Nitrofurantoin versus Fosfomycin for Acute Uncomplicated Cystitis

Reagent Strip for Urinalysis , Routine Urinalysis - Stock image

By Martina McGrath, MD
May 9, 2018

Acute uncomplicated cystitis is defined as infection localized to the bladder without signs of further extension such as fever, flank pain/tenderness, or systemic symptoms. It is a highly prevalent problem and over half of all women experience at least one urinary tract infection (UTI) in their lifetime.1 In otherwise healthy women, with normal urinary tract anatomy, treatment can commonly be instituted without the need for urine culture. Both nitrofurantoin and fosfomycin are currently recommended as first-line agents for treatment of uncomplicated cystitis. However, some older studies have suggested that fosfomycin may have inferior efficacy.2

The Study

To investigate this, Huttner et al. undertook an open-label, randomized study of women with uncomplicated UTI and compared rates of clinical resolution at 28 days in those treated with a single dose of fosfomycin 3 g versus nitrofurantoin 100 mg 3 times daily for 5 days.3

Women were enrolled with at least one symptom of UTI (dysuria, urgency, frequency, suprapubic pain) and a urinalysis showing nitrites or leukocyte esterase. Those with complicating features such as fever, flank pain, pregnancy, recent antibiotic use, or immunosuppressed state were excluded. Patients were randomized to fosfomycin or nitrofurantoin and attended two follow-up visits at 14 and 28 days after completion of antibiotics, i.e., 5 days after randomization (given the long half-life of fosfomycin). The primary outcome was clinical response, defined as resolution of infection, failure (requirement for additional treatment), or indeterminate.

The Results

Five hundred and thirteen women were randomized and 237 completed therapy in each group. Interestingly, only 77% of baseline cultures were positive, with similar rates in both groups. Infecting organisms and patterns of antibiotic resistance were also similar. However, the differences in clinical responses were quite marked. At 28-days posttreatment, 70% of those treated with nitrofurantoin had clinical resolution, as compared to only 58% of those receiving fosfomycin. Failure (defined as need for additional antibiotics, or discontinuation due to lack of efficacy) was common, and occurred in 27% and 39% respectively. In patients with E coli UTI, the difference was most pronounced, with a 28% lower response rate in those treated with fosfomycin versus nitrofurantoin. Rates of pyelonephritis, hospitalization, and other complications were low and similar in both treatment arms.

Why the difference? There does appear to be increasing bacterial resistance to Fosfomycin; this is a major issue in certain geographic areas, such as southern Europe. Furthermore, some data suggest that a single 3 g dose of fosfomycin may simply be insufficient to achieve sustained concentrations in urine to ensure adequate treatment.4 However, another factor worthy of consideration is the price differential between these two therapies—a single dose of fosfomycin costs over $90 whereas a 5-day course of nitrofurantoin comes in at closer to $50. This is significant given how common this condition is in the community.


While this study has a number of strengths, there is an important caveat. Patients were recruited from several centers in Europe with increasing development of resistant bacteria in recent years, including Poland, where nitrofurantoin is available over the counter. This may explain the lower-than-expected response rate in the nitrofurantoin-treated group in particular.

In summary, for treatment of acute uncomplicated UTI in otherwise healthy women, a 5-day course of nitrofurantoin had superior clinical response rates than a single dose of fosfomycin, but failure of therapy was common in both groups.


  1. Foxman B, Barlow R. D’Arcy H et al. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000:10(8): 509-515.
  2. Oteo J, Bautista V, Lara N et al. Spanish ESBL-EARS-Net Study Group. Parallel increase in community use of fosfomycin and resistance to fosfomycin in ESBL-producing E. Coli. J Antimicrob Chemother. 2010; 65(11):2459-2463.
  3. Huttner A, Kowalczyk A, Turjeman A et al. Effect of 5-day nitrofurantoin verus single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: A randomized clinical trial. JAMA doi:10.1001/jama.2018.3627.
  4. Wijma RA, Koch BCP, van Gelder T et al. High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers. Clin Microbiol Infect. doi:10:1016/j.cmi.2017.08.023.

Headshot of Dr. McGrathDr. Martina McGrath is an instructor in medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the medical editor for the Trends in Medicine blog  and the course director for the Update and Board Review in Internal Medicine online CME courses.

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