Accepted Manuscript

Nitrofurantoin versus other prophylactic agents in reducing recurrent urinary tract

infections in adult women. A Systematic Review and Meta-analysis

Jameca Renee Price, MD, MPH, MCR, Ms. Larissa A. Guran, MPH, W. Thomas
Gregory, MD, Marian S. McDonagh, PharmD

PII: S0002-9378(16)30475-6
DOI: 10.1016/j.ajog.2016.07.040
Reference: YMOB 11237

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 19 April 2016

Revised Date: 7 July 2016
Accepted Date: 15 July 2016

Please cite this article as: Price JR, Guran LA, Gregory WT, McDonagh MS, Nitrofurantoin versus
other prophylactic agents in reducing recurrent urinary tract infections in adult women. A Systematic
Review and Meta-analysis, American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/
j.ajog.2016.07.040.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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1 Title: Nitrofurantoin versus other prophylactic agents in reducing recurrent urinary tract

2 infections in adult women. A Systematic Review and Meta-analysis

4 Authors:

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5 Jameca Renee PRICE, MD, MPH, MCR

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6 Ms. Larissa A. GURAN, MPH

7 W. Thomas GREGORY, MD

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8 Marian S. McDONAGH, PharmD

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This study was conducted in Portland, Oregon at Oregon Health and Science University
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11 by the Urogynecology and Reconstructive Pelvic Surgery division of the department of

12 Obstetrics & Gynecology and the department of Medical Informatics and Clinical
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13 Epidemiology of the School of Medicine.

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14
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15 Affiliations:

16 Dr. Price and Dr. Gregory – Division of Urogynecology and Reconstructive Pelvic
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17 Surgery

18 Dr. McDonagh – Department of Medical Informatics and Clinical Epidemiology

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19
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20 Conflict of Interest:

21 The authors report no conflict of interest.

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23 These findings have not been presented previously at any meeting or conference.
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2 Corresponding author:

3 Dr. Jameca Renee Price

4 6841 SW Garden Home Road

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5 Portland, OR 97223

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6 Work: 1-503-494-3104

7 Fax (503) 494-8649

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8 jamecap@hotmail.com

9 jamecaprice@gmail.com

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11 Word counts:

12 Abstract: 394 words

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13 Main text: 3,572 words

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14
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15 Condensation:

16 A systematic review and meta-analysis comparing nitrofurantoin to other agents in

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17 reducing recurrent UTI and assessing side effects in adult women.

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18
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19 Short title:

20 Nitrofurantoin versus other agents in reducing recurrent UTI.

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22

23
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1 ABSTRACT

3 Objective: The objective of this review was to provide current pooled estimates of

4 randomized controlled trials (RCTs) comparing the effects of nitrofurantoin versus all

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5 other treatments including other antibiotics in reducing recurrent urinary tract infections

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6 in adult, non-pregnant women and assess relative adverse side effects.

7 Data sources: MEDLINE January 1, 1946 to January 31, 2015; Cochrane Central

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8 Register of Controlled Trials (CENTRAL), tCochrane Database of Systematic Reviews,

9 ClinicalTrials.gov, and Web sites of the National Institute for Clinical Excellence, and

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the National Guideline Clearinghouse from 2000 to 2015.
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11 Study eligibility criteria: This systematic review aims to provide guidance on gaps in

12 evidence to guide future research. A description of the inclusion criteria is available

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13 online. (www.crd.york.ac.uk/PROSPERO; Record number 23966)

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14 Study appraisal and synthesis methods: Quality of included studies was assessed using
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15 the Drug Effectiveness Review Project (DERP) tool. Studies were synthesized by

16 pooling data on similar outcomes across studies with similar design, methodology, and
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17 patient populations.

18 Results: Twelve RCTs involving 1063 patients were included. One study that had a
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19 serious flaw was rated poor in quality, one study rated good, and the remainder fair. No
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20 significant differences in prophylactic antibiotic treatment with nitrofurantoin and

21 norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methenamine hippurate,

22 estriol, or cefaclor were found in clinical (9 RCTs, 673 patients, RR = 1.06, 95% CI =

23 0.89 - 1.27, I2 65%) or microbiological cure in adult non-pregnant women with recurrent
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1 UTIs (12 RCTs, 1063 patients, RR = 1.06, 95% CI = 0.90 to 1.26, I2 76% ). Duration of

2 prophylaxis also did not significantly impact outcomes. There was a statistically

3 significant difference in overall adverse effects with nitrofurantoin resulting in greater

4 risk than other prophylactic treatments (10 RCTS, 948 patients, RR = 2.17, 95% CI =

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5 1.34 to 3.50; I2 61%) with a significant difference for withdrawals (12 RCTs, 1063

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6 patients, RR = 2.14, 95% CI = 1.28 to 3.56, I2 8%). Overall, the majority of

7 nitrofurantoin adverse effects were gastrointestinal.

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8 Conclusions: Nitrofurantoin had similar efficacy, but greater risk of adverse events than

9 other prophylactic treatments. Balancing the risks of adverse events, particularly

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gastrointestinal symptoms, should be considered if selecting nitrofurantoin.
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11

12 Key Words: Adult Women, Urinary tract infection, Meta-analysis, Prophylaxis

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13 Systematic Review, Recurrence, UTI

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14
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15
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1 INTRODUCTION

3 Accounting for over $2.6 billion in annual costs in the United States alone, the clinical

4 and financial burden from urinary tract infections is vast.(1) Over 8.1 million visits to

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5 health care providers related to urinary tract infections occur each year.(2) It is one of the

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6 most common bacterial infections in women and one of the most common diseases seen

7 in general practice.(3-5) Forty to 50% of women have at least one episode of

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8 uncomplicated UTI during their lifetime, and 20–30% will have a recurrent episode.(5, 6)

9 Moreover, evidence shows that between 20% and 50% of initial episodes have

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subsequent infections within 6 months.(7-9) The UTI incidence peaks during ages 18
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11 and 24 at 17.5%, but is still a substantial 9% for women of age 50 and over;

12 approximately 10% of those women who are postmenopausal report having had a UTI
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13 during the past year.(8)

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14
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15 Although strategies for managing recurrent UTIs are limited, there are multiple strategies

16 for recurrent UTI prevention. An option recommended by American College of

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17 Obstetrics and Gynecology is postcoital antibiotic prophylaxis and the Canadian Urologic

18 Association Guidelines recommends continuous, postcoital, or self-start options for

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19 antibiotics as well as vaginal estrogen cream.(10) Another strategy from ACOG

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20 recommends continuous once daily prophylaxis with nitrofurantoin, norfloxacin,

21 ciprofloxacin, trimethoprim, trimethoprim/sulfamethoxazole, levofloxacin, gatifloxacin,

22 or fosfomycin tromethamine for 6 to 12 months.(11) In a review by Geerlings, et al.,

23 nonantimicrobial options include cranberry products and lactobacillus crispatus

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1 intravaginal suppository in premenopausal women and in postmenopausal women options

2 include topical estrogen, oral capsules with L rhamnosus GR-1 and L reuteri RC -14.(12)

3 There are new promising strategies on the horizon for management of recurrent UTIs

4 which are prophylaxis with bacterial extracts such as the oral immunostimulant OM-89 or

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5 the vaginal vaccine Urovac.(12) However, more evaluation must be done before

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6 introduction into clinical practice.

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8 The issues of antibiotic resistance and the ecological adverse effects of antimicrobial

9 therapy are important motivators for better, more evidence-based, strategies. In the past

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decade, multiple key organizations, including the Infectious Diseases Society of America,
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11 the Centers for Disease Control and Prevention, the World Health Organization (WHO),

12 and the World Economic Forum, have made antibiotic resistance the focus of conferences
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13 and action plans. (13) Nitrofurantoin is a well-known and studied drug with limited
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14 antibiotic resistance since its use.(14) The focus of this review is to conduct a current
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15 evaluation of head to head comparisons of nitrofurantoin versus other drugs. Our

16 hypothesis is that nitrofurantoin treatment response is statistically significantly better than

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17 other drugs due to its low incidence of bacterial resistance in today’s current multidrug

18 resistant era. The PRISMA guidelines were utilized for study reporting. Recurrent UTI is
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19 defined as either 3 or more symptomatic UTI episodes in the past year (including the
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20 index infection) or 2 such episodes in the past 6 months. (12) Relapse is an infection

21 with the same bacteria that caused the initial infection and usually occurs within one to

22 two weeks after stopping treatment. (12) Reinfection is an infection after sterilization of

23 the urine. (12) This review only discusses the prevention of reinfections.
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2 OBJECTIVES

4 The aim of this systematic review is to compare nitrofurantoin with other drugs in

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5 reducing UTIs in non-pregnant women with recurrent UTIs and to compare adverse

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6 effects associated with their use. The goal is to provide guidance on gaps in evidence to

7 direct future research.

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8

9 MATERIALS AND METHODS

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11 A detailed description of the methods is available online in a protocol registered with the

12 PROSPERO registry (www.crd.york.ac.uk/PROSPERO; Record number 23966). An

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13 investigational review board reviewed and exempted this study. The PRISMA guidelines
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14 were utilized for study reporting.

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15

16 Information Sources and Search Strategy

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17 MEDLINE was searched from January 1, 1946 to May 31, 2016 and the Cochrane

18 Central Register of Controlled Trials (CENTRAL) with no date restriction for

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19 randomized and nonrandomized comparative studies using the following search terms:
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20 (1) recurrent [recur*], (2) urine or urinary [urine*],and (3) infectious or infection(s)

21 [infectious, infection*],(4) prevent [prevent*], (5) prophylaxis [prophyl*],

22 (6)chemoprophylaxis [chemoprophy*], (7) chemoprevent [chemoprevent*], (8) reduce

23 [reduc* or low* or few* or less*]and (9) risk [risk*], (10) episode [episode*], (11)
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1 chance [chance*], (12) incidence [inciden*] or (13) frequency[frequen*]. In addition, a

2 search for systematic reviews was conducted in MEDLINE, the Cochrane Database of

3 Systematic Reviews, ClinicalTrials.gov, and Web sites of the National Institute for

4 Clinical Excellence, and the National Guideline Clearinghouse from 2000 to 2016 with

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5 general search terms “women” “recurrent” “urinary” “infections”. Conference

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6 proceedings searches included the American Urologic Association, Society of

7 Urogynecology and Female Pelvic Medicine Society, International Urogynecologic

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8 Association, and American Urogynecologic Society. Experts in UTI prophylaxis were

9 consulted. Grey (unpublished) literature studies were searched through databases such as

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the World Bank Documents & Reports (http://www-wds.worldbank.org/) and National
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11 Research Register Projects Database (https://portal.nihr.ac.uk/) prior to its phased

12 shutdown from January 1, 2010 to June 20, 2015.

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13
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14 Study Selection
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15 Recurrent UTI is defined as either 3 or more symptomatic UTI episodes in the past year

16 (including the index infection) or 2 such episodes in the past 6 months are considered to
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17 meet the case definition for recurrent UTI. Titles and abstracts from the search strategy

18 were screened by one author to identify studies that potentially met the inclusion criteria,
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19 with decisions confirmed for accuracy by a second author. Differences were resolved
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20 through consensus with the review group. Abstract screening was conducted using

21 Abstrackr (http://abstrackr.cebm.brown.edu). The full text of these potentially eligible

22 studies was retrieved and independently assessed for eligibility by two review team

23 members. Any disagreement between them over the eligibility of particular studies was
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1 resolved through discussion with a third reviewer. Inclusion criteria were the following:

2 (1) women aged 18-85 with recurrent UTI; (2) nitrofurantoin versus trimethoprim,

3 cefaclor, sulfamethoxazole/trimethoprim, cefixime, vaginal estrogen, estrogen of all

4 types, cranberry supplements, bladder instillations, or fosfomycin; (3) studies reporting

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5 mean number of UTIs per recurrent UTI patient or reduction of UTIs, microbiological

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6 cure, or clinical cure; (4) study duration of at least 6 months of prophylaxis; (5) RCT or

7 nonrandomized comparative study. Observational studies (cohort and case–control

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8 studies) were included for the assessment of harms. Studies were included if they fulfilled

9 all the criteria. Primary outcome was microbiological or clinical cure. Additional

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outcomes reviewed were mean number of UTI per recurrent UTI patient or mean time to
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11 UTI. Secondary outcomes was mean time to UTI recurrence between UTI and adverse

12 events.
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13
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14 Studies with any of the following criteria were excluded: published in non-English
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15 language unless institution resources available for transcription, pregnant women, not

16 reporting primary data from original research, not reporting relevant outcomes, having
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17 greater than 20% of subjects not women.

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19 Data Extraction and Quality Assessment

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20 A standardized form from RevMan (a Review Manager software) was used to extract

21 data from the included studies for assessment of study quality and evidence synthesis.

22 Two review authors extracted data and study characteristics independently, discrepancies

23 were identified and resolved through discussion (with a third author where necessary).
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1 Extracted information included: study setting, study population and participant

2 demographics and baseline characteristics, details of the intervention and control

3 interventions, study methodology, recruitment and study completion rates, outcomes, and

4 timing of measurement. Missing data were requested from study authors.

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5

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6 Quality of included studies was assessed using the methods of the Drug Effectiveness

7 Review Project (DERP) quality assessment of randomized trials.(15) Three quality

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8 categories were used: good, fair, and poor. The DERP was developed to assess

9 effectiveness and safety of drugs in many widely used drug classes. Given this

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systematic review was focused on drug effectiveness in recurrent UTI prophylaxis,
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11 the DERP was used.
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12

13 Data Synthesis and Analysis

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14 A table of the findings from the included studies was structured around the type of
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15 intervention, target population characteristics, type of outcome and intervention content.

16 Studies were synthesized by pooling data on similar outcomes across studies with similar
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17 design, methodology, and patient populations. If studies were not similar on these

18 characteristics, we did not pool results. Sensitivity analysis was done if there were
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19 different outcomes within the same comparator agents to see if there was an impact on
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20 overall primary outcome.

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22 Statistical Analysis
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1 All meta-analyses were performed using StatsDirect statistical software (version 2.5.7;

2 stats Direct Ltd, Cheshire, UK). For all dichotomous outcomes, we calculated the pooled

3 relative risk ratio (RR) and 95% confidence interval (CI), using the random-effects model

4 (DerSimonian Laird). Comprehensive analyses of all included studies were done.

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5 Separate analyses of same comparators with nitrofurantoin were done.

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6

7 RESULTS

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9 Description of included studies

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The literature search yielded 1741 articles, of which 78 were reviewed in full text.
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11 (Figure 1) Of these studies, 12 RCTs met the inclusion criteria. These trials included a

12 total of 1063 patients, in whom 344 bacterial urinary tract infections were reported from
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13 10 studies. Remaining studies reviewed in full text were excluded for the following
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14 reasons: studies without nitrofurantoin prophylaxis therapy, nitrofurantoin therapy with

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15 acute bacterial infections, other prophylactic therapies with other drugs, not original

16 investigations, or duplicates of reports already identified. The characteristics and quality

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17 assessment of the included studies for the clinical trial studies presented in Tables 1 and

18 2. (28-39). Regarding commonly used non-antimicrobial options, there were no available

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19 studies that compared cranberry or probiotics to nitrofurantoin; however an estriol trial

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20 was included.

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22 The trials had sample sizes that ranged from 30 to 222 participants. The bacteriuria

23 episodes during prophylaxis ranged from 3 to 172 per trial and the mean interval time
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1 between bacteriuria or symptomatic UTI episodes were from 241 to 3,642 days. All

2 studies included were single centers and were undertaken in the USA, England, Finland,

3 Denmark, Germany, Peru, Poland, and Israel. Ten studies assessed the effect of recurrent

4 UTI prophylaxis of nitrofurantoin versus other agents, two assessed the biologic effects

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5 on the vaginal and fecal flora of nitrofurantoin versus other agents, and one study

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6 assessed the effect of recurrent UTI prophylaxis of nitrofurantoin versus other agents in

7 diabetic female patients. The studies assessing nitrofurantoin were done mainly between

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8 1977 and 2007. The most recent largest trial examined the effects of nitrofurantoin

9 versus estriol pessaries. With respect to patient-level characteristics of the studies, the

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mean age of the study participants ranged between 31 and 68 years. Three studies
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11 enrolled men in addition to women (less than 20% male) and 9 were undertaken

12 exclusively in female patients. Secondary prevention was the goal of the 11 studies. Five
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13 studies had specific renal requirements for trial inclusion criteria. One trial had only
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14 postmenopausal subjects and another trial had only elderly individuals. Reporting
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15 of key indicators of trial quality was limited, with earlier studies in particular providing

16 few details about the process of randomization, concealment of allocation, and use of
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17 intention to treat analysis techniques. The proportion of participants completing the trials

18 also varied substantially, from 36% to 92 %. Of the twelve trials, 84% were fair quality,
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19 8% were poor quality, and 8% were good quality.

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21 In 9 of the trials involving recurrent UTI, non-pregnant adult women, the patients

22 allocated to the nitrofurantoin treatment arm received a 50, 75, or 100 mg dose treatment

23 nightly with nitrofurantoin. The other two trials administered 50 mg every 12 hours and
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1 50 mg three times a day. Nitrofurantoin was compared with fluoroquinolones in three of

2 these trials, specifically, nitrofurantoin was compared with norfloxacin. In two other

3 trials, nitrofurantoin was compared with trimethoprim, two with methenamine, one with

4 estriol, one with fosfomycin, one with a Beta-lactam (cefaclor), and in the remaining two

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5 sulfamethoxazole/trimethoprim. In the group of trials that enrolled both women and men,

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6 nitrofurantoin was compared with methenamine hippurate,

7 sulfamethoxazole/trimethoprim, trimethoprim. Regarding the trial involving recurrent

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8 UTI diabetic women, nitrofurantoin was compared with fosfomycin and

9 sulfamethoxazole/trimethoprim.

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11 In 6 of the 11 included trials the daily nitrofurantoin treatment for 12 months was

12 compared with daily dose treatment of norfloxacin, trimethoprim,

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13 sulfamethoxazole/trimethoprim, methenamine hippurate, and cefaclor, respectively. In

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14 the remaining 5 trials, nitrofurantoin was compared with shorter treatment regimens.
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15 Specifically, the duration of the treatment regimens ranged from 6 to 9 months among

16 these trials.
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18 Outcomes
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19 Effectiveness outcomes

20 No significant difference was found regarding microbiological success between patients

21 treated with nitrofurantoin versus those treated with comparator(s), either in the separate

22 analysis comparing nitrofurantoin with each of the different types of antibiotic agents

23 used or in the comprehensive combined (12 RCTs, 1063 patients, RR = 1.06, 95% CI =
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1 0.90 to 1.26, I2 76%). Specific data are presented in Figure 2. For this outcome, an

2 analysis comparing shorter and longer durations of prophylaxis was done and we found

3 no significant difference between trials comparing daily 6 month nitrofurantoin regimens

4 and those greater than 6 months regimens (5 RCTs, 305 patients, RR = 0.93 95% CI =

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5 0.76-1.14, I2 56%, versus 7 RCTS, 758 patients, RR =1.01, 95% CI = 0.90-1.13, I2 84%

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6 respectively. We found no significant difference in clinical cure in the comprehensive

7 analysis (9 RCTs, 673 patients, RR = 1.06, 95% CI = 0.89 - 1.27, I2 65%). There was no

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8 unifying definition of clinical cure but instead this was defined by each study.

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There was no significant difference found between patients treated with nitrofurantoin
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11 versus those treated with comparator(s) in the separate analyses, as well as in the

12 comprehensive analysis regarding microbiological infection during prophylaxis (10

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13 RCTs, 897 patients, RR = 1.08, 95% CI = 0.66 to 1.76, I2 71%). There was not sufficient
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14 data to report comparison of relapse versus reinfection.

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15

16 Regarding prevention of bacteriuria episodes, there were 10 trials including 1040

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17 participants and 344 bacteriuria episodes. Due to the lack of reporting of standard

18 deviations, an overall reduction in risk could not be calculated for bacteriuria episodes or
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19 mean interval time between bacteriuria episodes.

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21 Safety outcomes

22 There was an increased risk of having an adverse event in patients treated with

23 nitrofurantoin versus those treated with comparators trimethoprim and methenamine

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1 hippurate in the separate analyses, respectively (3 RCTs, 265 patients, RR = 2.03, 95%

2 CI = 1.12 to 3.70, I2 = 5%; 2 RCTs, 244 patients, RR = 4.17, 95% CI = 2.11 to 8.25, I2 =

3 0%). There was an increased risk of an adverse risk overall (10 RCTS, 948 patients, RR

4 = 1.83, 95% CI = 1.18 to 2.84, I2 54%). (Figure 3). The majority of these adverse events

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5 were gastrointestinal symptoms. A summary of adverse events was listed in Table 3.

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6 There was a significant increased risk of study withdrawal due to adverse events (10

7 RCTs, 1002 patients, RR = 2.14, 95% CI = 1.29 to 3.56, I2 = 8%). No significant

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8 difference was found in study withdrawals due to adverse events in the separate analyses.

9 The majority of these withdrawals were due to gastrointestinal symptoms. Three deaths

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were noted in one study which was unrelated to study treatment.
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11

12 A microbiological cure funnel plot to assess potential publication bias in the randomized
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13 studies presented in Figure 4. When small studies with negative results are less likely to
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14 be published, publication bias often occurs. A publication bias was illustrated in the
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15 funnel plot based on the asymmetry around the pooled estimate which has spread

16 unevenly to the left side. This left-skewed distribution suggests that there might have
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17 been selection bias such as participants being excluded from the analysis after being

18 randomized into one of the arms or some of the small studies were biased toward the
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19 effectiveness of the intervention being tested.

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20

21 COMMENT

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1 Twelve randomized, clinical trials involving 1063 patients were included in this review.

2 No significant differences in prophylactic antibiotic treatment with nitrofurantoin,

3 norfloxacin, trimethoprim, sulfamethoxazole/trimethoprim, methenamine hippurate, or

4 cefaclor were found in clinical or microbiological cure in adult non-pregnant women with

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5 recurrent UTIs (9 RCTs, 673 patients, RR = 1.06, 95% CI = 0.89 - 1.27, I2 65%, and 12

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6 RCTs, 1063 patients, RR = 1.06, 95% CI = 0.90 to 1.26, I2 76%, respectively). There was

7 a statistically significant difference in overall adverse effects with nitrofurantoin

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8 prophylactic treatment versus other comparators both in the separate analyses of

9 nitrofurantoin versus trimethoprim and methenamine hippurate and comprehensive

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analysis (3 RCTs, 265 patients, RR = 2.03, 95% CI = 1.12 to 3.70; 2 RCTs, 244 patients,
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11 RR = 4.17 95% CI = 2.11 to 8.25 and 10 RCTS, 948 patients, RR = 2.17, 95% CI = 1.34

12 to 3.50). Overall, the majority of these effects were gastrointestinal symptoms.

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13
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14 The reason that nitrofurantoin was selected in this study as the intervention was due to its
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15 long study history, decreased antibiotic resistance, low costs, safety profile, and site

16 specificity. The majority of recurrent UTIs are caused by reinfection of rectal origin
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17 involving recolonization of the vaginal introitus and the lower urinary tract.(16) This is

18 considered as one etiology of resistant bacterial strains. In fact, resistant strains emerged
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19 frequently in feces when sulfonamides were used in 66-77% of observations by Tovian,

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20 et al.(17) The mechanism of action of nitrofurantoin is not well established; however it

21 achieves therapeutically active concentrations only in the urinary tract. A drug with

22 urinary tract specificity is ideal because it does not adversely affect or causes changes in

23 normal flora. In our review, the randomized study by Mavromanolakis et al, assessed the
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1 effects of norfoxacin, trimethoprim, sulfamethoxazole, and nitrofurantoin on aerobic

2 intestinal flora and also found the flora was not affected by nitrofurantoin.(18) These

3 findings in recurrent UTI women were similar to the review by the North American

4 Urinary Tract Infection Collaborative Alliance (NAUTICA) of 1142 outpatient E. Coli

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5 strains in UTI patients from the USA and Canada between 2003 and 2014.(31) Only

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6 1.1% of the E. Coli strains were resistant to nitrofurantoin in comparison to 37.7% and

7 21.3% to ampicillin and trimethoprim-sulfamethoxazole, respectively.(19)

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8

9 Continuous, postcoital, or self-initiated antimicrobial prophylaxis therapy is the current

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mainstay of recurrent UTI treatment. Due to increasing antibiotic resistance, the need for
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11 other prophylactic treatments is great because some of these antimicrobials fail due to

12 resistant bacteria especially if bacterial resistance levels are high such as E. Coli
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13 resistance to quinolones.(20) Geerlings et al reviewed the current antimicrobial and non-

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14 antimicrobial strategies in prevention of recurrent urinary tract infections in women. In

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15 patients with reinfections, recommendations confirmed the reliability of self-diagnosis

16 and self-treatment of recurrences in premenopausal and postmenopausal recurrent UTI

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17 women.(12) In our studies, methenamine was used for one year in patients without (or

18 with) urinary tract abnormalities. The findings in our methenamine comparison studies
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19 were found to have no significant difference to nitrofurantoin in microbiological cure.

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20 The current recommendation for methenamine hippurate use is 1 week maximum to

21 prevent UTI in patients without urinary tract abnormalities.(12) In our search, we were

22 unable to identify studies comparing nitrofurantoin to cranberry products or lactobacillus

23 crispatus intravaginal suppositories as prophylactic agents in premenopausal women with

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1 recurrent UTIs. Moreover, we were unable to find studies comparing nitrofurantoin to

2 prophylactic oral capsules with L rhamnosus GR-1 and L reuteri RC-14 in

3 postmenopausal women with recurrent UTIs. Therefore, we cannot comment on these

4 agents.

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5

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6 The adverse effects of nitrofurantoin use when given in short duration, found by Huttner

7 et al, were similar to those found with long term prophylactic treatment found in our

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8 review.(21) The systematic review and meta-analysis of controlled trials of short term

9 nitrofurantoin UTI treatment composed of clinical trials published from 1946 to 2014

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assessing efficacy and adverse events for less than 14 days of nitrofurantoin treatment.
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11 Toxicity was an infrequent finding occurring in 5-16% of the 17 reporting studies.(21)

12 These adverse events were mild, reversible and predominantly gastrointestinal. The
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13 meta-analysis confirmed no difference between nitrofurantoin and comparators. There

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14 were no observations of hypersensitivity reactions such as pulmonary fibrosis or

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15 hepatotoxicity.(21) In our systematic review, the controlled clinical trials were published

16 from 1977 to 2007 and, in addition to assessing efficacy; we assessed adverse events for
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17 long term duration (6 months to 1 year) nitrofurantoin treatment. Adverse side effects

18 occurred in 0-29% of the 9 reporting studies. There was one case reported in the Raz
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19 study of pneumonitis.(22) There were no findings of death related to nitrofurantoin use

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20 in these control trials. Acute pulmonary reaction incidence has been estimated to be

21 anywhere from 1 in 550 to 1 in 5400 individuals.(23) Chronic pulmonary reaction to

22 nitrofurantoin is less common than acute pulmonary reactions. Lung involvement is

23 common in elderly women.(24, 25) Early recognition of its potential contribution to a

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1 patient's respiratory decline is important and presents with slow onset of dyspnea and

2 cough beginning 6 months to years after nitrofurantoin use. No study has documented the

3 role of preventive guidelines in the early detection of long-term nitrofurantoin related

4 adverse reactions and none have addressed the cost-effectiveness of additional

PT
5 monitoring tests.(26)

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6

7 Our review had limitations. The majority of the included trials focused on

SC
8 microbiological cure rather than clinical outcomes. We were not able to comment on

9 cost or antibiotic resistance due to our study design and available studies and therefore

10
U
there is no recommendation regarding an alternate regimen in regarding those areas. Our
AN
11 conclusions regarding nitrofurantoin safety profile is limited by the larger number of

12 nitrofurantoin studies and limited number of other interventions. Moreover, due to the
M

13 low number of subjects in the included trials severe outcomes such as development of
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14 acute or chronic pulmonary toxicity were inadequately assessed. The majority of the
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15 trials were old (published between 1977 and 2007). In an era of increasing antibiotic

16 resistance, this may compromise the extrapolation of the meta-analysis findings in current
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17 outpatient practice. A large number of the included trials did not have a blinded design

18 and limited information regarding allocation concealment was reported. Therefore,

C

19 selection bias might have influenced our findings. Due to the short follow up lengths of
AC

20 the studies, there was not enough information to make conclusions about antimicrobial

21 resistance with other agents. We do feel that the limitation of the number of current

22 studies is that the current first line of prophylactic antibiotics for recurrent UTIs are

23 generic and therefore funding for studying them would need to be provided.
 ACCEPTED MANUSCRIPT
20

2 There is a need for comparative studies regarding the current first line antibiotic

3 prophylactic therapies given the current increased antibiotic resistance. The NAUTICA

4 study which reported higher rates of antibiotic resistance in US versus Canadian

PT
5 outpatient urinary isolates demonstrates the continuing evolution of resistance to

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6 antimicrobial agents.(19) There are innovative prophylactic strategies of promise on the

7 horizon such as vaccines, certain lactobacillus species, and bladder instillations. In a

SC
8 study by Da vita et al, women with recurrent UTIs were randomized to intravesical

9 hyaluronic acid 800 mg and chondroitin sulfate 1 g in saline solution once weekly for 4

10
U
weeks then once every 2 weeks versus long term antibiotic prophylaxis using
AN
11 sulfamethoxazole 200 mg and trimethoprim 40 mg once weekly for 6 weeks with

12 findings of decreased cystitis recurrence (1± 1.2 versus 2±1.4 p = 0.2).(16) Given the
M

13 theory of direct site therapy to help restore the glycosaminoglycan layer with bladder
D

14 instillations, this bladder instillation regimen would be interesting to compare to the

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15 current treatment regimen of nitrofurantoin since it is an antimicrobial drug with urinary

16 tract specificity.
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17

18 There are many gaps in the literature that need to be addressed. Consistent definition of
C

19 recurrent UTI is important for clinical decisions, research, and quality measurement. In
AC

20 the studies included there were various definitions of UTI. It is recommended for future

21 studies to use the definition provided by ACOG which is defined as 2 uncomplicated

22 UTIs in 6 months or, more traditionally, as ≥ 3 positive cultures within the preceding 12

23 months. (11) Due to the short term of follow up, we could not analyze antibiotic
 ACCEPTED MANUSCRIPT
21

1 resistance. This is an opportunity for future studies to do long term prospective

2 resistance surveillance of bacteria with the current first line prophylactic antibiotic agents

3 in local practice or health care system levels in order to guide antimicrobial decisions.

4 There were also limited studies of subpopulations such as postmenopausal women, those

PT
5 with well controlled diabetes without urological sequelae, or the elderly. Moreover,

RI
6 limited studies reviewed the role of MRSA and recurrent UTIs in women. There were

7 multiple dosing regimens used for nitrofurantoin prophylaxis in the included studies and

SC
8 this gives opportunity for further trials to identify the regimen that achieves the best

9 clinical and microbiological cure rates while maintaining its tolerability.

10
U
AN
11 In conclusion, nitrofurantoin had similar efficacy, but greater risk of adverse events than

12 other prophylactic treatments. Balancing the risks of adverse events, particularly

M

13 gastrointestinal symptoms, should be considered if selecting nitrofurantoin for urinary

D

14 tract infection treatment. However, the overall clinical implications are not clear given
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15 the current studies and highlights the need for future well designed clinical trials in the

16 prevention of recurrent UTIs in women.

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17
18
C

19
20
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21
22
23

24 References
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1 1. Foxman B. The epidemiology of urinary tract infection. Nature Reviews Urology.

2 2010;7(12):653-60.

3 2. Schappert SM, Rechsteiner EA, National Center for Health Statistics (US). Ambulatory medical
4 care utilization estimates for 2006. . 2008.

5 3. Lugtenberg M, Burgers JS, Zegers-van Schaick JM, Westert GP. Guidelines on uncomplicated

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6 urinary tract infections are difficult to follow: perceived barriers and suggested interventions.
7 BMC family practice. 2010;11(1):1.

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8 4. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for
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10 women. Infectious Diseases Society of America (IDSA). Clin Infect Dis. 1999 Oct;29(4):745-58.

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11 5. Hooton TM, Besser R, Foxman B, Fritsche TR, Nicolle LE. Acute uncomplicated cystitis in an era
12 of increasing antibiotic resistance: a proposed approach to empirical therapy. Clinical infectious
13 diseases. 2004;39(1):75-80.

14
U
6. Kunin CM. Urinary tract infections in females. Clinical Infectious Diseases. 1994;18(1):1-10.
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15 7. Desforges JF, Stamm WE, Hooton TM. Management of urinary tract infections in adults. N
16 Engl J Med. 1993;329(18):1328-34.
M

17 8. Ikaheimo R, Siitonen A, Heiskanen T, Karkkainen U, Kuosmanen P, Lipponen P, et al.

18 Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of
19 179 women. Clin Infect Dis. 1996 Jan;22(1):91-9.
D

20 9. Foxman B, Barlow R, D'Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-reported
TE

21 incidence and associated costs. Ann Epidemiol. 2000;10(8):509-15.

22 10. Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent
23 urinary tract infection in women. Canadian Urological Association Journal. 2011;5(5):316-322.
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24 doi:10.5489/cuaj.11214.

25 11. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 91:
26
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Treatment of urinary tract infections in nonpregnant women. Obstet Gynecol. 2008

27 Mar;111(3):785-94.
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28 12. Geerlings SE, Beerepoot MA, Prins JM. Prevention of recurrent urinary tract infections in
29 women: antimicrobial and nonantimicrobial strategies. Infect Dis Clin North Am. 2014
30 Mar;28(1):135-47.

31 13. Nathan C, Cars O. Antibiotic resistance—problems, progress, and prospects. N Engl J Med.
32 2014;371(19):1761-3.

33 14. Kashanian J, Hakimian P, Blute M, Wong J, Khanna H, Wise G, et al. Nitrofurantoin: the
34 return of an old friend in the wake of growing resistance. BJU Int. 2008;102(11):1634-7.
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1 15. McDonagh MS, Jonas DE, Gartlehner G, Little A, Peterson K, Carson S, et al. Methods for the
2 drug effectiveness review project. BMC medical research methodology. 2012;12(1):1.

3 16. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents.
4 2001;17(4):259-68.

5 17. Toivanen A, Kasanen A, Sundquist H, Toivanen P. Effect of trimethoprim on the occurrence

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6 of drug-resistant coliform bacteria in the faecal flora. Chemotherapy. 1976;22(2):97-103.

7 18. Mavromanolakis E, Maraki S, Samonis G, Tselentis Y, Cranidis A. Effect of norfloxacin,

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8 trimethoprim-sulfamethoxazole and nitrofurantoin on fecal flora of women with recurrent
9 urinary tract infections. Journal of chemotherapy. 1997;9(3):203-7.

SC
10 19. Zhanel GG, Hisanaga TL, Laing NM, DeCorby MR, Nichol KA, Weshnoweski B, et al. Antibiotic
11 resistance in Escherichia coli outpatient urinary isolates: final results from the North American
12 Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents.
13 2006;27(6):468-75.

14
U
20. Omigie O, Okoror L, Umolu P, Ikuuh G. Increasing resistance to quinolones: A four-year
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15 prospective study of urinary tract infection pathogens. Int J Gen Med. 2009;2:171-5.

16 21. Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW.
17 Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob
M

18 Chemother. 2015 Sep;70(9):2456-64.

19 22. Raz R, Colodner R, Rohana Y, Battino S, Rottensterich E, Wasser I, et al. Effectiveness of

D

20 estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of

21 recurrent urinary tract infection in postmenopausal women. Clin Infect Dis. 2003 Jun
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22 1;36(11):1362-8.

23 23. Prakash UB. Pulmonary reaction to nitrofurantoin. Seminars in Respiratory Medicine;

24 Copyright© 1980 by Thieme Medical Publishers, Inc.; 1980.
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25 24. Israel K, Brashear R, Sharma H, Yum M, Glover J. Pulmonary Fibrosis and Nitrofurantoin 1–3.
26 Am Rev Respir Dis. 1973;108(2):353-6.
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27 25. Hainer BL, White AA. Nitrofurantoin pulmonary toxicity. J Fam Pract. 1981 Nov;13(6):817-23.
AC

28 26. Rego LL, Zimmern PE. Regular Monitoring of Older Women on Long-term Nitrofurantoin
29 Prophylaxis—What Does it Mean Practically? Urology Practice. 2016;3(1):7-11.

30 27. De Vita D, Giordano S. Effectiveness of intravesical hyaluronic acid/chondroitin sulfate in

31 recurrent bacterial cystitis: a randomized study. International urogynecology journal.
32 2012;23(12):1707-13.

33 28. Brumfitt W, Hamilton-Miller JM, Smith GW, al-Wali W. Comparative trial of norfloxacin and
34 macrocrystalline nitrofurantoin (Macrodantin) in the prophylaxis of recurrent urinary tract
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24

1 infection in women. Q J Med. 1991 Oct;81(294):811-20.

2 29. Kasanen A, Junnila SY, Kaarsalo E, Hajba A, Sundquist H. Secondary Prevention of Recurrent
3 Urinary Tract Infections: Comparison of the Effect of Placebo, Methenamine Hippurate,
4 Nitrofurantoin and Trimethoprim Alone. Scand J Infect Dis. 1982;14(4):293-6.

5 30. Brumfitt W, Cooper J, Hamilton-Miller JM. Prevention of recurrent urinary infections in

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6 women: a comparative trial between nitrofurantoin and methenamine hippurate. J Urol. 1981
7 Jul;126(1):71-4.

8 31. Brumfitt W, Hamilton-Miller J. A comparative trial of low dose cefaclor and macrocrystalline

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9 nitrofurantoin in the prevention of recurrent urinary tract infection. Infection. 1995;23(2):98-
10 102.

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11 32. Brumfitt W, Smith GW, Hamilton-Miller JM, Gargan RA. A clinical comparison between
12 Macrodantin and trimethoprim for prophylaxis in women with recurrent urinary infections. J
13 Antimicrob Chemother. 1985 Jul;16(1):111-20.

U
14 33. Scherwin J, Holm P. Long-term treatment with sulphamethoxazole/trimethoprim (Bactrim®)
15 and nitrofurantoin in chronic urinary tract infections. Chemotherapy. 1977;23(4):282-8.
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16 34. Vahlensieck Jr W, Westenfelder M. Nitrofurantoin versus trimethoprim for low-dose long-
17 term prophylaxis in patients with recurrent urinary tract infections. Int Urol Nephrol.
18 1992;24(1):3-10.
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19 35. Nunez U, Solis Z. Macrocrystalline nitrofurantoin versus norfloxacin as treatment and

20 prophylaxis in uncomplicated recurrent urinary tract infection. Current therapeutic research.
21 1990;48(2):234-45.
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22 36. Raz R, Boger S. Long-term prophylaxis with norfloxacin versus nitrofurantoin in women with
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23 recurrent urinary tract infection. Antimicrob Agents Chemother. 1991 Jun;35(6):1241-2.

24 37. Raz R, Colodner R, Rohana Y, Battino S, Rottensterich E, Wasser I, et al. Effectiveness of

25 estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of
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26 recurrent urinary tract infection in postmenopausal women. Clin Infect Dis. 2003 Jun
27 1;36(11):1362-8.

28 38. Stamey TA, Condy M, Mihara G. Prophylactic efficacy of nitrofurantoin macrocrystals and
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29 trimethoprim-sulfamethoxazole in urinary infections: biologic effects on the vaginal and rectal

30 flora. N Engl J Med. 1977;296(14):780-3.
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31 39. Ruxer J, Mozdzan M, Loba J, Markuszewski L. Fosfomycin, co-trimoxazole and nitrofurantoin

32 in the treatment of recurrent uncomplicated urinary tract infections in type 2 diabetes mellitus.
33 Wiad Lek. 2007;60(5-6):235-40.

34

35
36
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26

1
2

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3
4

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5
6
7 Table 1

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8 Characteristics of included studies
First Study Study Inclusion Exclusion Antibiotic Compared Group(s) (dosage, Follow up Study Results
author, year design, Population Criteria Criteria Group A duration) after
location,

U
(dosage, prophylaxis
setting duration) start

AN
Brumfitt, Single blind Women At least four History of allergy Macrocrystalline Norfloxacin 18 mo Number of
1991 RCT, (mean age UTI attacks to a quinolone, nitrofurantoin (200 mg QHS, 12 mo) symptomatic
London, Group A 38.9 ; in the nitrofurantoin, or (100 mg QHS, UTIs:
Royal Free Group B 37.2) preceding 12 to multiple agents, 12 mo)

M
Hospital, months with pregnancy, high Nitrofurantoin;
Urinary at least one possibility of death 31
Infection documented in the near future, Norfloxaccin;

D
Clinic urine culture acute 30
^5
10 CFU. hematopoietic
disease or Mean interval

TE
chemotherapy for between
any malignancy; infections:
GFR < 30 ml/min
EP
Nitrofurantoin 422
days
Norfloxacin
485 days
C
AC
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27

Kasanen, RCT, Women and Three or No UTI Macrocrystalline Group B: methanamine 12 mo Percentage of
1982 Finland, Men more UTI nitrofurantoin (1 g QHS, 12 mo) recurrence
(mean age infections (75 mg QHS, 12
Regional Group A 48.2; during the mo) Group C: trimethoprim Nitrofurantoin:

PT
Hospital of Group B 49.7; last year (100 mg QHS, 12 mo) 25.0
Loimaa, Group C 52.1; Methanamine:
Outpatient Group D 51.1) Group D: placebo tablet 34.2

RI
clinic (1 g QHS, 12 mo) Trimethoprim:
Gender, % 10.4
Turku female: 97% Placebo: 63.2

SC
University,
Nephrological
Outpatient
Clinic

U
Brumitt, RCT, Women At least three No UTI Nitrofurantoin Methanamine hippurate 12 mo The mean interval
1980 London, (mean age UTI attacks (50 mg QHS, 12 (1 g Q 12 hours, 12 mo) between

AN
Royal Free Group A 35.9 in the mo) symptomatic UTI
Hospital, ±16.7; preceding 12 episodes:
Urinary Group B 31.3 months with
Infection ±13.2) at least one Nitrofurantoin

M
Clinic documented 358.5 days
urine culture Methanamine
Hippurate

D
157 days

TE
Mean interval
between
bacteriuria
episodes:
EP
Nitrofurantoin
1936 days
Methanamine
C

Hippurate
640 days
AC
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28

Brumfitt Double blind Women At least four Known allergy or Macrocrystalline Cefaclor 12 mo Mean interval
1995 RCT, (median age UTI attacks intolerance to nitrofurantoin (250 mg QHS, 12 mo) between
London, Group A 45 (20- in the cephalosporin, (50 mg QHS, 12 symptomatic UTI
Royal Free 90); preceding 12 nitrofurantoin, or mo) episodes:

PT
Hospital, Group B 40 (18- months with renal insufficiency
Urinary 89) at least one (serum creatinine Nitrofurantoin 241
Infection of these ≥ 133 µmol/l) days;

RI
Clinic episodes Cefaclor 265
with growth days;
4
of ≥ 10 CFU

SC
in the Bacteriuric
presence of episodes:
pyuria and
symptoms Nitrofurantoin 12

U
Cefaclor 13

AN
M
D
TE
Brumfitt RCT, Women History of at No UTI Macrocrystalline Trimethoprim 12 mo Mean interval
1985 London, (mean age least three nitrofurantoin (100 mg QHS, 12 mo) between
Group A 40.9 attacks of (100 mg QHS, symptomatic
Royal Free ±18.5; urinary 12 mo) episodes:
EP
Hospital, Group B 37.6 ± infection in
Urinary 18.2 the previous Nitrofurantoin
Infection 12 months. 296.4 days
Clinic At least one Trimethoprim
C

episode 215.9 days

Royal Free required
AC

Hospital unequivocal Mean interval

School of laboratory between
Medicine, confirmation bacteriuric
Department episodes
of Medical
Microbiology Nitrofurantoin
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29

219.3 days
Trimethoprim
362 days

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RI
U SC
Scherwin CT, Denmark Women and History of Current UTI Nitrofurantoin Sulphamethoxazole/trimethoprim 12 mo Completion of the

AN
1977 Men two (100 mg QID, 1 (S/T) 12-month
Aarhus (median age 82, significant Serum creatinine week followed (400mg/80mg BID 1 week treatment period
Kommune range 50-96) bacteriuria < 2 mg% by 50 mg TID, followed by 400/80 QD, 12 mo) with persistent
5
Hospital, (>10 on two 12 mo) sterile urine

M
Department Gender, % successive outcome:
of Geriatrics female: 87% examinations 1 out of 13
Clinic of midstream patients on

D
urine nitrofurantoin
sensitive 12 out of 17

TE
intervention) patients in the S/T
group
Current UTI
EP
Vahlensieck RCT, Women and More than No UTI Nitrofurantoin Trimethoprim 6 mo Nitrofurantoin
1991 Germany men three UTIs (50 mg QHS, 6 (50 mg QHS, 6 mo) recurrence rate of
(median age every year Known allergies mo) 0.01 UTI per
C

Department Group A 43, to the test drugs, patient year

of Urology range 21-75; pregnancy,
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Clinic, Group B: 35, breast feeding, Trimethoprim

University of range 20-55) neuritis, liver recurrence rate of
Munchen insufficiency, renal 0.03 UTI per
Gender, % insufficiency, patient year
female: 95% porphyria,
glucose-6-
 ACCEPTED MANUSCRIPT

30

phosphate-
dehydrogenase
deficiency,
Stevens- Johnson

PT
syndrome, Lyell
syndrome,
exfoliative

RI
dermatitis,
thrombocytopenia,
leukopenia,

SC
anemia,
morphological or
functional
alterations of the

U
urinary tract, and
no possibility for

AN
6-month
compliance

Nunez Single-blind Women History of at Antimicrobial Macrocrystalline Norfloxacin 6 mo Nitrofurantoin

M
1990 RCT, Peru (mean age least two treatment during nitrofurantoin (400 mg BID x 10 days followed Clinical plus
Group A 44.7 ± UTIs during the previous 48 (100 mg QID x by 400 mg QHS, 6 mo) bacteriologic cure
Hospital 12.1 the previous hours, 10 days rate was

D
Arzobispo Group B 45.6 ± 12 months pyelonephritis, followed by 100 maintained at
Loayza, 11.2 ) (verified by urogenital mg QHS, 6 mo) 92.9% (26/28)

TE
Outpatient medical obstructive
clinic records) disease, venereal Norfloxacin :
disease, Clinical plus
Childbearing associated illness bacteriologic cure
EP
subjects on that might rate was
contraception interfere with the maintained at
for 6 mo evaluation of the 79.3% (23/29)
C

study
Current UTI medications,
AC

hypersensitivity to
study drugs, liver
disease, impaired
renal function,
nursing
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31

Raz RCT, Israel, Women History of Pregnant women Nitrofurantoin Norfloxacin 6 mo Nitrofurantoin: 3
1991 Zamenhoff (mean age three or more or planning (50 mg QHS, 6 (200 mg QHS, 6 mo) episodes per 6
Outpatient Group A 54.6 documented pregnancy mo) months to 0.3
Clinic Group B 51.2) episodes of episode per

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UTI during 6 months after
the last 6 prophylaxis
months

RI
Norfloxacin: 3.1
episodes per 6
months before

SC
treatment to 0.02
episode per 6
months after
prophylaxis

U
AN
M
D
TE
C EP
AC
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Raz RCT, Israel, Postmenopausal History of History of any Nitrofurantoin Estriol 9 mo Nitrofurantoin : 0.6
2003 Outpatient Women recurrent UTI HRT in the (100 mg QHS + (estriol-containing (0.5 mg) episodes per
clinic (mean age (defined as 3 previous year, sex placebo vaginal vaginal pessary woman and 0.8
Group A:66.9 ± or more hormone- pessary daily daily for 2 weeks and then once episodes per

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7.9 confirmed dependent for 2 weeks, every 2 weeks for 9 months patient per year.
Group B: 68 symptomatic malignancy, followed by together with oral placebo
±S.D. 7.2 episodes of current placebo capsules QHS, 9 mo) Estriol : 1.6

RI
UTI in the malignancy, pessary every 2 episodes of UTI
last year or vaginal bleeding, weeks, 9 mo) per woman and 2
at least 2 in active or recent episodes per

SC
the last 6 thromboembolic woman per year
months) disease,
indwelling
catheter, known

U
urinary retention
(PVR> 150 mL),

AN
long-term (2
weeks’ duration)
receipt of
antibiotic therapy

M
in the past 3
months, functional
or anatomic

D
abnormality of the
urogenital tract,

TE
DM, severe renal
or liver failure,
allergy to
nitrofurantoin.
C EP
AC
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33

Stamey CT, USA, Women History of Current UTI Macrocrystalline Trimethoprim-Sulfamethoxazole 12 mo Number of
1980 Outpatient (median age 36, three or more Nitrofuranotin (UTI Treatment for 10 days, recurrences
clinic range of 19-67) UTIs in the (UTI Treatment followed by 40 mg trimethoprim,
preceding 12 for 10 days, 200 mg sulfamethaxole QHS, 6 Nitrofurantoin:

PT
months were followed by 100 mo) 9
included mg QHS, 6 mo)
Trimethoprim-

RI
Sulfamethoxazole:
10

U SC
Ruxner RCT, Poland, Women History of 3 Current UTI not Macrocrystalline Group B: 9 mo Clinical and

AN
2007 Diabetes (median age UTI incidents sensitive to study Nitrofurantoin trimethoprim/sulfamethoxazole microbiological
Outpatient group A: in the last 12 agents, serum (100 mg q 12 (T/S) cure
clinic 58.9±6.8 months and creatinine greater hours x 7 days, (80/400 every 12 hours x 14
Group B: current than 1.5 mg/dl; then 100 mg days, then QHS, 6 mo) Nitrofurantoin: 20

M
60.7±9.0 bacteriuria the concentration QHS, 6 mo) Group C: T/S: 21
Group C: (10^5 CFU) of ALT, AST 2 fold fosfomycin (3 g x1, then 3 g q 30 Fosfomycin: 24
61.1±8.6) sensitive to exceeding the days, 6 mo)

D
study agents norm, bilirubin
above 1.3 mg/dl,

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kidney stones
diagnosed by
ultrasound,
complications of
EP
late diabetes,
hematological
disease,
alcoholism
C

1
2
AC

3
4
5
6
7
8
9
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1 Table 2: Quality Assessment of included studies

2
Acceptable

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Group Assessors Outcomes level of Overall
Study Randomization Concealment Selection
Comparability blinding Intention to overall quality
Criteria
treat attrition

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(≤30%)
Acceptable

SC
level of
differential
attrition

U
(<10%)
Brumfitt, Yes Yes Inclusion yes Yes No No Overall Yes Fair

AN
1991 Exclusion yes Differential
Yes

M
D
Kasanen,
1982
Yes Not clear
TE
Inclusion yes
Exclusion yes
Yes NR Yes Overall Not
clear
Fair to
Poor
EP
Differential
Not Clear
C
AC
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Brumfitt, Yes Not clear Inclusion yes Yes NR No Overall Yes Fair
1980 Exclusion yes Differential
Yes

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RI
SC
Brumfitt, Yes Yes Inclusion yes Yes No No Overall Yes Fair
1995 Exclusion yes Differential

U
Yes

AN
M
D
Brumfitt, Yes Not clear Inclusion yes Yes No No Overall Yes Fair
1985 Exclusion yes Differential

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EP Yes
C
AC
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Scherwin, No Not clear Inclusion yes Not clear No No Overall No Poor

1977 Exclusion yes Differential No

PT
RI
SC
Vahlensieck, Yes Not clear Inclusion yes Yes NR Yes Overall No Fair
1991 Exclusion yes Differential No

U
AN
M
D
Nunez, Yes Not clear Inclusion yes Yes No Yes Overall Yes Fair
1990 Exclusion yes Differential No

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AC
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Raz, Yes No Inclusion yes Yes NR No Overall Yes Fair

1991 Exclusion yes Differential
Yes

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RI
SC
Raz, Yes Yes Inclusion yes Yes Yes Yes Overall Yes Good
2003 Exclusion yes Differential

U
Yes

AN
M
D
Stamey, No No Inclusion yes Not clear NR No Overall Yes Poor
1980 Exclusion yes Differential not

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EP clear
C
AC
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Ruxer, Yes No Inclusion yes Yes NR No Overall Yes Fair

2007 Exclusion yes Differential
Yes

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RI
SC
1
2 NR: Not Reported
3

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4
5 Table 3: Summary of Drug Adverse Events

AN
6
7
Reported Adverse Events Nitrofurantoin Norfloxacin Methanamine Trimethoprim Trimethoprim- Pessary

M
Sulfamethoxazole Estriol

GI 65 49 4 5 0 0

D
TE
Oral/Vaginal Candidiasis/Vaginal Complaints 9 EP 10 0 4 0 12

Rash 8 5 1 2 0 0
C

Arthralgia/myalgia 1 10 0 0 0 0
AC

Pneumonitis 1 0 0 0 0 0
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Allergic 2 1 0 0 0 0

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Headache 5 0 1 0 0 0

RI
Other 8 2 5 0 0 2

SC
Unrelated Death 2 0 0 0 1 0

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1
2

AN
3
4 FIGURE LEGENDS
5
6 Figure 1. PRISMA flow diagram of the literature reviewing process

M
7
8 Figure 2. Relative Risk Meta-Analysis for Microbiological Cure
9

D
10 Figure 3. Relative Risk Meta-Analysis for Overall Side Effects
11

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12 Figure 4. Microbiological Cure Bias Assessment of Studies
13
14
15
EP
16
17
18
19
C

20
21
AC

22
23
24
25
26
27
28
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M
D
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C
AC
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AN
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D
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C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC