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Management of
Urinary Tract Infections in Adults
Walter E. Stamm, and Thomas M. Hooton
Urinary
tract infections account for more than 7 million visitsto
physicians’ offices and necessitate or complicate well over1 million
hospital admissions in the United States annually1,2.
It is helpful to categorize adult patients with urinary infection
into five groups: young women with acute uncomplicated cystitis,
young women with recurrent cystitis, young women with acute
uncomplicated pyelonephritis, all adults with complicated urinary
infection, and all adults with asymptomatic bacteriuria. This
review will highlight recent advances in the treatment of patients
in each of these categories, emphasizing cost-effective strategies
that may be particularly important in the coming era of managed
care.
Acute Uncomplicated Cystitis in
Young Women
A remarkably narrow spectrum of etiologic agents with highly
predictable profiles of antimicrobial susceptibility cause infections
in young women with acute uncomplicated cystitis: Escherichia
coli in 80 percent, Staphylococcus saprophyticus in 5 to 15
percent, and occasionally klebsiella species, Proteus mirabilis,
or other microorganisms3.
Several factors increase the riskof infection, including sexual
intercourse, the use of a diaphragmand a spermicide (and possibly
spermicide use alone), delayedpostcoital micturition, and a history
of a recent urinary infection4,5,6.
Localization studies indicate that as many as 30 percent of
patients who present clinically with a cystitis-like syndrome
may have subclinical upper urinary tract involvement7.
Sincenone of the currently available localization tests are
bothaccurate and feasible for use in practice, however, these
patientsare all initially treated as though they have cystitis.
A young woman presenting with acute dysuria usually has oneof
three types of infection: acute cystitis; acute urethritisdue to
Chlamydia trachomatis, Neisseria gonorrhoeae, or herpessimplex
virus; or vaginitis due to candida or trichomonas3.
Women with cystitis, urethritis, or vaginitis can usually be
presumptively differentiated on the basis of their presenting
symptoms, signs, and findings on urinalysis (Table
1). If needed,a urine culture can be used to confirm the
presence of acutecystitis. In symptomatic young women with suspected
cystitis,a urine culture demonstrating 100 or more colony-forming
unitsof a uropathogenic species per milliliter usually
indicatesinfection8,9.
Nearly all such patients can also be shown tohave pyuria by an
accurate and reproducible method such as theuse of a counting
chamber to enumerate cells in unspun urine.The leukocyte esterase
dipstick, a widely used office test toidentify patients with pyuria,
has a reported sensitivity of75 to 96 percent in detecting pyuria
associated with infection9.
For patients with a negative test who have urinary symptoms,
microscopical evaluation for pyuria or a culture should be performed.
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Since the
causative organisms and their antimicrobial-susceptibilityprofiles
are so predictable in women with acute cystitis, weand others have
advocated an abbreviated laboratory workup followedby empirical
therapy, on the grounds that this approach is efficacious,safe, and
cost effective10,11.
Thus, in patients with typicalsymptoms, the diagnosis can be
presumed if pyuria is presenton microscopy or leukocyte esterase
testing. No urine cultureis performed, and a short course of
empirical antimicrobialtherapy is given. No follow-up visit or
culture after therapyis recommended unless symptoms persist or
recur. If pyuria isabsent or there are atypical clinical features or
factors thatsuggest a complicated infection (Table
2), a culture shouldbe performed before therapy is started.
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A plethora
of studies have been conducted in recent years todefine the optimal
treatment for uncomplicated cystitis in women10,12,13,14,15,16,17,18,19.
With most antimicrobial agents, three-day regimens appear optimal,
with efficacy comparable to seven-day regimens but with fewer
side effects and lower cost (Table
2). Single-dose therapy canalso be used, but it generally
results in lower rates of cureand more frequent recurrences,
especially with drugs such asamoxicillin and oral cephalosporins,
which are very rapidlyexcreted and are often ineffective in patients
with occult renalinfection12,14,15.
For single-dose therapy, the best resultshave generally been
achieved with trimethoprim-sulfamethoxazole.Fluoroquinolones and
fosfomycin-tromethamine (where approvedfor use) have also been used
successfully14,15,17.
Even withtrimethoprim-sulfamethoxazole and fluoroquinolones,
however,therapy for three days or longer was more effective than
single-dosetherapy in most trials and in a meta-analysis12,14,15,16.
Single-dosetherapy with a fluoroquinolone is particularly prone to
failurein patients infected with S. saprophyticus15,17.
Regimens ofseven days or longer offer no additional therapeutic
benefitbut cost more and cause substantially more side effects
thatrequire medical intervention (primarily rash and yeast
vaginitis).Seven-day regimens (and a pretreatment culture) can be
reservedfor patients with factors, including pregnancy, that may
resultin lower rates of cure with shorter regimens (Table
2).
About one third of the bacterial strains causing uncomplicated
cystitis in the United States now demonstrate in vitro resistance
to amoxicillin and sulfonamides, and 15 to 20 percent are resistant
to nitrofurantoin12,13,14,15,17.
Resistance to trimethoprimand trimethoprim-sulfamethoxazole is 5 to
15 percent, variesgeographically, and appears to be increasing
nationwide, whereasresistance to the fluoroquinolones remains below
5 percent inmost places8,12,13,14,15,16,17,18.
The effects of an antimicrobialagent on the vaginal flora are also
important in the lastingeradication of bacteriuria12.
The concentrations of trimethoprimand the fluoroquinolones that have
been studied in vaginal secretionsare high, eradicating E. coli but
minimally altering normalanaerobic and microaerophilic vaginal
flora10.
Single-dose regimensusing these drugs are less effective than
multiple-day regimensin this regard,12
which probably explains why there are moreearly recurrent infections
after single-dose therapy with thesedrugs. Nitrofurantoin and
beta-lactam drugs are generally noteffective in eliminating E. coli
from the vagina.
Considering all factors, including current patterns of resistance
among uropathogens, the duration of urinary excretion of drug,
antimicrobial effects on the vaginal flora, safety, and cost,
trimethoprim-sulfamethoxazole and trimethoprim are the optimal
choices for empirical three-day therapy for uncomplicated cystitis
(Table
2). The fluoroquinolones are also highly effective andwell
tolerated in three-day regimens but are more expensive.In women with
uncomplicated cystitis, we use a fluoroquinoloneprimarily for
recurrent infections, treatment failures, infectionsin patients with
allergies to other drugs, and infections causedby strains resistant
to other antimicrobial agents. Only inareas where trimethoprim
resistance is common among the pathogenscausing uncomplicated
cystitis should fluoroquinolones be usedfor empirical therapy. We
and others have had less satisfactoryresults with three-day courses
of amoxicillin, cefadroxil, ornitrofurantoin in the management of
acute cystitis,15,20
evenwith susceptible microorganisms, but these regimens may be
usefulin selected patients or settings.
Recurrent Infections in
Women
About 20 percent of young women with an initial episode of cystitis
have recurrent infections. Occasionally, such recurrences are
due to a persistent focus of infection, but well over 90 percent
of recurrences in young women are episodes of exogenous reinfection,
typically months apart21,22.
Only rarely do such patients haveanatomical or functional
abnormalities of the urinary tract,and excretory urography,
cystography, and cystoscopy are thereforeof little use23.
The use of diaphragms and spermicides has beenassociated with
recurrence in some patients, probably becausethe spermicide induces
colonization of the vagina by E. coli24.
Alternatively, susceptibility may be genetic, since women who
do not secrete blood-group antigens (nonsecretors) are
overrepresentedamong those with recurrent infections and
uroepithelial cellsfrom such women have specific E. coli-binding
glycolipids thatare absent in women who secrete blood-group
antigens25,26.
Recurrent cystitis should be documented by culture at leastonce
and then managed by one of three strategies: continuousprophylaxis,
postcoital prophylaxis, or therapy initiated bythe patient (Figure
1)27,28,29.
In some women, prophylacticregimens have been successfully used for
years without the emergenceof antibiotic resistance30,31.
In women with recurrent episodesof cystitis who comply with
treatment, patient-initiated therapyundertaken when symptoms arise
provides a convenient, safe,inexpensive, and effective management
strategy29.
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Postmenopausal
women may also have frequent reinfections21,32.
These infections are sometimes attributable to residual urine
after voiding, which is often associated with bladder or uterine
prolapse. In addition, the lack of estrogen causes marked changes
in the vaginal microflora, including loss of lactobacilli and
increased colonization by E. coli32.
Antimicrobial prophylaxisor topically applied estradiol cream are
alternative preventivemeasures in such women28,32.
Acute Uncomplicated
Pyelonephritis in Young Women
The clinical spectrum of acute uncomplicated pyelonephritisin
young women ranges from gram-negative septicemia to a cystitis-like
illness with mild flank pain33.
E. coli accounts for more than80 percent of cases, and most of the
strains are a unique subgroupof E. coli (called uropathogenic
strains) that possess specificdeterminants of virulence that enable
them to infect the upperurinary tract of normal, healthy persons34.
These uropathogenicE. coli belong to a small number of O:K:H
serotypic groups,usually produce both hemolysin and aerobactin, and
generallyhave specific pyelonephritis-associated pili that mediate
theirattachment to uroepithelial cells.
Microscopical examination of unspun urine establishes the presumptive
diagnosis. Pyuria is nearly always present, and gram-negative
bacteria are usually seen. About 20 percent of patients have
urine cultures with <105 colony-forming units per
milliliter,however, and hence negative results on Gram’s staining of
theurine35.
Urine cultures should be obtained in all women withsuspected
pyelonephritis, and a blood culture should be obtainedin patients
who are hospitalized, since 15 to 20 percent arepositive33,35.
Twenty to 30 percent of organisms that cause pyelonephritisare
resistant to amoxicillin and first-generation cephalosporinsin
vitro, and thus these compounds should no longer be usedalone for
empirical treatment (Table
2)33,35,36.
In the absenceof nausea and vomiting and if the patient’s overall
degree ofillness is mild, therapy can safely be given orally in an
outpatientsetting (Table
2)36,37.
Patients with nausea, vomiting, or moderate-to-severeillness and
those who are pregnant require hospitalization forinitial parenteral
therapy with one of the regimens shown inTable
2. Typically, symptoms and signs improve or resolve after48 to
72 hours, and the remaining treatment can be given orally.In
selected patients, parenterally administered ceftriaxonecan be used
as outpatient therapy. Ampicillin and gentamicinshould be given
empirically if enterococcus species are suspectedon the basis of
Gram’s staining of the urine that reveals gram-positivecocci.
Treatment for longer than two weeks has no apparent benefit,even in
patients with positive blood cultures3,36.
Shorter regimens(e.g., five to seven days) are often effective in
patients whosefever abates rapidly, but they have not been evaluated
in well-controlledtrials.
If fever and flank pain persist after 72 hours of therapy, cultures
should be repeated and ultrasonography or computed tomography
should be considered to seek perinephric or intrarenal abscesses,
unrecognized urologic abnormalities, or obstruction. The routine
use of imaging procedures for all young women who present with
acute pyelonephritis is generally unrevealing and unnecessarily
expensive38;
imaging should be limited to patients with slowresolution of
infection, more than one episode, or other atypicalfeatures
(persistent hematuria, colicky pain, or childhood urinary
infections). It is useful to obtain a follow-up culture two
weeks after the completion of therapy.
Complicated Urinary Tract
Infections
Complicated urinary tract infections are those that occur ina
patient who has a functionally, metabolically, or anatomically
abnormal urinary tract or that are caused by pathogens thatare
resistant to antibiotics10,39.
These complicating factorsmay not be obvious at first, however. The
clinical spectrumranges from mild cystitis to life-threatening
urosepsis. Inaddition, there may be long periods of asymptomatic
bacteriuria.Unlike the narrow and predictable spectrum of causative
agentsin uncomplicated infection, a broad range of bacteria can
causecomplicated infections (Table
2), and many are resistant tomultiple antimicrobial agents.
Urine cultures must thereforebe obtained in patients suspected of
having complicated infectionin order to identify the infecting
pathogen and perform susceptibilitytesting.
The wide variety of underlying conditions, diverse spectrumof
possible etiologic agents, and paucity of controlled clinicaltrials
with stratification according to specific complicatingfactors make
generalizing about antimicrobial therapy difficult14,17.
For empirical therapy in patients with mild-to-moderate illness
who can be treated with oral medication as outpatients, the
fluoroquinolones provide a broad spectrum of antimicrobial activity
covering most expected pathogens and achieve high levels inthe
urine and urinary tract tissue (Table
2). If the infectingpathogen is known to be susceptible,
trimethoprim-sulfamethoxazoleis also a reasonable and less costly
therapeutic choice. Forinitial empirical therapy in more seriously
ill, hospitalizedpatients, ampicillin plus gentamicin or imipenem
plus cilastatinprovides coverage against most expected pathogens,
includingPseudomonas aeruginosa and most enterococci. A number of
otherparenteral antimicrobial agents can also be used (Table
2)14,17.
Therapy can be modified when the infecting strain has been identified
and antimicrobial susceptibilities are known. At least 10 to14
days of therapy is usually necessary; many patients initiallygiven
parenteral therapy can be switched to oral treatment afterclinical
improvement. Pseudomonas and enterococcal infectionsare especially
difficult to treat and may warrant more prolongedtherapy. Without
correction of the underlying anatomical, functional,or metabolic
defect, infection often recurs. For this reason,a urine culture
should be repeated one to two weeks after thecompletion of
therapy.
Urinary Tract Infections in
Younger Men
Urinary tract infections are rare in men less than 50 yearsold.
They have generally been considered indicative of an underlying
urologic abnormality and thus to be complicated infections40.
Recent studies, however, suggest that the uropathogenic strains
of E. coli that cause pyelonephritis in young women can also
cause uncomplicated infection (usually cystitis) in young men41,42.
Clinically, these infections often present with symptoms of
cystitis, but in some patients they mimic urethritis, causing
urethral discharge and urethral leukocytosis. Risk factors include
homosexuality (associated with exposure to E. coli through anal
intercourse), lack of circumcision (associated with enhanced
colonization of the glans and prepuce by E. coli), and havinga
sexual partner with vaginal colonization by uropathogens41,42,43.
Men with human immunodeficiency virus infection who have CD4
lymphocyte counts of less than 200 per cubic millimeter may
also be at increased risk for urinary infection, presumably
because of immunosuppression44.
Young healthy men who present with the cystitis syndrome andhave
no discernible complicating factors can be treated witha seven-day
regimen of trimethoprim-sulfamethoxazole, trimethoprim,or a
fluoroquinolone. Shorter regimens should be avoided. Pretreatment
urine culture is recommended. A urologic evaluation is usually
unrewarding in young men who respond to therapy40.
Catheter-Associated Urinary
Tract Infection
There are more than 1 million catheter-associated urinary infections
a year in the United States,45
and catheter-associated bacteriuriaremains the most common source of
gram-negative bacteremia inhospitalized patients46.
Recent studies have demonstrated thatbacteria adhere to the surface
of urinary catheters and initiatethe growth of biofilms composed of
bacteria, bacterial glycocalices,Tamm-Horsfall protein, and urinary
salts such as apatite andstruvite47.
Of clinical importance, biofilms appear to protectembedded bacteria
from antibiotics, causing treatment to fail48.
For this reason, one should consider replacing a catheter that
has been in place for more than two weeks when one is treating
a patient with a catheter-associated infection.
Prevention remains the best way to reduce the morbidity, mortality,
and costs of catheter-associated infection49,50.
Effective strategiesinclude sterile insertion and care of the
catheter, prompt removal,and the use of a closed collecting system45,49.
Other approachesthat have been effective in some studies but not
others includethe use of preconnected catheter-collecting-tube
units, theuse of disinfectants in collecting bags, the use of
silver-ion-coatedcatheters, and the regular periurethral application
of antimicrobialcreams45,49.
Although systemic antimicrobial agents preventor delay the onset of
bacteriuria, they are not routinely usedfor this purpose in patients
with catheters, because of costand the potential for the development
of antimicrobial resistance.Prophylactic systemic antimicrobial
agents may be useful, however,in selected patients at high risk who
are undergoing short-termcatheterization (e.g., patients undergoing
renal transplantation,urologic or gynecologic surgery, or surgery
involving a foreignbody).
In patients with catheters whose culture specimens are obtained
directly from the catheter, a level of 100 or more colony-forming
units per milliliter is evidence of infection, since these counts
usually persist or increase within 48 hours51.
Symptomatic episodesof infection should be treated with
antimicrobial agents, asrecommended for complicated urinary tract
infections. Treatmentof asymptomatic bacteriuria has little apparent
benefit in patientswith catheters. One study suggested, however,
that in women,asymptomatic bacteriuria after catheterization may
also warranttherapy52.
Further studies are needed to confirm these resultsand establish the
cost effectiveness of screening asymptomaticwomen with catheters for
bacteriuria.
When catheterization is long-term (more than 30 days), bacteriuria
eventually occurs in almost all patients53.
Periods of bacteriuriamay alternate with periods of sterile urine,
or bacteriuriamay become chronic; in both instances the infecting
strainsoften change. Bacteriuria is frequently polymicrobial49,53.
A recurrent problem is catheter encrustation and eventual
obstruction.Periodic catheter changes may prevent these
complications.
The prevention of bacteriuria and associated complications in
patients undergoing long-term catheterization has been largely
unsuccessful. In contrast, intermittent catheterization has
resulted in lower rates of bacteriuria than long-term indwelling
catheterization in studies with historical controls49,54.
Inpatients undergoing intermittent catheterization, bacteriuria
may be reduced by bladder irrigation with a solution of neomycin
and polymyxin or by oral methenamine, nitrofurantoin, or
trimethoprim-sulfamethoxazoleprophylaxis49,55.
Prophylactic regimens are not effective inpatients with long-term
indwelling catheters. Likewise, treatingepisodes of asymptomatic
bacteriuria does not reduce the complicationsof bacteriuria in
patients undergoing long-term catheterization56.
Asymptomatic Bacteriuria in
Patients without Catheters
In patients with asymptomatic bacteriuria, a level of 
105 colony-formingunits per milliliter (preferably on two
successive cultures)should be the diagnostic criterion for
infection9.
Screeningfor asymptomatic bacteriuria has little apparent value in
adults,with two exceptions: before urologic surgery and during
pregnancy.Postoperative complications, including bacteremia, are
reducedby recognizing and treating asymptomatic bacteriuria
beforeurologic surgery57.
All pregnant women should be screened forbacteriuria in the first
trimester and should be treated ifbacteriuria is present, to reduce
their markedly increased riskof acute pyelonephritis and the
accompanying risks of prematurityand low birth weight in their
infants58.
The results of susceptibilitytesting should be available to direct
therapy. We recommendthree-day courses of amoxicillin,
nitrofurantoin, an oral cephalosporin,or
trimethoprim-sulfamethoxazole. After successful treatment,monthly
urine cultures should be performed to detect recurrentbacteriuria58.
Asymptomatic bacteriuria occurs in as many as 40 percent of
elderly men and women, especially in nursing homes. Although
symptomatic infection (even pyelonephritis or sepsis) develops
in a few of these patients, such complications are rare anddo
not appear to justify either screening or the routine useof
antimicrobial agents for the prevention or treatment of asymptomatic
bacteriuria in this setting59.
Although asymptomatic bacteriuriahas been associated with an
increased risk of death in the elderlyin some studies, a causal link
has not been demonstrated60.
Conclusions
Management strategies designed for specific groups of patients
with urinary infection can maximize therapeutic benefits while
reducing costs and the incidence of adverse reactions. In women
with uncomplicated cystitis, the predictable nature of the etiologic
agents and their antimicrobial susceptibilities obviates the
need to identify the specific microbial agent routinely. In
such patients, three-day empirical therapy is highly effective,
inexpensive, and well tolerated. Recurrent cystitis in women
can be effectively managed by continuous antimicrobial prophylaxis,
postcoital prophylaxis, or patient-administered therapy at home.
Uncomplicated pyelonephritis in women results from infection
with specific uropathogenic strains of E. coli in patients with
anatomically normal urinary tracts. In such patients, antimicrobial
therapy for 10 to 14 days appears optimal, given entirely by
mouth in an outpatient setting for patients with mild illness
and initiated parenterally in sicker patients who require
hospitalization.Complicated infections encompass a broad spectrum of
clinicalconditions for which it is difficult to make all-inclusive
recommendationsfor empirical treatment. Controlled clinical trials
in whichpatients are stratified according to the type of
complicatingfactor are needed to define optimal treatment
strategies. Ingeneral, empirical regimens for such infections should
be broad-spectrum,since antibiotic-resistant strains are often
present, and therapyshould be given for at least 10 to 14 days.
Widespread resistanceto ampicillin, amoxicillin, sulfonamides, and
first-generationcephalosporins makes these drugs less attractive for
empiricaltherapy of most types of urinary infection. Given their
oralbioavailability and broad spectrum of activity against
urinarypathogens, the fluoroquinolones are especially useful in
theoutpatient management of complicated infections. There has
beendecreased emphasis on urologic evaluations in women with
acutepyelonephritis or recurrent infections. Except in selected
circumstances,screening for asymptomatic bacteriuria is unnecessary
in adults.
Supported in part by a grant (DK 40045) from the National
Institutesof Health.
Source Information
From the Division of Infectious Diseases, Department of
Medicine, University of Washington and Harborview Medical Center, 325 9th Ave.,
Seattle, WA 98104, where reprint requests should be addressed to Dr.
Stamm.
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Related Letters:
Management of Urinary Tract
Infections
Middendorf D. F., Hebert L. A., Hutt D. M., Spital
A., Stamm W. E., Hooton T. M.
Extract
| Full
Text
N Engl J Med 1994; 330:792, Mar 17, 1994.
Correspondence
Collection of Urine for
Culture
Jaffe J. S., Stamm W. E., Hooton T. M.
Extract
| Full
Text
N Engl J Med 1994; 331:617-618, Sep 1, 1994.
Correspondence
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