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Int J Antimicrob Agents. 2019 Aug 2. pii: S0924-8579(19)30207-9. doi: 10.1016/j.ijantimicag.2019.07.018. [Epub ahead of print]

Urinary antibacterial activity of fosfomycin and nitrofurantoin at registered dosages in healthy volunteers.

Author information

1
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: r.wijma@erasmusmc.nl.
2
Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
3
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
5
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands.
6
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.

Abstract

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.

KEYWORDS:

Fosfomycin; Healthy volunteers; Nitrofurantoin; Pharmacodynamics; Pharmacokinetics; Urinary tract infection

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