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Objectives: Guidelines do not distinguish between 50 mg or 100 mg nitrofurantoin as daily prophylaxis for recurrent urinary tract infection (UTI), although 50 mg might have a better safety profile. Our objective was to compare the effectiveness and safety of both regimens., Methods: Data were retrospectively collected from 84 Dutch GP practices between 2013 and 2020. Nitrofurantoin prescriptions of 100 mg and 50 mg every 24 hours in women were included. Cox proportional hazard regression analysis was used to calculate hazard ratios on first episode of UTI, pyelonephritis and (adverse) events. Patients were followed for the duration of consecutive repeated prescriptions, assuming non-informative right censoring, up to 1 year., Results: Nitrofurantoin prophylaxis was prescribed in 1893 patients. Median lengths of follow up were 90 days (interquartile range (IQR) 37-179 days) for 100 mg (n = 551) and 90 days (IQR 30-146 days) for 50 mg (n = 1342) with few differences in baseline characteristics between populations. Under 100 mg and 50 mg, 82/551 (14.9%) and 199/1342 (14.8%) developed UTI and 46/551 (8.3%) and 81/1342 (6.0%) developed pyelonephritis, respectively. Adjusted HRs of 100 mg versus 50 mg were 1.01 (95% CI 0.78-1.30) on first UTI, 1.37 (95% CI 0.95-1.98) on first pyelonephritis episode, 1.82 (95% CI 1.20-2.74) on first consultation for cough, 2.68 for dyspnoea (95% CI 1.11-6.45) and 2.43 for nausea (95% CI 1.03-5.74)., Conclusion: Daily prophylaxis for recurrent UTI with 100 mg instead of 50 mg nitrofurantoin was associated with an equivalent hazard on UTI or pyelonephritis, and a higher hazard on cough, dyspnoea and nausea. We recommend 50 mg nitrofurantoin as daily prophylaxis., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nitrofurantoin is a commonly prescribed antibiotic for uncomplicated urinary tract infections. The Dutch College of General Practitioners guideline recommends the use of this drug for the treatment of uncomplicated urinary tract infections in both male and female patients. Treatment with nitrofurantoin has several advantages. Resistance to this antibiotic is low and does not increase in the hospitalized patient population. Treatment with nitrofurantoin is generally well-tolerated. However, two independent studies estimated that approximately 27% of male patients are undertreated with nitrofurantoin. The main downside of nitrofurantoin is the low blood concentration that leads to insufficient tissue penetration. There is little evidence on how often prostatic tissues are involved in male urinary tract infections. Unrecognized tissue involvement can lead to breakthrough urinary tract infections despite nitrofurantoin treatment. Because of this, the safety of nitrofurantoin for male patients is unknown and treatment with this antibiotic should be administered with caution.

Given emerging uropathogen resistance to more recent antibiotics, old antibiotics used for uncomplicated urinary tract infection (UTI) warrant re-examination. In this study, the urinary antibacterial activities of fosfomycin and nitrofurantoin were investigated by determining the urinary inhibitory titre and urinary bactericidal titre against uropathogens in urine samples from female volunteers following administration of single-dose fosfomycin (3 g) or nitrofurantoin (50 mg q6h or 100 mg q8h). Urine samples were collected over 48 h (fosfomycin) or 6 or 8 h (nitrofurantoin), with drug levels quantified with every void. Fosfomycin concentrations ranged from <0.75 mg/L [lower limit of quantification (LLOQ)] to 5729.9 mg/L and nitrofurantoin concentrations ranged from <4 mg/L (LLOQ) to 176.3 mg/L (50 mg q6h) or 209.4 mg/L (100 mg q8h). There was discrepancy in the response to fosfomycin between Escherichia coli and Klebsiella pneumoniae, with fosfomycin displaying strong bactericidal activity for 48 h against E. coli but moderate bactericidal activity for 18 h against K. pneumoniae. This effect was not related to the strain's baseline minimum inhibitory concentration but rather to the presence of a resistant subpopulation. Maximum titres of nitrofurantoin were obtained during the first 2 h, but no antibacterial effect was found in most samples regardless of the dose. In the rare samples in which antibacterial activity was detectable, titres were comparable for both species tested. These findings confirm doubts regarding fosfomycin administration in UTIs caused by K. pneumoniae and reveal a discrepancy between nitrofurantoin's measurable ex vivo activity and its clinical effect over multiple dosing intervals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Use of nitrofurantoin has increased significantly since its recent repositioning as a first-line agent for uncomplicated cystitis by multiple guidelines. However, current dosing regimens were developed in an era before robust pharmacokinetic testing and may not be optimal. Furthermore, formulations have been modified over the years., Objectives: To reassess the plasma and urinary pharmacokinetic profile of macrocrystalline nitrofurantoin in two commonly used dosing regimens., Methods: In this open-label, randomized crossover pharmacokinetic trial, 12 healthy adult female volunteers were randomized to receive oral nitrofurantoin 100 mg q8h on days 1 and 2 and, after a washout period, 50 mg q6h on days 30 and 31, or the same dosing schemes in reversed order. Urine and blood were collected at steady state and analysed by UPLC. Pharmacokinetic analysis was performed by WinNonlin., Results: Plasma peak concentrations were low (mean 0.33 mg/L, SD 0.08, and 0.69 mg/L, SD 0.35, after 50 and 100 mg, respectively) and dose dependent. The AUC0-24 was higher (6.49 versus 4.43 mg·h/L, P = 0.021) for the 100 mg q8h dosing regimen, but the dose-normalized AUC was similar for the two regimens. In contrast, urinary concentrations were dose independent: increasing the nitrofurantoin dose delayed the time to peak urinary concentration, while steady-state AUC0-24 values remained unchanged (943.49 and 855.95 mg·h/L at 50 mg q6h and 100 mg q8h, respectively)., Conclusions: Plasma concentrations were relatively low and dose dependent. The dose-independent urinary concentrations suggest that excretion of nitrofurantoin into the urine is saturable. Pharmacodynamic studies are urgently required to determine the impact of these findings., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nitrofurantoin is an old antibiotic and an important first-line oral antibiotic for the treatment of uncomplicated urinary tract infections. However despite its long term use for over 60 years, little information is available with respect to its dose justification and this may be the reason of highly variable recommended doses and dosing schedules. Furthermore, nitrofurantoin is not a uniform product -crystal sizes of nitrofurantoin, and therefore pharmacokinetic properties, differ significantly by product. Moreover, pharmacokinetic profiling of some products is even lacking, or difficult to interpret because of its unstable chemical properties. Pharmacokinetic and pharmacodynamic data is now slowly becoming available. This review provides an overview of nitrofurantoins antibacterial, pharmacokinetic and pharmacodynamic properties. This shows that a clear rationale of current dosing regimens is scanty., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nitrofurantoin and nitroxoline are oral antibiotics for the treatment or prophylaxis of acute urinary tract infections. New interest in both these drugs is increasing because of the emergence of resistance to other antibiotics, but knowledge of their pharmacokinetics (PK) is lacking since they were developed before the advent of standardized research for drug approval. The aims of this review were to (i) summarize the PK data reported in the literature and (ii) to identify PK knowledge gaps. The current body of PK knowledge of both drugs appears to be poor and mainly based on old studies. Nitrofurantoin PK values were obtained from studies using many variables, e.g. formulations, crystal sizes and analytical methods, resulting in high interindividual variability in PK parameters and no uniform PK profile. Clinical experience and PK data for nitroxoline are even more limited since the drug is registered in only Germany and a few (Eastern European) countries. Clinical studies in relevant patient populations are needed with commercially available nitrofurantoin and nitroxoline formulations at approved dosing regimens to more fully characterize their PK profiles, and to investigate the influence of patient characteristics on these profiles in order to optimize efficacy and avoid toxicity and emergence of resistance. Only with this updated knowledge and efficacy data from well-structured trials can both drugs maintain their antimicrobial activity against uropathogens.

Objectives: Nitrofurantoin has been used for the prevention of urinary tract infection (UTI) for over 60 years. We conducted a systematic review and meta-analysis to assess its efficacy and safety in the prophylaxis of UTI., Methods: We performed a systematic review of all controlled trials in humans assessing nitrofurantoin for UTI prophylaxis published from 1946 to 2015. We further reviewed population-level cohort studies evaluating nitrofurantoin's toxicity. Meta-analyses assessing efficacy and adverse events were conducted on controlled trials., Results: Twenty-six controlled trials including 3052 patients fulfilled entry criteria for the systematic review and meta-analysis on efficacy and toxicity, and 16 population-level cohort studies were identified for review of toxicity. Overall quality was poor, with all studies at increased risk for various biases. When compared with no prophylaxis, nitrofurantoin is effective in the prevention of UTI (risk ratio 0.38 in favour of nitrofurantoin, 95% CI 0.30-0.48). Its prophylactic efficacy is superior to that of methenamine hippurate and comparable to that of other antibacterials. Compared with patients receiving other antibacterials, those receiving nitrofurantoin had an increased risk of 2.24 (95% CI 1.77-2.83) for a non-severe adverse effect. In all controlled trials, only one patient experienced a severe adverse effect (interstitial pneumonia). Cohort studies reported severe adverse effect frequencies of 0.02-1.5 per 1000 nitrofurantoin users., Conclusions: Nitrofurantoin is effective in the prevention of UTI. Its use may be associated with increased non-severe adverse effects; severe adverse effects occur infrequently. The risk of severe toxicity seems to increase with the duration of nitrofurantoin prophylaxis., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Nitrofurantoin's use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin's efficacy and toxicity in the treatment of lower UTI., Methods: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials., Results: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin's clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare., Conclusions: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)