathogens seen in uncomplicated and complicated UTIs, and identify the predominant gram-negative
and gram-positive organisms.
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| 4. Describe the current oral regimens for management of AUC and acute pyelonephritis (APN) and treatment options
when there is the likelihood of a drug-resistant uropathogen.
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| 5. Effectively employ strategies for the prevention of UTI and RUTI.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, Dr. Hooton and the planning committee reported
nothing to disclose.
Acknowledgements
Dr. Hooton was recorded at the 45th Annual Postgraduate Course, Advances in Medicine 2008, held January 13-18,
2008, in Miami Beach, FL, and sponsored by the University of Miami Miller School of Medicine. The Audio-Digest
Foundation thanks Dr. Hooton and the University of Miami Miller School of Medicine for their cooperation in the
production of this program.
Thomas M. Hooton, MD
Professor of Clinical Medicine, University of Miami Miller School of Medicine, Miami, FL
Epidemiology of Urinary Tract Infections (UTIs)
| Terminology: uncomplicated UTI—cystitis or pyelonephritis in young nonpregnant woman with no evidence of urologic
abnormality and symptoms <7 days; usually involves less resistant, easier to treat organisms; complicated UTI—in
all other patient populations (eg, men, older women, children)
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| Epidemiology: 7 to 8 million UTIs/yr in United States; incidence of acute uncomplicated cystitis (AUC) 50 to 70/100
per year in sexually active women; incidence of pyelonephritis 28/10,000 per year in women 18 to 49 yr of age
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| Morbidity of cystitis: typical complaints include symptoms lasting 6 days, activity restricted for 2.5 days, inability to
work for 1 day, and bed confinement for 0.5 days
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| Risk for recurrent UTI (RUTI): study by Foxman et al showed that 27% of women have RUTI within 6 mo of initial
UTI, and 3% have second recurrence within 6 mo; Scandinavian study found 48% of women who have had RUTI have
second recurrence within next 12 mo; risk for frequent RUTI unknown
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| Uncomplicated UTI in men: incidence 5 to 8/10,000 in men 21 to 50 yr of age; probably underreported; risk factors
include anal sex, sex with infected woman, and lack of circumcision; strains highly urovirulent; pathogen profile and susceptibility
same as in young women
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| Postulated sequence of events in UTI: causative organisms thought to originate from gut flora; organisms colonize
introitus of vagina, urethra, and bladder; most women develop asymptomatic bacteriuria over time; some go on to have
immune response and develop symptoms; some develop pyelonephritis; some women develop recurrent disease while
others never have another UTI; possible modulating factors genetic, behavioral, and virulence of organism
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| Postulated sequence of events in RUTI: from mouse model; Escherichia coli binds to and invades superficial epithelial
cells of bladder lining; over time, this leads to formation of intracellular bacterial colonies (IBCs); some cells exfoliate,
others detach; in process of detachment, bacteria extruded and invade other cells; theorized that reservoir can
form that allows bacteria to remain in bladder lining after cells exfoliate, and that this reservoir can cause RUTI in some
women; biofilm proposed
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Risk Factors
| For cystitis: coitus (dose-response effect); spermicide use (especially with diaphragm) strong risk factor for UTI (due to
alterations in vaginal flora); history of previous UTI strong risk factor for recurrence; recent antibiotic use; recurrent
cystitis—no clear association with fluid intake, voiding habits, post- or preintercourse micturition, wiping habits, type of
menstrual protection, douching practices, bathing habits, or type of underwear
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| Recent study: women with history of RUTI who presented with acute UTI; subjects followed with daily urine and vaginal
cultures for 90 days; 38 of 104 women had RUTI during this period (of these, 45% had periurethral colonization with
E coli 14 days before RUTI, and level increased up to time of acute UTI; 5% had same strain of E coli in urine at levels
of ≥103 /mL, and that level increased until acute episode); appears that stimulating event occurs 1 to 2 days before presentation
with UTI; study also found that 30% to 40% of women had intercourse just before RUTI
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| Household spread of E coli: recent studies by Johnson et al have looked at transmission of E Coli among human members
and pets in households of women with UTI; within-household sharing of same UTI-causing strain of E coli found to
be common and much more frequent than transmission across households; no greater likelihood that sexual partners
share same strain than other household members, suggesting transmission probably involves hygiene or oral ingestion
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Pathogen Prevalence in UTI
| Predominant organisms: E coli accounts for majority of uncomplicated episodes of cystitis; also predominant organism
in cases of complicated UTI but less common; small percentage of cases caused by other gram-negative pathogens;
Staphylococcus saprophyticus most common gram-positive organism in uncomplicated UTIs, but does not cause catheter-associated
UTI; Enterococcus most common gram-positive organism in complicated cases
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| Pretherapy urine cultures: generally not recommended (resistance profile typically predictable; results come back
too late; not predictive of treatment outcome; routine use not cost-effective); however, this practice may need reassessment,
due to increased drug resistance
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| Posttherapy urine cultures: expensive; no good data that identifying bacteriuria in patient whose symptoms have resolved
is helpful; in complicated and uncomplicated UTI, posttherapy urine culture in asymptomatic patient not warranted
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| Prevalence of resistance: speaker cites study by Gupta et al, which looked at patterns of antimicrobial resistance in
uropathogens causing AUC in large population of women from early to later 1990s; resistance to ciprofloxacin and nitrofurantoin
did not change; resistance to ampicillin started out high and remained high; resistance to trimethoprim-
sulfamethoxazole (TMP-SMZ) increased from 9% to 18%
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| Resistance and treatment outcome: only 50% of women with resistant strain of uropathogen who are treated with
TMP-SMZ show improvement; when patients with susceptible strain treated with TMP-SMZ, symptoms resolve in 100%
of cases (true for most antibiotics and for pyelonephritis as well as cystitis); placebo effect—data from recent placebo-
controlled trial of nitrofurantoin show 50% cure rate in patients treated with drug to which organism resistant (corresponds
with data suggesting that 50% of women have resolution of symptoms regardless of treatment)
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| Empiric therapy dilemma: antibiotics for treatment of UTI with no other indications and no cross-resistance (eg, fosfomycin
[Monurol]; nitrofurantoin) somewhat less effective than TMP-SMZ (emerging resistance) and fluoroquinolone
(concern about resistance)
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| Can TMP-SMZ resistance be identified? some data suggest that if woman currently on antibiotic (unlikely if she
presents with UTI) or has used TMP-SMZ within last 3 mo, likelihood of resistant strain high; history of recent travel
outside United States (especially to Mexico or other area with high rate of TMP-SMZ resistance) strong predictor of having
resistant strain (avoid giving TMP-SMZ in this situation)
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Treatment Strategies
| Recommendations: TMP-SMZ should be first-line drug for AUC if—no history of allergy to drug; no use of antibiotics
in past 3 to 6 mo; no recent hospitalization; prevalence of TMP-SMZ resistance in community not high; fluoroquinolones
should be considered for women who—have allergy to TMP-SMZ or risk factors for TMP-SMZ resistance, and
severe symptoms affecting their daily routine; might find it difficult to call or return for care; nitrofurantoin should be
considered as fluoroquinolone-sparing agent for women who—have allergy to TMP-SMZ or risk factors for TMP-
SMZ resistance, and mild to moderate symptoms; fluoroquinolones—avoid (reserved for more serious infections)
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| Amoxicillin–potassium clavulanate (Augmentin): trial by speaker et al compared 3-day regimens of amoxicillin
–potassium clavulanate vs ciprofloxacin; amoxicillin–potassium clavulanate did not perform nearly as well as ciprofloxacin,
even in those subjects with drug-susceptible strains of uropathogen; β-lactams do not perform well in
management of uncomplicated cystitis; speaker suggests poor performance due to noneradication of vaginal colonization
(likely cause of RUTI)
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| Cefpodoxime: in study comparing cefpodoxime to TMP-SMZ, good cure rates with both drugs at 4 to 7 days and 28
days posttherapy; speaker currently involved in study comparing cefpodoxime to fluoroquinolone; drug is alternative to
fluoroquinolones
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| Nitrofurantoin vs TMP-SMZ: study compared 5-day and 7-day regimens of nitrofurantoin to 3-day regimen of TMP-
SMZ; at 4 wk posttherapy, cure rates with 5-day regimen of nitrofurantoin equivalent to, if not better than, 3-day regimen
of TMP-SMZ (probably due to resistance)
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| Regimens for acute cystitis: include TMP-SMZ double strength (DS) q12h, ciprofloxacin, or levofloxacin q24h for 3
days; consider cefpodoxime if resistance suspected and avoidance of fluoroquinolone desired; speaker would not use
amoxicillin–potassium clavulanate
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Pyelonephritis
| Incidence and pathogenesis: fairly common; estimated ratio of pyelonephritis to cystitis 1:18 to 1:28; risk factors for
APN—similar to those for cystitis; coitus strongest risk factor; previous UTI in past 12 mo and diabetes also associated
with high risk; underlying pathogens—E coli most common, followed by other gram-negative organisms; few cases
caused by gram-positive pathogens, although S saprophyticus accounts for 2% to 3%
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| Treatment of APN: study by Talan et al compared 7-day regimen of ciprofloxacin to 14-day regimen of TMP-SMZ for
treatment of uncomplicated APN; cure rates (clinical resolution and bacterial eradication) with ciprofloxacin were at least
equivalent to those with TMP-SMZ, and statistically better at 22 to 48 days after therapy; among women treated with
TMP-SMZ, drug resistance associated with greater clinical and bacteriologic failure rates; speaker would not currently
recommend TMP-SMZ for pyelonephritis, because prevalence of resistance too high (unless underlying pathogen known
to be susceptible); oral regimens for APN—ciprofloxacin (500 mg q12h); ciprofloxacin XR (1000 mg q24h); levofloxacin
(250-500 mg q24h); TMP-SMZ DS (q12h) or amoxicillin (500 mg q8h) if pathogen known to be susceptible
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| RUTI in women: usually reinfection (in 66% of cases, same strain of pathogen that caused initial infection); retreat with
short-course regimen of antibiotic; urologic evaluation not generally indicated; strategies for prevention—behavior modification
(although not proven, reasonable to recommend that patients increase fluid intake, void soon after intercourse,
practice optimal wiping patterns; advise patients that spermicide strongly associated with RUTI); cranberry products; estrogen
(can greatly reduce rate of RUTI in postmenopausal women by normalizing vaginal flora); antimicrobial prophylaxis
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Prevention of UTI
| Potential benefits of non-antimicrobial strategies: avoidance of side effects, drug resistance, and high cost;
probiotics—natural approach that may prove beneficial; cranberry products—cranberries and blueberries contain
proanthocyanidins, which can prevent expression of P fimbriae, thus blocking attachment of E coli to uroepithelial cells;
Cochrane group—concluded that some evidence for use of cranberry in young women (optimum dosage or method of
administration unclear), and that further properly designed trials with relevant outcomes needed (being funded by National
Institutes of Health [NIH])
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| Antimicrobial management of RUTI: if woman has had ≥3 UTIs in past year, and is bothered by symptoms, antibiotic
management reasonable approach
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| Prophylaxis for RUTI: generally recommended for 6 mo, then stop and observe; once prophylaxis stopped, many
women revert to having routine RUTIs; can reinitiate prophylaxis (if necessary) for another 6 to 12 mo; shown to be safe and
effective for several years; UTIs that occur in woman who has received prophylaxis tend to be susceptible to antibiotic used;
continuous prophylaxis regimens—include TMP-SMZ (half of single-strength dose taken once in evening) and nitrofurantoin
(50 mg); postcoital prophylaxis regimens—indicated when UTIs seem related to sexual intercourse; highly effective
with almost any drug used; can be given before or after intercourse
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| Self-diagnosis/self-treatment of RUTI: validated in 3 studies; women highly accurate in making diagnosis; self-administration
of antibiotics extremely efficacious; no adverse events related to strategy; necessary conditions—strong
patient–physician relationship; reserved for patients who have had RUTI and can recognize symptoms; if using fluoroquinolone,
make sure patient using effective method of birth control
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| Asymptomatic bacteriuria in catheterized patients: refer to Infectious Disease Society of America (IDSA)
guidelines on approach to screening and treatment of asymptomatic bacteriuria; guidelines being drafted on how to reduce
risk for catheter-associated UTI
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Questions and Answers
| Role of over-the-counter (OTC) probiotics for preventing UTI? anything that replenishes lactobacilli “makes
sense”; these products never proven effective; current studies looking at vaginal suppositories that contain strain of Lactobacillus
crispatus (phase 1 trials have reported success at colonizing vagina); ongoing trial looking at reducing risk for
recurrence in women with history of RUTI; speaker wary of OTC products; cranberry makes sense, but speaker skeptical
about other products
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| Are laboratory studies necessary for diagnosis of UTI? number of studies looking at most cost-effective way to
diagnose UTI; desirable to document pyuria in every woman who presents with dysuria, frequency, or some combination
thereof, as pyuria strong indicator for UTI; no evidence of pyuria in 5% to 10% of patients with classic symptoms of UTI
(eg, 105 /mL of E coli); while not 100% positive, if patient does not have pyuria, start thinking about other possible conditions;
documentation of pyuria not necessary to make diagnosis; if woman presents with dysuria-frequency syndrome and
no vaginal symptoms, UTI most likely and reasonable to treat
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Suggested Reading
Arone F et al: Rational use of antibiotics in acute uncomplicated cystitis: a pharmaco-epidemiological study. J Chemother
17:184, 2005; Bent S, Saint S: The optimal use of diagnostic testing in women with acute uncomplicated cystitis. Am J Med
113 Suppl 1A:20S, 2002; Christiaens TC et al: Randomised controlled trial of nitrofurantoin versus placebo in the treatment
of uncomplicated urinary tract infection in adult women. Br J Gen Pract 52:729, 2002; Colgan R et al: Risk factors for
trimethoprim-sulfamethoxazole resistance in patients with acute uncomplicated cystitis. Antimicrob Agents Chemother 52:846,
2008; Czaja CA, Hooton TM: Update on acute uncomplicated urinary tract infection in women. Postgrad Med 119:39,
2006; Foxman B et al: Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 10:509, 2000;
Foxman B, Brown P: Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect
Dis Clin North Am 17:227, 2003; Gupta K et al: Increasing prevalence of antimicrobial resistance among uropathogens
causing acute uncomplicated cystitis in women. JAMA 281:736, 1999; Gupta K et al: Patient-initiated treatment of uncomplicated
recurrent urinary tract infections in young women. Ann Intern Med 135:9, 2001; Gupta K et al: Short-course nitrofurantoin
for the treatment of acute uncomplicated cystitis in women. Arch Intern Med 167:2207, 2007; Hooton TM:
Fluoroquinolones and resistance in the treatment of uncomplicated urinary tract infection. Int J Antimicrob Agents 22 Suppl
2:65, 2003; Hooton TM: Recurrent urinary tract infection in women. Int J Antimicrob Agents 17:259, 2001; Hooton TM
et al: Acute uncomplicated cystitis in an era of increasing antibiotic resistance: a proposed approach to empirical therapy. Clin
Infect Dis 39:75, 2004; Hooton TM et al: Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis
in women: a randomized trial. JAMA 293:949, 2005; Howell AB: Bioactive compounds in cranberries and their role in prevention
of urinary tract infections. Mol Nutr Food Res 51:732, 2007; Johnson JR et al: Escherichia coli colonization
patterns among human household members and pets, with attention to acute urinary tract infection. J Infect Dis 197:218, 2008;
Kavatha D et al: Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of uncomplicated acute
cystitis in women. Antimicrob Agents Chemother 47:897, 2003; Lundstedt AC et al: Inherited susceptibility to acute
pyelonephritis: a family study of urinary tract infection. J Infect Dis 195:1227, 2007; Nicolle LE: A practical guide to the management
of complicated urinary tract infection. Drugs 53:583, 1997; Nicolle LE: Catheter-related urinary tract infection.
Drugs Aging 22:627, 2005; Nicolle LE: Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis.
Urol Clin North Am 35:1, 2008; Nicolle LE et al: Infectious Diseases Society of America guidelines for the diagnosis
and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 40:643, 2005; Scholes D et al: Risk factors associated
with acute pyelonephritis in healthy women. Ann Intern Med 142:20, 2005; Talan DA et al: Comparison of ciprofloxacin (7
days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women: a randomized trial. JAMA
283:1583, 2000.
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