Accepted Manuscript

Nitrofurantoin’s efficacy and safety as prophylaxis for urinary tract infections: a

systematic review of the literature and meta-analysis of controlled trials

Anouk E. Muller, Els M. Verhaegh, Stephan Harbarth, Johan W. Mouton, Angela

Huttner

PII: S1198-743X(16)30304-4
DOI: 10.1016/j.cmi.2016.08.003
Reference: CMI 682

To appear in: Clinical Microbiology and Infection

Received Date: 7 June 2016

Revised Date: 3 August 2016
Accepted Date: 6 August 2016

Please cite this article as: Muller AE, Verhaegh EM, Harbarth S, Mouton JW, Huttner A, Nitrofurantoin’s
efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature
and meta-analysis of controlled trials, Clinical Microbiology and Infection (2016), doi: 10.1016/
j.cmi.2016.08.003.

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 ACCEPTED MANUSCRIPT
1 Nitrofurantoin’s efficacy and safety as prophylaxis for urinary tract infections: a

2 systematic review of the literature and meta-analysis of controlled trials

4 Anouk E. Muller1, Els M. Verhaegh2, Stephan Harbarth3, Johan W. Mouton4, Angela Huttner3

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5 Medical Centre Haaglanden-Bronovo, The Hague, The Netherlands

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2
6 Laboratory of Medical Microbiology and Immunology, St Elisabeth Hospital, Tilburg, The

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7 Netherlands

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8 Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva,

9 Switzerland
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10 Dept. of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
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12 Corresponding author: Anouk E. Muller, muller.research@gmail.com, Medical Centre Haaglanden-

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13 Bronovo, The Hague, The Netherlands

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14 Key words: nitrofurantoin, prophylaxis, urinary tract infection, toxicity, meta-analysis

15 Word count (Main text): 2,699

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16 Running title: Nitrofurantoin for UTI prophylaxis: review and meta-analysis

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18 Abstract

19 Objectives. Nitrofurantoin has been used for the prevention of urinary tract infection (UTI) for over

20 60 years. We conducted a systematic review and meta-analysis to assess nitrofurantoin’s efficacy and

21 safety in the prophylaxis of UTI.

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22 Methods. We performed a systematic review of all human controlled trials assessing nitrofurantoin

23 for UTI prophylaxis published from 1946 to 2015. We further reviewed population-level cohort

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24 studies evaluating nitrofurantoin’s toxicity. Meta-analyses assessing efficacy and adverse events

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25 were conducted on controlled trials.

26 Results. Twenty-six controlled trials including 3052 patients fulfilled entry criteria for the systematic

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review and meta-analysis on efficacy and toxicity, and 16 population-level cohort studies were
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28 identified for review of toxicity. Overall quality was poor, with all studies at increased risk for various

29 biases. When compared to no prophylaxis, nitrofurantoin is effective in the prevention of UTI (risk
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30 ratio 0.38 in favour of nitrofurantoin, 95% CI 0.30 – 0.48). Its prophylactic efficacy is superior to that
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31 of methenamine hippurate and comparable to that of other antibacterials. Compared to those

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32 receiving other antibacterials, patients receiving nitrofurantoin had an increased risk of 2.24 (95% CI

33 1.77 – 2.83) for a non-severe side effect. In all controlled trials, only one patient experienced a severe
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34 side effect (interstitial pneumonia). Cohort studies reported severe side effect frequencies of 0.02-

35 1.5 per 1000 nitrofurantoin users.

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36 Conclusions. Nitrofurantoin is effective in the prevention of UTI. Its use may be associated with
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37 increased non-severe side effects; severe side effects occur infrequently. The risk of severe toxicity

38 seems to increase with the duration of nitrofurantoin prophylaxis.

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40 Introduction

41 After its FDA approval in 1953, nitrofurantoin became standard therapy for lower urinary tract

42 infections (UTI) until the late 1970s, when other antibiotics became available and its use decreased

43 substantially. In 2011, however, the drug was again recommended as first-line therapy for lower UTI

44 due to increasing resistance to newer antibiotics, such as fluoroquinolones [1].

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45 There is now great interest in this old antibiotic, about which much information is still lacking

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46 [2]. Approved before requirements for rigorous methods for drug development, nitrofurantoin’s

47 optimal dosing remains unknown, as does its overall safety profile. In a recent meta-analysis, we

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48 reviewed nitrofurantoin’s clinical and microbiologic efficacy and toxicity when given short-term (≤14

49 days) for therapy of acute lower UTI [3], but this antibiotic is frequently given for months or years at

50
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a time as UTI prophylaxis. The clinical effectiveness of prophylactic nitrofurantoin has been studied in
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51 several trials with small numbers of patients, but to our knowledge no meta-analysis has pooled and
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52 compared these results.

53 Equally important, this drug is known for severe and at times irreversible side effects, the
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54 most feared among them pulmonary fibrosis and hepatitis [4, 5]. Yet their actual incidence remains
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55 opaque: almost all descriptions of severe toxicity are single case reports and thus possibly result

56 from, and drive, a significant publication bias. Indeed, in 1985 D’Arcy reviewed the major adverse
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57 drug reactions to nitrofurantoin from published reports as well as information submitted worldwide

58 to the developers of the drug, Norwich-Eaton Pharmaceuticals, by all manufacturers from all sources
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59 [6]. Calculated frequencies for all pulmonary reactions combined and hepatic toxicity were
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60 surprisingly low, at 0.001% and 0.0003% of nitrofurantoin courses, respectively [6]. Yet some

61 clinicians continue to question these calculations, as, anecdotally, many of those prescribing this

62 drug have witnessed one or more cases of severe toxicity.

63 The aim of this study is thus to examine the clinical effectiveness and evidence-based

64 incidence of toxicity of nitrofurantoin when administered as prophylaxis for UTI.

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66 Methods

67 Using the MeSH descriptor ‘nitrofurantoin’, two reviewers (A.H. and E.V.) searched the MEDLINE,

68 EMBASE and Cochrane Library databases for all published material from 1946 to August 2015. There

69 were no language restrictions; Preferred Reporting Items for Systematic Reviews and Meta-Analyses

70 guidelines were followed [7].

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71 Entry criteria for the systematic review on efficacy and toxicity

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72 For the systematic review of the efficacy of long-term or short-term, prophylactic nitrofurantoin, only

73 human controlled clinical studies, whether randomized or not, were included. Studies evaluating

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74 nitrofurantoin as treatment for active UTI were excluded. Studies were divided in groups based on

75 duration of prophylaxis and no distinction was made regarding the use of nitrofurantoin for primary

76
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vs secondary prophylaxis vs pre-emptive treatment of UTI. For the systematic review of toxicity,
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77 uncontrolled and/or observational human cohort studies were also included in a separate search in
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78 an effort to maximize information yield (including pharmacovigilance reports). For all included trials

79 and cohorts, there were no restrictions on the duration of prophylaxis. Detailed entry criteria for the
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80 efficacy review are shown in Table 1.

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81 Outcomes

82 The primary outcome of interest is nitrofurantoin’s efficacy in the prevention of UTI as defined by the
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83 respective studies. Of note, some earlier studies required only the presence of bacteriuria for UTI
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84 (see supplementary data). Secondary outcomes, also assessed according to the definitions used in
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85 the studies, are the incidence of adverse events (AE) and patient-reported outcomes (symptoms,

86 quality of life). All AE were evaluated, but emphasis was placed on data specifically pertaining to

87 pulmonary and hepatic toxicity, hospital admissions and death, skin findings (including severe

88 reactions such as Stevens–Johnson syndrome), haematological and neurological events (in particular

89 peripheral neuropathy), and gastrointestinal events (nausea, vomiting, abdominal pains, diarrhoea).

90 When available, results of intention-to-treat (ITT) analyses were preferentially extracted over those

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91 of per-protocol analyses. The emergence of resistance among uropathogens during antibiotic

92 prophylaxis was assessed whenever these data were reported.

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94 Data extraction for the systematic review of efficacy and toxicity

95 All article abstracts and/or main texts were reviewed independently by A.M. and E.V. against entry

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96 criteria for the review’s primary and secondary outcomes of nitrofurantoin efficacy and toxicity,

97 respectively. Both authors then independently conducted data abstraction of the final sample,

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98 examining and recording the trial characteristics and outcomes using a pre-designed data abstraction

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99 form for information pertaining to trial demographics, intervention, comparator(s), methodology,

100 outcomes and overall quality. Reviewers’ results were then crosschecked for reliability.

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101 Disagreement on an article led to its review by a third author (J.M.); consensus was reached by
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102 discussion among all authors.

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104 Risk of bias and quality assessment

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105 A.M. and E.V. independently assessed the quality of studies using the Cochrane Collaboration’s tool
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106 for assessing risk of bias [8]. Inter-rater reliability was assessed by means of inter-rater agreement

107 percentages and kappa values. All studies meeting entry criteria for efficacy and toxicity evaluation
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108 were included regardless of quality.

109
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110 Meta-analyses of controlled trials

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111 Meta-analyses were performed using Review Manager (version 5.3, Nordic Cochrane Centre,

112 Cochrane Collaboration, Copenhagen 2014). Risk ratios (RR) for dichotomous data (microbiological

113 cure, clinical cure and AE) were calculated for individual trials with 95% CIs. Heterogeneity in trial

114 results was assessed using the I2 measure of inconsistency. When I2 was ≤30% of the total analysis we

115 used a fixed-effects model; otherwise a random-effects model was used [8]. Only studies reporting

116 the number of patients with at least one UTI or bacteriuria (numerator) in relation to the total

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117 number of patients included in the study (denominator) could be included in meta-analyses. Initially

118 all controlled trials were included, independent of the antibiotic used as comparator and of

119 respective dosing regimens; we then excluded studies that did not disclose the exact number of

120 patients in the two arms of the comparison. Sensitivity analyses were performed based on various

121 selections of randomized controlled trials in separate analyses.

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122

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123 Results

124 Results of the systematic search of the literature for trials on nitrofurantoin’s efficacy in UTI

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125 prophylaxis are shown in Figure 1. Of 3,787 articles on nitrofurantoin, 209 were human clinical trials.

126 Ultimately 26 of these fulfilled review entry criteria.

127
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These were published between 1971 and 2014 and tested nitrofurantoin either as long-term
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128 prophylaxis for UTI (n=20) [9-28] or as short-term (3-14 days) prophylaxis after surgery (n=6) [29-34].
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129 In the latter studies, surgeries were mainly for urogenital tract abnormalities or transurethral

130 prostate resection; only adults were included; and efficacy of prophylaxis was evaluated upon its
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131 discontinuation. In the other 20 trials, nitrofurantoin durations were longer (range 14 days – 24
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132 months) [9-28]; adults and children were included, and efficacy outcomes were measured while

133 prophylaxis was ongoing. Among all 26 trials, 21 (81%) were randomised and 7 (27%) were double-
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134 blind. Detailed summaries of included trials can be found in the supplementary material (Table S1).

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136 Risk-of-bias assessments and inter-rater agreement

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137 Inter-rater agreement was high, with 100% agreement (κ, 1.0) in overall quality assessment and 89-

138 100% agreement (κ, 0.78 – 1.0) in risk-of-bias assessments (Table S2). Both reviewers found the

139 majority of the studies to be of poor quality; only five of the 26 (19%) were deemed good or fair. All

140 studies were judged to be at risk for at least one bias; two were at risk for all major biases evaluated.

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142 Efficacy of nitrofurantoin prophylaxis in the prevention of UTI

143 Twenty-six studies were included in the meta-analysis; summaries of each are found in Table S1. In a

144 meta-analysis (Figure 2) of trials comparing nitrofurantoin prophylaxis of any duration (n=571) to

145 placebo or no prophylaxis (n=837), the relative risk (RR) for UTI occurrence among nitrofurantoin

146 recipients was significantly reduced (RR 0.38 in favour of nitrofurantoin, 95% CI 0.30 – 0.48), with no

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147 heterogeneity (I2= 0%). When durations were assessed separately, risk remained similarly decreased

148 (0.39 [95% CI 0.27 – 0.56] and 0.38 [95% CI 0.28 – 0.50, both in favour of nitrofurantoin] for short-

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149 term and long-term prophylaxis, respectively).

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150 While a meta-analysis comparing short-term nitrofurantoin prophylaxis (n=115) to other

151 antibiotics (n=210) yielded some differences in efficacy for the three subgroups of comparators,

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152 none were significant (Figure 3). Similarly, the meta-analysis comparing long-term nitrofurantoin
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153 prophylaxis (n=511) to other antibacterials (n=808) yielded no significant differences (overall RR 0.93

154 in favour of nitrofurantoin [95%CI 0.69-1.26], except for the subgroup of patients receiving the
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155 antiseptic methenamine hippurate [RR 0.6 in favour of nitrofurantoin, 95% CI 0.43 – 0.85, p=0.004,
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156 heterogeneity I2=0%]; Figure 4). A meta-analysis was performed to address potential differences in
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157 nitrofurantoin dosing regimens for long-term prophylaxis in adult patients (100 mg qd, 75 mg qd,

158 50mg qd and 50 mg bid); no significant differences were observed (p=0.08, I2=53%). In analyses for
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159 both short- and long-term nitrofurantoin prophylaxis, prophylaxis with a quinolone trended toward

160 superior clinical outcomes, but results were not significant probably because of the limited number
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161 of patients included.

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162 The number needed to treat to prevent one patient with UTI was derived from the meta-

163 analysis on the effect of nitrofurantoin compared to placebo or no prophylaxis. For short-term (3-14

164 days) or long-term (>14 days) prophylaxis, 8 or 3 patients would need nitrofurantoin prophylaxis to

165 prevent UTI in one patient, respectively. Irrespective of the duration of prophylaxis, 4 patients would

166 require prophylaxis to prevent UTI in one patient [9, 11, 19, 22, 23, 26-31, 33, 34]. Of note, because

167 they did not report incidences as the studies included in the meta-analyses, four controlled trials

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168 could not be included in meta-analyses but were consistent with meta-analysis findings (see

169 Supplement) [35-38].

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171 Toxicity of nitrofurantoin prophylaxis

172 Severe toxicity

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173 In the 17 controlled trials reporting outcomes of the efficacy of long term prophylaxis (median

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174 duration of planned nitrofurantoin prophylaxis six months [range 3–24 months]), only one of 511

175 patients (0.2%; 95% CI <0.01 – 1.2%) experienced a severe side effect: an interstitial pneumonia was

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176 diagnosed at month 37 of prophylaxis (after the official end of the study period) and resolved fully

177 after nitrofurantoin discontinuation [28]. No patient receiving short-term prophylaxis experienced

178 severe toxicity.

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179 The 16 observational, population-level cohort studies reporting severe nitrofurantoin toxicity
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180 over time are summarised in Table S3. They were of varying quality; only one included prospectively

181 collected data. In most, durations of prophylaxis and follow-up were not reported. The frequency of
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182 combined severe AE as defined in the respective studies ranged from 0.02 to 1.5 events per 1000
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183 nitrofurantoin users [6, 39-49]. Pulmonary AE were almost always aggregated then divided into

184 acute, subacute, chronic and miscellaneous reactions. Acute reactions were reported most
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185 frequently (0.13-0.9 AE per 1000 nitrofurantoin users [6, 46, 50]. Only one study examined

186 pulmonary fibrosis as an individual entity in patients with prolonged nitrofurantoin use: 1.3 events
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187 per 1000 nitrofurantoin users were reported [46]. One study reported an increased incidence of
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188 serious side effects with longer durations of prophylaxis. The incidence was 1/24,800 prescriptions

189 for ≤ 1 month’s duration and 1/577 – 1/862 prescriptions for > 4 months’ duration [48].

190 Only three studies reported frequencies of liver-related AE; ratios of hepatic events to

191 patients taking nitrofurantoin were 1:1369 [47], 1:3000-5000 [45], and 1:8064 [43]. For pulmonary

192 events the numbers also varied, with event-to-treated patient ratios of 1:667 [39] and 1:5000, the

193 latter figure specifically for first-time users of the drug [46].

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194

195 Non-severe side effects of nitrofurantoin prophylaxis

196 The meta-analysis on non-severe side effects such as nausea, vomiting, pruritus and headache was

197 performed on the 14 controlled studies assessing AE; all of these were long-term prophylaxis studies

198 (Figure 5). Overall, nitrofurantoin (n=503) was associated with increased side effects in comparison

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199 with other antibiotics (RR 2.24 in favour of the control, 95% CI 1.77–2.83, p<0.00001, heterogeneity

200 I2=7%). This effect was significant for four of the six subgroups: the beta-lactams (RR 1.98, 95%CI 1.19

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201 – 3.32, p=0.009, heterogeneity I2=32%), trimethoprim (RR 2.2 95% CI 1.51–3.20, p=<0.0001,

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202 heterogeneity I2=0%), methenamine hippurate (RR 4.22 95% CI 2.06–8.67, p<0.0001, heterogeneity

203 I2=0%), trimethoprim/sulfamethoxazole (RR 2.17, 95% CI 0.16-29.1, p=0.56, heterogeneity I2= not

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204 applicable) and D-mannose powder (RR 3.71, 95% CI 1.68–8.19, p=0.001, heterogeneity I2= not
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205 applicable) all in favour of the controls. Only the quinolones appeared comparable to nitrofurantoin

206 (p=0.26).
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207
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208 Emergence of resistance

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209 The emergence of resistance among uropathogens during antibacterial prophylaxis was not

210 systematically assessed as an outcome in the controlled studies (Table S1). In the small randomised
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211 trial by Schlager and others, weekly urine cultures in children receiving nitrofurantoin prophylaxis
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212 demonstrated the gradual replacement of Escherichia coli by resistant strains such as Klebsiella and
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213 Pseudomonas spp., though these caused no infections. No similar change was seen in children

214 receiving placebo [11]. In the Brendstrup trial comparing nitrofurantoin to trimethoprim prophylaxis

215 in children over six months, six of the 67 (9%) children randomised to nitrofurantoin carried strains

216 resistant to it at baseline; during prophylaxis, 4/60 (7%) had at least one resistant bacterium. In

217 contrast, while five of the 63 (8%) patients receiving trimethoprim carried bacteria resistant to this

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218 drug at baseline, 28/60 (47%) harboured a trimethoprim-resistant bacterium by the study’s end [16].

219 No other studies provided both baseline and follow-up microbiologic data.

220

221 Discussion

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222 Systematic review and meta-analyses indicate that nitrofurantoin’s efficacy as prophylaxis against

223 UTI is comparable to that of other antibiotics and superior to that of the antiseptic methenamine

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224 hippurate and placebo. This is in line with the Cochrane review on antibiotics for preventing UTI in

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225 non-pregnant women [51], concluding that antibiotic intake reduced the number of clinical and

226 microbiological recurrences. While both long- and short-term prophylaxis with a quinolone trended

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227 toward superior clinical outcomes, these differences did not achieve statistical significance.
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228 Indeed, the results must be taken with caution: the majority of studies scored poorly on

229 quality and risk-of-bias assessments, and outcome evaluations were variable and often subjective.
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230 Most trials did not explicitly define (symptomatic) UTI; for some (particularly those conducted before

231 1990), asymptomatic bacteriuria was considered sufficient. In turn, both the definition of bacteriuria
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232 and the methods used to detect it varied among studies. Indeed, the considerable between-study
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233 heterogeneity (I2) observed in the meta-analyses for efficacy and non-severe toxicity with long-term

234 use indicates that the variation in results among study groups is due to trial dissimilarities rather than
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235 chance. We examined several potential sources of this heterogeneity, such as the various trials’
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236 quality scores, dosing regimens, and durations of prophylaxis, but none of these proved accountable.
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237 Yet it is noteworthy that even with these weaknesses, the meta-analyses presented here

238 repeatedly yielded the same overall results—regarding not only nitrofurantoin’s efficacy as UTI

239 prophylaxis, but also its non-severe AE. Non-severe AE such as nausea, pruritus and headache were

240 significantly more frequent with nitrofurantoin. These findings contrast with those of the meta-

241 analysis on short-term (≤14 days) nitrofurantoin used as therapy for active UTI [3], which revealed no

242 differences in toxicity between nitrofurantoin and other antibiotics.

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243 Among the 1197 patients in the controlled trials receiving nitrofurantoin as either short- or

244 long-term prophylaxis, only one experienced severe toxicity, confirming earlier observations [3] that

245 severe toxicity rarely occurs with short-term use. For more information on the incidence of severe

246 events such as pulmonary and hepatic hypersensitivity, we thus turned to longitudinal, population-

247 level datasets. But these findings must also be considered with caution. These observational studies

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248 were of varying quality and design. Outcome measures were heterogeneous and inexact; some

249 studies’ results are based on the number of AE reported to data safety committees combined with

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250 nitrofurantoin sales data. Such datasets did not allow for the distinction between short- and long-

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251 term nitrofurantoin users. Severe events were often aggregated; only one study specifically reported

252 incidence of pulmonary fibrosis requiring hospitalization in long-term users [46]. And underreporting

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253 of AE is commonplace; one study estimates a report-to-event ratio of roughly 30% [52]. Yet, for
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254 context, the rate of 0.02 to 1.5 severe events/1000 users is lower than that of telithromycin for

255 hepatitis alone (70 events/1000 users) [53] and is comparable to that of ciprofloxacin for irreversible
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256 Achilles tendon rupture (0.89 events/1000 users) [54].

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257 One of the few datasets including information on individual durations of antibiotic therapy is
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258 that of the Agence nationale du medicament et des produits de la santé (ANSM). This body issued a

259 safety warning in 2011 after severe AE were documented in 1:700 patients receiving nitrofurantoin
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260 for over 4 months between 2005 and 2010 [48]. The agency recommended against the use of

261 nitrofurantoin, even short-term as treatment for acute UTI; a 35% reduction in nitrofurantoin use
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262 followed, with collateral increases in fluoroquinolone use [55]. The agency released a subsequent
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263 report in 2014, when the number of nitrofurantoin prescriptions averaged roughly 250,000 per year

264 [49]; among these, the frequency of severe pulmonary AE during had dropped sharply (1:20,408

265 prescriptions), coming into line with other reports such as that of Penn et al [40]. Adverse event

266 frequency clearly increased with duration of therapy [48].

267 As noted above, the results of this review and its meta-analyses are limited by the quality of

268 the studies included. The actual incidence of severe toxicity remains unknown, but it is clear that it

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269 (1) is relatively rare and (2) increases in proportion to the duration of nitrofurantoin use. Further, our

270 systematic search of the literature did not yield any robust information on nitrofurantoin’s efficacy

271 and toxicity in special populations such as the elderly and those with renal insufficiency. Given their

272 increasing prevalence and nitrofurantoin’s exponentially increasing use, nitrofurantoin therapy and

273 prophylaxis in these populations will require further systematic study.

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274

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275 Conclusion

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276 When used for the prevention of UTI, nitrofurantoin’s clinical efficacy appears equivalent to that of

277 other antibiotics. While its non-severe toxicity profile appears somewhat less favourable than those

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278 of comparators, severe toxicity is rare. Clinicians should be aware, however, that the risk of severe
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279 toxicity seems to increase with the duration of nitrofurantoin prophylaxis.

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282 Acknowledgments

283 None.

284

285 Funding

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286 This work was supported in part by the European Commission under the Life Science Health Priority

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287 of the 7th Framework Program (AIDA grant agreement 278348).

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288

289 Conflicts of interest

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290 None

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292 References

293 1. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical

294 practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A

295 2010 update by the Infectious Diseases Society of America and the European Society for

PT
296 Microbiology and Infectious Diseases. Clin Infect Dis 2011;52(5):e103-20.

297 2. Muller AE, Theuretzbacher U, Mouton JW. Use of old antibiotics now and in the future from a

RI
298 pharmacokinetic/pharmacodynamic perspective. Clin Microbiol Infect 2015;21(10):881-5.

299 3. Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW.

SC
300 Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob

U
301 Chemother 2015;70(9):2456-64.
AN
302 4. Hydes T, Wright M, Jaynes E, Nash K. Nitrofurantoin immune-mediated drug-induced liver

303 injury: a serious complication of a commonly prescribed medication. BMJ Case Rep 2014;2014.
M

304 5. Yeong TT, Lim KH, Goubet S, Parnell N, Verma S. Natural history and outcomes in drug-

305 induced autoimmune hepatitis. Hepatol Res 2015.

D

306 6. D'Arcy PF. Nitrofurantoin. Drug Intell Clin Pharm 1985;19(7-8):540-7.

TE

307 7. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic

308 reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097.
EP

309 8. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of interventions.
C

310 http://www.cochrane-handbook.org: The Cochrane Collaboration; 2011.

AC

311 9. Kranjcec B, Papes D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract

312 infections in women: a randomized clinical trial. World J Urol 2014;32(1):79-84.

313 10. Lettgen B, Troster K. [Prophylaxis of recurrent urinary tract infections in children. Results of

314 an open, controlled and randomized study about the efficacy and tolerance of cefixime compared to

315 nitrofurantoin]. Klin Padiatr 2002;214(6):353-8.

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316 11. Schlager TA, Anderson S, Trudell J, Hendley JO. Nitrofurantoin prophylaxis for bacteriuria and

317 urinary tract infection in children with neurogenic bladder on intermittent catheterization. J Pediatr

318 1998;132(4):704-8.

319 12. Brumfitt W, Hamilton-Miller JM. A comparative trial of low dose cefaclor and

320 macrocrystalline nitrofurantoin in the prevention of recurrent urinary tract infection. Infection

PT
321 1995;23(2):98-102.

322 13. Vahlensieck W, Jr., Westenfelder M. Nitrofurantoin versus trimethoprim for low-dose long-

RI
323 term prophylaxis in patients with recurrent urinary tract infections. A prospective randomized study.

SC
324 Int Urol Nephrol 1992;24(1):3-10.

325 14. Brumfitt W, Hamilton-Miller JM, Smith GW, al-Wali W. Comparative trial of norfloxacin and

U
326 macrocrystalline nitrofurantoin (Macrodantin) in the prophylaxis of recurrent urinary tract infection
AN
327 in women. Q J Med 1991;81(294):811-20.

328 15. Raz R, Boger S. Long-term prophylaxis with norfloxacin versus nitrofurantoin in women with
M

329 recurrent urinary tract infection. Antimicrob Agents Chemother 1991;35(6):1241-2.

D

330 16. Brendstrup L, Hjelt K, Petersen KE, Petersen S, Andersen EA, Daugbjerg PS, et al.
TE

331 Nitrofurantoin versus trimethoprim prophylaxis in recurrent urinary tract infection in children. A

332 randomized, double-blind study. Acta Paediatr Scand 1990;79(12):1225-34.

EP

333 17. Carlsen NL, Hesselbjerg U, Glenting P. Comparison of long-term, low-dose pivmecillinam and

334 nitrofurantoin in the control of recurrent urinary tract infection in children. An open, randomized,
C

335 cross-over study. J Antimicrob Chemother 1985;16(4):509-17.

AC

336 18. Brumfitt W, Smith GW, Hamilton-Miller JM, Gargan RA. A clinical comparison between

337 Macrodantin and trimethoprim for prophylaxis in women with recurrent urinary infections. J

338 Antimicrob Chemother 1985;16(1):111-20.

339 19. Lindan R, Joiner E. A prospective study of the efficacy of low dose nitrofurantoin in

340 preventing urinary tract infections in spinal cord injury patients, with comments on the role of

341 pseudomonads. Paraplegia 1984;22(2):61-5.

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 ACCEPTED MANUSCRIPT
342 20. MacDonald I, Hill AV, Whitworth JA, Kincaid-Smith P. Prevention of recurrent urinary tract

343 infection in adults. Aust N Z J Med 1983;13(2):177-8.

344 21. Holland NH, Kazee M, Duff D, McRoberts JW. Antimicrobial prophylaxis in children with

345 urinary tract infection and vesicoureteral reflux. Rev Infect Dis 1982;4(2):467-74.

346 22. Stamm WE, Counts GW, McKevitt M, Turck M, Holmes KK. Urinary prophylaxis with

PT
347 trimethoprim and trimethoprim-sulfamethoxazole: efficacy, influence on the natural history of

348 recurrent bacteriuria, and cost control. Rev Infect Dis 1982;4(2):450-5.

RI
349 23. Kasanen A, Junnila SY, Kaarsalo E, Hajba A, Sundquist H. Secondary prevention of recurrent

SC
350 urinary tract infections. Comparison of the effect of placebo, methenamine hippurate, nitrofurantoin

351 and trimethoprim alone. Scand J Infect Dis 1982;14(4):293-6.

U
352 24. Brumfitt W, Cooper J, Hamilton-Miller JM. Prevention of recurrent urinary infections in
AN
353 women: a comparative trial between nitrofurantoin and methenamine hippurate. J Urol

354 1981;126(1):71-4.
M

355 25. Hardy JC. [Prevention of recurrent urinary tract infection with cinoxacin. A comparative study
D

356 with nitrofurantoin]. Acta Urol Belg 1980;48(4):481-7.

TE

357 26. Smellie JM, Katz G, Gruneberg RN. Controlled trial of prophylactic treatment in childhood

358 urinary-tract infection. Lancet 1978;2(8082):175-8.

EP

359 27. Bailey RR, Roberts AP, Gower PE, De Wardener HE. Prevention of urinary-tract infection with

360 low-dose nitrofurantoin. Lancet 1971;2(7734):1112-4.

C

361 28. Freeman RB, Smith WM, Richardson JA, Hennelly PJ, Thurm RH, Urner C, et al. Long-term
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362 therapy for chronic bacteriuria in men. U.S. Public Health Service cooperative study. Ann Intern Med

363 1975;83(2):133-47.

364 29. Jackson D, Higgins E, Bracken J, Yandell PM, Shull B, Foster RT, Sr. Antibiotic prophylaxis for

365 urinary tract infection after midurethral sling: a randomized controlled trial. Female Pelvic Med

366 Reconstr Surg 2013;19(3):137-41.

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 ACCEPTED MANUSCRIPT
367 30. Bag S, Kumar S, Taneja N, Sharma V, Mandal AK, Singh SK. One week of nitrofurantoin before

368 percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a

369 prospective controlled study. Urology 2011;77(1):45-9.

370 31. Rogers RG, Kammerer-Doak D, Olsen A, Thompson PK, Walters MD, Lukacz ES, et al. A

371 randomized, double-blind, placebo-controlled comparison of the effect of nitrofurantoin

PT
372 monohydrate macrocrystals on the development of urinary tract infections after surgery for pelvic

373 organ prolapse and/or stress urinary incontinence with suprapubic catheterization. Am J Obstet

RI
374 Gynecol 2004;191(1):182-7.

SC
375 32. Valdevenito Sepulveda JP. [Antibiotics in transurethral resection of the prostate in patients

376 with low risk of infectious complications: randomized prospective comparative study]. Arch Esp Urol

U
377 2004;57(1):48-57.
AN
378 33. Bhatia NN, Karram MM, Bergman A, Evans RP. Antibiotic prophylaxis following lower urinary

379 tract instrumentation. Urology 1992;39(6):583-5.

M

380 34. Holl WH, Rous SN. Is antibiotic prophylaxis worthwhile in patients with transurethral
D

381 resection of prostate? Urology 1982;19(1):43-6.

TE

382 35. Johnson HW, Anderson JD, Chambers GK, Arnold WJ, Irwin BJ, Brinton JR. A short-term study

383 of nitrofurantoin prophylaxis in children managed with clean intermittent catheterization. Pediatrics
EP

384 1994;93(5):752-5.

385 36. Lohr JA, Nunley DH, Howards SS, Ford RF. Prevention of recurrent urinary tract infections in
C

386 girls. Pediatrics 1977;59(4):562-5.

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387 37. Kasanen A, Kaarsalo E, Hiltunen R, Soini V. Comparison of long-term, low-dosage

388 nitrofurantoin, methenamine hippurate, trimethoprim and trimethoprim-sulphamethoxazole on the

389 control of recurrent urinary tract infection. Ann Clin Res 1974;6(5):285-9.

390 38. Nyren P, Runeberg L, Kostiala AI, Renkonen OV, Roine R. Prophylactic methenamine

391 hippurate or nitrofurantoin in patients with an indwelling urinary catheter. Ann Clin Res

392 1981;13(1):16-21.

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393 39. Geerts AF, Eppenga WL, Heerdink R, Derijks HJ, Wensing MJ, Egberts TC, et al. Ineffectiveness

394 and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in

395 primary care. Eur J Clin Pharmacol 2013;69(9):1701-7.

396 40. Penn RG, Griffin JP. Adverse reactions to nitrofurantoin in the United Kingdom, Sweden, and

397 Holland. Br Med J (Clin Res Ed) 1982;284(6327):1440-2.

PT
398 41. Uhari M, Nuutinen M, Turtinen J. Adverse reactions in children during long-term

399 antimicrobial therapy. Pediatr Infect Dis J 1996;15(5):404-8.

RI
400 42. Danielson DA, Douglas SW, 3rd, Herzog P, Jick H, Porter JB. Drug-induced blood disorders.

SC
401 Jama 1984;252(23):3257-60.

402 43. Beard K, Belic L, Aselton P, Perera DR, Jick H. Outpatient drug-induced parenchymal liver

U
403 disease requiring hospitalization. J Clin Pharmacol 1986;26(8):633-7.
AN
404 44. Beard K, Perera DR, Jick H. Drug-induced parenchymal renal disease in outpatients. J Clin

405 Pharmacol 1988;28(5):431-5.

M

406 45. Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the
D

407 use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 1988;8(3):599-606.

TE

408 46. Jick SS, Jick H, Walker AM, Hunter JR. Hospitalizations for pulmonary reactions following

409 nitrofurantoin use. Chest 1989;96(3):512-5.

EP

410 47. Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, presentation,

411 and outcomes in patients with drug-induced liver injury in the general population of Iceland.
C

412 Gastroenterology 2013;144(7):1419-25, 25 e1-3; quiz e19-20.

AC

413 48. National Agency for the Safety of Medicines and Health Products. COMMISSION NATIONALE

414 DE PHARMACOVIGILANCE, Compte rendu de la réunion du mardi 24 mai 2011 Saint Denis: 2011.

415 49. Jantzen H. Nitrofurantoine -Actualisation de donnees de Pharmacovigilance. RICAI; 15-12-

416 2015; Paris2015.

417 50. Anonymous. Be aware of the risk of pulmonary fibrosis in long-term treatment with

418 nitrofurantoin (Nitrofurantoin-DAK). Danish Pharmacovigilance Update 2015;6(2):4.

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419 51. Albert X, Huertas I, Pereiro, II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing

420 recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev

421 2004(3):CD001209.

422 52. Bottiger LE, Westerholm B. Drug-induced blood dyscrasias in Sweden. Br Med J

423 1973;3(5875):339-43.

PT
424 53. FDA. KETEK® (telithromycin) Tablets Label 2007 [Available from:

425 http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021144s012lbl.pdf.

RI
426 54. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH.

SC
427 Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ

428 2002;324(7349):1306-7.

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429 55. Slekovec C, Leroy J, Huttner A, Ruyer O, Talon D, Hocquet D, et al. When the precautionary
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430 principle disrupts 3 years of antibiotic stewardship: nitrofurantoin in the treatment of urinary tract

431 infections. J Antimicrob Chemother 2014;69(1):282-4.

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434 Table 1. Inclusion criteria for studies included in the systematic review of nitrofurantoin’s efficacy

435 and non-severe toxicity as prophylaxis of UTI.

Study design

Included: Excluded:

• Controlled clinical trials • Uncontrolled trials

•

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Animal studies
• In vitro studies
Participants

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Included: Excluded:

• Human patients of all ages and both genders in all • Animal studies
settings •

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In vitro studies
Interventions

Included: Excluded:

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• Oral nitrofurantoin at any dose and any duration • Nitrofurantoin combined with another
for primary or secondary prophylaxis of UTI* antibacterial targeting uropathogens
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• Nitrofurantoin for treatment of uncomplicated
and complicated UTI
• Nitrofurantoin for treatment or prophylaxis of
conditions outside the urinary tract
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Comparators
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Included: Excluded:
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• Placebo • Nitrofurantoin with another antibacterial

• No treatment targeting uropathogens
• A different drug • Non-systemic administration
• Nitrofurantoin at a different dose, frequency, or
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436 UTI: urinary tract infection

437 *In literature published before 1990, asymptomatic bacteriuria was often considered sufficient for a diagnosis
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438 of UTI.
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440

441

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442 Figure 1. Flow chart of the retrieval of studies evaluated in the meta-analysis of the efficacy of

443 nitrofurantoin prophylaxis.

444

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447 Figure 2. Results of the meta-analysis for the prevention of UTI when nitrofurantoin is compared to

448 placebo/nothing. R: duration of prophylaxis, d: days, w: weeks, m: months, C-: comparator, F:

449 female, M: male, O: duration of observation, A: adult, C: child.

450

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454 Figure 3. Results of the meta-analysis for the prevention of UTI when nitrofurantoin is compared to

455 other antibiotics for short-term prophylaxis. R: duration of prophylaxis, d: days, C-: comparator, F:

456 female, M: male, O: duration of observation, TMP/SXT: trimethoprim/sulfamethoxazole, CFR:

457 cefadroxil, CIP: ciprofloxacin

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460
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461 Figure 4. Results of the meta-analysis for the prevention of UTI when nitrofurantoin is compared to

462 other antibiotics used for long-term prophylaxis. R: duration of prophylaxis, d: days, C-: comparator,

463 F: female, M: male, A: adult, C: child, PEN: penicillin, AMX: amoxicillin, PMC: pivmecillinam, CEC:

464 cefaclor, CFX: cefixime, CIN: cinoxacin, NOR: norfloxacin, TMP/SXT: trimethoprim/sulfamethoxazole,

465 TRM: trimethoprim, MH: methenamine hippurate, MM: methenamine mandelate, SMT:

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466 sulfamethizole, MAN: D-mannose

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468

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469 Figure 5. Results of the meta-analysis for (mild) side effects for long term use of nitrofurantoin

470 compared to other antibiotics. R: duration of prophylaxis, d: days, C-: comparator, F: female, M:

471 male, A: adult, C: child, PEN: penicillin, AMX: amoxicillin, PMC: pivmecillinam, CEC: cefaclor, CFX:

472 cefixime, CIN: cinoxacin, NOR: norfloxacin, TMP/SXT: trimethoprim/sulfamethoxazole, TRM:

473 trimethoprim, MH: methenamine hippurate, MM: methenamine mandelate, SMT: sulfamethizole,

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474 MAN: D-mannose

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