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TREATMENT REVIEW

Practical Management of
Recurrent Urinary Tract Infections
in Premenopausal Women
J. Curtis Nickel, MD, FRCSC
Department of Urology, Queens University, Kingston, ON, Canada

Recurrent urinary tract infections (UTIs) are a major healthcare concern


for premenopausal, healthy, sexually active women. A practical approach to
the management and prevention of recurrent UTIs should be simple, practical,
and cost effective. Low-dose or postcoital antimicrobial therapy can be effective
for women with constellations of many recurrent UTIs, but for women with
2 to 4 UTIs per year, the most cost-effective and empowering management
strategy is patient-initiated antimicrobial treatment.
[Rev Urol. 2005;7(1):11-17]

2005 MedReviews, LLC

Key words: Urinary tract infection (UTI) Cystitis Antimicrobial therapy Antibiotic
prophylaxis Urinalysis Nitrofurantoin

R
ecurrent urinary tract infections (UTIs) in premenopausal, sexually active
women with anatomically normal urinary tracts are not perceived as a
major clinical problem by the urology community. UTIs account for more
than 7 million visits to physicians per year (1.2% of all office visits by women).1-3
The financial impact of UTIs, including recurrent and uncomplicated cases, is
greater than 1 billion dollars in the United States alone.4 Over 80% of women who

VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY 11


Recurrent UTIs in Premenopausal Women continued

had previous UTIs have recurrent and then later with some pessimism.14 clear up spontaneously changes sus-
infections over the first 18 months of Sulfanilamide, introduced in 1937, ceptibility to recurrences. Mabeck6
observation.5 Of these recurrent ushered in the era of modern antimi- found that 46.5% (20 of 43) of
infections, three quarters are caused crobial therapy for UTIs.15 untreated patients had recurrent
by reinfection with different organ- infections within 12 months, com-
isms.6,7 Women with frequent reinfec- Has Modern Medicine pared with about 40% of antimicro-
tions have a rate of 0.13 to 0.22 UTIs Created Recurrent UTIs? bial-treated patients. Similarly, Asscher
per month (1.6 to 2.6 infections per In the 1800s, a woman suffering and colleagues17 found that reinfec-
year).6,7 For premenopausal, healthy, from cystitis was bedridden for many tions occurred in 34% of patients with
and active females, recurrent UTIs are weeks while the physician attempted asymptomatic bacteriuria treated with
a major healthcare concern. to assist Mother Nature in achieving antibiotics, compared with 29%
a cure. The patient usually recovered receiving a placebo during a 3- to
Historical Management of if she did not develop pyelonephritis 5-year follow-up. It is possible that
UTIs in Women or more complicated UTI. Felix autoimmunity can result from only
In the 1800s, management of bladder Guyon (18311920)16 observed that symptomatic bacteriuria. These are
inflammation included conservative many patients with cystitis did not interesting observations, but, unfor-
initial treatments (bedrest, warm experience recurrences after recovery. tunately, the modern woman does
herbal compresses, baths, opiate- He proposed that this acquired not want to suffer 4 weeks of cystitic
symptoms while waiting for her
immune system to heal the infection.
Recurrent UTIs are a significant problem for many women, despite our
broad array of very successful antimicrobial agents. Evaluation of Women
with Recurrent UTIs
Urinalysis
based enemas) whereas more aggres- immunity was a result of autovacci- Microscopy is a valuable adjunctive
sive therapy was reserved for nation from absorption of toxins or diagnostic tool for patients with uri-
patients who did not improve or from bacteria in a state of modified nary symptoms, and, if available,
deteriorated during initial therapy. virulence. This is an interesting should be considered for patients
Aggressive treatment included observation, considering that recur- presenting with cystitis. There are
mustard- or ammonia-based plasters, rence is currently a significant problem limitations in detecting microscopic
oral alkali, bleeding (cupping, leeches, for many women, despite our broad bacteriuria and pyuria because of
or direct bleeding) and large doses of array of very successful antimicrobial lack of standardization for the
acid solutions.8 In the later 1800s, agents. Is it possible that with our microscope itself (including magnifi-
William Osler9 described an initial modern medical practice of initiating cation) and the volume of urine that
treatment consisting of absolute rest, early antimicrobial therapy for symp- can be observed, as well as if the
cold applied to the loins or dry cups
to the lumbar region, and amylnitrite
and quinine in large doses. If these Urine culture is the gold standard for the diagnosis of UTI, although
treatments were ineffective, therapy urine must be collected properly and cultured quickly or refrigerated.
involved acetates of lead and opium,
followed by ergot, gallic and tannic
acid, or diluted sulphuric acid. The tomatic cystitis we have created the urine is spun or unspun, stained or
era of modern evidence-based urolo- scenario of recurrent UTIs in pre- unstained. However, if microscopy is
gy began with the recognition that menopausal women? When Mabeck6 performed, the absence of pyuria
cystitis (suppuration of the bladder) followed 23 untreated nonpregnant should cause a physician to recon-
was infectious in origin. Beginning women with acute symptomatic cys- sider UTI as a diagnosis. Indirect dip-
in the 1900s, trials with chemothera- titis, 21 lost their symptoms after stick test for bacteriuria (nitrite) or
peutic agents such as hexamine, 4 weeks (even though the bacteriuria pyuria (leukocyte esterase) can be
phenazopyridine, hexylresorcinol, did not disappear as quickly). helpful. Although they are less sensi-
and Mercurochrome10-13 were under- However, these studies did not neces- tive than microscopic examination
taken, initially with some success sarily suggest that allowing a UTI to of the urine, they provide additional

12 VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY


Recurrent UTIs in Premenopausal Women

confirmation of a UTI when contem- probably not necessary to repeat a always be the most appropriate
plating empiric therapy and while urine culture at each episode. Urine screening procedures.
culture results are pending. culture would be mandatory, however,
if the patient does not respond to Traditional Management of
Urine Culture empiric therapy. Recurrent UTIs
Urine culture is a standard criterion for Traditionally, it was taught that sig-
the diagnosis of UTI, although prob- Other Investigations nificant bacteriuria had to be con-
lems exist for this gold standard. Many patients with recurrent UTIs firmed by culture before antibiotics
Urine must be collected properly (mid- are referred for urologic opinion and were prescribed. Employing this tra-
stream or catheterized specimen) and subsequently undergo both radio- ditional approach, each UTI episode
cultured quickly or refrigerated. logic investigations and cystoscopy. in young women was associated on
Traditionally, significant bacteriuria Radiologic studies are unnecessary average with 6.1 days of symptoms,
is noted when the bacterial colony- for the evaluation of the healthy, sex- 2.4 days of restricted activity, 1.2 days
forming unit counts reach 105/mL. ually active, premenopausal woman.18 of not attending work or school, and
The problem with this somewhat Similarly, cystoscopy rarely will detect 0.4 days of bedrest.19 Although many
teachers adhere to this traditional
approach (perhaps based on a
Renal ultrasonography is the preferred urinary tract screening misguided evidence-based criterion,
imaging technique because it is noninvasive, easy to perform, and rela- FDA guidelines, or interpretation of
tively inexpensive. costbenefit ratios), most physicians
will treat an uncomplicated UTI with
antibiotics, based on a description of
artificial cutoff is that many women significant pathology that would the patients symptoms, particularly
with symptomatic UTIs present with change the outcome of therapy.18 if confirmed by urinalysis (either
much lower bacterial counts (such However, further investigations are microscopy or nitrite/leukocyte
as 102/mL), whereas patients with important if a patient is believed to esterase dipstick) (Figure 1).
asymptomatic bacteriuria can have have any of the following: hema- First-line therapy for acute uncom-
much higher counts. turia, a complicated UTI suggested plicated cystitis in women includes
by a history of calculi, obstruction nitrofurantoin (the macrocrystalline
Should Cultures Be Performed at (upper or lower urinary tract), neuro- preparation is better tolerated),
All in Women With Recurrent UTIs? pathic bladder, recent genitourinary trimethoprim-sulphamethoxasole
Because there are many inherent surgery or catheterization, unusual (TMP-SMX), trimethoprim (TMP)
limitations and inaccuracies in urine organisms (such as tuberculosis, fun- alone, or a fluoroquinolone (particu-
collection and culture results, one has gus, or urea-splitting organisms), larly in areas where TMP-SMX resist-
to carefully evaluate the rationale for compromised immune system, dia- ance rates approach 20%). Three days
obtaining a urine culture in all patients betes, or renal failure. Similarly, of therapy appears to be optimal
presenting with simple uncomplicated investigations are required in patients because it results in similar cure rates
cystitis. As will be noted later in this who do not respond to appropriate but with decreased costs and fewer
article, a clinical diagnosis of UTI antimicrobial therapy after 5 to 6 days side effects compared with 710 days
is based on symptoms, and empiric of treatment. The excretory urogram of therapy, and lower recurrence
therapy with modern antibiotics is has been the traditional routine exam- rates compared with single-dose
extremely successful. It can be argued ination method of evaluating patients therapy (reviewed by Schaeffer.)20
that it would be cost effective in with complicated UTI and although it
patients with recurrent UTIs to first remains useful, it is not the ideal Prevention of Recurrent UTIs
establish the presence of significant screening test today. Currently, renal Conservative Approach to Prevention
bacteriuria associated with an episode ultrasonography is the preferred uri- A number of risk factors, other than
of symptomatic cystitis, and then nary tract imaging technique because sexual activity, have been identified
document that both symptoms and it is noninvasive, easy to perform, in patients with recurrent UTIs.
bacteriuria resolve with antimicro- and relatively inexpensive. CT and Contraceptive methods employing a
bial therapy. Once this has been con- MRI offer the best anatomical detail, diaphragm and/or spermicides (includ-
firmed in a specific patient, it is but because of cost they may not ing spermicide-covered condoms) and

VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY 13


Recurrent UTIs in Premenopausal Women continued

Figure 1. A proposed practices (see Table 1) has proven to


treatment algorithm for
First UTI episode premenopausal women be effective in reducing the incidence
presenting with recur- of recurrent UTIs.
rent urinary tract infec-
tion (UTI).
Antimicrobial Prophylaxis
Physician diagnosis
Culture
The 2 contemporary strategies
employing a prophylactic antibiotic
regime to prevent recurrent UTIs
include long-term low-dose prophy-
Empiric antimicrobial therapy
lactic antimicrobial treatment or post-
coital antibiotic treatment. However,
it does not appear that these strategies
Recurrence of UTI alter the long-term risk of recurrence.
Patients with frequent UTIs who take
prophylactic antimicrobial agents for
Lifestyle changes1
extended periods (for example, as
Cranberry juice/extract long as 6 months) decrease their
infections during prophylaxis, but
the rate of infection returns to pre-
Recurrent UTI treatment rates when prophylaxis is
stopped.26,27 Long-term antibiotics do
not appear to alter the patients basic
susceptibility to infections.20
4 UTI/year 4 UTI/year Antimicrobial agents used for long-
term low-dose prophylaxis include
TMP-SMX (or TMP alone), nitrofuran-
Constellations Episodic toin, cephalexin, and the fluoro-
of UTIs UTIs quinolones. The dose is usually about
a quarter the usual daily dose. Nitro-
furantoin (because of rapid absorption
Low-dose Postcoital Patient-initiated
in the upper intestinal tract) produces
antimicrobial antimicrobial antimicrobial minimal fecal resistance and less
prophylaxis2 prophylaxis3 therapy4 vaginitis. It is, however, associated
with more adverse reactions (eg, acute
1. Lifestyle changes: discontinue spermicides, feminine hygiene products, practice proper toileting habits pulmonary reactions, allergic reac-
2. Culture for breakthrough UTI; change antibiotic
3. Patient-initiated therapy for breakthrough UTI tions, liver problems). Most of these
4. Culture if no response by 48 hours; change antibiotic
long-term adverse reactions occur in
older patients. TMP-SMX is a power-
ful prophylactic agent in preventing
tampon use have been associated with tobacilli has been suggested but not reinfections in the female by clearing
increased risk of UTI.21,22 Contraceptive proven.24 It is probable that in the E. coli from the rectal and vaginal
methods should be changed, spermi- future, some form of immunization flora, but can be poorly tolerated with
cidal agents should be discontinued, program will be the key to preven- potentially life-threatening side
and patients should consider using tion of recurrent UTIs.25 It is probably effects and the development of TMP-
pads instead of tampons. Drinking appropriate to suggest that patients SMX resistant strains within the gut
cranberry juice or cranberry extract stay hydrated, void regularly, avoid flora. Fluoroquinolones are probably
appears to be a safe and possibly feminine hygiene products such as the most effective agent for UTI pro-
effective method of reducing the fre- vaginal douches and scented bubble phylaxis but should probably be
quency of recurrent UTIs in some baths, and practice proper toilet restricted to women with acute symp-
women.23 Attempting to change the habits (including early postcoital tomatic cystitis in which there is sig-
vaginal flora by douching with lac- voiding), although none of these nificant antimicrobial resistance or to

14 VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY


Recurrent UTIs in Premenopausal Women

patients with intolerance to TMP-


SMX, TMP, or nitrofurantoin. Nicolle Table 1
and Ronald28 summarized the effec- Prevention Strategies for Women with
tiveness of prophylactic therapy in the Recurrent Urinary Tract Infection
management of women with recurrent
UTIs and noted that recurrences dur- Conservative lifestyle changes (see text)
ing prophylaxis are decreased by 95%. Cranberry juice/extract prophylactic therapy
Acute cystitis is more common in Physician-directed episodic antimicrobial therapy
sexually active women and a number
Low-dose prophylactic antimicrobial therapy
of studies have shown that postinter-
course therapy with antimicrobials Postcoital prophylactic antimicrobial therapy
such as nitrofurantoin, cephalexin, Patient-initiated antimicrobial therapy
and TMP-SMX taken as a single dose
effectively reduces the incidence of
reinfection.29,30 The rationale behind effectiveness and cost of patient-ini- believed that fluoroquinolones are
postintercourse therapy27 is based on tiated single-dose antibiotic therapy the ideal medication for self-start
the fact that intercourse results in the to antibiotic prophylaxis for women therapy because of their broad spec-
introduction of bacteria from the with frequent UTIs. Thirty-eight trum of activity compared to other
urethra into the bladder. In the absence women were randomized to either potential alternatives (nitrofurantoin
of voiding, the bacteria grow after continuous low-dose TMP-SMX or and TMP-SMX). The culture should
overnight incubation to the point intermittent self-administration of a be brought to the office as soon as
where voiding and other host defense single postcoital dose of TMP-SMX. possible and if the culture is positive
mechanisms do not eradicate them. The infection rate in the prophylaxis and the patient asymptomatic, then
An antibiotic taken immediately after group was 0.2 UTI/patient-year versus another culture should be performed
intercourse presumably kills or arrests 2.2 UTI/patient-year in the self-treat- 7 to10 days after therapy to determine
the growth of sensitive bacteria ment group. This study was also efficacy. If the patient has symptoms
before they reach the critical concen- important in confirming that a UTI that do not respond initially to antimi-
tration required to establish an infec- can be diagnosed by patients. In fact, crobial therapy, additional culture
and susceptibility tests of the initial
culture specimens are performed
An antibiotic taken immediately after intercourse presumbably kills or and therapy adjusted accordingly.
arrests the growth of sensitive bacteria before they establish an infection. Although this approach is scientifi-
cally and clinically sound, it may not
be time- and cost-effective, and
tion in a susceptible individual. This 35 of the 38 UTIs diagnosed by patients would be required to submit
approach appears to be efficacious, patients were confirmed by culture. a minimum of 2 urine cultures. With
cost effective, and well tolerated by Thirty of the 35 UTIs responded clin- success rates in excess of 95% with
patients. In a placebo-controlled ically and microbiologically to treat- fluoroquinolone therapy, one might
trial,30 the infection rate observed ment. No complications occurred in question the usefulness of cultures in
with postcoital TMP-SMX was 0.3 any of the 5 failures. women with recurrent UTIs, except,
per patient-year compared with It has been suggested that a more of course, in the case of patients who
3.6 per patient-year in placebo-treated accurate approach to self-diagnosis do not respond clinically to empiric
women. Depending on frequency of and self-start therapy would be to antibiotic therapy.
intercourse, postcoital prophylaxis give patients a dip slide device to Gupta and colleagues33 allowed
usually results in less antibiotic culture the urine and instruct them women to diagnose their UTIs and
use than does continuous low-dose to perform a urine culture when immediately initiate treatment with
antimicrobial prophylaxis. symptoms of UTI occur.32 The patient 3 days of fluoroquinolone antibiotics.
would then self-start a 3-day course To analyze the accuracy of self-diag-
Patient-Directed Self-Treatment of empiric full-dose antimicrobial nosis in the study, a midstream spec-
of Recurrent UTIs therapy immediately after performing imen of urine (MSSU) was submitted
Wong and colleagues31 compared the the culture. The same investigators32 to the laboratory for culture. Repeat

VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY 15


Recurrent UTIs in Premenopausal Women continued

urine cultures were submitted 10 and a frustrating constellation of very management plan saves valuable
30 days after treatment as part of the frequent UTIs (and it is recognized time (for both the physician and
experimental protocol. The investi- that UTIs tend to cluster in some patient), reduces expense (eg, unnec-
gators also interviewed the patients women). Although it does not change essary cultures, office visits, time off
posttherapy. One hundred and sev- the long-term prognosis of future work), and allows for an early initia-
enty-two women (average age UTIs, it certainly allows the patient tion of therapy with no apparent
23 years), predominantly white, un- the chance of a long period without increase in treated episodes.
married, and sexually active, had cystitis-like symptoms. For sexually
at least 2 UTIs the previous year. active women with frequent UTIs, References
Eighty-eight of these 172 women postcoital antibiotic therapy appears 1. Patton JP, Nash DB, Abrutyn E. Urinary tract
infections: economic considerations. Med Clin
self-diagnosed 172 UTIs. A uropatho- to successfully reduce the frequency North Am. 1991;75:495-513.
gen was cultured in 84%, sterile pyuria of symptomatic recurrent episodes 2. Hooton TM, Stamm WE. Diagnosis and treat-
ment of uncomplicated urinary tract infection.
was identified in 11%, and in only 5% of cystitis. For motivated and active Infect Dis Clin North Am. 1997;11:551-581.
was pyuria or bacteriuria not detected. women who suffer 2 to 4 UTIs per year, 3. Schappert SM. Ambulatory care visits to physi-
Clinical cures (complete eradication a patient-initiated treatment strategy cian offices, hospital outpatient departments,
and emergency departments: United States, 1996.
of symptoms) were noted in 92%, for their recurrent UTIs should be Vital Health Stat. 1999;13:I-IV, 1-39.
microbiological cures (eradication of considered. It is appropriate to make 4. Rosenberg M. Pharmacoeconomics of treating
bacteria) were noted in 96%. There sure that at least 1 symptomatic uncomplicated urinary tract infections. Int J
Antimicrob Agents. 1999;11:247-251, discussion
were no adverse events and almost episode of cystitis is associated with 261-264.
100% of the patients were very happy a positive culture and that patients 5. Harrison WO, Holmes KK, Belding ME, et al. A
with this management plan. symptomatically resolve on a 3-day prospective evaluation of recurrent urinary
tract infections in women. Clinical Research
course of antibiotics. Once this is 1974;22:125A.
A Practical Plan for Women established, there is evidence that 6. Mabeck CE. Treatment of uncomplicated uri-
nary tract infection in non-pregnant women.
With Recurrent UTIs women with recurrent UTIs can Postgraduate Med J. 1972;48:69-75.
For premenopausal women with accurately self-diagnose and self- 7. Guttmann D. Follow-up of urinary tract infec-
recurrent UTIs, particularly sexually treat uncomplicated cystitis (as accu- tion in domiciliary patients. In: Brumfitt W,
Asscher AW, eds. Urinary Tract Infection,
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8. Todd R. Clinical Lectures on Certain Diseases of
quo and dogmatic approach of strategy for many women. Physicians, the Urinary Organs and Dropsies. Philadelphia:
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Main Points
Recurrent urinary tract infections (UTIs) in healthy premenopausal women are a major health concern, and UTIs account for
7 million physician visits per year at a cost of 1 billion dollars.
Treatment of UTI in women has evolved from historically very conservative treatments, such as bedrest and herbal compresses, to
current modern practices, which include use of antibiotics such as nitrofurantoin, trimethoprim-sulphamethoxosole (TMP-SMX),
trimethoprim (TMP), and the oral fluoroquinolones.
Risk factors for recurrent UTIs include use of a diaphragm and/or spermicides, and tampon use. Certain lifestyle changes are suggested
to help reduce incidence of UTIs, but they have not been proven to be effective.
Two other contemporary strategies employed in preventing recurrent UTIs are long-term low-dose prophylactic antimicrobial
treatment and postcoital antibiotic treatment. These treatments have proven effective over extended periods of use (more than
6 months), but patients return to pretreatment rates of infection after prophylaxis is stopped.
Studies have shown that patients can effectively diagnose their own UTIs and self-initiate treatments with the same success rate
as physicians. This is a self-empowering strategy for many women and also helps save time and money. Physicians should still
play an important management role.

16 VOL. 7 NO. 1 2005 REVIEWS IN UROLOGY


Recurrent UTIs in Premenopausal Women

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sulphonphthalein. J Urol. 1919;2:107-126. 75:1308-1313. prevention by prophylactic antibiotics after sex-
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50 cases of infections of the urinary tract. Walsh PC, Retik AB, Vaughan ED, Jr, Wein AJ, 28. Nicolle LE, Ronald AR. Recurrent urinary tract
J Urol. 1925:14:119-133. eds. Campbells Urology, 8th ed. Philadelphia: WB infection in adult women: diagnosis and
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studies on the use of mercurochrome as a gen- N Engl J Med. 1996;335:468-474. prophylaxis based on an understanding of the
eral germicide. J Urol. 1921;5:353-388. 22. Gupta K, Hillier SL, Hooton TM, et al. Effects of pathogenesis. J Urol. 1983;129:1153-1157.
14. Braasch WF. A review of recent progress in contraceptive method on vaginal microbial 30. Stapleton A, Latham RH, Johnson C, Stamm
urology. J Urol. 1925;14:183-192. flora: a prospective evaluation. J Inf Dis. WE. Postcoital antimicrobial prophylaxis for
15. Crenshaw J, Cook E. Limitations, dangers, and 2000;181:595-601. recurrent urinary tract infection: a randomized
failures of sulfanilamide. J Urol. 1939;41:64-74. 23. Walker EB, Barney DP, Mickelsen JN, et al. double-blind placebo controlled trial. JAMA.
16. Guyon F. Annales des Maladies des Organes Cranberry concentrate: UTI prophylaxis. J Fam 1990;264:703-706.
Genito-Urinaires, 1892. Pract. 1997;45:167-168. 31. Wong ES, McKevitt M, Running K, et al.
17. Asscher AW, Chick S, Radford N, et al. Natural 24. Reid G, Burton J. Use of Lactobacillus to pre- Management of recurrent urinary tract infec-
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AW, eds. Urinary Tract Infection Proceedings. 25. Uehling DT, Hopkins WJ, Balish E, et al. 32. Schaeffer AJ, Stuppy BA. Efficacy and safety of
London: Oxford University Press;1973:51-61. Vaginal mucosal immunization for recurrent self-start therapy in women with recurrent uri-
18. Nickel JC, Wilson J, Morales A, Heaton J. urinary tract infection: phase II clinical trial. nary tract infections. J Urol. 1999;161:207-211.
Value of urological investigation in a targeted J Urol. 1997;157:2049-2052. 33. Gupta K, Hooton TM, Roberts PL, Stamm WE.
group of women with recurrent urinary tract 26. Stamm WE, Counts GW, Wagner KF, et al. Patient-initiated treatment of uncomplicated
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