Recurrent uncomplicated urinary tract infections (RUTIs) are one of the commonest presentations to urologists. They are defined as at least three UTIs per year or 2 UTIs in the last 6 months. 6–8 million young women are estimated to have an acute cystitis each year and 25% of those will develop recurrent UTIs, which are a major cause of morbidity and health care costs. Prevention of RUTIs includes various strategies such as prophylactic antibiotics or non-antibiotic measures. Our aim is to conduct a systematic review and network meta-analysis of randomized controlled trials (RCTs) published in the English literature to evaluate the effectiveness and safety of prophylactic antibiotics and non-antibiotics measures for the prevention of recurrent UTIs in female patients.

We searched PubMed, Scopus, Cochrane Central Register of Controlled Trials (Central), Web of science, and Ovid for relevant studies published up to August 2018. We only included RCTs that compared prophylactic antibiotics or non-antibiotic measures in terms of long-term effectiveness and adverse events. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank the various treatments.

A total of 13 RCTs including 1279 participants were included in our study comparing prophylactic antibiotics or non-antibiotic measures with placebo. The longest duration of follow up period was 12 months. At 6 months follow-up  D−mannose, Nitrofurantoin (NFM), TMP−SMZ, Estriol and Trimethoprim (TMP) were associated with a lower incidence of UTIs compared to placebo  (OR = 0.10,95% CI = [0.04; 0.24], OR = 0.15,95% CI = [0.09; 0.25] , OR = 0.17,95% CI = [0.08; 0.35] , OR = 0.29,95% CI = [0.13; 0.65] and OR = 0.35,95% CI = [0.13; 0.92]), respectively. D−mannose was the highest ranking in efficacy (P-score= 0.94) followed by NFM (P-score= 0.78), TMP−SMZ (P-score= 0.72), Estriol (P-score= 0.46) and TMP (P-score= 0.41). At 12 months follow up Norfloxacin, TMP, NFM, Methenamine Hippurate were associated with a lower incidence of UTIs compared to placebo (OR = 0.02, 95% CI = [0.00; 0.34], OR = 0.07, 95% CI = [0.03; 0.13], OR = 0.19, 95% CI = [0.11; 0.36] and OR = 0.30, 95% CI = [0.14; 0.67]), respectively. Norfloxacin  was the highest ranking in efficacy (P-score= 0.94) followed by TMP (P-score= 0.84), NFM (P-score= 0.60) and Methenamine Hippurate (P-score= 0.42). TMP and NFM had higher adverse events compared to placebo  at six months (OR = 81.17, 95% CI = [1.48; 4438.59] and OR = 81.17, 95% CI = [4.88; 1349.76]) and 12 months (OR = 5.32, 95% CI = [1.51; 18.75]).  There was no significant difference in adverse events between the other treatments and placebo at 6 and 12 month.

To the best of our knowledge, this is the first network meta-analysis to compare the efficacy of all available forms of prophylactic antibiotics with non-antibiotics interventions for recurrent UTI treatment during follow up periods of 6 months and 1 year. D-mannose was the top-ranking non-antimicrobial agent at reducing RUTIs at 6 months compared to Placebo. Nitrofurantoin was the top-ranking antibiotic associated with the reduction in UTIs at the 6 months follow up, however, it had the highest risk of adverse events compared to other treatments. Norfloxacin, Trimethoprim and Nitrofurantoin were the top-ranking antibiotics at achieving a lower incidence of RUTIs during the follow up of 1 year.

At 6 month and 1 year follow up, D-mannose and Norfloxacin were the highest effective prophylactic agents respectively in preventing recurrent UTIs compared to Placebo. However, further prospective, long-term, randomized, and controlled trials with large sample size and longer follow up period are needed to confirm these findings.