Nitrofurantoin vs. Fosfomycin in UTI

In Review

Huttner A, et al. "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. 319(17):1781-1789.
PubMed • Full text

Clinical Question

In adult women with an uncomplicated urinary tract infection (UTI), how does a 5-day course of nitrofurantoin compare to single dose fosfomycin for clinical and microbiological resolution?

Bottom Line

In women with uncomplicated UTI, 5-day treatment with nitrofurantoin three times daily is more likely to achieve clinical and microbiologic resolution after 28 days compared to single dose fosfomycin for uncomplicated UTI's in non-pregnant women.

Major Points

With over half of women reporting a Urinary Tract Infection (UTI) in their lifetime, this common ambulatory infection carries a potential burden estimated of 2-billion annually in the USA alone. Nitrofurantoin and fosfomycin are first line agents in the treatment of uncomplicated UTI, but have not been sufficiently compared head to head for clinical or bacteriologic efficacy. Meta-analyses have shown nitrofurantoin and fluoroquinolones comparable in efficacy for UTIs, however the effect of fosfomycin in relation to other antibiotics as been shown in few clinical trials. In at least two previous trials comparing the two, similar efficacy was demonstrated, but this was prior to widespread use and thus higher resistance rates for fosfomycin. The single-dose of fosfomycin may not be a fair comparison as it may not be the optimal dosing pharmacokinetically or dynamically given it is a time-dependent killer.

This trial compared the clinical and bacteriologic efficacy of 5-day nitrofurantoin 100mg three times daily to single oral dose of 3g fosfomycin. In this multinational, open-label, randomized-control trial, 513 female patients were analyzed in an intention-to-treat analysis as well as several sensitivity analysis. In the primary outcome of 28 day clinical response, 70% of patients in the nitrofurantoin group demonstrated success over 58% in the fosfomyin group (95% CI 4-21%; P = 0.004; NNT 8). Bacteriological responsealso at 28 days was superior for nitrofurantoin (74% vs. 63% ([95% CI 1-20%; P = 0.04; NNT 9]). In the sub-population of E.coli infection there was an even greater difference in outcomes between the two drugs.

There are several potential sources of bias in this trial, the first being the open-label design where reporting of clinical symptoms may have been influenced simply by the nature of patients perception with 5-days of treatment. Approximately a quarter of patients were culture negative, also which could have influenced the findings. The comparison may not have been fair as the dose of nitrofurantoin was higher than the guideline recommended dose and the single dose of fosfomycin may not be optimized for its pharmacokinetic and dynamic properties. Overall, the trial demonstrated statistically significant superior clinical resolution with nitrofurantoin in comparison to fosfomycin, however, there may still be a space for fosfomycin which further study will need to clarify.

Guidelines

IDSA Guidelines for Antimicrobial Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women (2010) , adapted

• First line agent options for uncomplicated lower urinary tract infection (A-1):
  • Nitrofurantoin monohydrate/macrocrystals 100mg bid X 5 days
  • Trimethoprim-sulfamethoxazole 160/800mg (one DS tablet) bid X 3 days
  • Fosfomycin trometamol 3g single dose
  • Pivmecillinam 400 mg bid x 5 days

Design

• Multinational open-label, analyst-blinded, randomized clinical trial with allocation concealment
• N=513
  • Nitrofurantoin (n=255)
  • Fosfomycin (n=258)
• Setting: ambulatory clinics and hospital units in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel
• Enrollment: October 2013 to May 2017
• Follow-up: 2 visits at 14 (±2) days and 28 (±7) days after completion of treatment
• Analysis: intention-to-treat
• Primary outcome: clinical response in the 28 (±7) days following completion of therapy

Population

Inclusion Criteria

• Women ≥ 18 years old
• At least 1 symptom of acute lower UTI (dysuria, frequency, suprapubic tenderness)
• Urine dipstick positive for nitrates or leukocyte esterase

Exclusion Criteria

• Pregnancy and lactation
• Suspected upper UTI (symptoms of fever, chills, or flank pain)
• Antibiotic use or symptoms of UTI in the past 4 weeks
• Indwelling urinary catheter or otherwise complicated UTI
• Immunosuppression (untreated HIV infection, chemotherapy, radiation, high dose corticosteroids, other immunosuppressants)
• Renal insufficiency (CrCl < 30 mL/min)

Baseline Characteristics

Nitrofurantoin Group displayed

• Demographics: median age 43 years, outpatient 93%, female 100%
• Physiologic parameters: median number of inclusion symptoms 3, Positive urine culture 94%
• Antimicrobials: Antibiotics in past year 33%, At risk of resistant organisms 65%, Previous UTI 16%
• Culture results: Escherichia coli 57%, Klebsiella spp 10%, Proteus spp 4%, Enterococcus spp 7%, Group B Streptococcus 4%, Enterobacter spp 3%, Mixed flora 26%

Interventions

• Nitrofurantoin 100mg PO three times daily for 5 days, or
• A single oral 3g dose of fosfomycin

Outcomes

"Comparisons are nitrofurantoin vs fosfomycin therapy"

Primary Outcomes

Clinical response in the 28 (±7) days following completion of therapy

70% vs. 58% (95% CI 4-21%; P = 0.004; NNT 8)

Secondary Outcomes

Clinical resolution at 14 days after therapy completion

75% vs. 66% (95% CI 1-17%; P = 0.03; NNT 11)

Bacteriologic response to 28 days after therapy completion

74% vs. 63% (95% CI 1-20%; P = 0.04; NNT 9)

Bacteriologic success through to 14 days

82% vs. 73% (95% CI 0.4-18%; P = 0.04; NNT 11)

Duration of initial symptoms

4 days [IQR 2-14] vs. 3 days [IQR 2-14]; P = 0.30

Subgroup Analysis

E.coli infections sub-population, clinical response in the 28 (±7) days following completion of therapy

78% vs. 50% (95% CI 15-40%; P < 0.001; NNT 4)

E.coli infections sub-population, bacteriologic response to 28 days after therapy completion

72% vs. 58% (95% CI 2-27%; P = 0.03; NNT 7)

Adverse Events

Development of pyleonephritis

0.4% vs. 2% (95% CI −0.5% to 4.2%; P = 0.22)

At least 1 reported adverse event in the 7 days following randomization

7.8% vs. 5.8%.

Criticisms

• Open-label design may have influenced clinical symptom response reporting by participants
  • Secondary microbiological response may help mitigate this bias
• The nitrofurantoin dose used (300mg per day) is higher than the guideline recommended dose (200mg per day)
  • Would using a longer course of fosfomycin demonstrated better efficacy?
  • Commonly used dose in some areas of Europe so may be more pragmatic
• Resistance rates to fosfomycin and nitrofurantoin among the study sites varied and may not be comparable to those in locations with differing antibiotic use
  • fosfomycin is not indicated to treat all gram-negative infections commonly associated with UTIs
  • Local antibiograms and susceptibility patterns must be taken into consideration when applying these results.
• The study did not report how the patients received the medications. Though it is assumed the medication was provided by the study, if the patient was required to obtain the medication on their own, the cost of fosfomycin may be a deterrent to adherence.
• A quarter of enrolled patients were culture negative, potentially affecting the findings of this trial

Funding

• European Commission under the Life Science Health Priority of the 7th Framework Program
  • The Lodz site received funding from the Polish Ministry of Science and Higher Education