Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review With Practice Recommendations

Review Article
1 58
2 59
3 60
4 61
5 62
6 63
7 Treatment and Prevention of Recurrent Lower Urinary Tract 64
8 Infections in Women: A Rapid Review with Practice 65
9 Recommendations 66
10 67
11 68
Ariana L. Smith, Jason Brown, Jean F. Wyman, Amanda Berry, Diane K. Newman
12 69
13
and Ann E. Stapleton 70
14 From the Division of Urology (ALS, DKN) and School of Nursing (JB), University of Pennsylvania and Children’s Hospital of 71
Philadelphia (AB), Philadelphia, Pennsylvania, School of Nursing, University of Minnesota, Minneapolis, Minnesota (JFW), and
15 Division of Allergy and Infectious Disease, University of Washington, Seattle, Washington (AES)
72
16 73
17 74
Purpose: Recurrent lower urinary tract infections in women are a highly prev-
18 Abbreviations 75
alent and burdensome condition for which best practice guidelines for treatment
19 and Acronyms 76
and prevention that minimize harm and optimize well-being are greatly needed.
20 CHM ¼ Chinese herbal medicine 77
To inform development of practice recommendations, a rapid literature review of
21 CS ¼ chondroitin sulfate 78
original research, systematic reviews, meta-analyses and practice guidelines was
22 79
conducted. HA ¼ hyaluronic acid
23 80
Materials and Methods: PubMed , Embase , Opus, Scopus , Google Scholar, NF ¼ nitrofurantoin
24 81
The Cochrane Library and the U.S. National Guideline Clearinghouse electronic PAC ¼ A-type proanthocyanidins
25 82
databases were searched from inception to September 22, 2017. Articles and RCT ¼ randomized controlled trial
26 83
practice guidelines were included if they were in English, were peer reviewed,
27 rUTI ¼ recurrent urinary tract 84
included women, involved treatment or prevention strategies for recurrent uri-
28 infection 85
nary tract infection and reported an outcome related to recurrence rates of uri-
29 TMP-SMX ¼ trimethoprim- 86
nary tract infection. Critical appraisal of original studies was conducted using the
30 sulfamethoxazole 87
Cochrane risk of bias tool, and of systematic reviews using the AMSTAR 2 tool.
31 UTI ¼ urinary tract infection 88
32 Results: Of 1,582 citations identified 74 met our study inclusion criteria. These 89
33 comprised 49 randomized controlled trials, 23 systematic reviews (16 with meta- Accepted for publication April 30, 2018. 90
34 analyses) and 2 practice guidelines. No study reported a multi-targeted treat- No direct or indirect commercial incentive 91
35 ment approach. There was a lack of high quality studies and systematic reviews associated with publishing this article.
92
The corresponding author certifies that,
36 evaluating prevention strategies for recurrent urinary tract infection. when applicable, a statement(s) has been 93
37 Conclusions: We recommend an algorithmic approach to care that includes ed- included in the manuscript documenting 94
ucation on lifestyle and behavioral modifications and addresses specific pop- institutional review board, ethics committee or
38 ethical review board study approval; principles
95
39 ulations of women with antimicrobial based and nonantibiotic alternatives. This of Helsinki Declaration were followed in lieu of 96
40 approach includes the use of vaginal estrogen with or without lactobacillus formal ethics committee approval; institutional 97
containing probiotics in postmenopausal women, low dose post-coital antibiotics animal care and use committee approval; all
41 human subjects provided written informed 98
42 for recurrent urinary tract infection associated with sexual activity in premen- consent with guarantees of confidentiality; 99
43 opausal women, low dose daily antibiotic prophylaxis in premenopausal women IRB approved protocol number; animal approved 100
project number.
44 with infections unrelated to sexual activity, and methenamine hippurate and/or 101
Supplementary references 51-131 for this
45 lactobacillus containing probiotics as nonantibiotic alternatives. Future research article can be obtained at http://jurology.com/. 102
46 should involve consistent use of terminology, validated instruments to assess 103
47 response to interventions and patient perspectives on care. Our treatment al- 104
48 gorithm is based on the best available evidence and fills a gap in the literature 105
49 and practice regarding effective strategies to prevent recurrent urinary tract 106
50 infection in women. 107
51 108
52 Key Words: urinary tract infections, recurrence, prevention and control, 109
53 women, anti-bacterial agents 110
54 111
INC.
55 0022-5347/18/2006-0001/0 https
56 THE JOURNAL OF UROLOGY
®
://doi
2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, .org/
57 10.10
16/j.j
Dochead: Review Article REV 5.5.0 DTD JURO15681_proof 19 September 2018 4:18 pm EO: JU-18-405
uro.2018.04.088 112
Vol. 200, 1-18, December 2018
Printed in U.S.A.
j 1 113 www.jurology.com
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2 RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN
115 SYMPTOMATIC recurrent lower urinary tract in- the treatment and prevention of rUTI in healthy 172
116 fections are a highly prevalent, burdensome and women based on a synthesis of the literature. 173
117 costly condition leading healthy ambulatory women 174
118 to seek care from a variety of medical specialties, as 175
119 well as nonmedical online media resources and METHODS 176
120 1
blogs. Recurrent UTIs affect women of all ages, This rapid literature review followed a streamlined 177
121 races and ethnicities regardless of socioeconomic approach to systematically identify and summarize 178
122 status, education level or sexual orientation. They studies and practice guidelines, and followed the report- 179
123 ing guidelines outlined in the PRISMA (Preferred
significantly impact quality of life, daily activities 180
Reporting Items for Systematic Reviews and Meta-
124 2
and mental health of women. The definition of 181
125 Analyses) statement.12
rUTI varies in the existing literature and consensus 182
126 3
has not been achieved. For the purposes of this Search Strategy 183
127 article (and to reflect Food and Drug Administration We searched PubMed, Embase, Opus, Scopus, Google 184
128 criteria), rUTI is defined as 2 or more symptomatic Scholar, The Cochrane Library and the U.S. National 185
129 episodes in 6 months or 3 episodes in 1 year. Be- Guideline Clearinghouse from inception to September 186
130 tween 20% and 30% of women who have had 1 22, 2017. The search terms included database specific 187
131 episode of UTI will have a rUTI, and approximately subject headings and keywords were used that were 188
132 similar to the PubMed search terms (infection*) AND 189
25% of these women will experience subsequent
133 ((((“Urinary Tract Infections”[Mesh] OR uti OR “urinary
1
recurrent episodes. In the United States annual 190
tract infection*” OR rUTI)) AND urinary[title] AND
134 health care costs are estimated at $2 billion as a 191
("Recurrence"[Mesh] OR recurr*[title] OR repeat*
135 result of outpatient visits, diagnostic tests and pre- 192
[title]))) AND English[lang]). We also manually searched
136 scriptions.
4,5
This condition is relevant to several references of all included studies and systematic reviews 193
137 medical and nursing specialties including internal for additional relevant citations. 194
138 medicine, geriatric medicine, women’s health, ob- 195
139 stetrics/gynecology, urology, infectious disease and Eligibility Criteria 196
140 emergency medicine. We included RCTs, systematic reviews, meta-analyses 197
141 and professional society clinical practice guidelines 198
Antibiotic use for the treatment of sporadic and
142 focusing on the treatment and prevention of rUTI in
rUTIs varies with respect to category of drug, dose 199
nonpregnant adult ambulatory women. Only publica-
143 and duration of therapy. Although the Infectious 200
tions in English were included in analysis. We
144 Diseases Society of America has published guide- excluded studies on diagnosis, imaging, pathophysi- 201
145 lines for the treatment of uncomplicated UTI,
6
ology, acute UTI, males (without female predominance 202
146 7
catheter associated UTIs and asymptomatic bacte- or subgroup analysis), children (with mean age less 203
147 8 than 18 years), institutionalized patients, catheter 204
riuria, to our knowledge no universally accepted
148 related UTI, congenital abnormalities of the urinary 205
treatment algorithm exists to guide clinical practice
149 tract, spinal cord injury, transplant recipients, neuro- 206
for rUTI in women. Furthermore, there is insuffi- genic bladder, immunosuppression, chemotherapy or
150 cient Level 1 evidence to compare existing ap- 207
151 recent surgery.
proaches. Several strategies currently used to treat 208
152 rUTI include broadening the antibiotic spectrum, 209
Data Collection and Analysis
153 lengthening treatment course and/or increasing Titles and abstracts were screened by at least 1 author, 210
154 9
antibiotic dose. These strategies have not been with 2 authors determining the final section of included 211
155 proven efficacious and elicit tremendous concern for studies based on full text evaluation. Disagreements 212
156 potential harm to the individual and the community. were resolved through discussion with all authors. Data 213
157 In addition, they effectively oppose antimicrobial extraction was divided among the 6 authors, with 2 au- 214
158 stewardship programs, in which shortening courses thors extracting data from each eligible study using a 215
159 10 standardized, pre-piloted Excel spreadsheet. Specific 216
of antimicrobial treatment is a common goal. study characteristics (sample size, participant de-
160 Studies of providers’ choices of antimicrobials for 217
mographics, exposure/comparator conditions, outcomes
161 the treatment of UTI show a high rate of non- 218
and adverse events) were extracted from the RCTs, along
162 adherence to clinical guidelines, raising concerns with ratings for the domain items from the Cochrane 219
163 about the role of this common infection in promoting 220
13 14
164 11 risk of bias tool and the Oxford levels of evidence. 221
antimicrobial resistance in the community.
165 Specific characteristics were also extracted from sys-
Guidelines for the management of rUTIs are 222
166 tematic reviews/meta-analyses (number of studies
needed to prevent overuse of antibiotics, improve included, total population, outcomes for exposure/
223
167 selection of antimicrobial agents, decrease the risk 224
comparator conditions and individual items from the
168 of antibiotic resistance, reduce adverse effects of 225
AMSTAR 2 tool).15 The primary outcome assessed was
169 antibiotic use and improve the care of women with 226
the proportion of patients with recurrent symptomatic
170 rUTI. Our objective was to develop UTI (according to defined clinical criteria described in 227
171 recommendations for 228
RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN 3
229 each study) for each group. We provide a qualitative Quality of Included Studies and Systematic 286
230 description of our results. Reviews 287
231 The quality of the included RCTs was generally poor 288
232 Quality Appraisal (tables 1 and 2). Study design issues included inad- ½T1 289
233 Two authors evaluated the risk of bias of original studies equate allocation concealment, lack of blinding and ½T2 290
234 according to the criteria outlined by the international post- randomization exclusions. More recent studies 291
235 Cochrane Collaboration for RCTs.13 Trials were consid- tended to be of better quality. Significant heteroge- 292
236 ered low risk of bias if all individual criteria were low and neity was found across studies. Not all studies used 293
were considered high risk of bias if at least 1 criterion was
237 the same criteria for UTI and in general, criteria 294
rated high (and believed by the reviewers to introduce
238 bias). Confidence in the overall results of systematic re- were poorly defined. Adverse events were generally 295
239 views and meta-analyses was evaluated using AMSTAR reported at low rates. However, the methodology 296
240 2.15 AMSTAR 2 confidence ratings are based on the re- for collecting adverse events was poorly 297
241 sponses to critical and noncritical items, with an overall described in most studies. Given the 298
242 assessment of high (0 or 1 noncritical weakness), moder- methodological problems with many of these 299
243 ate (more than 1 noncritical weakness but no critical studies it is possible that any estimate of effect 300
244 flaws), low (1 critical flaw) and critically low (more than 1 size may be exaggerated. The overall confidence 301
245 critical flaw). in the results of the systematic reviews and meta- 302
246 analyses was mostly low or critically low (table ½T3 303
247 3). The major problems were not listing excluded 304
248 RESULTS studies, lack of an a priori review protocol, no 305
249 Study and Guideline Selection evaluation of publication bias and not including a 306
250 We identified 1,582 potentially relevant records. risk of bias assessment. Three Cochrane Reviews 307
251 After screening and full text review, we included 74 received a high confidence rating. 308
252 articles, including 49 RCTs, 23 systematic reviews 309
253 (16 with meta-analyses) and 2 clinical guidelines Lifestyle and Behavioral Modifications 310
254 ½F1 from professional organizations (fig. 1). Studies have failed to consistently identify a corre- 311
255 lation between rUTI and voiding patterns before or 312
256 Records iden fied through database 313
257 searching
Addi onal records iden fied through 314
(n = 1582)
258 other sources
315
Iden fica on
(n = 27)
259 316
260 317
261 Records a er duplicates removed
318
262 (n = 743) 319
263 320
264 Records excluded (579) 321
265 • Main reasons: unrelated
322
Screening
to research ques on,

266 Records screened involved renal disease, 323
267 (n =743) transplant, spinal cord
injury, commentary or
324
268 editorial 325
269 326
270 327
271 328
272 Full-text ar cles reviewed Ar cles excluded (89)
329
Eligibility
for eligibility • Pa ents with structural

273 (n =164) abnormali es and 330
274 catheters (14)
• Non-RCT (39)
331
275 • Non-systema c review 332
276 (28)
333
• Abstract (6)
277 • Acute UTI (3) 334
278 335
279 336
Included
Studies included in
280 qualita ve synthesis
(n = 74)
337
281 338
282 339
283 340
284 341
285 Figure 1. PRISMA flow diagram of search results and decision process
342
Table 1. Summary of studies on antibiotic prophylaxis for the prevention of rUTI in nonpregnant women
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Dochead: Review Article
Oxford Level of
Mean [median] Length of Evidence (Cochrane
References Sample Size Age (range) Intervention (dose) Comparator (dose) Prophylaxis Outcomes/Results Quality)
Antibiotic vs placebo control:
21
Bailey et al 50 Not reported NF (50 mg nightly) Placebo (nightly) 7.6 Mos (mean, Greater reduction of UTI in NF group (22/25) vs 2B (poor)
NF), 3.5 mos placebo (10/25) (p <0.01)
(placebo)
22
Gower 50 31 (20e60) Cephalexin (125 mg nightly) Placebo (nightly) 12 Mos Greater reduction in UTIs in cephalexin group vs 2B (fair)
placebo during 6-mo followup (p <0.01)
98
Landes et al 78 Not reported Povidone-iodine Usual care 17 Mos (mean) Greater reduction in UTIs in povidone-iodine 2B (poor)
ointment group per followup yr
(twice daily)
RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

Nicolle et al23 30 49 (not reported) Norfloxacin (200 mg nightly) Placebo (nightly) 12 Mos Greater reduction in UTIs in norfloxacin group vs 2B (poor)
REV 5.5.0 DTD
placebo for those who completed 12-mo

followup (p <0.05)
Rudenko and 302 44 (25e63) Fosfomycin (3 gm every 10 Placebo (once every 6 Mos Fewer infections/pt-yr in fosfomycin group vs 1B (poor-fair)
Dorofeyev24 nights) 10 nights) placebo (p <0.001)
Schaeffer et al99 30 34 (20e69) Cinoxacin (500 mg nightly) Placebo (nightly) 6 Mos No difference between groups in reduction of UTIs 2B (poor)
25
Scheckler et al 41 18e35 (18e65) Cinoxacin (500 mg daily) Placebo (daily) 6 Mos Greater number of asymptomatic pts in cinoxacin 2B (fair)
categorical group (18/20) vs placebo (11/21) in 6 mos of
followup (p <0.05)
JURO15681_proof
Stapleton et al27 27 [23] (not reported) TMP-SMX (40/200 mg post- Placebo (post-coital) þ 6 Mos TMP-SMX (14/16) was more effective in preventing 1B (poor)
coital) þ placebo (daily) placebo (daily) UTI than placebo (2/11) over 6-mos followup
Antibiotic vs other antibiotic, with or without placebo control:
28
Brumfitt et al 72 39 (not reported) NF (100 mg nightly) TMP (100 mg nightly) 12 Mos In TMP group 56% abacteriuric vs NF group 2B (fair)
89% (p <0.05), no difference in symptoms
groups.
betweenSide effects greater with NF (p <0.05)
100
Costantini et al 124 58 (not reported) Fosfomycin (3 gm once weekly) Prulifloxacin (600 mg 3 Mos No difference between fosfomycin vs prulifloxacin 1B (poor)
weekly) during 12 wks prophylaxis þ 12 mos followup
29
19 September 2018
Pfau and Sacks 33 31 (18e59) Ofloxacin (100 mg post-coital) Norfloxacin (200 mg) or 14.7 Mos No difference in UTI reduction between groups 2B (poor)
ciprofloxacin (125 mg (mean) over 15-mo followup
post-coital)
Raz et al30 139 67 (46e84) Estriol vaginal pessary (0.5 mg NF (100 mg nightly) þ 9 Mos Greater reduction in UTI episodes in NF group 1B (fair)
daily for 2 wks, then every 2 placebo vaginal pessary (p <0.001). NF group 48% vs estriol group 33%
wks) þ placebo (nightly) (daily for 2 wks, then had no UTI over 9-mo followup (p <0.01)
every 2 wks)
31
Raz et al 99, 50 rUTI 32 (18e48) Ciprofloxacin (250 mg once) Ciprofloxacin (750 mg once) Single dose Cure rate 92% in high dose group vs 68% in 2B (fair)
low dose group at 28 days (p <0.05)
4:18 pm
26
Stamm et al 53 [52e56] (17e73) TMP-SMX (40/200 mg nightly) Each antibiotic in treatment 6 Mos Greater reduction in UTI in all treatment groups vs 1B (poor-fair)
or NF (100 mg nightly) or arm compared to each placebo during 6-mo prophylaxis period (p
TMP (100 mg nightly) if other þ placebo <0.001). No difference in UTIs between groups
allergic to SMX or NF (nightly) during 6-mo followup
Antibiotic continuous/intermittent vs intermittent dosing:
EO: JU-18-405
Melekos et al33 135 [29e31] (18e46) Ciprofloxacin (125 mg post- Ciprofloxacin (125 mg 12 Mos No difference in UTI rate during 12 mos 1B (poor)
coital) nightly) of prophylaxis or after 12 mos of
Raz et al101 109 42 (18e87) Amoxicillin (500 mg once) þ Placebo (once) þ followup 1B (poor-fair)
amoxicillin/ clavulanic acid amoxicillin/clavulanic 3 Days Cure rate (by urine culture) at 7 days with single
(500/ 125 mg once) þ acid (250/125 mg every 8 dose vs 3-day course was 54% vs 75% þ at
placebo (every 8 hrs for 3 hrs for 3 days) 28 days was 50% vs 66% (p <0.05). No
days) difference in symptomatic UTI between groups
(Continued on next page)
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monthly)
for 7
Prophylaxis
onset of
ofo
Mo
Length of
mg6 Mo
antibioti
individualizedantibiotic
bedtime)
(dose)
dose
(singledose
type 2 diabetes days then once daily)
(dose)
each specified
12
(40/200 mg
daily
Mos
(36gm
Intervention
Continuous(single
once daily at at
TMP-SMX (40/200
(100 mg twice
exposure)*,†
Comparator
individualized
intermittently
nightly)*
symptoms)
496
Fosfomycin
post-prophylactic followup (none to 2 years). 553
Intermittent
TMP-SMX
497 Administration was once daily, post-coital, 554
with
457 after intercourse, 514
* For each antibiotic 1 specific dose was used, including 50 mg per day furantoin, 200/40 mg per day SMZ-TMP, 200 mg per day norfloxacin, 125 mg per day ciprofloxacin, 500 mg per day amoxicillin, 250 mg per day cefaclor or 250 mg
(Cochrane
498 intermittent or at specific intervals (ie weekly). 555
NF
Oxford Level of
1B (poor)
2B (poor)
1B (poor)
458 frequency
voiding of urination,
habits, wiping 515
63 (not reported)
[median]
Age (range)
Quality)
459 patterns,
use of hot douching,
tubs, bubble 516
Not reported
59 (50e70)
Evidence
460 baths,
of tightbody mass type
clothing, index,of 517
Mean
461 volume of fluid 518

462 without16,17
consumed.
or a Spermicide 519
463 contraceptive
implicated as adiaphragm
risk factor 520
Adverse events in intermittent group 64% vs
Outcomes/ResultsSample Size
464 active women.18,19 521

Intermittent group had more symptomatic28 rUTI
No differences in UTIs or antibiotics used68

episodes vs continuous group (p <0.001)
50
No difference in treatment rates or adverse
between groups during 12-mo followup.
465 Prevention
there strategies for
are supporting 522
466 indirect
ling blooddata include
glucose in 523
93% in continuous group (p <0.05)
467 patients
ing with diabetes,
disruption of normal 524
468 vaginalcleansers,
harsh microbiota andwith 525
469 avoiding(more
courses prolongedthan 5 days), 526
events at 3 þ 6 mos
470 broad spectrum

necessary or un-
antibiotics. 527
† Including sexual intercourse, traveling, working or walking for a long time, emiction holdback, diarrhea or constipation, determined according to the patient’s experience.
471 Logical hygiene

generally advised practices
despite 528
472 limitedobtaining
rately data since thisaccu- 529
473 information
These practiceshas include
been 530
474 maintaining
dration, voidingadequate
after hy- 531
475 intercourse,
longed holding avoiding
of urine,pro- 532
476 and
anal avoiding
and vaginal sequential 533
477 intercourse.
microbiota asStudies the source 534
478 of pathogenic
rUTI, suggesting bacteria
that in 535
per day cefuroxime. The antibiotic prescribed depended on previous antimicrobial susceptibility testing and was changed every 2 to 4 weeks.
479 travel may affect risk.20 536

480 537
481 Therapeutic Interventions 538
482 Antibiotic prophylaxis. A 539
483 total of 19 RCTs
sample size 1,419) on the (overall 540
484 use of antibiotic prophy-
laxis in women with rUTI 541
485 were
Theseassessed
studies were (table 1). 542
486 conducted in
between 1970 and 2014several 543
487 with the majority
19) published more than (14 of 544
488 20 years ago.
sizes of the includedThe sample 545
489 studies
302, withranged
9 of from 19 27 546
490 studies having
participants and 5014 orof 547
491 19 having 100
participants. Tenor offewer
the 548
492 includedcontrol
placebo studiesgroup used anda 549
493 the remaining
had 1 or more9 other studies 550
494 antibiotic treatments
comparator. Several as 551
495 antibiotics
variable were studied
durations of use 552
(few days to 2 years) and
499 In 12 of 19 studies significant differences in rUTI 556

500 rates were found between 557
501 treatment
ator arms. Ofandthecompar-
8 studies 558
502 thatplacebos
to compared 7 treatment
showed a 559
503 significant
rUTIs reduction
during the in 560
21e27
504 prophylactic
od. treatment
The remaining 561
505 studiesto compared
ment another and 1 treat-
4 562
506 of 11 showed
differences in significant
the 563
507 another.28e31 In 3 small 564
Table 1 (continued )
508 studies single

antibiotics low dose
immediately 565
509 after active
ally intercourse
womenforwere sexu-
as 566
102
Zhong et al35
34
References
510 effective as
phylaxis and daily
more pro- 567
Wong et al
Ruxer et al
511 effective than

Self-start single dose 568
512 antimicrobial
less therapy
effective than daily 569
513 cost when instituted at the 570
onset of symptoms.34 In
Table 2. RCTs of nonantibiotic prevention studies for rUTIs in women
627
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623
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6
Oxford Level of
Evidence (Cochrane
References Country No. Mean Age (range) Intervention Comparator Findings/Results Quality)
Acupuncture:
39
Alraek et al Norway 98 39 (18e60) Acupuncture 2x/wk for 4 No treatment Trend toward reduction of UTI in acupuncture 1b (poor)
wks according to pt group during 6-mo followup (p¼0.08)
diagnosis
40
Aune et al Norway 67 35 (18e60) Acupuncture 2x/wk for 4 wks, Sham acupuncture or no Half as many UTIs in acupuncture group vs 1b (poor)
points chosen individually for treatment sham (p <0.05), 1/3 as many UTIs in
each pt acupuncture vs no treatment (p <0.01)
Cranberry:
Barbosa-Cesnik et al43 United States 319 21 (not reported) Cranberry juice 8 oz (PAC Placebo juice twice daily No difference in recurrence rates 2b (fair)

112 mg) twice daily between groups
REV 5.5.0 DTD
Beerepoot et al103 Netherlands 221 35 (22e46) Cranberry extract capsule 500 Placebo twice daily þ Mean number of UTIs was 1.8 in TMP-SMX 2b (fair)
mg (PAC 4.55 mg) twice daily TMP-SMX 480 mg group vs 4.0 in cranberry group (p¼0.02).
þ placebo nightly nightly Increased resistance rates with TMP-SMX
McMurdo et al104 Scotland 137 63 (45e93) Cranberry extract capsule 500 TMP 100 mg nightly Slightly more UTIs in cranberry vs TMP group 2b (fair)
mg (PAC not stated) nightly (RR 1.6, p¼0.08), more withdrawals from
TMP group.
105
Singh et al India 72 39 (15e76) Cranberry capsule 60 mg (PAC Lactobacillus capsule Cranberry group 33% experienced UTI vs 2b (poor)
60 mg) twice daily twice daily lactobacillus group 89% (p <0.001)
JURO15681_proof
Stapleton et al106 United States 176 25 (not reported) Cranberry juice 4 or 8 oz (PAC Placebo juice daily Cranberry juice 4 or 8 oz did not reduce 2b (fair)
56 or 112 mg) daily risk of UTI
107
Vostalova et al Czech Republic 182 37 (not reported) Cranberry fruit powder capsule Placebo daily Cranberry fruit powder group 10.8% 1b (fair)
500 mg (PAC 2.8 mg) daily experienced UTI vs placebo 25.8%
(p¼0.04)
D-mannose:
Kranjcec et al47 Croatia 308 49 (20e79) D-mannose powder 2 gm nightly NF 50 mg nightly or no D -mannose þ NF had lower risk of rUTI vs no 1b (poor)
treatment treatment (RR 0.239, 95% CI 0.146
19 September 2018
e0.932, p <0.0001), absolute risk

reduction 45%
Estrogen:
Cardozo et al108 UK 72 73 (59e91) Oral estriol 3 mg daily Placebo daily Estriol þ placebo improved rUTI with no 2b (fair)
difference between groups
Eriksen109 Norway 108 68 (47e87) Estradiol vaginal ring 2 mg No treatment Estradiol group 51% experienced rUTI vs 1b (poor)
(replaced at 12 þ 24 wks) 80% no treatment group (p¼0.008)
110
Kirkengen et al Norway 44 78 (61e91) Oral estriol 3 mg/day x 4 wks, 1 Placebo tablets Estriol significantly reduced UTI rate vs 2b (poor)
mg/day last 8 wks placebo (p¼0.05) in last 8 wks of 12ewk
4:18 pm
study
Raz et al30 Israel 171 67 (46e84) Estriol vaginal pessary daily for 2 NF nightly þ daily rUTI 124 episodes in estriol group vs 48 in NF 2b (fair)
wks, then every 2 wks þ placebo pessary for 2 group (p <0.0003). Estriol reduced
oral placebo nightly wks then every 2 bacteriuric episodes (2/womaneyr) but
wks less than NF (0.5 UTIs/womeneyr)
EO: JU-18-405
51
Raz and Stamm Israel 93 65 (51e81) Estriol cream 0.5 mg nightly for rUTI in estriol group significantly lower vs 1b (fair)
2 wks then twice weekly Placebo cream nightly placebo (0.5 vs 5.9 episodes/pteyr, p
for 2 wks then <0.001). In estriol group 61% had
twice weekly lactobacilli on vaginal culture vs 0%
placebo
684
683
682
681
680
679
678
677
676
675
674
673
672
671
670
669
668
667
666
665
664
663
662
661
660
659
658
657
656
655
654
653
652
651
650
649
648
647
646
645
644
643
642
641
640
639
638
637
636
635
634
633
632
631
630
629
628
741
740
739
738
737
736
735
734
733
732
731
730
729
728
727
726
725
724
723
722
721
720
719
718
717
716
715
714
713
712
711
710
709
708
707
706
705
704
703
702
701
700
699
698
697
696
695
694
693
692
691
690
689
688
687
686
685
Oxford Level of
Evidence (Cochrane
References Country No. Mean Age (range) Intervention Comparator Findings/Results Quality)
Herbal medicine:
58
Albrecht et al Germany 174 54 (18e75) Angocin Anti-Infekt N Placebo twice daily No difference in UTIs during treatment or 2b (fair)
(horseradish root 80 mg þ followup. Per protocol analysis: significant
nasturtium 200 mg) reduction of UTI in treatment group
Hyaluronic acid:
62
Damiano et al Italy 57 35 (not reported) Intravesical HAþCS weekly for 4 Placebo instillations Significant decrease in UTI rate/pt at 12 mos 1b (good)
wks then monthly for 5 mos weekly for 4 wks then in HAþCS group vs placebo (86.6%
monthly 47.6 vs -9.6% 24.6, mean diff 77%,
95% CI 72.3e80.8, p¼0.0002)

De Vita and Giordano63 Italy 28 60 (not reported) Intravesical HAþCS weekly x 4 TMP-SMX 40/200 mg Significant reduction in rUTIs in HAþCS 1b (fair)
REV 5.5.0 DTD
wks then every 2 wks x 2 weekly x6 group at 12 mos, nonsignificant reduction

at 2 mos
64
Lipovac et al Austria 20 28 (17e34) HA once weekly x 4 wks then None Unclear, states HA significantly reduces 2b (poor)
monthly incidence of UTI
Methenamine hippurate:
111
Kasanen et al Finland 290 50.5 (not reported) Methenamine hippurate 1 gm, Placebo þ each other Recurrence rate 63.2% in placebo, 25% in 2b (poor)
NF 75 mg or TMP 100 mg NF, 34.2% in methenamine, 10.4% in TMP
nightly
JURO15681_proof
112
Cronberg et al Sweden 13 Not reported (40e80) Methenamine hippurate 1 Placebo Methenamine group 11 UTIs vs placebo 41 2b (poor)
gm twice daily (73% reduction, p <0.01)
Probiotics:
Baerheim et al113 Norway 47 36 (18e50) L. casei, L. rhamnosus vaginal Placebo vaginal No difference in infection rates 2b (poor)
suppository suppository between groups
Beerepoot et al114 Netherlands 252 64 (not reported) L. rhamnosus þ L. reuteri orally Placebo twice daily Lactobacillus intervention did not meet 2b (fair)
twice daily þ placebo nightly þTMP-SMX 480 noninferiority criteria but did not
mg nightly increase antimicrobial resistance
Czaja et al72
19 September 2018
United States 30 22 (18e35) L. crispatus vaginal suppository Placebo vaginal Phase 1, intervention safe 2b (poor)
daily x 5 days suppository
Stapleton et al73 United States 100 21 (18e36) L. crispatus vaginal suppository Placebo vaginal High level colonization with L. crispatus in 1b (good)
daily x 5 days then weekly suppository treatment group associated with UTI risk
reduction (RR 0.7, p <0.01)
Vaccines:
77
Bauer et al Germany 453 40 (18e65) OM-89 (UroVaxom) 1 capsule Placebo Mean UTI rate significantly lower in active 1b (fair)
daily in mos 1e3 þ first group vs placebo (p <0.003). Distribution
10 days of mos 7e9, no of UTIs lower in active vs placebo
4:18 pm
treatment mos 4e6 þ 10 (p¼0.001)

e12
Hopkins et al115 United States 75 48 (19e74) Urovac vaginal vaccine at 3 Vaginal placebo at 6 Vaccine plus booster significantly reduced 1b (fair)
time points þ 3 boosters or time points rate of E. coli UTIs vs placebo (p¼0.0015)
Urovac at 3 time points þ 3
EO: JU-18-405
placebo boosters
Huttner et al116 Switzerland 188 41 (18e70) Single injection of bioconjugate Placebo injection No reduction in incidence of UTIs caused by 1b (poor)
vaccine vaccine serotype E. coli, significantly
fewer UTIs caused by any E. coli serotype
in vaccine vs placebo (p¼0.002)
7
798
797
796
795
794
793
792
791
790
789
788
787
786
785
784
783
782
781
780
779
778
777
776
775
774
773
772
771
770
769
768
767
766
765
764
763
762
761
760
759
758
757
756
755
754
753
752
751
750
749
748
747
746
745
744
743
742
2b (poor)
2b (poor)
799 a small underpowered study, when instituted pre- inad
Evidence (Cochrane
Oxford Level of
800 ventively (each time a patient experienced a condi- equ
1b (poor)
801 Quality) tion predisposing to UTI) efficacy was similar to atel
802 daily prophylaxis with fewer complications. Re-
35 y
803 sults of antibiotic dosing and treatment compari- pow
804 sons can be seen in table 1. ered
805 At various lengths of post-prophylactic followup and/
booster group 55% had no UTIs vs 22% in

Delay to first UTI in booster group vs placebo
þ vs vaccine without booster (p¼0.02). In
placebo þ vaccine without booster group

to first UTI in both treatment groups (13
806 or
placebo. In those off antibiotics, delay
all studies showed no lasting difference in rUTI
vs placebo or between OM-89S vs NF

No difference in rUTI between OM-89S
807 of
wks) vs placebo (8.7 wks) (p¼0.45)
rates between treatment and comparator groups.

poo
No difference between vaccine þ
808 This finding demonstrates a lack of lasting impact

Findings/Results
809 of prevention after cessation of therapy. Adverse r

810 events included nausea, diarrhea, vaginal qual
4
811 candidiasis, skin rashes, vaginal and skin burning, ity.
1
812 and pruritus, and were largely nonsignificant
813 between groups in small sample size studies, Ho
(p¼0.06)
814 whereas a greater number and type were seen in wev

815 higher powered studies.
22,29,32,36 er,
816 When continuous antibiotics were compared to even
817 intermittent, rates of gastrointestinal and other 2
818 adverse events were significantly higher in the pro
perl
Vaginal placebo at 3
Vaginal placebo at 6
35
819 continuous treatment group. Resistant bacteria
Comparator
Placebo or NF 50
820 y
were found in the treatment or posttreatment
time points
time points
desi
mg daily
821 period in 7 of 10 studies investigating this

21,22,24e26,28,30,34,37 gne
822 issue.
d,
823 Changes in normal physiological vaginal, periure- dou
824 thral and anal microbiota after prolonged ble-
825 antibiotic prophylaxis were found during treatment
Urovac vaginal vaccine at 3 time
blin
high dose (2 amp vaccine) at
low dose (1 amp vaccine) or
Urovac at 3 time points þ 3

SolcoUrovac vaginal vaccine
826 periods in 4 of 5 studies that assessed it.

21,24e26,34
d,
points plus 3 boosters or
827 Meta-analyses support the use of continuous plac

Intervention
OM-89S 6 mg daily or OM-89S

daily for first 10 days of mo
828 antimicrobial prophylaxis for 6 to 12 months for the ebo

placebo boosters
829 37
treatment of rUTI. Two meta-analyses suggested
3 time points
cont
830 that nitrofurantoin was superior to other antibiotics roll
831 but carries a higher risk of adverse events.
36,38
ed
832 While antibiotic prophylaxis appears efficacious, RC
833 all the studies were of fair to poor quality. Ts
834 fun
Acupuncture. Two RCTs (overall sample size 165)
(18e82)
(18e74)
835 ded
Mean Age (range)
836 were identified which investigated a 4-week

by
837 acupuncture regimen to prevent rUTI in
(18e80)
39,40 the
838 women. Both studies found a significant Nat
reduction in rUTI compared to sham and/or
47
49
839 ion
840 placebo during the 6-month observation period. The al
841 treatment is considered safe. However, the Inst
45144
91
54
mechanism is unclear, and limitations of the

No.
842 itut
843 studies such as lack of blinding, small sample es
844 size and a self-selected population leave us of
United States
United States
845 with insufficient evidence to recommend Hea

Country
846 acupuncture to prevent rUTI. lth

847 Cranberry products. Overall 6 RCTs (total sample size faile
848 1,107) on the use of cranberry were considered d
to
Germany
849 (table 2). The use of cranberry products has a long

850 history in the management of rUTI. However,
851 despite this storied past and the generation of
References
117
Uehling et al118
Uehling et al
852 several Cochrane reviews, evidence is sparse that

Wagenlehner et al119
41,42
853 cranberry has any efficacy in preventing rUTI.
854 Dosing of the active ingredient, PAC, has varied
855 across studies, many of which have been
856 875 894
857 876 895
858 877 896
859 878 897
860 879 898
861 880 899
862 881 900
863 882 901
864 883 902
865 884 903
866 885 904
867 886 905
868 887 906
869 888 907

870 889 908
871 890 909
872 891 910
873 892 911
874 893 912
913 show a statistically significant benefit of cranberry beneficial than antibiotic alone in treating Hyalu
914 juice in young women.
43,44 acute UTI and may reduce the incidence of rUTI. ronic
915 The studies were small and some are generalizable acid.
Cranberry failed again in the most recent trial of
916 this intervention among women residing in nursing only to postmenopausal women. Further studies are Thre
917 45 needed. e
homes, attempting to replicate a classic study
918 RCTs
showing cranberry juice reduced asymptomatic
919 46 (sam
bacteriuria among older women. An accompanying ple
920 editorial summarized the many issues with
921 size
published data on cranberry for rUTI and urged 105)
922 clinicians to avoid actively recommending cranberry on
923 for prevention of rUTI.
41
A Cochrane review the
924 also advised against the use of cranberry juice, and use
925 recommended that other types of cranberry of
926 products need to stan- dardize the active ingredient hyal
927 in future studies.
42
uroni
928 c acid
929 D-mannose. We assessed 1 RCT (sample size 308) on
the use of D-mannose (table 2). This agent has been intra
930 vesic
931 considered for the prevention of rUTI as it can
al
932 inhibit the adhesion of bacteria to uroepithelial
instil
933 cells and be easily obtained without a
47 latio
934 prescription. At this point there is insufficient ns
935 evidence to recommend D-mannose. were
936 Estrogen. Five RCTs (overall sample size 444) on the evalu
937 use of estrogen were assessed (table 2). Menopause ated
938 brings a reduction in vaginal estrogen, an increase (tabl
939 in vaginal pH and alteration in the vaginal e 2).
940 microbiota away from the lactobacillus dominant The
941 environment associated with vaginal health. glyco
942 Instead, the vagina is more readily colonized by sami
48
943 gram-negative uropathogens. Topical estrogen nogly
944 therapy reduces vaginal pH, reduces gram-negative can
945 bacterial colonization while restoring HA
946 lactobacillus, and decreases recurrence of UTI.
49e52 prote
947 Paradoxically, systemic estrogen does not reduce cts
948 50
rUTI. Meta- analyses showed that vaginal and
949 estrogen prevents rUTI in postmenopausal resto
950 women but is associated with vaginal irritation res
951 50 the
and poor adherence. There is still patient
952 uroth
confusion regarding the safety of vaginal
953 eliu
estrogen. Data do not show an increased risk of
954 m.
recurrence of breast cancer,
955 HA
endometrial hyperplasia or carcinoma in women
comb
956 who use vaginal estrogen for urogenital
53,54 ined
957 symptoms as there is no associated increase in with
958 serum estrogen.
55e57
CS
959
Herbal medicine. One RCT (sample size 174) on the has
960
use of a European herbal medicine was assessed and been
961 inves
was found to reduce rUTI compared to placebo (table
962 58 tigat
2).
963 ed in
A 2015 Cochrane review of Chinese herbal medicine
964 singl
to treat rUTI included 5 trials (written in
965 e
Chinese) comparing CHM with conventional
966 cente
antibiotic treatment, and comparing CHM plus
967 59 rs in
968 antibiotic with antibiotic alone. The results,
Euro
969 summarized in table 3, suggest that CHM alone
pe,
or in conjunction with antibiotic may be more
pri re is insufficient clinical evidence to recommend 970 1022

mar HA and it is currently not approved in the United 971 1023
ily States. 972 1024
in Methenamine hippurate. There were 2 RCTs (sample 973 1025
retr size 303) assessed on the use of methenamine hippu- 974 1026
osp rate (table 2). This agent acts as a bacteriostatic 975
ecti agent via the production of formaldehyde from 976
ve 67 977
hexamine.
and 978
Unlike with conventional antibiotics, acquired
pro 68 979
spe resistance does not appear to develop. Some
experts suggest that the use of methenamine 980
ctiv
hippurate may give patients the confidence to 981
e,
delay intervention for mild symptoms, thereby 982
sm
lessening the use of empiric antibiotic therapy. 983
all
Whether methenamine can actually assist in 984
sa
mpl clearing low level bacteriuria as a method of 985
e preventing the development of significant symptoms 986
size remains unknown. Strategies that reduce 987
stu antibiotic use may be important to decrease 988
die patient side effects and antibiotic resistance. A 989
s.
60 2012 Cochrane review presented weak evidence in 990
e65 support of methenamine hippurate in preventing 991
rUTI and concluded it is safe with a low rate of 992
The
met adverse events.
69 993
a- 994
Probiotics. Four RCTs (overall sample size 429) were
ana 995
assessed on the use of probiotics (table 2).
lysi 996
Individual microbiome health may affect
s 997
susceptibility to UTI as well as symptom
out 70,71 998
severity and recovery.
co 999
Alterations in the vaginal microbiome have
mes 1000
been found before and during acute UTI. One
are 1001
way to theoretically influence the microbiome is
not 1002
to administer exogenous probiotics or live bacteria
gen 1003
thought to have a beneficial effect on the host.
eral 1004
There is some evidence in the literature supporting
iza the use of orally administered lactobacillus 1005
ble 72e75 1006
containing products to prevent rUTI, yet most
as 1007
of the oral probiotics marketed for the prevention
diff 1008
of rUTI are based on L. rhamnosus, a less
ere 1009
prevalent vaginal strain. A Cochrane review of
nt 1010
this topic found no significant reduction in rUTI
HA 1011
inst but relied on small studies of poor quality with no
76 1012
illat dosage consistency. 1013
ion Three studies addressed vaginally administered
1014
regi probiotics but only 1 study using L. crispatus was
76 1015
me of adequate quality. Colonization success 1016
ns was assessed in this study and treatment deemed 1017
wer promising. However, only a single study of 100
72 1018
e women has been published to date. 1019
use Vaccines. Six RCTs on the use of vaccines were eval- 1020
66
d. uated (table 2). OM-89 (Uro-Vaxom ), an oral 1021
The vaccine available in Europe comprised of a
Table 3. Summary of systematic reviews and meta-analyses reporting on interventions for the prevention or treatment of rUTI in nonpregnant women
10
1083
1082
1081
1080
1079
1078
1077
1076
1075
1074
1073
1072
1071
1070
1069
1068
1067
1066
1065
1064
1063
1062
1061
1060
1059
1058
1057
1056
1055
1054
1053
1052
1051
1050
1049
1048
1047
1046
1045
1044
1043
1042
1041
1040
1039
1038
1037
1036
1035
1034
1033
1032
1031
1030
1029
1028
1027
Results (RR or other statistic,

Search No. Studies (total No.), 95% CI), Heterogeneity [I2 Quality Rating
References Range Focus Participant Characteristics (p value), if reported] (AMSTAR 2) Conclusions
Prevention trials:
Antimicrobial therapies
120
Chew and Fihn 1970e1998 Assess antibiotic
7 (576), Nonpregnant Not a meta-analysis Critically low Continuous antibiotic prophylaxis using TMP, TMP-
prophylaxis for rUTI
women with history of SMX, NF, ciprofloxacin or norfloxacin significantly
recurrent cystitis reduced rates of rUTI
Daily use þ post-coital use of ciprofloxacin were
similar in reducing rUTIs
Use of NF or a quinolone within 2 hrs after sexual

REV 5.5.0 DTD
intercourse significantly reduced recurrent cystitis

Albert et al37 1966e2004 Determine efficacy þ 19 (1,120), Nonpregnant Antibiotics reduced microbiological recurrence Low Continuous antibiotic prophylaxis for 6e12 mos
(Cochrane) safety of prophylactic women age 14þ (0e0.9 person-yr in antibiotic group vs 0.8 reduced UTI rate
antibiotics to prevent e3.6 with placebo; RR 0.21, 0.13e0.34; NNT NF showed more severe adverse events than
rUTI 1.85) þ clinical recurrences (RR 0.15, 0.08 other antibiotics
e0.28, NNT 1.85)
Lichtenberger 1991e2011 Assess antimicrobial Unclear, women with rUTI Not a meta-analysis Critically low Continuous antimicrobial prophylaxis, postecoital
121
and Hooton prophylaxis for rUTI prophylaxis þ intermittent selfetreatment are
JURO15681_proof
effective in prevention of rUTIs

Choice of antimicrobial should be based on suscepti-
bility pattern of organisms causing previous UTIs þ
history of drug allergies
69
Lee et al 1950e2012 Determine harms þ 13 (2,032), populations at Effective in pts without renal tract abnormal- High Short-term methenamine hippurate may be effective in
(Cochrane) benefits of risk for UTI, majority of ities (RR 0.24, 0.07e0.89) [69.8%] preventing UTI
methenamine studies in women Rate of adverse events was low
hippurate in rUTIs
36
19 September 2018
Price et al 1946e2015 Compare NF vs other 12 (1,063), Women age 18 No difference between NF þ comparator in Critically low NF has similar efficacy but greater risk of adverse
drugs for reducing e85 receiving outpatient microbiological success (RR 1.06, 0.90e1.26) events than other prophylactic treatments (norfloxacin,
rUTI care for rUTI [65%] or clinical cure (RR 1.06, 0.89e1.27) TMP, TMP-SMX, methenamine hippurate, estradiol or
Duration of prophylaxis did not affect outcome cefaclor) in preventing rUTI
(RR 0.93, 0.76e1.14)
NF had greater adverse effects than other
drugs (RR 2.14, 1.28e3.56) [61%]
Ahmed et al38 Up to 2016 Assess effectiveness þ 3 (534), Postmenopausal Long-term antibiotics reduced rUTI by 24% (RR Critically low Long-term antibiotic therapy reduces rUTIs without
4:18 pm
safety of long-term women 0.76, 0.61e0.95; NNT 8.5) [20% (0.02)] increase in adverse events
antibiotic therapy in No significant risk of mild (RR 1.52, 0.76
rUTI prevention e3.03) or serious adverse events (RR 0.90,
0.31e2.66)
EO: JU-18-405
Estrogen therapy
50
Perrotta et al 1950e2007 Estimate efficacy þ 9 (3,345), Postmenopausal Oral estrogen did not reduce UTI vs Low Oral estrogen was not effective in rUTI prevention
(Cochrane) safety of oral or women placebo (RR 1.08, 0.88e1.33; 4 studies; Vaginal estrogen was effective in preventing rUTI but
vaginal estrogens for 2,798 women) [0%] this varies by estrogen type þ treatment duration
preventing rUTI Vaginal estrogen reduced rUTIs compared to 2 Studies comparing vaginal estrogen to antibiotics
placebo (RR 0.25, 0.13e0.50 [cream], RR 0.64, were inconclusive
0.47e0.86 [ring, 2 studies) [not reported]
1140
1139
1138
1137
1136
1135
1134
1133
1132
1131
1130
1129
1128
1127
1126
1125
1124
1123
1122
1121
1120
1119
1118
1117
1116
1115
1114
1113
1112
1111
1110
1109
1108
1107
1106
1105
1104
1103
1102
1101
1100
1099
1098
1097
1096
1095
1094
1093
1092
1091
1090
1089
1088
1087
1086
1085
1084
1197
1196
1195
1194
1193
1192
1191
1190
1189
1188
1187
1186
1185
1184
1183
1182
1181
1180
1179
1178
1177
1176
1175
1174
1173
1172
1171
1170
1169
1168
1167
1166
1165
1164
1163
1162
1161
1160
1159
1158
1157
1156
1155
1154
1153
1152
1151
1150
1149
1148
1147
1146
1145
1144
1143
1142
1141

Search No. Studies (total No.), 95% CI), Heterogeneity [I2 Quality Rating
Vaccines
78
Bauer et al 1984e2002 Assess efficacy of oral 5 (601), Women with rUTI All individual studies showed significant Low Uro-Vaxom was effective þ safe in preventing UTIs
immunotherapy with without anatomical differences in favor of Uro-Vaxom vs
Uro-Vaxom to prevent urinary tract placebo (Mann-Whitney >0.5)
rUTI abnormalities
Naber et al79 Up to 2008 Assess efficacy þ 7 (1,220), in Uro-Vaxom Fewer UTIs with Uro-Vaxom vs placebo after 6 Critically low Uro-Vaxom is effective in preventing UTIs
safety of studies more than 93% þ 12 mos (WMD -0.36, -0.48 - -0.24; Vaginal vaccine may be effective but needs

immunoactive women (949); in vaginal WMD booster cycle
prophylaxis for rUTI vaccine Product “B” -0.516, -0.80 - -0.22, respectively) [I2, not May also reduce vulvovaginal infections
REV 5.5.0 DTD
studies 220 women reported, p¼0.002]

Short primary immunization was not effective,
longer primary þ booster treatment may be
effective [not reported]
Cranberry products
Jepson and Up to 2006 Determine effectiveness 9 (1,011), Children þ adults In meta-analysis of 2 studies cranberry Critically low Some evidence that cranberry containing products
122
Craig
JURO15681_proof
of cranberry or with history of rUTI products were more effective than placebo/ (juice or capsules) may decrease number of symp-
blueberry products in water for rUTI at 12 mos (RR 0.62, 0.40e0.97) tomatic UTIs
prevention of UTI [0% (0.55 for all trials)]
Jepson et al42 Up to 2012 Assess effectiveness of 24 (4,473), Susceptible Cranberry products did not reduce occurrence Low Cranberry juice is not recommended for UTI prevention
(Cochrane) cranberry products in populations of symptomatic UTI over 12 mos in women þ other cranberry preparations need to quantify active
preventing UTIs with rUTI (RR 0.74, 0.42e1.31) [55%] ingredient þ potency before being evaluated or rec-
ommended for use
Wang et al123 Up to 2011 Evaluate cranberry 13 (1,616) in Qualitative þ In 3 RCTs cranberry products were Low Consumption of cranberry containing products may
19 September 2018
containing products 10 (1,494) in quantitative more effective than control in prevention of protect against UTI in women
for UTI prevention þ synthesis, children þ rUTI in women (RR 0.53, 0.33e0.83) [0%
examine factors adults with rUTI (0.54)]
influencing their Across all populations there was no difference
effectiveness
in rUTI prevention among cranberry products
or doses
Wang124 2006e2011 Evaluate cranberry 11 (1,369), Female children Not a meta-analysis Critically low Although in majority of trials (64%) cranberry products,
based products in or women primarily in juice or cocktail forms, reduce UTIs,
4:18 pm
prevention of rUTIs evidence is inconclusive

Fu et al125 Up to July Assess effect of 7 (1,498), Nonpregnant Cranberry reduced UTI risk by 26% (RR 0.74, Critically low Cranberry may be effective in preventing uncompli-
2017 cranberry on rUTI women 0.55e0.98) [54%] cated rUTIs in generally healthy women
Probiotics
EO: JU-18-405
126
Grin et al Up to 2012 Assess efficacy of 5 (294), No difference between Lactobacillus þ Critically low Probiotic strains of Lactobacillus are safe but more
Lactobacillus Premenopausal adult control in preventing rUTI (RR 0.85, RCTs are needed to make a recommendation
probiotics for women
preventing rUTI 0.58e1.25) [19% (0.41)] Vaginal suppositories containing L. crispatus CTV-05 or
Sensitivity analysis (2 RCTs, sample size combination of L. rhamnosus GR-1 þ L. fermentum
127) where vagina achieved colonization B-54 were most effective
with Lactobacilli, probiotic reduced rUTI (RR
0.51,
0.26e0.99)
127
Chisholm 2009e2014 Assess role of probiotics 3 (552), Women with UTIs, 1 No meta-analysis Critically low Low to moderate evidence that different strains of
in preventing rUTI included healthy women Lactobacilli probiotics are effective in preventing UTIs
1254
1253
1252
1251
1250
1249
1248
1247
1246
1245
1244
1243
1242
1241
1240
1239
1238
1237
1236
1235
1234
1233
1232
1231
1230
1229
1228
1227
1226
1225
1224
1223
1222
1221
1220
1219
1218
1217
1216
1215
1214
1213
1212
1211
1210
1209
1208
1207
1206
1205
1204
1203
1202
1201
1200
1199
1198
11
1311
1310
1309
1308
1307
1306
1305
1304
1303
1302
1301
1300
1299
1298
1297
1296
1295
1294
1293
1292
1291
1290
1289
1288
1287
1286
1285
1284
1283
1282
1281
1280
1279
1278
1277
1276
1275
1274
1273
1272
1271
1270
1269
1268
1267
1266
1265
1264
1263
1262
1261
1260
1259
1258
1257
1256
1255
12

2
Search No. Studies (total No.), 95% CI), Heterogeneity [I Quality Rating
Schwenger et Up to 2015 Compare probiotics (any 9 (735), Susceptible children 6 RCTs (sample size 352) with no reduction in High Insufficient evidence to determine whether probiotics
76
al formulation) to þ adult pts or healthy rUTI between probiotics þ placebo (RR 0.82, reduce risk of rUTI
(Cochrane) placebo or no therapy people 0.60e1.12) [23%]
to prevent UTI In 1 study (sample size 223) no reduction in
rUTI between probiotics þ antibiotics (RR
1.12, 0.95e1.33)
Other therapies
Matthews and 1966e2011 Assess nonantibiotic 13 (unknown), Older adults, Not a meta-analysis Critically low Several nonantibiotics may be effective in preventing

REV 5.5.0 DTD
Lancaster128 prophylaxis for rUTI age 65þ rUTIs in postmenopausal women, cranberries
100e500 mg daily, vaginal estrogen þ methenamine
hippurate 1 gm twice daily
Beerepoot 1984e2013 Assess effectiveness, 17 (2,165), Adults, mostly Oral immunostimulant (OM-89) decreased rUTI Critically low Oral immunostimulant OM-89 appears to be most
129
et al tolerability þ safety women (RR 0.61, 0.48e0.78, 4 trials, sample size 891) promising to prevent rUTIs
of nonantibiotic with good safety profile [69.3% (0.21)] Vaginal estrogen may reduce rUTIs in postmenopausal
prophylaxis (including Urovac, vaginal vaccine, slightly reduced rUTI women but is associated with vaginal irritation
acupuncture) for rUTI Although there was significant decrease in rUTI with
JURO15681_proof
(RR 0.81, 0.68e0.96, 3 trials, sample size

220), immunization booster increased time to other interventions (Urovac, cranberries þ acupunc-
reinfection [0% (0.311)] ture), larger trials are needed
Vaginal estrogens showed trend toward pre-
venting rUTI (RR 0.42, 0.16e1.10, 2 trials,
sample size 201), vaginal irritation in 6%
e20% [0% (0.540)]
Cranberries decreased rUTIs (RR 0.53, 0.33
19 September 2018
e0.83, 2 trials, sample size 250), 0% (0.418)

Acupuncture decreased rUTI (RR 0.48, 0.29
e0.79, 2 trials, sample size 165)
De Vita et al66 Up to 2012 Evaluate effectiveness 4 (143), Women In 4 studies, decreased UTI rate/pt-yr (MD Critically low Some evidence that intravesical HA þ HA-CS
of intravesical HA -3.41, -4.33 - -2.49 [90% (0.00001)]. Longer significantly reduces rUTI þ mean time to recurrence
alone þ HA-CS in time to recurrence (MD 187.35, 94.33
treatment of e280.37) [97% (0.0001)]
recurrent bacterial
In pooled analysis of 2 RCTs HA-CS
cystitis
4:18 pm
decreased UTI rate/pt-yr (MD -2.45, - -0.28

[94% (<0.00001)]
Longer mean time to UTI recurrence (MD
128.86, 106.15e151.57) [0% (<0.0001)]
130
EO: JU-18-405
Eells et al 1966e2014 Compare effectiveness 5 (not reported); With 2 or Daily antibiotic (NF) prophylaxis was most Critically low Daily antibiotic use is more effective for rUTI pre-
of 5 prevention more adequate published effective strategy, compared to daily cranberry vention than nonantibiotic þ alternative therapies
strategies using trials on each strategy, pills, daily estrogen therapy þ acupuncture,
Markov chain Monte women with 3 or more reducing UTI rate to 0.4/yr
Carlo model UTIs/yr
1368
1367
1366
1365
1364
1363
1362
1361
1360
1359
1358
1357
1356
1355
1354
1353
1352
1351
1350
1349
1348
1347
1346
1345
1344
1343
1342
1341
1340
1339
1338
1337
1336
1335
1334
1333
1332
1331
1330
1329
1328
1327
1326
1325
1324
1323
1322
1321
1320
1319
1318
1317
1316
1315
1314
1313
1312
Quality Rating
(3 reduce rUTI incidenc

(AMSTAR 2)
treating rUTI during

it difficult to form with Critically low
with
treatment more than antibiotics

14
for High
or in conjunction
1389
placebo or baseline, local reactions 0%-36%

Vaginal estrogen decreased UTIs compared to
1446
reduced
antibiotics had higher efficacy than

did notas TMP-SMX
antibiotics alone in acute UTI (RR 1.24, 1.04
study (RR 0.53, 0.35e0.80) [0%] (2 studies,

Systematic Reviews and Meta-Analyses
e1.47) [0%] þ reduced rUTIs 6 mos after

for sample
1390
than antibiotics
1447
þ may
[0%] þ in
1369 A lyophilized lysate of 18
total of 23 systematic selected
reviews Escherichia
on the prevention coli 1426
491) appears to be most effective

1391
of infection[80%]
1448
be beneficial
1370 andstrains, may of

trigger
rUTI immunity through increased 1427
95% CI), Heterogeneity [I2
1392 treatment were located, of which 16
intervention
1449
(3 studies,
decrease rUTIs).with safer profile (1 small study)

(p value), if reported]
77
1371 makes efficacious 1428
0.28, 0.09e0.82)
lymphocyte
included and macrophage
a meta-analysis. activity.
The prevention Meta-
strategies
as effective
1393 1450
1.11e33)
(5 studies, sample size 596)
1372 approach analysesinofthese
examined RCTs reviews
conclude arethat Uro-Vaxom
shown in table is 3. safe
In 1429
1394
282)
1451
efficacy
(oral estrogen
after
(RR 1.21, may
1373
1395 and effective
general, studiesinincluded
reducingin UTI
the recurrence
reviews were forof6 low
to 12 1430
as sole
effects
1452
(RR phase
size
78,79
1374 to months compared
fair quality, to placebo
with small sample (table
sizes 3). Longer
and hetero- 1431
sideclinical
studies most
antibiotics
1396
6 mos
Oral lactobacillus 1453
sample size 120)

higher
Conclusions
sample
1375 protection against making
infection itmaydifficult
be achieved with 3 1432
CHM þ alone.
1397 geneity of results to derive
acute
1454
CHM
Antibiotics
1376 10-day booster courses.77 Uro-Vaxom is

monthlyconclusions. 1433
studies, for
optimal
definitive
nonantibiotic intervention
rUTI rates
1398
acute UTI
CHM had
1455
therapy
greater
1377
1399 among the EAU recommendations to prevent rUTI 1434
1456
Lack of high quality
reducing UTIs size
Clinical
but isPractice Guidelines
Vaginal estrogen
1378 1435
women, age 51þconclusions about
1400 not available in the United States. The

Two professional society practice guidelines were 1457
1379
1401 efficacy of a vaginal vaccine (Product B) comprised 1436
1458
1380 of 6 heat killed E. coli strains and 4 other 1437
Participant Characteristics
9 (1,028), Postmenopausal
No. Studies (total No.),
7 (542), Women age 16þ
1381 uropathogenic bacteria was the subject of 3 small 1438

with rUTIs, majority
1382 trials.79 Benefit compared to placebo was not 1439

postmenopausal
1383 observed in patients receiving only primary 1440

1384 vaccine. Women receiving booster vaccines who 1441
1385 were sexually active and less than 52 years old had 1442
1386 a significant reduction in E. coli UTIs compared to 1443
1387 placebo. Vaginal vaccines against UTI are not 1444
1388 commercially available and larger trials are needed. 1445
harms of CHM in rUTI
Determine benefits þ
pharmacological
agents to prevent
Focus
treatment
Evaluate
rUTI
identified and are summarized in the Appendix. The

1402 Society of Obstetricians and Gynaecologists of 1459
1403 1460
Canada (2010) guideline focuses specifically on
1404 rUTIs,80 and a more recent guideline from the EAU 1461
1405 1462
(European Association of Urology) addresses uro-
1406 1463
logical infections, with rUTI in women as 1 of the
1407 topics addressed.81 1464
1408 1465
1409 Antibiotic Stewardship 1466
1410 Antibiotic stewardship in patients with rUTI starts 1467
1411 with treating all acute UTIs according to clinical 1468
1412 practice guidelines using short duration NF, TMP- 1469
1413 SMX or fosfomycin as first line therapy.6 While 1470
1414 used in practice, there is no evidence to suggest 1471
1415 longer courses or greater potency antibiotics are 1472
1416 needed in patients with rUTI. In fact, these ap- 1473
Up to 2015
1970e2015
1417 proaches may be associated with more recurrences 1474

Search
Range
1418 in women due to loss of protective periurethral and 1475

1419 vaginal microbiota.82e84 Natural history studies 1476
1420 have shown that rUTI tends to occur in clusters,85 1477

1421 often with periods of same strain asymptomatic 1478
Flower et al59
References
Treatment trial:
between symptomatic episodes.20

(Cochrane)
1422 bacteriuria 1479

Garcia et
Due~nas-
1423 Nevertheless, treatment of asymptomatic bacteri- 1480

al131
1424 uria increases the risk of symptomatic infection and 1481

1425 bacterial resistance as well as health care costs.86,87 1482
1483 A 2016 national epidemiological study on rUTI on prevention of rUTI. as well

1484 found that urine culture directed care resulted in as
1485 fewer UTI related hospitalizations and less intrave- Treatment and Prevention Recommendations potentia
1486 88
nous antibiotic use. In addition, although subse- Several treatment and prevention strategies were l harm.
1487 quent episodes of UTI are often caused by the same found in the literature that bring potential benefit A
1488 bacterial strain, resistance profiles may vary.
20,89,90
thoroug
1489 In a cohort from Ireland looking at E. coli UTI, h
1490 there was a high likelihood of persistent resistance analysis
1491 to ampicillin (84.9%), amoxicillin-clavulanate of
1492 (54.5%), ciprofloxacin (83.8%) and TMP (78.3%).
91 existing
1493 However, the likelihood of persistent resistance to strategie
1494 NF was only s with
1495 20.2% at 3 months and 5.7% at 9 months, with only our
1496 a panel of
1497 2.6% prevalence of resistance with initial infection. multidis
1498 Antibiotic resistance among microorganisms has ci-
1499 become more prevalent and is believed to be the result plinary
1500 of overuse, poor selection of antimicrobial agents care
1501 and unnecessarily long duration of treatment.
92 provider
1502 Antibiotic associated collateral damage is critical, s and
1503 potentially producing long-term adverse effects in research
1504 the individual patient as well as society as a ers was
1505 whole.
93 per-
1506 Several studies have shown that fluoroquinolones formed
1507 and cephalosporins are more likely than other to
1508 classes of antibiotics to alter fecal microbiota, and provide
1509 cause Clostridium difficile infection and other a
1510 damage. In fact, in July 2016 the Food and Drug clinical
1511 Administration issued an advisory warning that algorith
1512 fluoroquinolones should not be used to treat m for
1513 uncomplicated UTIs because the disabling and the
1514 serious adverse effects result in an unfavorable preventi
1515 risk-benefit ratio.
94,95
Since the publication of the on of
1516 2011 Infectious Diseases Society of America rUTI in
1517 6 women.
guidelines, fluoroquinolones have not been
1518 In
recommended as first line therapy for uncomplicated
1519 patients
UTI, but the new advisory calls into question their
1520 with
use even as second line agents. Despite the label
1521 rUTI a
change, many providers continue to use
1522 pretreat
fluoroquinolones for UTI because they suspect
1523 ment
pyelonephritis or consider the UTI a “complicated”
1524 urine
case, potentially due to recurrent or persistent
1525 bacteriuria. Beta lactam antibiotics are also not culture
1526 considered first line therapy because of collateral should
1527 damage effects and their propensity to pro- mote be
1528 96,97 obtained
more rapid recurrence of UTI. However, these
1529 when an
agents are used often, especially in cases
1530 acute
considered complicated due to recurrent or
1531 UTI is
persistent bacteriuria.
sus-
1532 Prudent, rational use of available antibiotics is
pected.
1533 the responsibility of all prescribers and should
If
1534 include a precise indication for antibiotic treatment,
initiatio
1535 appropriate choice of drug, dose, route and treat-
n of
1536 ment length based on bacterial identification and
92 empiric
1537 susceptibility when available. Understanding the antibioti
1538 negative impact of antibiotic use on the gut and c
1539 vaginal microbiota is critical to advance the science treatme
nt is side effects and cost is important. Self-start 1540

requ antibiotic therapy can also be considered in 1541
este reliable patients who are willing to obtain urine 1542
d, specimens before starting therapy and 1543
use communicate effectively with their provider. 1544
prior Avoid classifying patients with rUTI as 1545
cultu “complicated” as this often leads to use of broad 1546
re spectrum antibiotics with long durations of treat- 1547
data ment. Reserve the classification of complicated UTI 1548
(if for those with congenital or acquired structural and/ 1549
avail or functional abnormalities of the urinary tract and/ 1550
able) or immune suppression or pregnancy. Avoid treat- 1551
to ment of asymptomatic bacteriuria in women with 1552
choos rUTI, as this has been shown to foster antimicrobial 1553
e resistance and increase the number of rUTI epi- 1554
87
amo sodes. If a patient has persistent symptoms 1555
ng despite treatment, repeat the urine culture to 1556
first assess for ongoing bacteriuria before prescribing 1557
line additional antibiotics. Use nitrofurantoin when 1558
treat possible as a first line agent for re-treatment since
91 1559
men resistance is low and, if present, decays quickly. 1560
ts We recommend an algorithmic approach to pre- 1561
while vention of rUTI that includes education on 1562
cultu lifestyle and behavioral modifications, and 1563
re is addresses specific populations of women with 1564
pend antimicrobial based and nonantibiotic alternatives 1565
ing. (fig. 2). This approach includes the use of vaginal 1566
Cons estrogen with or without lactobacillus containing 1567
idera probiotics in postmenopausal women, use of low 1568
tion dose post-coital antibiotics for rUTI associated 1569
of with sexual activity in premenopausal women, low
1570
antib dose daily antibiotic prophylaxis in premenopausal
1571
iotic women with infections unrelated to sexual activity,
1572
resis and methenamine hippurate and/or lactobacillus
1573
tanc containing probiotics as nonantibiotic alternatives.
1574
e Antibiotic choice for prophylaxis should take into
1575
pat- account patient prior organism identification and
1576
tern susceptibility profile, drug allergies and antibiotic
½F2 1577
s in stewardship.
the 1578
patie 1579
Limitations and Strengths
nt 1580
Despite an extensive review of the literature and
and 1581
interpretation and assessment by a multidisciplinary
the group of practitioners and researchers, these recom- 1582
com mendations are based on existing data of primarily 1583
muni fair to poor quality. Diagnostic strategies in the 1584
ty 1585
(local 1586
anti- 1587
biogr 1588
ams) 1589
as 1590
well 1591
as 1592
patie 1593
nt 1594
aller 1595
gies, 1596
1597 1654
1598 Confirm diagnosis of rUTIs; >2 culture positive UTIs in 6 months or >3 in one year
1655
1599 1656
1600 1657
1601 1658
1602 Perform thorough history and physical exam to assess for complicating factors that may prompt additional testing
#
1659
1603 1660
1604 1661
1605 1662
1606 1663
1607 Educa on and advise on behavioral modifica ons and lifestyle modifica ons* 1664
1608 1665
1609 1666
1610 1667
1611 1668
1612 Postmenopausal rUTIs Premenopausal post-coital Premenopausal and rUTI 1669
1613 Consider ini a on of vaginal infec ons unrelated to sexual ac vity
1670
estrogen with or without Consider ini a on of low dose Consider ini a on of daily low
1614 lactobacillus containing an bio c within 2 hours of dose an bio c prophylaxis for 1671
1615 probio cs sexual ac vity for 6-12 months 6-12 months 1672
1616 1673
1617 If pa ent desires non- If pa ent desires non- 1674
1618 an bio c alterna ve an bio c alterna ve 1675
Consider methenamine Consider methenamine
1619 1676
hippurate and/or lactobacillus hippurate and/or lactobacillus
1620 containing probio cs containing probio cs 1677
1621 1678
1622 1679
1623 1680
1624 1681
1625 An bio c choice should take into account pa ent’s prior organism iden fica on and suscep bility profile, drug 1682
1626 allergies,can
intervals andbe
anconsidered
bio c stewardship. Nitrofurantoin
to avoid selec 50 mg, trimethoprim-sulfamethoxazole
on of an microbial resistance. 40/200 mg, 1683
trimethoprim 100 mg are preferred over fluoroquinolones and/or cephalosporins. Rota ng an bio cs at 3-month
1627 1684
1628 1685
1629 # Complica ng factors include: Congenital abnormali es of urinary tract, spinal cord injury, transplant recipients, 1686
neurogenic bladder, immunosuppression, chemotherapy, nephrolithiasis or recent surgery
1630 1687
1631 * Behavioral/lifestyle modifica ons include: Controlling blood glucose in diabe cs, avoiding disrup on of normal 1688
1632 vaginal flora with spermicides and/ or harsh cleansers, avoiding prolonged an bio c courses (>5 days), broad 1689
1633 spectrum or unnecessary an bio cs, maintaining adequate hydra on, voiding a er intercourse, avoiding 1690
prolonged holding of urine, and avoiding sequen al anal and vaginal intercourse.
1634 1691
1635 1692
1636 1693
1637 Figure 2. Clinical algorithm for prevention of rUTIs in women 1694
1639 evaluation of complicated rUTI were beyond the Nonantibiotic strategies are supp
1638 1695
1640 scope of this focused review. orted
1641 and
1642 can
1643 CONCLUSION be
1644 Treatment and prevention strategies that minimize consi
1645 harm and optimize well-being in women with rUTI dered
1646 are greatly needed. Insufficient high level evidence to
1647 exists in the literature to support a single approach foste
1648 to the care of women with rUTI. However, there r
1649 are antibiotic and nonantibiotic options for judic
1650 prevention with evidence to support their use. ious
1651 Literature sur- rounding antibiotic prophylaxis is use
1652 largely based on older studies that do not of
1653 incorporate the standards of more current research. antib
iotic regarding effective strategies to prevent rUTI in 1696

thera women. Larger scale RCTs comparing these options 1697
py in as well as combination therapy are needed to better 1698
the understand the risk-benefit ratio, cost- 1699
com effectiveness and optimal antibiotic use. Future 1700
muni research should involve consistent use of terminol- 1701
ty. ogy, validated instruments to assess response to in- 1702
Prim terventions, longer followup periods and patient 1703
ary perspectives on care. 1704
prev 1705
entio 1706
n of 1707
rUTI 1708
inclu 1709
des 1710
antib
iotic
stew
ards
hip
with
appr
opria
tely
selec
ted
drug
,
dose
and
dura
tion.
Our
prev
entio
n
algor
ithm
is
base
d on
the
best
avail
- able
evid
ence
and
fills
a gap
in
the
liter
atur
e
and
pract
ice
1711 APPENDIX 1768
1712 Clinical Practice Guidelines Recommendations for the Prevention and Treatment of rUTIs in Women 1769
1713 1770
1714 Society of Obstetricians and European Association
1771
1715 Prevention or Treatment Recommendation for Women with rUTIs Gynaecologists of Canada (2010) of Urology (2015)
1772
1716 Antimicrobial prophylaxis 1773
1717 Antimicrobial prophylaxis should be considered only after counseling and X 1774
behavioral modification have been attempted
1718 Before any antimicrobial prophylaxis is initiated, eradication of a previous UTI X X 1775
1719 should be confirmed by a negative urine culture 1e2 weeks after treatment 1776
1720 Continuous antimicrobial prophylaxis should be considered when X 1777
nonantimicrobial measures have been unsuccessful; choice of antimicrobial
1721 should be based upon identification and susceptibility pattern of the 1778
1722 organism causing the patient’s UTI and history of drug allergies* 1779
1723 Continuous daily antibiotic prophylaxis during a 6 to 12-month period should X 1780
be offered to women with rUTIs†
1724 Acute self-treatment is recommended in appropriately selected patients X X 1781
1725 Nonantimicrobial interventions
1782
1726 1783
1727 Patients should be informed that cranberry products are effective in reducing X
rUTI 1784
1728 Daily consumption of cranberry products, giving a minimum of 36 mg/day X 1785
1729 proanthrocyanindin A 1786
1730 Acupuncture in women who are unresponsive to or intolerant of antibiotic X
prophylaxis 1787
1731 Probiotics and vaccines are not recommended X 1788
1732 Intravaginal probiotics that contain Lactobacillus rhamnosus GR-1 or X 1789
1733 Lactobacillus reuteri RC-14 can be used once or twice weekly
for prophylaxis 1790
1734 1791
Immunotherapy
1735 Immunoactive prophylaxis with OM-89 (Uro-Vaxom) X
1792
1737 1794
If spermicide is used, consider an alternative form of contraception X
1738 Post-coital antimicrobial prophylaxis X X 1795
1739 1796
* Recommended antimicrobials include trimethoprim-sulfamethoxazole, trimethoprim, nitrofurantoin, cefaclor, cephalexin, norfloxacin, ciprofloxacin and fosfomycin.
1740 Specific dosages with expected UTIs per year per drug are provided.
1797
1741 † Recommended antimicrobials include cotrimoxazole, nitrofurantoin, cephalexin, trimethoprim, trimethoprim-sulfamethoxazole or a quinolone. 1798
1742 1799
1743 1800
1744 1801
1745
REFERENCES 1802
1746 1. Geerlings SE: Clinical presentations and epide- and disease burden. Infect Dis Clin North Am 10. Barlam TF, Cosgrove SE, Abbo LM et al: Imple- 1803
1747 miology of urinary tract infections. Microbiol 2014; 28: 1. menting an antibiotic stewardship program: 1804
Spectr 2016; 4: doi: 0.1128/microbiolspec.UTI- guidelines by the tious Diseases Society of
1748
1 Infec
ety for Healthcare Epide-
1805
0002-2012. 6. Gupta K, Hooton TM, Naber KG et al: Interna-
1749 tional clinical practice guidelines for the treat- America and the 1806
miology of America. n Infect Dis 2016; 62: e51.
ment of acute uncomplicated cystitis and
1750 2. Wagenlehner F, Wullt
1767 B, Ballarini S et al: Social
and economic burden of recurrent urinary tract
occurrence, recurrence, bacteriology, risk factors, 1807
pyel
1751 onep
infections and quality of life: a patient web-
1752 based study (GESPRIT). Expert Rev Pharmacoe- hritis
1753 con Outcomes Res 2018; 18: 107. in
1754 wom
3. Malik RD, Wu YR and Zimmern PE: Definition of en: a
1755
recurrent urinary tract infections in women: 2010
1756 which one to adopt? Female Pelvic Med upd
1757 Reconstr Surg 2017; doi: 10.1097/ ate
1758 SPV.0000000000000509. by
1759 the
4. NAMCS and NHAMCS Web Tables: Table 1. Infec
1760 Annual number and percent distribution of tious
1761 ambulatory care visits by setting type according Dise
1762 to diagnosis group: United States, 2009-2010. ases
1763 Available at https://www.cdc.gov/nchs/data/ Soci
ahcd /combin ed _tables/200 9-2010_combined_ ety
1764
web_t able 01.pdf. of
1765 Ame
1766 5. Foxman B: Urinary tract infection syndromes: rica
and cal Practice Guidelines from the Infectious 11. Zatorski C, Zocchi M, Cosgrove SE et al: A
the Diseases Society of America. Clin Infect Dis single center observational study on
1808
Euro 2010; 50: 625. emergency department clinician non-adherence 1809
pean to clinical practice guidelines for treatment 1810
Soc 8. Nicolle LE, Bradley S, Colgan R et al: Infectious
of uncomplicated urinary tract infections. 1811
iety Diseases Society of America guidelines for the
BMC Infect Dis
for diagnosis and treatment of asymptomatic 1812
2016; 16: 638.
Micr bacteriuria in adults. Clin Infect Dis 2005; 40: 1813
643. 12. Moher D, Liberati A, Tetzlaff J et al:
obiol 1814
ogy Preferred reporting items for systematic reviews
9. Sterling M, Lamin E, Skokan A et al: Practice
and meta- analyses: the PRISMA statement.
1815
and patterns across specialties in the treatment of
Infec Ann Intern Med 2009; 151: 264. 1816
women with recurrent UTIs in an academic
- healthcare system. J Urol, suppl., 2017; 197:
1817
13. Higgins JP, Altman DG, Gøtzsche PC et al:
tiou e296, abstract MP23-09. The Cochrane Collaboration’s tool for
1818
s 1819
assessing risk of bias in randomised trials.
Dise
BMJ 2011; 343: d5928. 1820
ases.
Clin 14. Centre for Evidence-Based Medicine: 1821
Infec Oxford Centre for Evidence-based Medicine e 1822
t Levels of Evidence (March 2009). Available 1823
Dis at https:// www.cebm.net/2009/06/oxford- 1824
2011 centre-evidence- based-medicine-levels-
; 52: evidence-march-2009/.
e10
3.
7.
Hoo
ton
TM,
Brad
ley
SF,
Car
den
as
DD
et
al:
Dia
gno
sis,
prev
enti
on,
and
treat
men
t of
cath
eter
-
asso
ciat
ed
urin
ary
tract
infe
ctio
n in
adul
ts:
200
9
Inte
rnat
iona
l
Clini
1825 15. Shea BJ, Reeves BC, Wells G et al: AMSTAR 2: a 27. Stapleton A, Latham RH, Johnson C et al: tract infection in older adults: systematic review 1882
1826 critical appraisal tool for systematic reviews that Postcoital antimicrobial prophylaxis for recurrent and meta-analysis of randomised trials. BMJ 1883
1827 include randomized or non-randomised studies of urinary tract infection. A randomized, double- Open 2017; 7: e015233.
healthcare interventions, or both. BMJ 2017; blind, placebo-controlled trial. JAMA 1990;
1884
1828 358: j4008. 264: 703. 39. Alraek T, Soedal LI, Fagerheim SU et al: 1885
1829 Acupuncture treatment in the prevention of un- 1886
16. Scholes D, Hooton TM, Roberts PL et al: Risk 28. Brumfitt W, Smith GW, Hamilton-Miller JM et complicated recurrent lower urinary tract
1830 1887
factors for recurrent urinary tract infection in al: A clinical comparison between Macrodantin infections in adult women. Am J Public
1831 young women. J Infect Dis 2000; 182: 1177. and trimethoprim for prophylaxis in women 1888
Health
1832 with recurrent urinary infections. J Antimicrob 2002; 92: 1609. 1889
17. Epp A, Larochelle A, Urogynaecology Committee
1833 Che- mother 1985; 16: 111. 1890
et al: Recurrent urinary tract infection. J 40. Aune A, Alraek T, LiHua H et al: Acupuncture in
1834 Obstet Gynaecol Can 2010; 32: 1082. 29. Pfau A and Sacks TG: Effective postcoital 1891
the prophylaxis of recurrent lower urinary tract
1835 quinolone prophylaxis of recurrent urinary
infection in adult women. Scand J Prim Health 1892
18. Hooton TM, Scholes D, Hughes JP et al: A
1836 prospective study of risk factors for
tract infections in women. J Urol 1994; 152: Care 1998; 16: 37. 1893
1837 136.
symptomatic urinary tract infection in young 1894
1838 41. Nicolle LE: Cranberry for prevention of urinary
women. N Engl J Med 1996; 335: 468. 30. Raz R, Colodner R, Rohana Y et al: Effectiveness
tract infection?: time to move on. JAMA 2016;
1895
1839 19. Strom BL, Collins M, West SL et al: Sexual
of estriol-containing vaginal pessaries and
316: 1873. 1896
1840 nitrofurantoin macrocrystal therapy in the pre-
activity, contraceptive use, and other risk vention of recurrent urinary tract infection in
1897
1841 factors for symptomatic and asymptomatic postmenopausal women. Clin Infect Dis 2003;
42. Jepson RG, Williams G and Craig JC: Cranberries 1898
1842 bacteriuria. A case-control study. Ann Intern Med for preventing urinary tract infections. Cochrane
36: 1362.
Database Syst Rev 2012; 10: CD001321.
1899
1987; 107: 816.
1843 1900
31. Raz R, Rottensterich E, Hefter H et al: Single-
1844 20. Czaja CA, Stamm WE, Stapleton AE et al: Pro-
dose ciprofloxacin in the treatment of uncom- 43. Barbosa-Cesnik C, Brown MB, Buxton M et al: 1901
1845 spective cohort study of microbial and inflam- Cranberry juice fails to prevent recurrent urinary
plicated urinary tract infection in women. Eur J 1902
matory events immediately preceding tract infection: results from a randomized placebo-
1846 Escherichia coli recurrent urinary tract infection
Clin Microbiol Infect Dis 1989; 8: 1040. 1903
controlled trial. Clin Infect Dis 2011; 52: 23.
1847 in women. J Infect Dis 2009; 200: 528. 32. Hooton TM: Clinical practice. Uncomplicated uri- 1904
1848 nary tract infection. N Engl J Med 2012; 366: 1028. 44. Stapleton AE: Cranberry-containing products are 1905
21. Bailey RR, Roberts AP, Gower PE et al: Preven- associated with a protective effect against
1849 tion of urinary-tract infection with low-dose 33. Melekos MD, Asbach HW, Gerharz E et al: 1906
urinary tract infections. Evid Based Med 2013;
1850 nitrofurantoin. Lancet 1971; 2: 1112. Post- intercourse versus daily ciprofloxacin 18: 110. 1907
1851 prophylaxis for recurrent urinary tract infections
22. Gower PE: The use of small doses of cephalexin
1852 in premenopausal women. J Urol 1997; 157: 45. Juthani-Mehta M, Van Ness PH, Bianco L et al:
(125 mg) in the management of recurrent urinary 935.
1853 tract infection in women. J Antimicrob Chemo-
1854 ther, suppl., 1975; 1: 93. 34. Wong ES, McKevitt M, Running K et al: Man- 1911
1855 agement of recurrent urinary tract infections
23. Nicolle LE, Harding GK, Thompson M et al: 1912
with patient-administered single-dose therapy.
1856 Prospective, randomized, placebo-controlled trial 46. Avorn J, Monane M, Gurwitz JH et al: Reduction 1913
Ann Intern Med 1985; 102: 302. of bacteriuria and pyuria after ingestion of
1857 of norfloxacin for the prophylaxis of recurrent 1914
urinary tract infection in women. Antimicrob 35. Zhong YH, Fang Y, Zhou JZ et al: Effectiveness cranberry juice. JAMA 1994; 271: 751.
1858 1915
Agents Chemother 1989; 33: 1032. and safety of patient initiated single-dose versus
1859 continuous low-dose antibiotic prophylaxis for
47. Kranj cec B, Papes D and Altarac S: D- 1916
1860 24. Rudenko N and Dorofeyev A: Prevention of mannose powder for prophylaxis of recurrent 1917
recurrent urinary tract infections in post-
recurrent lower urinary tract infections by long- urinary tract infections in women: a randomized
1861 menopausal women: a randomized controlled 1918
term administration of fosfomycin trometamol. clinical trial. World J Urol 2014; 32: 79.
1862 study. J Int Med Res 2011; 39: 2335. 1919
Double blind, randomized, parallel group,
1863 placebo controlled study. 36. Price JR, Guran LA, Gregory WT et al: Nitro- 48. Raz P: Urinary tract infection in elderly women. 1920
1864 Arzneimittelforschung furantoin vs other prophylactic agents in Int J Antimicrob Agents 1998; 10: 177.
1921
1865 2005; 55: 420. reducing recurrent urinary tract infections
49. Griebling TL and Nygaard IE: The role of estro- 1922
in adult women: a systematic review and
1866 25. Scheckler WE, Burt RA and Paulson DF: Com- meta- analysis. Am J Obstet Gynecol 2016; 215: gen replacement therapy in the management of 1923
1867 parison of low-dose cinoxacin therapy and pla- 548. urinary incontinence and urinary tract infection in 1924
1868 cebo in the prevention of recurrent urinary postmenopausal women. Endocrinol Metab Clin
North Am 1997; 26: 347.
1925
tract infections. J Fam Pract 1982; 15: 901. 37. Albert X, Huertas I, Pereir o II et al:
1869 Antibiotics for preventing recurrent urinary tract 1926
1870 26. Stamm WE, Counts GW, Wagner KF et al: infection in non-pregnant women. Cochrane 50. Perrotta C, Aznar M, Mejia R et al: Oestrogens 1927
1871 Antimicrobial prophylaxis of recurrent urinary for preventing recurrent urinary tract infection in
Database Syst Rev 2004; CD001209. 1928
tract infections: a double-blind, placebo- postmenopausal women. Cochrane Database
1872 controlled trial. Ann Intern Med 1980; 92: 770. 38. Ahmed H, Davies F, Francis N et al: Long-term 1929
Syst Rev 2008; 2: CD005131.
1873 antibiotics for prevention of recurrent urinary 1930
1874 1931
1875 1932
1876 1933
1877 EDITORIAL COMMENTS 1934
1878 Recurrent lower urinary tract infections in women at inconvenient times, and have very bothersome 1935
1879 are a frustrating problem for patient and provider. symptoms. Repeat courses of antibiotics put them 1936
1880 Patients suffer with these infectious episodes, often at risk for yeast vaginitis and gastrointestinal 1937
1881 1938
Dochead: Review Article DIS 5.5.0 DTD JURO15681_proof 19 September 2018 4:18 pm EO: JU-18-405
Effect of cranberry capsules on bacteriuria plus 1908

pyuria among older women in nursing homes: a 1909
randomized clinical trial. JAMA 2016; 316: 1879. 1910
1939 disturbances including C. difficile colitis. These authors also place significant emphasis on antibiotic 2001
1940 women also suffer from constant worry about when stewardship. One of the most surprising pieces of 2002
1941 2003
their next infection is going to strike. information is that women with recurrent UTIs do
1942 2004
Providers are also frustrated by this problem not meet criteria for complicated UTI and, thus, do
1943 2005
1944
since there exists very little high quality data to not need 7 days of antibiotics. They are better
2006
1945 formulate recommendations for these women. There served with a short 3-day course of a narrow spec-
2007
1946 is more dogma than actual data and women resort trum antibiotic that will avoid changing their gut 2008
1947 to unconventional treatments, wanting prevention and vaginal flora. 2009
1948 and not just treatment. 2010
1949 This review article addresses the lack of evidence 2011
Anne Pelletier-Cameron
1950 regarding this clinical problem and provides sound Department of Urology 2012
1951 advice to give patients based on the available data University of Michigan 2013
1952 combined with basic principles of bacteriology. The Ann Arbor, Michigan 2014
1953 2015
1954 2016
1955 This rapid review with practice recommendations sufficient to convince the reader and the interna- 2017
1956 on the treatment and prevention of recurrent lower tional scientific community of the vast gaps in 2018
1957 urinary tract infections in women is timely as the knowledge of rUTIs. At a time when good antibiotic 2019
1958 1 2020
number of women affected by this condition, espe- stewardship, enhanced patient perception of the
1959 2021
1960
cially the older group, is rapidly growing in all of negatives (risks, side effects) of antibiotic therapies 2022
1961 our practices. The authors should be congratulated and the escalating costs of many of these preven- 2023
1962 for their large and detailed search of the best tative and therapeutic alternatives are in the lime- 2024
1963 available literature on this topic and for offering a light, this article should serve as a wake-up call and 2025
1964 succinct algorithm of the favored alternatives for encouragement to intensify our studies on a “highly 2026
1965 rUTI prevention and treatment. Notably, a quick prevalent and burdensome condition.” 2027
1966 glance at reference 3 pointing out the lack of 2028
1967 consensus in the definition of rUTIs, and at the 2029
1968 quality rating (AMSTAR 2) column in table 3 2030
1969 Philippe E. Zimmern
documenting the “low or critically low” level of 2031
University of Texas Southwestern Medical Center
1970 evidence in the presented data in 20 of 23 reviews, 2032
Dallas, Texas
1971 2033
should be more than
1972 2034
1973 2035
1974 2036
1975 REFERENCE 2037
1976 1. Malik RD, Wu YR, Christie AL et al: Impact of allergy and resistance on antibiotic selection for recurrent urinary tract infections in older women. Urology 2018; 113: 2038
26.
1977 2039
1978 2040
1979 2041
1980 2042
1981 2043
1982 2044
1983 2045
1984 2046
1985 2047
1986 2048
1987 2049
1988 2050
1989 2051
1990 2052
1991 2053
1992 2054
1993 2055
1994 2056
1995 2057
1996 2058
1997 2059
1998 2060
1999 2061
2000 2062
Dochead: Review Article DIS 5.5.0 DTD JURO15681_proof 19 September 2018 4:18 pm EO: JU-18-405

Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review With Practice Recommendations

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Review Article

to research ques on,

for eligibility • Pa ents with structural

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

placebo for those who completed 12-mo

461 volume of fluid 518

464 active women.18,19 521

No differences in UTIs or antibiotics used68

between groups during 12-mo followup.

470 broad spectrum

471 Logical hygiene

479 travel may affect risk.20 536

499 In 12 of 19 studies significant differences in rUTI 556

508 studies single

511 effective than

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

e0.932, p <0.0001), absolute risk

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

wks then every 2 wks x 2 weekly x6 group at 12 mos, nonsignificant reduction

treatment mos 4e6 þ 10 (p¼0.001)

booster group 55% had no UTIs vs 22% in

placebo þ vaccine without booster group

all studies showed no lasting difference in rUTI

vs placebo or between OM-89S vs NF

rates between treatment and comparator groups.

808 This finding demonstrates a lack of lasting impact

809 of pre- vention after cessation of therapy. Adverse r

814 whereas a greater number and type were seen in wev

821 period in 7 of 10 studies investigating this

Urovac at 3 time points þ 3

826 periods in 4 of 5 studies that assessed it.

827 Meta-analyses support the use of continuous plac

OM-89S 6 mg daily or OM-89S

828 antimicrobial prophylaxis for 6 to 12 months for the ebo

836 were identified which investigated a 4-week

mechanism is unclear, and limitations of the

845 with insufficient evidence to recommend Hea

846 acupuncture to prevent rUTI. lth

849 (table 2). The use of cranberry products has a long

852 several Cochrane reviews, evidence is sparse that

869 888 907

pri re is insufficient clinical evidence to recommend 970 1022

Results (RR or other statistic,

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

intercourse significantly reduced recurrent cystitis

effective in prevention of rUTIs

Results (RR or other statistic,

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

studies 220 women reported, p¼0.002]

prevention of rUTIs evi- dence is inconclusive

Results (RR or other statistic,

RECURRENT LOWER URINARY TRACT INFECTIONS IN WOMEN

(RR 0.81, 0.68e0.96, 3 trials, sample size

e0.83, 2 trials, sample size 250), 0% (0.418)

decreased UTI rate/pt-yr (MD -2.45, - -0.28

(3 reduce rUTI incidenc

treating rUTI during

treatment more than antibiotics

placebo or baseline, local reactions 0%-36%