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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
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IMPORTANCE Urinary tract infection is among the most common reasons for an outpatient
visit and antibiotic use in adult populations. The increasing prevalence of antibacterial
resistance among community uropathogens affects the diagnosis and management of this
clinical syndrome.
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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. Trimethoprimsulfamethoxazole (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.
CONCLUSIONS AND RELEVANCE Immediate antimicrobial therapy with trimethoprim-
sulfamethoxazole, nitrofurantoin, or fosfomycin is indicated for acute cystitis in adult women.
Increasing resistance rates among uropathogens have complicated treatment of acute
cystitis. Individualized assessment of risk factors for resistance and regimen tolerability is
needed to choose the optimum empirical regimen.
Author Affiliations: Department of
Family and Community Medicine,
Baylor College of Medicine, Houston,
Texas (Grigoryan); Houston VA
Center for Innovations in Quality,
Effectiveness and Safety (IQuESt),
Michael E. DeBakey Veterans Affairs
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 ([email protected]).
JAMA. 2014;312(16):1677-1684. doi:10.1001/jama.2014.12842
Section Editor: Mary McGrae
McDermott, MD, Senior Editor.
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Clinical Review & Education Review
Urinary Tract Infections in the Outpatient Setting
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 uncomplicated cystitis, defined as the acute onset of dysuria, frequency, or urgency in a healthy, nonpregnant woman without known
functional or anatomical abnormalities of the urinary tract. This condition accounts for more than 8 million office visits annually, including emergency department and urgent care visits.1 Management of
acute uncomplicated cystitis is evolving because increasing antimicrobial resistance limits options for oral therapy.2
The Infectious Diseases Society of America (IDSA) 2010 clinical practice guidelines updated previous guidelines on treating uncomplicated UTI in women,3 and a recent comprehensive review focused on treating UTI in older adults.4 However, a current review of
treatment regimens for UTI in young adults (ⱕ65 years) in a primary care setting is particularly relevant in this era of increased multidrug-resistant uropathogens in the community.2,5 The diagnosis
of UTI is reviewed with an emphasis on management strategies. Evidence regarding the optimal therapies for uncomplicated acute cystitis 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 Englishlanguage studies published before July 21, 2014, on optimal treatment regimens (eMethods in the Supplement). Because resistance
rates to trimethoprim-sulfamethoxazole, fluoroquinolones, and
β-lactam agents have increased over the past decade,6 we excluded 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 included 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 studies that included enrolled patients with factors suggesting complicated 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 clinical 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 susceptible to the treatment agent. We also reviewed bibliographies of
the retrieved articles as well as systematic reviews for additional relevant studies. Two reviewers independently assessed the quality of
included studies using an established quality checklist.8 Discordance was resolved through consensus of the 3 authors. We used the
American Heart Association grading scale and level of evidence for recommendations (Box 1).9 A weighted average of efficacy rates was calculated by multiplying the clinical efficacy rate by the sample size in
each study across trials for cure rates. In addition to efficacy, we evaluated antimicrobial resistance.
For antimicrobial-sparing approaches and UTI in special populations (men and women with diabetes), we performed a systematic 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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Box 1. American Heart Association Grading Scale and Level
of Evidence9
A-I: conditions for which there is evidence and/or general agreement 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 divergence 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 agreement 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 agreement 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 divergence of opinion about the usefulness/efficacy of a procedure/
treatment, data derived from a single randomized trial or nonrandomized studies.
B-III: conditions for which there is evidence and/or general agreement that the treatment is not useful/effective and in some cases may
be harmful; data derived from a single randomized trial or nonrandomized studies.
C-I: conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective; consensus opinion of experts.
C-II: conditions for which there is conflicting evidence and/or divergence of opinion about usefulness/efficacy of a procedure or treatment; consensus opinion of experts.
C-III: conditions for which there is evidence and/or general agreement 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. Definitions 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 ineligible studies on treatment, 33 studies on treatment of UTI were included in our final review (eFigure in the Supplement).
Diagnosis of UTI
The diagnosis of UTI is usually based on systemic or localized symptoms in conjunction with a positive urine culture. Host characteristics can further classify the UTI syndrome as complicated or uncomplicated (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 symptoms of UTI (dysuria, urgency, or frequency) and the absence of vaginal discharge had a greater than 90% probability of having acute
cystitis.10 Additional testing with a urine dipstick for leukocyte esterase 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
Review Clinical Review & Education
Box 3. Example of a Telephone Management Strategy for Acute
Uncomplicated Cystitis
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, frequency, 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
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 management strategies found that obtaining a urine sample either for dipstick testing or for culture in women with symptoms of acute cystitis 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 infections (>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 cystitis and the high rate of recurrence, a streamlined approach to diagnosis 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 management 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 complicated UTI, pyelonephritis, or other diagnoses, such as sexually transmitted diseases (STDs). Women who meet criteria for acute cystitis 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 symptoms, fever or back pain, new or multiple sexual partners, and diabetes 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 primary outcome was symptom scores at days 3 and 10 after enrollment, 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 retrospective evaluation of telephone management and allowed inclusion of
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
Therapy Regimensb
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 emphasizing telephone management of nonpregnant adult women in which
40% of intervention women were treated by telephone.12,13 The primary 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 infection (0.5%-1.5%). There were no cases of sepsis or hospitalization 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 consistent with clinical trials of standard UTI management.13 Another retrospective study of telephone management reported a pyelonephritis 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 regimen to keep at home (or a prescription to fill) with instructions to initiate 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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Table 1. Treatment Regimens and Early Efficacy Rates for Acute Uncomplicated Cystitisa
Drug
Trimethoprim-sulfamethoxazole22-24
Nitrofurantoin
24,33,36,f
β-lactams
Early Clinical Cure
Early Bacterial Cure
AHA Level
of Evidence
160/800 mg twice daily for 3-7 d
32 (18-58)
91 (86-100)
91 (85-100)
A-I
35 (16-89)
92 (87-95)
87 (82-92)
A-I (7 d)
3-g single dose
38 (15-92)
91 (83-95)
83 (78-98)
A-I
Varies by agent; 3-7 d
35 (18-89)
90 (81-98)
91 (78-96)
B-IIIe
Varies by agent; 3-d regimen
30 (18-59)
86 (79-98)
81 (74-98)
A-III
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
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 avoiding 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 included 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 chlamydia and 1 case of pyelonephritis.
Conversely, studies evaluating accuracy of cystitis selfdiagnosis in emergency department settings have found low agreement between patients and clinicians and a high rate (17%-21%) of
chlamydia diagnoses.19-21 Many women in the emergency department studies did not have an established relationship with a clinician or had multiple sex partners or vaginal discharge and thus did
not meet criteria for patient-initiated therapy. In summary, patientinitiated therapy has been found to be safe and effective only in specific circumstances.
Treatment Regimens for Uncomplicated Acute Cystitis
in Adult Women
Trimethoprim-Sulfamethoxazole
Three RCTs published since 2000 compared trimethoprimsulfamethoxazole 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 trimethoprimsulfamethoxazole 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 trimethoprimsulfamethoxazole group who had a trimethoprim-sulfamethoxazole–
susceptible uropathogen, compared with those who had a trimethoprim-sulfamethoxazole–resistant uropathogen (84% vs 41%,
respectively; P < .001). Thus, it is helpful to know the local rate of
trimethoprim-sulfamethoxazole resistance among community uropathogens because efficacy rates will differ based on the prevalence of in vitro resistance. If the local resistance prevalence cannot 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
1680
Estimated Efficacy (Range), %c
100 mg twice daily for 5-7 d,22,25-27
50 mg 4 times daily for 7 d28
Fosfomycin trometamol26,28-32
Fluoroquinolones23,32-40,d
Dosage
Age of Study
Participants,
Mean (Range), yb
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
uncomplicated cystitis.
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 evidence A-I) if the resistance prevalence is less than 20% and if the local 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 nitrofurantoin and trimethoprim-sulfamethoxazole found no difference in outcomes 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 efficacy comparable with 3 days of trimethoprim-sulfamethoxazole and
minimalresistance(levelofevidenceA-I).3 A5-dayregimencanbeconsidered 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 comparable with that of other first-line agents, but the bacterial efficacy 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 fosfomycin was compared with nitrofurantoin given for 7 days.26,28 In both
trials, no significant difference was found for clinical cure rates between 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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Review Clinical Review & Education
Table 2. Randomized Clinical Trials Addressing Non-Antimicrobial Approaches to the Treatment of Uncomplicated Urinary Tract Infection in
Nonpregnant Women
Source
No. of
Women
Regimen
Nitrofurantoin or placebo
Christiaens et
al,46 2002
78
Nitrofurantoin, 100 mg 4× daily for 3 d
Placebo 4× daily for 3 d
Pivmecillinam or placebo
Ferry et al,47,48
2004 and 2007
1143
79
Pivmecillinam, 400 mg 2× daily for 3 d
119/216 (55%)
53/212 (25%)
58/60 (97%)
Delayed antibiotics
41/53 (77%)
Antibiotics based on symptom score
52/58 (90%)
Antibiotics based on dipstick
40/50 (80%)
Ciprofloxacin, 250 mg 2× daily for 3 d
Higher cure rate with
pivmecillinam.
Antibiotic use overall (P = .02a)
Empirical immediate antibiotics
Ibuprofen, 400 mg 3× daily for 3 d
a
14/33 (42%)
137/214 (64%)
Ciprofloxacin or ibuprofen
Higher cure rate with
nitrofurantoin.
Symptom resolution at day 8-10 (P < .001a)
132/213 (62%)
Antibiotics based on urinalysis
Bleidorn et al,49
2010
24/34 (70%)
Pivmecillinam, 200 mg 2× daily for 7 d
Antibiotics
309
Conclusion
Pivmecillinam, 200 mg 3× daily for 7 d
Placebo 3× daily for 7 d
Little et al,11
2010
Outcome
Symptomatic cure on day 7 (P = .01a)
Antibiotic use significantly
different. Women who delayed
antibiotics for ≥48 h had 37%
longer duration of symptoms
(P < .001).
38/47 (81%)
Symptom resolution on day 4 (P = .74a)
17/33 (51.5%)
21/36 (58%)
No significant difference. 1/3 of
women in ibuprofen group
returned for reconsultation.
Comparing regimen groups.
tients, no difference was found regarding clinical and microbiological 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 ciprofloxacin, and 3 trials included norfloxacin. Overall, both clinical and microbiological 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 ciprofloxacin (98% and 93%) were observed in 2 large high-quality studies in which 96% to 98% of the uropathogens were susceptible to
ciprofloxacin.33,36
Therefore, fluoroquinolones are considered alternative antimicrobials for acute uncomplicated cystitis. Although highly efficacious for uncomplicated cystitis if the uropathogens are susceptible, 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 uncomplicated cystitis.24,33,36 Both clinical and bacterial cure rates of β-lactams 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 recent 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 antibiotics for UTI treatment using direct and indirect treatment comparisons concluded that amoxicillin-clavulanate is less effective than
many other treatments.44
In summary, β-lactam agents, including amoxicillinclavulanate and cefpodoxime-proxetil, have inferior efficacy compared 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 approaches to treatment of acute cystitis. Non-antimicrobial approaches that have been investigated include symptomatic treatment with ibuprofen, placebo treatment, and treatment with
cranberry products. Delayed antimicrobial therapy has also been
studied as an antimicrobial-sparing strategy. No RCTs have addressed whether cranberry products can be used to treat acute cystitis, 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 placebo vs nitrofurantoin in 78 young women presenting with symptoms of acute cystitis, excluding those with fever, diabetes, recurrent or recent UTI, and other conditions. Symptomatic cure at 7 days
was lower in the placebo group (42%) compared with the treatment group (70%, P = .01). However, these numbers are potentially misleading in favor of the placebo group, because 10 women
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Table 3. Studies Addressing Treatment of UTI in Men and Women With Diabetes
Source
Population
Ulleryd et al,55
2003
Men with urinary
symptoms and fever
No. of Participants
72
Drekonja
et al,56 2013
Men treated for UTI
33 336
Schneeberger
et al,57 2008
Women with and
without diabetes
treated for UTI
210 624 total:
10 366 with
diabetes, 200 258
without
Study Design
Outcomes
RCT comparing ciprofloxacin, 500 mg
twice daily for 2 vs 4 weeks
Symptom resolution at 14 d: no difference with
2 weeks (92%) vs 4 weeks (97%); P > .05
Retrospective observational study of
outcomes with shorter duration of
treatment (≤7 d) vs longer duration (>7 d)
Early recurrence in <30 d: no difference
between short-duration therapy (3.9%) vs
longer duration (4.2%); P = .16
Retrospective observational study of
duration of treatment for UTI and
recurrence rates
Treatment duration was longer and recurrent
rates were higher in premenopausal and
postmenopausal women with diabetes than
those without; P < .01 for all
Abbreviations: RCT, randomized clinical trial; UTI, urinary tract infection.
dropped out of the placebo group for worsening symptoms, compared 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 antibiotic therapy over placebo (Table 2). One of 855 pivmecillinamtreated 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 earlier 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, clinical cure, or bacterial cure, although adverse events (any) were more
likely in the women treated with antibiotics. To summarize, available evidence does not support placebo treatment of adult, nonpregnant women who present with symptoms of acute cystitis; placebo 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 antibiotic-sparing approaches for a common condition such as acute cystitis might dramatically reduce overall use of antibiotics. Little et al11
randomized 309 nonpregnant women with suspected acute cystitis 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 antibiotics. 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 Symptom 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 supports 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 delaying 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, nonpregnant, nondiabetic women with uncomplicated cystitis. The ap1682
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 observational 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 longerduration 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 summary, the duration of therapy for acute UTI in men should be limited 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 diabetes 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 comparisons). 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 expert 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 abnormal 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 evidence 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 resistance among Escherichia coli to the fluoroquinolones (~20%) is about
10-fold higher than to fosfomycin (1%-2%) and is increasing.58 Fluo-
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Urinary Tract Infections in the Outpatient Setting
Review Clinical Review & Education
roquinolones are key therapeutic agents for many bacterial infections outside the urinary tract, but fosfomycin and nitrofurantoin are
exclusively used for UTI and do not need to be “saved” for other infections. β-Lactam agents, including amoxicillin-clavulanate and
cefpodoxime-proxetil, are not as effective as the first-line therapies. 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 management of acute cystitis.3 An important caveat is that there are limited 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 diabetic women with acute cystitis should receive the same treatment as nondiabetic women or whether risk stratification of diabetic 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 research. Even uncomplicated cystitis in adults is increasingly difficult to treat, requiring individualized assessment of risk factors for
resistant uropathogens and acceptance of potentially reduced clinical 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 improve are also important.
Conclusions
Immediate antimicrobial therapy with trimethoprim-sulfamethoxazole, nitrofurantoin, or fosfomycin is indicated for acute cystitis in
adult women. Increasing resistance rates among uropathogens have
complicated treatment of acute cystitis, but telephone management without an office visit or culture is still an appropriate and efficient approach for most cases of uncomplicated cystitis. Individualized assessment of risk factors for resistance and regimen
tolerability is needed to choose the optimum empirical regimen.
ARTICLE INFORMATION
REFERENCES
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.
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