Clinical Review & Education

Review

Diagnosis and Management of Urinary Tract Infections

in the Outpatient Setting
A Review
Larissa Grigoryan, MD, PhD; Barbara W. Trautner, MD, PhD; Kalpana Gupta, MD, MPH

Related article page 1687

IMPORTANCE Urinary tract infection is among the most common reasons for an outpatient Supplemental content at
visit and antibiotic use in adult populations. The increasing prevalence of antibacterial jama.com
resistance among community uropathogens affects the diagnosis and management of this
CME Quiz at
clinical syndrome.
jamanetworkcme.com and
CME Questions page 1689
OBJECTIVES To define the optimal approach for treating acute cystitis in young healthy
women and in women with diabetes and men and to define the optimal approach for
diagnosing acute cystitis in the outpatient setting.

EVIDENCE REVIEW Evidence for optimal treatment regimens was obtained by searching
PubMed and the Cochrane database for English-language studies published up to July 21,
2014.

FINDINGS Twenty-seven randomized clinical trials (6463 patients), 6 systematic reviews, and
11 observational studies (252 934 patients) were included in our review. Acute uncomplicated
cystitis in women can be diagnosed without an office visit or urine culture. Trimethoprim-
sulfamethoxazole (160/800 mg twice daily for 3 days), nitrofurantoin monohydrate/
macrocrystals (100 mg twice daily for 5-7 days), and fosfomycin trometamol (3 g in a single
dose) are all appropriate first-line therapies for uncomplicated cystitis. Fluoroquinolones are
effective for clinical outcomes but should be reserved for more invasive infections. β-Lactam
agents (amoxicillin-clavulanate and cefpodoxime-proxetil) are not as effective as empirical
first-line therapies. Immediate antimicrobial therapy is recommended rather than delayed
treatment or symptom management with ibuprofen alone. Limited observational studies
support 7 to 14 days of therapy for acute urinary tract infection in men. Based on 1
observational study and our expert opinion, women with diabetes without voiding
abnormalities presenting with acute cystitis should be treated similarly to women without
diabetes.
Author Affiliations: Department of
Family and Community Medicine,
CONCLUSIONS AND RELEVANCE Immediate antimicrobial therapy with trimethoprim-
Baylor College of Medicine, Houston,
sulfamethoxazole, nitrofurantoin, or fosfomycin is indicated for acute cystitis in adult women. Texas (Grigoryan); Houston VA
Increasing resistance rates among uropathogens have complicated treatment of acute Center for Innovations in Quality,
cystitis. Individualized assessment of risk factors for resistance and regimen tolerability is Effectiveness and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs
needed to choose the optimum empirical regimen.
Medical Center, Houston, Texas
(Trautner); Section of Infectious
Diseases, Department of Medicine
and Department of Surgery, Baylor
College of Medicine, Houston, Texas
(Trautner); Section of Infectious
Diseases, Department of Medicine,
Boston Veterans Affairs Healthcare
System and Boston University School
of Medicine, Boston, Massachusetts
(Gupta).
Corresponding Author: Kalpana
Gupta, MD, MPH, Boston Veterans
Affairs Healthcare System, 1400 VFW
Pkwy, MED 111, West Roxbury, MA
02132 (kalpana.gupta@va.gov).
Section Editor: Mary McGrae
JAMA. 2014;312(16):1677-1684. doi:10.1001/jama.2014.12842 McDermott, MD, Senior Editor.

1677

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 Clinical Review & Education Review
U
rinary tract infections (UTIs) can be classified as different
clinical syndromes depending on the symptoms and host
characteristics. The most common form of UTI is acute un-
complicated cystitis, defined as the acute onset of dysuria, fre-
quency, or urgency in a healthy, nonpregnant woman without known
functional or anatomical abnormalities of the urinary tract. This con-
dition accounts for more than 8 million office visits annually, includ-
ing emergency department and urgent care visits.1 Management of
acute uncomplicated cystitis is evolving because increasing antimi-
crobial resistance limits options for oral therapy.2
The Infectious Diseases Society of America (IDSA) 2010 clini-
cal practice guidelines updated previous guidelines on treating un-
complicated UTI in women,3 and a recent comprehensive review fo-
cused on treating UTI in older adults.4 However, a current review of
treatment regimens for UTI in young adults (ⱕ65 years) in a pri-
mary care setting is particularly relevant in this era of increased mul-
tidrug-resistant uropathogens in the community.2,5 The diagnosis
of UTI is reviewed with an emphasis on management strategies. Evi-
dence regarding the optimal therapies for uncomplicated acute cys-
titis in young healthy women, in women with diabetes, and in men
with UTI is specifically addressed.
Methods
PubMed and the Cochrane database were searched for English-
language studies published before July 21, 2014, on optimal treat-
ment regimens (eMethods in the Supplement). Because resistance
rates to trimethoprim-sulfamethoxazole, fluoroquinolones, and
β-lactam agents have increased over the past decade,6 we ex-
cluded data on these agents if the study was published before 2000.
In contrast, resistance to nitrofurantoin and fosfomycin has not
meaningfully increased since their introduction6,7; therefore, we in-
cluded data on these agents without restricting the publication date.
We excluded antibiotics that are currently not available in the
United States, as well as studies that only included pregnant women,
children younger than 12 years, or adults older than 65 years or stud-
ies that included enrolled patients with factors suggesting compli-
cated UTI: pyelonephritis, urological procedure in the prior 2 weeks,
and known anatomical or functional abnormalities of the urogenital
tract. For uncomplicated cystitis, we included only randomized clini-
cal trials (RCTs) and required a minimum of 50 patients in each group,
providing 80% power to detect a 20% difference in efficacy. Trials
were not excluded based on whether the infecting organism was sus-
ceptible to the treatment agent. We also reviewed bibliographies of
the retrieved articles as well as systematic reviews for additional rel-
evant studies. Two reviewers independently assessed the quality of
included studies using an established quality checklist.8 Discor-
dance was resolved through consensus of the 3 authors. We used the
American Heart Association grading scale and level of evidence for rec-
ommendations (Box 1).9 A weighted average of efficacy rates was cal-
culated by multiplying the clinical efficacy rate by the sample size in
each study across trials for cure rates. In addition to efficacy, we evalu-
ated antimicrobial resistance.
For antimicrobial-sparing approaches and UTI in special popu-
lations (men and women with diabetes), we performed a system-
atic review but did not restrict the search to RCTs because so few
RCTs were identified. A PubMed search was performed for studies
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Urinary Tract Infections in the Outpatient Setting
Box 1. American Heart Association Grading Scale and Level
of Evidence9
A-I: conditions for which there is evidence and/or general agree-
ment that a given treatment is useful and effective; data derived from
multiple randomized clinical trials (RCTs).
A-II: conditions for which there is conflicting evidence and/or diver-
gence of opinion about the usefulness/efficacy of a treatment; data
derived from multiple randomized studies.
A-III: conditions for which there is evidence and/or general agree-
ment that the treatment is not useful/effective and in some cases may
be harmful; data derived from multiple RCTs.
B-I: conditions for which there is evidence and/or general agree-
ment that a given treatment is useful and effective; data derived from
a single randomized trial or nonrandomized studies.
B-II: conditions for which there is conflicting evidence and/or diver-
gence of opinion about the usefulness/efficacy of a procedure/
treatment, data derived from a single randomized trial or nonran-
domized studies.
B-III: conditions for which there is evidence and/or general agree-
ment that the treatment is not useful/effective and in some cases may
be harmful; data derived from a single randomized trial or nonran-
domized studies.
C-I: conditions for which there is evidence and/or general agree-
ment that a given procedure or treatment is useful and effective; con-
sensus opinion of experts.
C-II: conditions for which there is conflicting evidence and/or diver-
gence of opinion about usefulness/efficacy of a procedure or treat-
ment; consensus opinion of experts.
C-III: conditions for which there is evidence and/or general agree-
ment that the procedure/treatment is not useful/effective and in some
cases may be harmful; consensus opinion of experts.
on telephone management and patient-initiated therapy of UTI. Defi-
nitions used in this review for clinical cure, microbiological cure, early
cure, late cure, and uncomplicated UTI are outlined in Box 2.
Results
Nine observational cohort studies, 1 systematic review, and 1 RCT on
diagnosis of UTI were included in our review. After excluding ineli-
gible studies on treatment, 33 studies on treatment of UTI were in-
cluded in our final review (eFigure in the Supplement).
Diagnosis of UTI
The diagnosis of UTI is usually based on systemic or localized symp-
toms in conjunction with a positive urine culture. Host characteris-
tics can further classify the UTI syndrome as complicated or uncom-
plicated (Box 2). A urine culture is typically not available to guide
diagnosis or therapy at the acute presentation. A meta-analysis found
that women presenting to outpatient clinics with at least 2 symp-
toms of UTI (dysuria, urgency, or frequency) and the absence of vagi-
nal discharge had a greater than 90% probability of having acute
cystitis.10 Additional testing with a urine dipstick for leukocyte es-
terase would not further improve the likelihood of true infection,
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 Urinary Tract Infections in the Outpatient Setting
Box 2. Definitions of Research and Clinical End Points
Clinical cure: resolution or improvement of symptoms.a
Microbiological (bacterial) cure: a urine culture that is negative or a
reduction in the uropathogen colony count.b
Early cure, clinical or microbiological: infection resolution within 2
weeks of treatment initiation.a
Late cure, clinical or microbiological: infection resolution at 4 to 6
weeks after treatment initiation.a
Uncomplicated urinary tract infection: the acute onset of dysuria, fre-
quency, or urgency in a healthy, nondiabetic, adult, nonpregnant
woman without known functional or anatomical abnormalities of the
urinary tract.
High-quality trial: a trial with a large sample size that includes a clearly
specified randomization plan, blinding, and follow-up of more than
80%.
a Therapy Regimensb
The definition of cure, whether clinical or microbiological, can vary by study.
b
The amount of reduction in the uropathogen colony count varies by study.
given the high pretest probability. A randomized trial of manage-
ment strategies found that obtaining a urine sample either for dip-
stick testing or for culture in women with symptoms of acute cys-
titis was not associated with benefits in symptom scores or time to
reconsultation compared with immediate empirical therapy.11 Thus,
an office visit without a urine culture is an acceptable management
strategy for acute cystitis. Women with relapse or recurrent infec-
tions (>2 within 6 months), women with complicated infection, or
those in whom multidrug-resistant organisms are suspected based
on previous microbiology or exposure to antimicrobials should have
a urine culture performed. Given the high incidence of acute cysti-
tis and the high rate of recurrence, a streamlined approach to diag-
nosis and management is appealing for patients and clinicians alike
if safe and effective. Other approaches to managing acute cystitis
without a urine culture can be considered, including telephone man-
agement and patient-initiated therapy.
Telephone Management
A variety of telephone management approaches have been
studied.12-15 Most involve screening for symptoms compatible with
acute cystitis and reviewing the presence of risk factors for compli-
cated UTI, pyelonephritis, or other diagnoses, such as sexually trans-
mitted diseases (STDs). Women who meet criteria for acute cysti-
tis and do not have a history suggesting a complicated UTI,
pyelonephritis, or other diagnosis are managed by telephone with
a prescription called into their pharmacy, thus avoiding an office visit.
In general, these studies excluded women with any vaginal symp-
toms, fever or back pain, new or multiple sexual partners, and dia-
betes or other complicating conditions (Box 3).
Only 1 small RCT (n = 72) compared telephone vs office-based
care of women with acute onset of urinary symptoms.14 The pri-
mary outcome was symptom scores at days 3 and 10 after enroll-
ment, and these did not differ between the women in each group.
Overall satisfaction with care was not different between groups. Two
larger studies each evaluated approximately 4000 women seen
through health maintenance organizations. One was a retrospec-
tive evaluation of telephone management and allowed inclusion of
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Review Clinical Review & Education
Box 3. Example of a Telephone Management Strategy for Acute
Uncomplicated Cystitis
Individuals Eligible for Telephone Management
Adult women with acute onset (duration, <7-10 days) of at least 1
of the following: dysuria, frequency, urgency, or gross hematuria.
• No flank or abdominal pain
• No fever (>100.5° F)
• Ability to urinate in past 4 hours
• Able to take oral medications
• Not pregnanta
• No comorbid conditions (eg, immunosuppression)a
• No voiding abnormalities (eg, neurogenic bladder)
• No history of sexually transmitted disease or new sex partner
• No vaginal symptoms
• No recent urinary tract infection (past 4-6 weeks) or urological
procedure
Modify based on local susceptibility rates.
Preferred:
Fosfomycin, one 3-g dose
Nitrofurantoin, 100 mg twice a day for 5 days
Trimethoprim-sulfamethoxazole, 1 double-strength tablet twice
daily for 3 days
Alternative:
Ciprofloxacin, 250 mg twice daily for 3 days
a
One study allowed inclusion of women less than 20 weeks pregnant or with
diabetes.13
b
The regimens listed have not necessarily been studied in a telephone
management strategy but are based on our current recommendations for
treatment of acute cystitis in women.
women less than 20 weeks pregnant, aged 60 years or older, or with
diabetes, with a modified regimen only specified for pregnancy.13
The second study was a before-after study of a guideline empha-
sizing telephone management of nonpregnant adult women in which
40% of intervention women were treated by telephone.12,13 The pri-
mary outcome for both studies was the rate of return visits within
6 to 8 weeks for specific diagnoses that included cystitis (13%-
14.9%), pyelonephritis (ⱕ1%), or a gynecological or chlamydial in-
fection (0.5%-1.5%). There were no cases of sepsis or hospitaliza-
tion related to these outcomes, and 1 study reported that 85% of
women preferred telephone management for their next episode of
UTI.12,13 The return rates for cystitis and pyelonephritis are consis-
tent with clinical trials of standard UTI management.13 Another ret-
rospective study of telephone management reported a pyelone-
phritis rate of 2.2% but included only 237 women.15
Patient-Initiated Therapy
Women with a history of UTI can often identify symptoms indicating
onset of subsequent UTIs. In self-diagnosis or patient-initiated therapy,
women with a previous UTI are provided with an antimicrobial regi-
men to keep at home (or a prescription to fill) with instructions to ini-
tiate therapy at the onset of symptoms. An existing patient-clinician
relationship and education of the patient to seek care if there are any
new symptoms (vaginal discharge/irritation or back pain/fever), a late
or missed menstrual period, or a new sex partner are essential for the
successful implementation of this approach. This strategy allows
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 Clinical Review & Education Review
Table 1. Treatment Regimens and Early Efficacy Rates for Acute Uncomplicated Cystitisa
Drug Dosage
Trimethoprim-sulfamethoxazole22-24 160/800 mg twice daily for 3-7 d
Nitrofurantoin 100 mg twice daily for 5-7 d,22,25-27
50 mg 4 times daily for 7 d28
Fosfomycin trometamol26,28-32 3-g single dose
Fluoroquinolones23,32-40,d Varies by agent; 3-7 d
24,33,36,f
β-lactams Varies by agent; 3-d regimen
Abbreviation: AHA, American Heart Association.
a
All of the studies in this table included only women.
b
Data missing for 2 studies.23,38
c uncomplicated cystitis.
Estimated efficacy refers to early cure rates assessed at first visit after
treatment, typically within 2 weeks after start of treatment, and are weighted
averages or ranges calculated from the referenced clinical trials.
women to address their symptoms rapidly and efficiently, while avoid-
ing missed diagnoses of STDs or pyelonephritis. Three studies have
evaluated this approach; 2 studies each included approximately 35
women attending specialty clinics for recurrent UTI and a third in-
cluded 172 women from a university population.16-18 All found that the
rate of correct diagnosis among patients was more than 90%. In the
university student population, there was 1 diagnosed case of chla-
mydia and 1 case of pyelonephritis.
Conversely, studies evaluating accuracy of cystitis self-
diagnosis in emergency department settings have found low agree-
ment between patients and clinicians and a high rate (17%-21%) of
chlamydia diagnoses.19-21 Many women in the emergency depart-
ment studies did not have an established relationship with a clini-
cian or had multiple sex partners or vaginal discharge and thus did
not meet criteria for patient-initiated therapy. In summary, patient-
initiated therapy has been found to be safe and effective only in spe-
cific circumstances.
Treatment Regimens for Uncomplicated Acute Cystitis
in Adult Women
Trimethoprim-Sulfamethoxazole
Three RCTs published since 2000 compared trimethoprim-
sulfamethoxazole with another agent in young women with acute
uncomplicated cystitis (Table 1 and eTable 1 in the Supplement).22-24
Early clinical and bacterial cure rates were 85% to 100% in these
open-label trials. In the largest trial, overall clinical cure (30 days
after therapy) was achieved in 79% of the trimethoprim-
sulfamethoxazole group, and early clinical and microbiological cure
rates were 90% and 91%, respectively.22 There was a significantly
higher clinical cure rate among women in the trimethoprim-
sulfamethoxazole group who had a trimethoprim-sulfamethoxazole–
susceptible uropathogen, compared with those who had a trimeth-
oprim-sulfamethoxazole–resistant uropathogen (84% vs 41%,
respectively; P < .001). Thus, it is helpful to know the local rate of
trimethoprim-sulfamethoxazole resistance among community uro-
pathogens because efficacy rates will differ based on the preva-
lence of in vitro resistance. If the local resistance prevalence can-
not be estimated, individual risk factors, including use of
trimethoprim-sulfamethoxazole in the preceding 6 months or travel
to an endemic area of resistance, can be used to anticipate
resistance.41,42 The incidence of adverse effects ranged from 1% to
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Urinary Tract Infections in the Outpatient Setting
Age of Study Estimated Efficacy (Range), %c
Participants, AHA Level
Mean (Range), yb Early Clinical Cure Early Bacterial Cure of Evidence
32 (18-58) 91 (86-100) 91 (85-100) A-I
35 (16-89) 92 (87-95) 87 (82-92) A-I (7 d)
38 (15-92) 91 (83-95) 83 (78-98) A-I
35 (18-89) 90 (81-98) 91 (78-96) B-IIIe
30 (18-59) 86 (79-98) 81 (74-98) A-III
d
Data on fluoroquinolones were compiled from regimens of ciprofloxacin
(9 trials23,32-34,36-40) and norfloxacin (3 trials23,35,38).
e
Fluoroquinolones are considered alternative antimicrobials for acute
f
Data on β-lactams were derived from clinical trials examining
amoxicillin-clavulanate and cefpodoxime proxetil.
31% between the studies. The most frequent adverse effects were
nausea, diarrhea, headache, and dizziness.22,23
In summary, trimethoprim-sulfamethoxazole (160/800 mg twice
daily for 3 days) is an appropriate choice for therapy (level of evi-
dence A-I) if the resistance prevalence is less than 20% and if the lo-
cal antibiogram or individual risk factors do not predict resistance.
Nitrofurantoin
Five RCTs compared nitrofurantoin with other antimicrobial agents
for uncomplicated cystitis (Table 1 and eTable 2 in the
Supplement).22,25-28 Three of these trials were double-blind and
compared a 7-day course of nitrofurantoin with other antimicrobial
agents.26-28 In a recent trial of 338 women, a 5-day regimen was as
effective as the traditional 7-day course of nitrofurantoin.22 Two
meta-analyses comparing early clinical cure rates with nitrofuran-
toin and trimethoprim-sulfamethoxazole found no difference in out-
comes between these 2 agents.3,43 Late clinical cure rates were also
similar in a recent Cochrane meta-analysis (risk ratio, 1.01; 95% CI,
0.94-1.09).43 There was no significant difference in adverse events.43
Nitrofurantoin monohydrate/macrocrystals (100 mg twice daily
for 5-7 days) is an appropriate choice for therapy because of its effi-
cacy comparable with 3 days of trimethoprim-sulfamethoxazole and
minimalresistance(levelofevidenceA-I).3 A5-dayregimencanbecon-
sidered in lieu of 7 days on the basis of 1 RCT finding it comparable with
3 days of trimethoprim-sulfamethoxazole (level of evidence B-I).22
Fosfomycin
Six RCTs compared the efficacy of a 3-g single dose of fosfomycin
trometamol with other antimicrobial agents for uncomplicated
cystitis.26,28-32 Overall, the clinical cure (Box 2) of fosfomycin is com-
parable with that of other first-line agents, but the bacterial effi-
cacy is lower (Table 1 and eTable 3 in the Supplement). In the 2 large
double-blind RCTs, the effectiveness of a 3-g single dose of fosfo-
mycin was compared with nitrofurantoin given for 7 days.26,28 In both
trials, no significant difference was found for clinical cure rates be-
tween the 2 treatment groups. However, in the study by Stein,26 the
microbiologic cure rate at the first follow-up visit was significantly
lower with fosfomycin (78%) than with nitrofurantoin (86%;
P = .02). A recent meta-analysis compared the effectiveness and
safety profile of fosfomycin vs other antibiotics in patients with
cystitis.7 In the subgroup of trials involving nonpregnant female pa-
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 Urinary Tract Infections in the Outpatient Setting Review Clinical Review & Education

Table 2. Randomized Clinical Trials Addressing Non-Antimicrobial Approaches to the Treatment of Uncomplicated Urinary Tract Infection in
Nonpregnant Women
No. of
Source Women Regimen Outcome Conclusion
Nitrofurantoin or placebo Symptomatic cure on day 7 (P = .01a)
Christiaens et Nitrofurantoin, 100 mg 4× daily for 3 d 24/34 (70%) Higher cure rate with
78
al,46 2002 nitrofurantoin.
Placebo 4× daily for 3 d 14/33 (42%)
Pivmecillinam or placebo Symptom resolution at day 8-10 (P < .001a)
Pivmecillinam, 200 mg 3× daily for 7 d 132/213 (62%)
Ferry et al,47,48 Pivmecillinam, 200 mg 2× daily for 7 d 137/214 (64%) Higher cure rate with
1143
2004 and 2007 pivmecillinam.
Pivmecillinam, 400 mg 2× daily for 3 d 119/216 (55%)
Placebo 3× daily for 7 d 53/212 (25%)
Antibiotics Antibiotic use overall (P = .02a)
Empirical immediate antibiotics 58/60 (97%)
Antibiotic use significantly
Delayed antibiotics 41/53 (77%) different. Women who delayed
Little et al,11
309 antibiotics for ≥48 h had 37%
2010 Antibiotics based on symptom score 52/58 (90%) longer duration of symptoms
Antibiotics based on dipstick 40/50 (80%) (P < .001).

Antibiotics based on urinalysis 38/47 (81%)

Ciprofloxacin or ibuprofen Symptom resolution on day 4 (P = .74a)
No significant difference. 1/3 of
Bleidorn et al,49 Ciprofloxacin, 250 mg 2× daily for 3 d 17/33 (51.5%)
79 women in ibuprofen group
2010
returned for reconsultation.
Ibuprofen, 400 mg 3× daily for 3 d 21/36 (58%)
a
Comparing regimen groups.

tients, no difference was found regarding clinical and microbiologi-
cal success or occurrence of adverse events.7
In summary, fosfomycin trometamol (3 g in a single dose) is an
appropriate choice for therapy for uncomplicated cystitis (level of
evidence A-I) and has minimal resistance.
Fluoroquinolones
Ten RCTs since 2000 studied the efficacy of fluoroquinolones for
uncomplicated cystitis.23,30-36,38,39 Nine trials included ciprofloxa-
cin, and 3 trials included norfloxacin. Overall, both clinical and mi-
crobiological efficacy of fluoroquinolones are comparable with that
of other first-line agents (Table 1 and eTable 4 in the Supplement).
The quality of most of the included trials was high.33-37 The lowest
bacterial cure rate for ciprofloxacin (78%) was observed in a recent
small Turkish study where the ciprofloxacin sensitivity rate was only
59%.32 No significant difference was found between the clinical cure
rates for single-dose fosfomycin and ciprofloxacin treatment (83%
and 80%, respectively).32 High early clinical cure rates for cipro-
floxacin (98% and 93%) were observed in 2 large high-quality stud-
ies in which 96% to 98% of the uropathogens were susceptible to
ciprofloxacin.33,36
Therefore, fluoroquinolones are considered alternative antimi-
crobials for acute uncomplicated cystitis. Although highly effica-
cious for uncomplicated cystitis if the uropathogens are suscep-
tible, increasing resistance rates may hamper effectiveness of
empirical use, and these agents are needed for treatment of other
more invasive infections (level of evidence B-III).
β-Lactams
Three RCTs evaluated the efficacy of β-lactam antibiotics in uncom-
plicated cystitis.24,33,36 Both clinical and bacterial cure rates of β-lact-
ams are lower than those of other antimicrobial agents (Table 1 and
eTable 5 in the Supplement). Early and late clinical cure rates of
amoxicillin-clavulanate were 79% and 58%, respectively, in a large,
high-quality, double-blind trial with 370 women.33 Low clinical cure
rates in this trial were associated with high vaginal colonization with
uropathogens measured before and after therapy.33 Another re-
cent high-quality trial found lower clinical and microbiological cure
rates for cefpodoxime compared with ciprofloxacin.36 A network
meta-analysis of RCTs comparing efficacies of all relevant antibiot-
ics for UTI treatment using direct and indirect treatment compari-
sons concluded that amoxicillin-clavulanate is less effective than
many other treatments.44
In summary, β-lactam agents, including amoxicillin-
clavulanate and cefpodoxime-proxetil, have inferior efficacy com-
pared with other UTI antimicrobial agents (level of evidence A-III).
Other Approaches to Treating Uncomplicated Acute Cystitis
in Women
There is limited evidence regarding antimicrobial-sparing ap-
proaches to treatment of acute cystitis. Non-antimicrobial ap-
proaches that have been investigated include symptomatic treat-
ment with ibuprofen, placebo treatment, and treatment with
cranberry products. Delayed antimicrobial therapy has also been
studied as an antimicrobial-sparing strategy. No RCTs have ad-
dressed whether cranberry products can be used to treat acute cys-
titis, and extensive studies on cranberry products to prevent UTI have
not confirmed a clear benefit.45
Treatment of UTI with placebo has been studied in 2 RCTs
(Table 2).46-48 Christiaens et al46 performed a blinded RCT of pla-
cebo vs nitrofurantoin in 78 young women presenting with symp-
toms of acute cystitis, excluding those with fever, diabetes, recur-
rent or recent UTI, and other conditions. Symptomatic cure at 7 days
was lower in the placebo group (42%) compared with the treat-
ment group (70%, P = .01). However, these numbers are poten-
tially misleading in favor of the placebo group, because 10 women

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 Clinical Review & Education Review
Table 3. Studies Addressing Treatment of UTI in Men and Women With Diabetes
Source Population No. of Participants
Ulleryd et al,55 Men with urinary 72
2003 symptoms and fever
Drekonja Men treated for UTI 33 336
et al,56 2013
Schneeberger Women with and 210 624 total:
et al,57 2008 without diabetes 10 366 with
treated for UTI diabetes, 200 258
without
Abbreviations: RCT, randomized clinical trial; UTI, urinary tract infection.
dropped out of the placebo group for worsening symptoms, com-
pared with 2 such dropouts in the treatment group. One of 38
women in the placebo group developed pyelonephritis (2.6%). The
placebo vs pivmecillinam study by Ferry et al47,48 also favored an-
tibiotic therapy over placebo (Table 2). One of 855 pivmecillinam-
treated women developed pyelonephritis, in comparison with 1 of
288 women in the placebo group.
A meta-analysis50 of RCTs of antibiotics vs placebo for women
with uncomplicated cystitis included these 2 studies as well as 3 ear-
lier studies, 2 of which studied single-dose therapy51,52 and 1 of which
did not report clinical or microbiological cure rates.53 Antibiotics were
superior to placebo when measured by clinical improvement, clini-
cal cure, or bacterial cure, although adverse events (any) were more
likely in the women treated with antibiotics. To summarize, avail-
able evidence does not support placebo treatment of adult, non-
pregnant women who present with symptoms of acute cystitis; pla-
cebo is not helpful and may even be harmful (level of evidence A-III).
Delayed Therapy and Ibuprofen Therapy
AnotherapproachtomanagementofUTIisdelayedantibiotictherapy
or treatment with anti-inflammatory agents (ibuprofen) rather than
antibiotics. The rationale for these approaches is that some women
have symptom resolution without antimicrobial therapy, and anti-
biotic-sparing approaches for a common condition such as acute cys-
titis might dramatically reduce overall use of antibiotics. Little et al11
randomized 309 nonpregnant women with suspected acute cysti-
tis to 5 different management approaches (Table 2). Although the
duration of moderate symptoms was the same in all groups, 77% of
women in the delayed antibiotics group ultimately received antibi-
otics. In addition, the women who delayed antibiotics for 48 hours
or more had a 37% longer duration of symptoms (P < .001). A single,
double-blinded RCT compared ibuprofen and ciprofloxacin in 29
women who presented with dysuria, frequency, or both.49 Symp-
tom resolution was similar in the 2 groups, but 33% of patients in
the ibuprofen group received antibiotic treatment for worsening
symptoms. A larger trial of ibuprofen vs fosfomycin for women with
symptoms of acute cystitis is ongoing.54 Available evidence sup-
ports immediate antimicrobial treatment for women who present
with acute UTI symptoms as the best means to achieve rapid and
effective control of symptoms. Current evidence suggests that de-
laying antibiotic therapy and ibuprofen therapy are not helpful and
may be harmful (level of evidence B-III).
Treatment of UTI in Other Patient Populations
Most studies on UTI treatment were performed in adult, nonpreg-
nant, nondiabetic women with uncomplicated cystitis. The ap-
1682 JAMA October 22/29, 2014 Volume 312, Number 16
Copyright 2014 American Medical Association. All rights reserved.
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Urinary Tract Infections in the Outpatient Setting
Study Design Outcomes
RCT comparing ciprofloxacin, 500 mg Symptom resolution at 14 d: no difference with
twice daily for 2 vs 4 weeks 2 weeks (92%) vs 4 weeks (97%); P > .05
Retrospective observational study of Early recurrence in <30 d: no difference
outcomes with shorter duration of between short-duration therapy (3.9%) vs
treatment (≤7 d) vs longer duration (>7 d) longer duration (4.2%); P = .16
Retrospective observational study of Treatment duration was longer and recurrent
duration of treatment for UTI and rates were higher in premenopausal and
recurrence rates postmenopausal women with diabetes than
those without; P < .01 for all
proach to UTI in men and women with diabetes is based on far more
limited evidence. We identified only 1 RCT and 1 observational study
since 2000 addressing male UTI55,56 and only a single observa-
tional study in diabetic women (Table 3).57 The RCT of male UTI found
that 2 weeks of therapy was sufficient for treating febrile UTI that
involves the prostate,55 while the observational trial found that
therapy for men with UTI in the outpatient setting for 7 days or less
was associated with similar early recurrence rates as longer-
duration therapy.56 These 2 studies together suggest that therapy
longer than 7 to 14 days may not be beneficial in men with acute UTI;
however, neither study adequately addressed the question, and the
minimal duration of therapy has not been well established. In sum-
mary, the duration of therapy for acute UTI in men should be lim-
ited to 7 to 14 days (level of evidence B-II), and in our practice, based
on our expertise, we treat for 7 days.
The optimal duration and type of therapy for women with dia-
betes and acute cystitis is also not defined. The observational study
by Schneeberger at al57 found that diabetic women, in comparison
with nondiabetic women, received a longer course of therapy, had
a higher recurrence rate within 30 days, and were more likely to be
hospitalized for UTI in the postmenopausal group (P < .01 for all com-
parisons). From this observational study, we cannot determine
whether diabetic women are truly at higher risk for recurrent UTI or
whether their clinicians suspect them to be at higher risk and thus
are more likely to prescribe antimicrobial therapy. However, our ex-
pert opinion is that diabetic women presenting with acute cystitis
should be managed similarly to women without diabetes (level of
evidence C-I). This recommendation does not apply to diabetic
women with more serious presentations or with evidence of abnor-
mal voiding.
Discussion
Acute uncomplicated cystitis is a common condition that can often
be successfully diagnosed and treated without a urine culture.
Culture-sparing strategies include telephone management, patient
self-diagnosis, and office visits without urine culture. Clinical trial evi-
dence supports trimethoprim-sulfamethoxazole (160/800 mg twice
daily for 3 days), nitrofurantoin monohydrate/macrocrystals (100 mg
twice daily for 5-7 days), and fosfomycin trometamol (3 g in a single
dose) as first-line therapies for uncomplicated cystitis. The choice
between these agents should be influenced by individual factors such
as resistance prevalence, cost, and tolerability. The rate of resis-
tance among Escherichia coli to the fluoroquinolones (~20%) is about
10-fold higher than to fosfomycin (1%-2%) and is increasing.58 Fluo-
jama.com
 Urinary Tract Infections in the Outpatient Setting Review Clinical Review & Education

roquinolones are key therapeutic agents for many bacterial infec-
tions outside the urinary tract, but fosfomycin and nitrofurantoin are
exclusively used for UTI and do not need to be “saved” for other in-
fections. β-Lactam agents, including amoxicillin-clavulanate and
cefpodoxime-proxetil, are not as effective as the first-line thera-
pies. Immediate antimicrobial therapy is recommended rather than
delayed treatment and or symptom management with ibuprofen
alone. Thus, our comprehensive systematic review is in agreement
with the recommendations of the IDSA guideline update on man-
agement of acute cystitis.3 An important caveat is that there are lim-
ited data on outcomes among women with uropathogens resistant
to the treatment drug, and increasing resistance may result in lower
efficacy rates in clinical practice compared with what is observed in
a clinical trial setting.
Men with acute cystitis should be treated for 7 to 14 days. One
of the most controversial issues in UTI management is whether dia-
betic women with acute cystitis should receive the same treat-
ment as nondiabetic women or whether risk stratification of dia-
betic women for a longer or different type of therapy is necessary
based on diabetes-related complications such as neurogenic blad-
der. These gaps in knowledge are important areas for future re-
search. Even uncomplicated cystitis in adults is increasingly diffi-
cult to treat, requiring individualized assessment of risk factors for
resistant uropathogens and acceptance of potentially reduced clini-
cal efficacy of empirical regimens. Educating patients regarding the
potential for resistance to the drug they are being prescribed and
need for reevaluation and urine culture if symptoms do not im-
prove are also important.
Conclusions
Immediate antimicrobial therapy with trimethoprim-sulfamethoxa-
zole, nitrofurantoin, or fosfomycin is indicated for acute cystitis in
adult women. Increasing resistance rates among uropathogens have
complicated treatment of acute cystitis, but telephone manage-
ment without an office visit or culture is still an appropriate and ef-
ficient approach for most cases of uncomplicated cystitis. Individu-
alized assessment of risk factors for resistance and regimen
tolerability is needed to choose the optimum empirical regimen.

ARTICLE INFORMATION REFERENCES uncomplicated urinary tract infection? JAMA. 2002;

Author Contributions: Dr Grigoryan had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. All authors
contributed equally to this work.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Grigoryan, Gupta.
Study supervision: Trautner, Gupta.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Gupta served as a consultant for Paratek Pharm,
Boehringer Ingelheim, and Melinta Therapeutics
and owns equity interests in Aegis Women’s Health
Technology. No other disclosures were reported.
Funding/Support: Support for this work includes
resources and use of facilities at Boston Veterans
Affairs Healthcare System, West Roxbury,
Massachusetts (K.G.), and at the Houston VA
Center for Innovations in Quality, Effectiveness and
Safety (CIN13-413) at the Michael E. DeBakey
Veterans Affairs Medical Center, Houston, Texas
(B.W.T.). Dr Grigoryan also received support from a
National Research Service Award (5 T32 HP10031).
Role of the Funder/Sponsor: The supporting
agencies had no role in the design and conduct of
the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The opinions expressed reflect those of
the authors and not necessarily those of the
Department of Veterans Affairs, the US
government, or Baylor College of Medicine.
Submissions:We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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