Oral nitrofurantoin-fosfomycin

Multicenter, randomized clinical trial to compare fosfomycin vs. nitrofurantoin for the treatment of lower urinary tract infection (UTI) in women at high risk of antibiotic-resistant pathogens.

Wijma RA, Huttner A, van Dun S, Kloezen W, Abbott IJ, Muller AE, Koch BCP, Mouton JW.: Urinary antibacterial activity of fosfomycin and nitrofurantoin at registered dosages in healthy volunteers. Int J Antimicrob Agents. 2019 Oct;54(4):435-441.

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Wijma RA, Hoogtanders KEJ, Croes S, Mouton JW, Brüggemann RJM.:  Development and validation of a fast and sensitive UHPLC-DAD assay for the quantification of nitrofurantoin in plasma and urine. J Pharm Biomed Anal. 2019 Sep 10;174:161-167. background logo AIDA-fine line

Wijma RA, Fransen F, Muller AE, Mouton JW.: Optimizing dosing of nitrofurantoin from a PK/PD point of view: What do we need to know? Drug Resist Updat. 2019 Mar;43:1-9.
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Huttner A, Wijma RA, Stewardson AJ, Olearo F, Von Dach E, Harbarth S, Brüggemann RJM, Mouton JW, Muller AE.:The pharmacokinetics of nitrofurantoin in healthy female volunteers: a randomized crossover study. J Antimicrob Chemother. 2019 Jun 1;74(6):1656-1661.
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Wijma RA, Huttner A, Koch BCP, Mouton JW, Muller AE.:Review of the pharmacokinetic properties of nitrofurantoin and nitroxoline. J Antimicrob Chemother. 2018 Nov 1;73(11):2916-2926.
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Huttner A, Kowalczyk A, Turjeman A, Babich T, Brossier C, Eliakim-Raz N, Kosiek K, Martinez de Tejada B, Roux X, Shiber S, Theuretzbacher U, von Dach E, Yahav D, Leibovici L, Godycki-Cwirko M, Mouton JW, Harbarth S.: Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018 May 1;319(17):1781-1789.
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Fransen F, Melchers MJB, Lagarde CMC, Meletiadis J, Mouton JW.: Pharmacodynamics of nitrofurantoin at different pH levels against pathogens involved in urinary tract infections. J Antimicrob Chemother. 2017 Dec 1;72(12):3366-3373.
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Wijma RA, Bahmany S, Wilms EB, van Gelder T, Mouton JW, Koch BCP.: A fast and sensitive LC-MS/MS method for the quantification of fosfomycin in human urine and plasma using one sample preparation method and HILIC chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Sep 1;1061-1062:263-269

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Fransen F, Melchers MJB, Lagarde CMC, Meletiadis J, Mouton JW.: Pharmacodynamics of nitrofurantoin at different pH levels against pathogens involved in urinary tract infections. J Antimicrob Chemother. 2017 Sep 11.
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Huttner A, Brossier C, Von Dach E, Kowalczyk A, Godycki-Cwirko M, Babitch T, Turjeman A, Leibovici L, Theuretzbacher U, Mouton J, Harbarth S: Increasing nitrofurantoin resistance in Escherichia coli urinary isolates in a country with over-the-counter antibiotic sales. Abstract EV0557, ECCMID Vienna 2017
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Kowalczykl A, Harbarth S, Huttner A, Leibovici L, Mouton J, Godycki-Cwirko M: Protocol for clinical trial: “Randomized clinical trial comparing fosfomycin vs. nitrofurantoin for treatment of uncomplicated lower urinary tract infection in female adults at increased risk of antibiotic-resistant bacterial infection, AIDA”. Annual Meeting of General Practice Research on Infections Network (GRIN), Oxford 2016.
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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. Clin Microbiol Infect. 2016 Aug 17
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Fransen F, Melchers MJ, Meletiadis J, Mouton JW: Pharmacodynamics and differential activity of nitrofurantoin against ESBL-positive pathogens involved in urinary tract infections. J Antimicrob Chemother. 2016 Jun 7.
Nitrofurantoin was bactericidal against all species, demonstrating an unusual differential pattern of activity with concentration-dependent-type killing behaviour against E. cloacae and time-dependent killing behaviour against E. coli, which may have significant consequences on species-dependent dosing regimens. The results also demonstrate that the pharmacodynamic properties of some drugs cannot be generalized within a family, here the Enterobacteriaceae.
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Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Sep;70(9):2456-64

When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.

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L. Jakobsen, N. Frimodt-Møller Fosfomycin PK/PD in Experimental Urinary Tract Infection ICAAC 2014, Poster A-046

Background: Fosfomycin (FOS) has become an attractive drug of choice for treatment of urinary tract infections (UTI) due to the rise of antimicrobial resistant uropathogens, especially the difficult-to-treat extended-spectrum β-lactamase producers. Although an old antimicrobial agent, the predictive PK/PD indices of FOS have not been elucidated for UTI. Methods: In OF-1 mice, PK of FOS after single sc. doses of 0.75, 7.5, and 30 mg/mouse (~ 25-1000 mg/kg) were determined in blood and urine (sampling times after dosing: 15 min – 4 hours). FOS concentrations were measured by bioassay. Dose-dependent PK (T>MIC, Cmax/MIC, AUC24/MIC) were analyzed using the Hill equation (GraphPad Prism). Efficacy of 6 FOS dosage regimens (total dose of 0.05 – 1.6 mg/mouse; dosing frequency of 6-72 hours) was investigated using the murine model of ascending UTI to estimate the most predictive PK/PD indices. Infection was induced by inoculating 50 μl (5×106 CFU) E. coli (NU14; FOS MIC 0.75 mg/L) via a catheter (retracted after inoculation) transurethrally and treatment was initiated sc. 1 day post infection for 3 days with FOS or saline. Urine, bladder, and kidneys were collected 4 days post infection for CFU determination. Results: Peak FOS serum concentrations of 30 to 800 mg/l were seen at the 3 doses used, with a serum elimination T½ of 30 min, and urine peak FOS concentrations from 2000- 90000 mg/l sustained above MIC for 6 – 18h. Six dose regimens were chosen which resulted in varying the serum PKPD indices: Time>MIC % from 5 – 80%, and the AUC/MIC ratios from 25 – 400 h, respectively. All doses significantly reduced CFUs as related to control, untreated mice (% reduction, lowest to highest doses; median control counts); urine: 80 – 100% (control mice: Log 6,8 CFU/ml; bladder: ca. 50% (control mice: Log 5,7 CFU/bladder); kidneys: 50-100% (control mice: log 2,9 CFU/kidney). The optimal PKPD indices for urine CFU/ml were (R2): AUC/MIC, 0,82; and Time>MIC of 1.dose: 0,82. Low correlations were found for Time>MIC % in all tissues, and for all indices for kidney counts. Conclusions: FOS was very effective in reducing urine counts even at a dose of 0,47 mg/mouse BID. Bladder counts remained at Log 3 CFU/bladder in all mice even after a dose of 30 mg/mouse, while this dose eradicated all bacteria in the kidneys in 5/6 mice. The optimal PKPD indices included AUC/MIC ratio (> 200), or Time>MIC of 1. Dose (>2 h).